Eprints.soton.ac.uk
Diagnosis and Management of Paget’s disease of Bone in Adults:A clinical guidelineStuart H Ralston1, Luis Corral-Gudino2, Cyrus Cooper3 Roger M Francis4, William D Fraser5, Luigi Gennari6, Nuria Guanabens7, M Kassim Javaid8, Robert Layfield9, Terence W O’Neill10,11, R Graham G Russell8,12, Michael D Stone13, Keith Simpson4, Diana Wilkinson4, Ruth Wills14, M. Carola Zillikens15, and Stephen P Tuck16.1Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh EH4 2XU, UK; 2Internal Medicine Department, Hospital Universitario Río Ortega, University of Valladolid, Valladolid, Spain; 3MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton SO16 6YD, UK; 4Paget’s Association, Moorfield House, Moorside Rd, Swinton, Manchester M27 0EW, UK; 5Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, UK; 6Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Santa Maria alle Scotte, Viale Bracci, 53100-Siena, Italy; 7Hospital Clinic, IDIBAPS, CiberEHD, University of Barcelona, Barcelona, Spain; 8Botnar Research Centre, NDORMS, University of Oxford, Oxford OX3 7LD, UK; 9University of Nottingham Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK; 10Arthritis Research UK Centre for Epidemiology, University of Manchester, UK; 11NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK, 12The Mellanby Centre for Bone Research, University of Sheffield, UK, 13Bone Research Unit, Cardiff University, Cardiff, UK 14International Medical Press, Admiral House, 76-78 Old Street, London, EC1V 9AZ,., 15Department of Internal Medicine, Erasmus Medical Center Rotterdam, the Netherlands. 15Department of Rheumatology, The James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK; 16Institute of Cellular Medicine, Newcastle University, Newcastle upon TyneCorrespondence to: Stuart H Ralston MD FRCPProfessor of RheumatologyCentre for Genomic and Experimental MedicineMRC Institute of Genetics and Molecular MedicineUniversity of Edinburgh EH4 2XUUKEmail: stuart.ralston@ed.ac.uk AbstractAn evidence based clinical guideline for the diagnosis and management of Paget’s disease of Bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget’s Association (UK). A systematic review of diagnostic tests, pharmacological and non-pharmacological treatment options was conducted which sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important. Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of the metabolically active disease in patients with PDB. Serum total alkaline phosphatase (ALP) is recommended as a first line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB.Bisphosphonates are recommended for the treatment of bone pain associated with Paget’s disease. Zoledronic acid is recommended as the bisphosphonate most likely to give a favourable pain response. Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalising total ALP in PDB. Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another.The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone research Society (UK) and the British Geriatric Society. The GDG noted that there had been a lack of research on patient-focused clinical outcomes in PDB and identified several areas where further research was needed.Introduction Paget’s disease of the bone is a non-malignant skeletal disorder characterised by focal abnormalities in bone remodelling at one (monostotic) or more (polyostotic) skeletal sites. Almost any bone can be affected, but there is a predilection for the pelvis, spine, femur, tibia and skull ADDIN EN.CITE <EndNote><Cite><Author>Davie</Author><Year>1999</Year><RecNum>1913</RecNum><DisplayText><style face="superscript">(1)</style></DisplayText><record><rec-number>1913</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">1913</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Davie, M.</author><author>Davies, M.</author><author>Francis, R.</author><author>Fraser, W.</author><author>Hosking, D.</author><author>Tansley, R.</author></authors></contributors><auth-address>R. Jones and A. Hunt Orthopaedic Hospital, Oswestry, UK</auth-address><titles><title>Paget's disease of bone: a review of 889 patients</title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>11S-12S</pages><volume>24</volume><number>5 Suppl</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>Adult</keyword><keyword>Age Distribution</keyword><keyword>Aged</keyword><keyword>alkaline phosphatase</keyword><keyword>blood</keyword><keyword>bone</keyword><keyword>Disease</keyword><keyword>enzymology</keyword><keyword>epidemiology</keyword><keyword>Female</keyword><keyword>Great Britain</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Multicenter Studies</keyword><keyword>Osteitis Deformans</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>Patients</keyword><keyword>phosphatase</keyword><keyword>Prevalence</keyword><keyword>review</keyword><keyword>Sex Distribution</keyword><keyword>therapy</keyword></keywords><dates><year>1999</year><pub-dates><date>5/1999</date></pub-dates></dates><label>10612</label><urls><related-urls><url>;(1).The main risk factors for PDB include, increasing age, male gender, and ethnic background PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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==
ADDIN EN.CITE.DATA (2,3). The risk of developing PDB increases with age, with an approximate doubling in incidence each decade after the age of 50 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA (2). Paget’s is also more common in males (1.4:1) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
PFJlY051bT45MzYzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw
dCI+KDIpPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+OTM2MzwvcmVj
LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBn
ZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIwIj45MzYzPC9rZXk+PC9mb3JlaWdu
LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250
cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj52YW4gU3RhYSwgVC5QLjwvYXV0aG9yPjxhdXRob3I+
U2VsYnksIFAuPC9hdXRob3I+PGF1dGhvcj5MZXVma2VucywgSC5HLjwvYXV0aG9yPjxhdXRob3I+
THlsZXMsIEsuPC9hdXRob3I+PGF1dGhvcj5TcHJhZmthLCBKLk0uPC9hdXRob3I+PGF1dGhvcj5D
b29wZXIsIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+
TWVkaWNhbCBSZXNlYXJjaCBDb3VuY2lsIEVudmlyb25tZW50YWwgRXBpZGVtaW9sb2d5IFVuaXQs
IFVuaXZlcnNpdHkgb2YgU291dGhhbXB0b24sIFNvdXRoYW1wdG9uIEdlbmVyYWwgSG9zcGl0YWws
IFVuaXRlZCBLaW5nZG9tPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+SW5jaWRlbmNlIGFu
ZCBuYXR1cmFsIGhpc3Rvcnkgb2YgUGFnZXQmYXBvcztzIGRpc2Vhc2Ugb2YgYm9uZSBpbiBFbmds
YW5kIGFuZCBXYWxlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KLiBCb25lIE1pbmVyLiBSZXM8
L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NDY1LTQ3MTwvcGFnZXM+PHZvbHVtZT4x
Nzwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8
L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+YTwva2V5d29yZD48a2V5d29yZD5h
Z2U8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BcnRocm9wbGFzdHk8
L2tleXdvcmQ+PGtleXdvcmQ+YmFjayBwYWluPC9rZXl3b3JkPjxrZXl3b3JkPmJvbmU8L2tleXdv
cmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+PGtleXdvcmQ+ZGlhZ25vc2lzPC9rZXl3b3Jk
PjxrZXl3b3JkPkRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+RW5nbGFuZDwva2V5d29yZD48a2V5
d29yZD5lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZnJhY3R1cmU8L2tleXdvcmQ+PGtl
eXdvcmQ+Z2VuZGVyPC9rZXl3b3JkPjxrZXl3b3JkPmhlYXJpbmc8L2tleXdvcmQ+PGtleXdvcmQ+
SGVhcmluZyBMb3NzPC9rZXl3b3JkPjxrZXl3b3JkPmhpcDwva2V5d29yZD48a2V5d29yZD5oaXAg
YXJ0aHJvcGxhc3R5PC9rZXl3b3JkPjxrZXl3b3JkPmhpc3Rvcnk8L2tleXdvcmQ+PGtleXdvcmQ+
SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPktuZWU8L2tleXdvcmQ+PGtleXdvcmQ+bWVuPC9r
ZXl3b3JkPjxrZXl3b3JkPk5lb3BsYXNtPC9rZXl3b3JkPjxrZXl3b3JkPk9BPC9rZXl3b3JkPjxr
ZXl3b3JkPm9zdGVvYXJ0aHJpdGlzPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0PC9rZXl3b3JkPjxr
ZXl3b3JkPlBhZ2V0JmFwb3M7czwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3MgZGlzZWFz
ZTwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3MgZGlzZWFzZSBvZiBib25lPC9rZXl3b3Jk
PjxrZXl3b3JkPnBhaW48L2tleXdvcmQ+PGtleXdvcmQ+UGF0aWVudHM8L2tleXdvcmQ+PGtleXdv
cmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaDwva2V5d29yZD48a2V5d29y
ZD5SaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+
V2FsZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRh
dGVzPjxkYXRlPjMvMjAwMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD41MzA1PC9s
YWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292
L3B1Ym1lZC8xMTg3ODMwNTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0Np
dGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (2) and in certain ethnic groups PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwv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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwv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ADDIN EN.CITE.DATA (3). White Caucasians are most commonly affected PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwv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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwv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ADDIN EN.CITE.DATA (3) and the disease has been estimated to affect about 1% of people over the age of 55 years in the United Kingdom PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA (2). It is also common in other European countries such as France, Spain and Italy and in people of European descent who have emigrated to other regions of the world, such as Australia, New Zealand, the United States of America and Canada PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwv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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwv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ADDIN EN.CITE.DATA (3). Paget’s disease is rare in Scandinavian countries, the Indian subcontinent, and Asian countries. Archaeological studies of skeletal remains suggest that these differences in prevalence could be consistent with PDB having arisen as the result of genetic mutations that predispose to the disease in people from North-West Europe many centuries ago, with spread to other regions of the world through emigration ADDIN EN.CITE <EndNote><Cite><Author>Mays</Author><Year>2010</Year><RecNum>5754</RecNum><DisplayText><style face="superscript">(4)</style></DisplayText><record><rec-number>5754</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">5754</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mays, S.</author></authors></contributors><auth-address>Department of Archaeological Sciences, English Heritage, Fort Cumberland, Portsmouth, UK. simon.mays@english-.uk</auth-address><titles><title>Archaeological skeletons support a northwest European origin for Paget's disease of bone</title><secondary-title>J. Bone Miner. Res</secondary-title></titles><pages>1839-1841</pages><volume>25</volume><number>8</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>bone</keyword><keyword>Disease</keyword><keyword>England</keyword><keyword>etiology</keyword><keyword>europe</keyword><keyword>genetic</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>PDB</keyword><keyword>Population</keyword><keyword>Prevalence</keyword><keyword>review</keyword><keyword>Skeleton</keyword><keyword>Support</keyword><keyword>Western</keyword></keywords><dates><year>2010</year><pub-dates><date>8/2010</date></pub-dates></dates><label>9642</label><urls><related-urls><url>;(4).At a cellular level, PDB is characterised by increased numbers and activity of osteoclasts coupled to an increase in osteoblast activity ADDIN EN.CITE <EndNote><Cite><Author>Meunier</Author><Year>1980</Year><RecNum>5973</RecNum><DisplayText><style face="superscript">(5)</style></DisplayText><record><rec-number>5973</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">5973</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meunier, P.J.</author><author>Coindre, J.M.</author><author>Edouard, C.M.</author><author>Arlot, M.E.</author></authors></contributors><titles><title>Bone histomorphometry in Paget's disease. Quantitative and dynamic analysis of pagetic and nonpagetic bone tissue</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>1095-1103</pages><volume>23</volume><number>10</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>analysis</keyword><keyword>AS</keyword><keyword>Biopsy</keyword><keyword>blood supply</keyword><keyword>bone</keyword><keyword>Bone and Bones</keyword><keyword>Bone Remodeling</keyword><keyword>Calcinosis</keyword><keyword>calcium</keyword><keyword>Disease</keyword><keyword>histomorphometry</keyword><keyword>Humans</keyword><keyword>hyperparathyroidism</keyword><keyword>Hypertrophy</keyword><keyword>Osteitis Deformans</keyword><keyword>osteoblast</keyword><keyword>osteoblasts</keyword><keyword>Osteoclasts</keyword><keyword>osteosclerosis</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>pathology</keyword><keyword>Patients</keyword><keyword>Population</keyword><keyword>secondary</keyword><keyword>Tetracycline</keyword></keywords><dates><year>1980</year><pub-dates><date>10/1980</date></pub-dates></dates><label>7280</label><urls><related-urls><url>;(5). Bone formation is increased but disorganised, with formation of woven bone which is mechanically weak and subject to deformity and fracture. The focal increases in osteoclast and osteoblast activity in PDB are also accompanied by marrow fibrosis and increased vascularity of bone. The pathogenesis of PDB is incompletely understood but genetic factors play a key role. Many affected individuals have a family history PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2ZhZXI8L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2ZhZXI8L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (6,7) and an autosomal dominant pattern of inheritance with incomplete penetrance may be observed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JhbGVzLVBpZ2E8L0F1dGhvcj48WWVhcj4xOTk1PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JhbGVzLVBpZ2E8L0F1dGhvcj48WWVhcj4xOTk1PC9Z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ADDIN EN.CITE.DATA (8-10). The most important susceptibility gene for PDB is SQSTM1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXVyaW48L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXVyaW48L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (11,12) which encodes p62, a protein involved in the nuclear factor kappa B (NF?B) signalling pathway ADDIN EN.CITE <EndNote><Cite><Author>Moscat</Author><Year>2009</Year><RecNum>6213</RecNum><DisplayText><style face="superscript">(13)</style></DisplayText><record><rec-number>6213</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">6213</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Moscat, J.</author><author>Diaz-Meco, M.T.</author></authors></contributors><auth-address>Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. jorge.moscat@uc.edu</auth-address><titles><title>p62 at the crossroads of autophagy, apoptosis, and cancer</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>1001-1004</pages><volume>137</volume><number>6</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>ACTIVATION</keyword><keyword>activity</keyword><keyword>apoptosis</keyword><keyword>Autophagy</keyword><keyword>Biology</keyword><keyword>cancer</keyword><keyword>Cell Death</keyword><keyword>human</keyword><keyword>Humans</keyword><keyword>Medicine</keyword><keyword>metabolism</keyword><keyword>Neoplasms</keyword><keyword>NF-kappa B</keyword><keyword>p62</keyword><keyword>protein</keyword><keyword>Proteins</keyword><keyword>Research</keyword><keyword>Research Support</keyword><keyword>review</keyword><keyword>RNA-Binding Proteins</keyword><keyword>signaling</keyword><keyword>Support</keyword><keyword>survival</keyword><keyword>transcription</keyword><keyword>Transcription Factor</keyword></keywords><dates><year>2009</year><pub-dates><date>6/12/2009</date></pub-dates></dates><label>9582</label><urls><related-urls><url>;(13). Mutations in SQSMT1 have been identified in 40-50% of familial cases and between 5-10% of patients who do not report having a family history PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Jpc3NldHRlPC9BdXRob3I+PFllYXI+MjAwNjwvWWVh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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Jpc3NldHRlPC9BdXRob3I+PFllYXI+MjAwNjwvWWVh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=
ADDIN EN.CITE.DATA (9,14,15). Most of the causal mutations impair the ability of p62 to bind ubiquitin and this leads to activation of receptor activator of nuclear kappa B ligand (RANKL) induced NF?B signalling with increased osteoclast activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaW48L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaW48L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (16). Rarely, familial PDB or PDB-like disorders may occur in association with mutations in other genes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWdoZXM8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWdoZXM8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (17-19). In some of these syndromes, PDB is part of a multisystem disorder accompanied by myopathy and neurodegeneration PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (20,21). Several other common risk alleles have been identified through genome wide association that increase susceptibility to PDB but which in themselves are not causal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGJhZ2hhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGJhZ2hhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48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ADDIN EN.CITE.DATA (22). Environmental factors also play a role in PDB as evidenced by the fact that reductions in prevalence and severity have been observed in many countries over the past 25 years, most marked in regions that previously had a high prevalence PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xsYW5kPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xsYW5kPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
UmVjTnVtPjg1MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi
PigzLDIzLTI5KTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjg1MTwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2
MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIwIj44NTE8L2tleT48L2ZvcmVp
Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv
bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJvbGxhbmQsIE0uSi48L2F1dGhvcj48YXV0aG9y
PlRvbmcsIFAuQy48L2F1dGhvcj48YXV0aG9yPk5hb3QsIEQuPC9hdXRob3I+PGF1dGhvcj5DYWxs
b24sIEsuRS48L2F1dGhvcj48YXV0aG9yPldhdHRpZSwgRC5KLjwvYXV0aG9yPjxhdXRob3I+R2Ft
YmxlLCBHLkQuPC9hdXRob3I+PGF1dGhvcj5DdW5keSwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9j
b250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RGVsYXllZCBEZXZlbG9wbWVudCBvZiBQYWdldCZh
cG9zO3MgRGlzZWFzZSBpbiBPZmZzcHJpbmcgSW5oZXJpdGluZyBTUVNUTTEgTXV0YXRpb25zPC90
aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkouIEJvbmUgTWluZXIuIFJlczwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwYWdlcz40MTEtNDE1PC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+PG51bWJl
cj4zPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9u
PjxrZXl3b3Jkcz48a2V5d29yZD40NTwva2V5d29yZD48a2V5d29yZD40ODwva2V5d29yZD48a2V5
d29yZD5hPC9rZXl3b3JkPjxrZXl3b3JkPmFnZTwva2V5d29yZD48a2V5d29yZD5hbGthbGluZSBw
aG9zcGhhdGFzZTwva2V5d29yZD48a2V5d29yZD5ib25lPC9rZXl3b3JkPjxrZXl3b3JkPmNsaW5p
Y2FsPC9rZXl3b3JkPjxrZXl3b3JkPmRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNl
PC9rZXl3b3JkPjxrZXl3b3JkPkRPTUFJTjwva2V5d29yZD48a2V5d29yZD5mYW1pbGlhbDwva2V5
d29yZD48a2V5d29yZD5GYW1pbHk8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpYzwva2V5d29yZD48
a2V5d29yZD5tZWFzdXJlbWVudDwva2V5d29yZD48a2V5d29yZD5tZXRob2Q8L2tleXdvcmQ+PGtl
eXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5tdXRhdGlvbjwva2V5d29yZD48a2V5d29y
ZD5tdXRhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFn
ZXQmYXBvcztzPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3Jk
PjxrZXl3b3JkPlBhcmVudHM8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aWVudHM8L2tleXdvcmQ+PGtl
eXdvcmQ+UGVuZXRyYW5jZTwva2V5d29yZD48a2V5d29yZD5QaGVub3R5cGU8L2tleXdvcmQ+PGtl
eXdvcmQ+cGhvc3BoYXRhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Umlzazwva2V5d29yZD48a2V5d29y
ZD5zZXF1ZXN0b3NvbWU8L2tleXdvcmQ+PGtleXdvcmQ+c2VydW08L2tleXdvcmQ+PGtleXdvcmQ+
c3FzdG0xPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT4zLzIwMDc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+ODMzMTwv
bGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdv
di9wdWJtZWQvMTcxODEzOTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9D
aXRlPjxDaXRlPjxBdXRob3I+Q3VuZHk8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNOdW0+
MTgxNTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTgxNTwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBnZXR0MDFwemV6cXZ4Zjlz
dGUwZTU1OSIgdGltZXN0YW1wPSIwIj4xODE1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl
IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv
cnM+PGF1dGhvcj5DdW5keSwgSC5SLjwvYXV0aG9yPjxhdXRob3I+R2FtYmxlLCBHLjwvYXV0aG9y
PjxhdXRob3I+V2F0dGllLCBELjwvYXV0aG9yPjxhdXRob3I+UnV0bGFuZCwgTS48L2F1dGhvcj48
YXV0aG9yPkN1bmR5LCBULjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h
ZGRyZXNzPkRlcGFydG1lbnQgb2YgTWVkaWNpbmUsIEZhY3VsdHkgb2YgTWVkaWNhbCAmYW1wOyBI
ZWFsdGggU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQXVja2xhbmQsIE5ldyBaZWFsYW5kPC9hdXRo
LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGFnZXQmYXBvcztzIGRpc2Vhc2Ugb2YgYm9uZSBpbiBO
ZXcgWmVhbGFuZDogY29udGludWVkIGRlY2xpbmUgaW4gZGlzZWFzZSBzZXZlcml0eTwvdGl0bGU+
PHNlY29uZGFyeS10aXRsZT5DYWxjaWYuIFRpc3N1ZSBJbnQ8L3NlY29uZGFyeS10aXRsZT48L3Rp
dGxlcz48cGFnZXM+MzU4LTM2NDwvcGFnZXM+PHZvbHVtZT43NTwvdm9sdW1lPjxudW1iZXI+NTwv
bnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5
d29yZHM+PGtleXdvcmQ+YTwva2V5d29yZD48a2V5d29yZD5hY3Rpdml0eTwva2V5d29yZD48a2V5
d29yZD5hZ2U8L2tleXdvcmQ+PGtleXdvcmQ+YWxrYWxpbmUgcGhvc3BoYXRhc2U8L2tleXdvcmQ+
PGtleXdvcmQ+QVM8L2tleXdvcmQ+PGtleXdvcmQ+Ymxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+Ym9u
ZTwva2V5d29yZD48a2V5d29yZD5Cb25lIGFuZCBCb25lczwva2V5d29yZD48a2V5d29yZD5Db21w
YXJhdGl2ZSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5EZW1vZ3JhcGh5PC9rZXl3b3JkPjxrZXl3
b3JkPmRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3Jk
PmVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+
SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Mb25naXR1
ZGluYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1l
ZGljaW5lPC9rZXl3b3JkPjxrZXl3b3JkPk5ldyBaZWFsYW5kPC9rZXl3b3JkPjxrZXl3b3JkPk5F
Vy1aRUFMQU5EPC9rZXl3b3JkPjxrZXl3b3JkPk9zdGVpdGlzIERlZm9ybWFuczwva2V5d29yZD48
a2V5d29yZD5QYWdldDwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3M8L2tleXdvcmQ+PGtl
eXdvcmQ+UGFnZXQmYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztz
IGRpc2Vhc2Ugb2YgYm9uZTwva2V5d29yZD48a2V5d29yZD5wYXRob2xvZ3k8L2tleXdvcmQ+PGtl
eXdvcmQ+UGF0aWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGhvc3BoYXRhc2U8L2tleXdvcmQ+PGtl
eXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnBsYXNtYTwva2V5d29yZD48
a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlJlc2VhcmNoIFN1cHBvcnQsTm9u
LVUuUy5Hb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5k
ZXg8L2tleXdvcmQ+PGtleXdvcmQ+U3VwcG9ydDwva2V5d29yZD48a2V5d29yZD50cmVuZHM8L2tl
eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRl
PjExLzIwMDQ8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+NzI4MTwvbGFiZWw+PHVy
bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQv
MTU0NTUxODc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRl
PjxBdXRob3I+RG95bGU8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxSZWNOdW0+MjIyNTwvUmVj
TnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjIyNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr
ZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIg
dGltZXN0YW1wPSIwIj4yMjI1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5Eb3lsZSwgVC48L2F1dGhvcj48YXV0aG9yPkd1bm4sIEouPC9hdXRob3I+PGF1dGhvcj5BbmRl
cnNvbiwgRy48L2F1dGhvcj48YXV0aG9yPkdpbGwsIE0uPC9hdXRob3I+PGF1dGhvcj5DdW5keSwg
VC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt
ZW50IG9mIFJhZGlvbG9neSwgVW5pdmVyc2l0eSBvZiBPdGFnbywgRHVuZWRpbiwgTmV3IFplYWxh
bmQ8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QYWdldCZhcG9zO3MgZGlzZWFzZSBpbiBO
ZXcgWmVhbGFuZDogZXZpZGVuY2UgZm9yIGRlY2xpbmluZyBwcmV2YWxlbmNlPC90aXRsZT48c2Vj
b25kYXJ5LXRpdGxlPkJvbmU8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48
ZnVsbC10aXRsZT5Cb25lPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjE2LTYxOTwv
cGFnZXM+PHZvbHVtZT4zMTwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxyZXByaW50LWVkaXRp
b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+YTwva2V5
d29yZD48a2V5d29yZD5hZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29y
ZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPmFsa2FsaW5lIHBob3NwaGF0YXNl
PC9rZXl3b3JkPjxrZXl3b3JkPkFTPC9rZXl3b3JkPjxrZXl3b3JkPmJsb29kPC9rZXl3b3JkPjxr
ZXl3b3JkPkNvbXBhcmF0aXZlIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3JkPkNvbmZpZGVuY2UgSW50
ZXJ2YWxzPC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpZGVt
aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5odW1hbjwv
a2V5d29yZD48a2V5d29yZD5MYWJvcmF0b3JpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5
d29yZD48a2V5d29yZD5tYXJrZXI8L2tleXdvcmQ+PGtleXdvcmQ+bWVuPC9rZXl3b3JkPjxrZXl3
b3JkPm1ldGhvZDwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29y
ZD5OZXcgWmVhbGFuZDwva2V5d29yZD48a2V5d29yZD5ORVctWkVBTEFORDwva2V5d29yZD48a2V5
d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5Pc3RlaXRpcyBEZWZvcm1hbnM8L2tleXdvcmQ+PGtl
eXdvcmQ+UGFnZXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3b3JkPjxrZXl3
b3JkPlBhZ2V0JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPnBob3NwaGF0YXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPnBsYXNtYTwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3
b3JkPjxrZXl3b3JkPnJhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlJhZGlvbG9neTwva2V5
d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+cmV2
aWV3PC9rZXl3b3JkPjxrZXl3b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0PC9rZXl3b3Jk
Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMS8y
MDAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjY1MjU8L2xhYmVsPjx1cmxzPjxy
ZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzEyNDc3
NTc3PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0
aG9yPlBvb3I8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNOdW0+NzEwNTwvUmVjTnVtPjxy
ZWNvcmQ+PHJlYy1udW1iZXI+NzEwNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw
PSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0
YW1wPSIwIj43MTA1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg
QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Qb29y
LCBHLjwvYXV0aG9yPjxhdXRob3I+RG9uYXRoLCBKLjwvYXV0aG9yPjxhdXRob3I+Rm9ybmV0LCBC
LjwvYXV0aG9yPjxhdXRob3I+Q29vcGVyLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1
dG9ycz48YXV0aC1hZGRyZXNzPk5hdGlvbmFsIEluc3RpdHV0ZSBvZiBSaGV1bWF0b2xvZ3kgYW5k
IFBoeXNpb3RoZXJhcHksIEJ1ZGFwZXN0LCBIdW5nYXJ5PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48
dGl0bGU+RXBpZGVtaW9sb2d5IG9mIFBhZ2V0JmFwb3M7cyBkaXNlYXNlIGluIEV1cm9wZTogdGhl
IHByZXZhbGVuY2UgaXMgZGVjcmVhc2luZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KLiBCb25l
IE1pbmVyLiBSZXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+MTU0NS0xNTQ5PC9w
YWdlcz48dm9sdW1lPjIxPC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxyZXByaW50LWVkaXRp
b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+YTwva2V5
d29yZD48a2V5d29yZD5hZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+
PGtleXdvcmQ+Ym9uZTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3Jk
PmVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5ldXJvcGU8L2tleXdvcmQ+PGtleXdvcmQ+
RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkhlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r
ZXl3b3JkPjxrZXl3b3JkPkh1bmdhcnk8L2tleXdvcmQ+PGtleXdvcmQ+THVtYmFyIFZlcnRlYnJh
ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPm1lbjwva2V5d29yZD48
a2V5d29yZD5tZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29y
ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Pc3RlaXRpcyBEZWZvcm1hbnM8L2tleXdv
cmQ+PGtleXdvcmQ+UGFnZXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3b3Jk
PjxrZXl3b3JkPlBhZ2V0JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0JmFw
b3M7cyBkaXNlYXNlIG9mIGJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+UGVsdmlzPC9rZXl3b3JkPjxr
ZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+cmFkaW9ncmFwaHk8L2tleXdvcmQ+
PGtleXdvcmQ+UmFkaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJlc2VhcmNoPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlc2VhcmNoIFN1cHBvcnQ8L2tleXdvcmQ+PGtleXdvcmQ+UmhldW1hdG9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPlNhY3J1bTwva2V5d29yZD48a2V5d29yZD5TZWNvbmQ8L2tleXdvcmQ+
PGtleXdvcmQ+U2V4IERpc3RyaWJ1dGlvbjwva2V5d29yZD48a2V5d29yZD5TdXBwb3J0PC9rZXl3
b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4x
MC8yMDA2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjEwMDY0PC9sYWJlbD48dXJs
cz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8x
Njk5NTgwODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+
PEF1dGhvcj5Db3JyYWwtR3VkaW5vPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjE2
NjA8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjE2NjA8L3JlYy1udW1iZXI+PGZvcmVpZ24t
a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0dDAxcHplenF2eGY5c3Rl
MGU1NTkiIHRpbWVzdGFtcD0iMCI+MTY2MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu
YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz
PjxhdXRob3I+Q29ycmFsLUd1ZGlubywgTC48L2F1dGhvcj48YXV0aG9yPkJvcmFvLUNlbmdvdGl0
YS1CZW5nb2EsIE0uPC9hdXRob3I+PGF1dGhvcj5EZWwgUGluby1Nb250ZXMsIEouPC9hdXRob3I+
PGF1dGhvcj5SYWxzdG9uLCBTLkguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh
dXRoLWFkZHJlc3M+U2VydmljaW8gZGUgTWVkaWNpbmEgSW50ZXJuYSwgSG9zcGl0YWwgRWwgQmll
cnpvLCBQb25mZXJyYWRhLCBMZW9uLCBTcGFpbjsgKFJFVElDRUYuKSBJbnN0aXR1dG8gZGUgSW52
ZXN0aWdhY2lvbiBCaW9tZWRpY2EgZGUgU2FsYW1hbmNhLCBJQlNBTCwgU2FsYW1hbmNhLCBTcGFp
bi4gRWxlY3Ryb25pYyBhZGRyZXNzOiBsY29ycmFsQHNhbHVkY2FzdGlsbGF5bGVvbi5lczwvYXV0
aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVwaWRlbWlvbG9neSBvZiBQYWdldCZhcG9zO3MgZGlz
ZWFzZSBvZiBib25lOiBBIHN5c3RlbWF0aWMgcmV2aWV3IGFuZCBtZXRhLWFuYWx5c2lzIG9mIHNl
Y3VsYXIgY2hhbmdlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Cb25lPC9zZWNvbmRhcnktdGl0
bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Qm9uZTwvZnVsbC10aXRsZT48L3Bl
cmlvZGljYWw+PHBhZ2VzPjM0Ny0zNTI8L3BhZ2VzPjx2b2x1bWU+NTU8L3ZvbHVtZT48bnVtYmVy
PjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+
PGtleXdvcmRzPjxrZXl3b3JkPmE8L2tleXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tleXdvcmQ+
PGtleXdvcmQ+QVM8L2tleXdvcmQ+PGtleXdvcmQ+Ym9uZTwva2V5d29yZD48a2V5d29yZD5Db2hv
cnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPmVw
aWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5ldXJvcGU8L2tleXdvcmQ+PGtleXdvcmQ+Z2Vu
ZXRpYzwva2V5d29yZD48a2V5d29yZD5JbmNpZGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+SmFwYW48
L2tleXdvcmQ+PGtleXdvcmQ+TWVkbGluZTwva2V5d29yZD48a2V5d29yZD5NZXRhLUFuYWx5c2lz
PC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZDwva2V5d29yZD48a2V5d29yZD5tZXRob2RzPC9rZXl3
b3JkPjxrZXl3b3JkPm1vZGVsPC9rZXl3b3JkPjxrZXl3b3JkPk1vZGVsczwva2V5d29yZD48a2V5
d29yZD5OZXcgWmVhbGFuZDwva2V5d29yZD48a2V5d29yZD5ORVctWkVBTEFORDwva2V5d29yZD48
a2V5d29yZD5Pc3RlaXRpczwva2V5d29yZD48a2V5d29yZD5Pc3RlaXRpcyBEZWZvcm1hbnM8L2tl
eXdvcmQ+PGtleXdvcmQ+UGFnZXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3
b3JkPjxrZXl3b3JkPlBhZ2V0JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0
JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+UERCPC9rZXl3b3JkPjxr
ZXl3b3JkPlBvcHVsYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48
a2V5d29yZD5yZXZpZXc8L2tleXdvcmQ+PGtleXdvcmQ+c2Vjb25kYXJ5PC9rZXl3b3JkPjxrZXl3
b3JkPlNwYWluPC9rZXl3b3JkPjxrZXl3b3JkPnRyZW5kczwva2V5d29yZD48L2tleXdvcmRzPjxk
YXRlcz48eWVhcj4yMDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OC8yMDEzPC9kYXRlPjwvcHVi
LWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjEwMzIwPC9sYWJlbD48dXJscz48cmVsYXRlZC11cmxzPjx1
cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzY0MzY3OTwvdXJsPjwvcmVs
YXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5Db3JyYWwtR3Vk
aW5vPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVtPjE2NjE8L1JlY051bT48cmVjb3Jk
PjxyZWMtbnVtYmVyPjE2NjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i
IGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0dDAxcHplenF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0i
MCI+MTY2MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj
bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q29ycmFsLUd1
ZGlubywgTC48L2F1dGhvcj48YXV0aG9yPkdhcmNpYS1BcGFyaWNpbywgSi48L2F1dGhvcj48YXV0
aG9yPlNhbmNoZXotR29uemFsZXosIE0uRC48L2F1dGhvcj48YXV0aG9yPk1pcm9uLUNhbmVsbywg
Si5BLjwvYXV0aG9yPjxhdXRob3I+QmxhbmNvLCBKLkYuPC9hdXRob3I+PGF1dGhvcj5SYWxzdG9u
LCBTLkguPC9hdXRob3I+PGF1dGhvcj5EZWwgUGluby1Nb250ZXMsIEouPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBJbnRlcm5hbCBN
ZWRpY2luZSwgUkVUSUNFRiwgSG9zcGl0YWwgZWwgQmllcnpvLCBNZWRpY29zIHNpbiBGcm9udGVy
YXMgNy4gUG9uZmVycmFkYSwgMjQ0MTEsIExlb24sIFNwYWluLiBsY29ycmFsQHNhbHVkY2FzdGls
bGF5bGVvbi5lczwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNlY3VsYXIgY2hhbmdlcyBp
biBQYWdldCZhcG9zO3MgZGlzZWFzZTogY29udHJhc3RpbmcgY2hhbmdlcyBpbiB0aGUgbnVtYmVy
IG9mIG5ldyByZWZlcnJhbHMgYW5kIGluIGRpc2Vhc2Ugc2V2ZXJpdHkgaW4gdHdvIG5laWdoYm9y
aW5nIHJlZ2lvbnMgb2YgU3BhaW48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+T3N0ZW9wb3Jvcy4g
SW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjQ0My00NTA8L3BhZ2VzPjx2b2x1
bWU+MjQ8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG
aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPmE8L2tleXdvcmQ+PGtleXdv
cmQ+YWN0aXZpdHk8L2tleXdvcmQ+PGtleXdvcmQ+YWxrYWxpbmUgcGhvc3BoYXRhc2U8L2tleXdv
cmQ+PGtleXdvcmQ+QVM8L2tleXdvcmQ+PGtleXdvcmQ+Ym9uZTwva2V5d29yZD48a2V5d29yZD5E
aXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybmFsIE1lZGljaW5lPC9rZXl3b3JkPjxrZXl3
b3JkPk1lZGljaW5lPC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZDwva2V5d29yZD48a2V5d29yZD5t
ZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0PC9rZXl3
b3JkPjxrZXl3b3JkPlBhZ2V0JmFwb3M7czwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3Mg
ZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3MgZGlzZWFzZSBvZiBib25lPC9r
ZXl3b3JkPjxrZXl3b3JkPlBhdGllbnRzPC9rZXl3b3JkPjxrZXl3b3JkPlBEQjwva2V5d29yZD48
a2V5d29yZD5waG9zcGhhdGFzZTwva2V5d29yZD48a2V5d29yZD5Qb3B1bGF0aW9uPC9rZXl3b3Jk
PjxrZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+Umlzazwva2V5d29yZD48a2V5
d29yZD5TcGFpbjwva2V5d29yZD48a2V5d29yZD50cmVuZHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48
ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIvMjAxMzwvZGF0ZT48L3B1
Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD4xMDMyNjwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48
dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjIzOTUzMTI8L3VybD48L3Jl
bGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Q29vcGVyPC9B
dXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVjTnVtPjE2MjQ8L1JlY051bT48cmVjb3JkPjxyZWMt
bnVtYmVyPjE2MjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlk
PSJ6ZnB4ZXBweGV2djAwZ2V0dDAxcHplenF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMCI+MTYy
NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3
PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Q29vcGVyLCBDLjwvYXV0
aG9yPjxhdXRob3I+U2NoYWZoZXV0bGUsIEsuPC9hdXRob3I+PGF1dGhvcj5EZW5uaXNvbiwgRS48
L2F1dGhvcj48YXV0aG9yPktlbGxpbmdyYXksIFMuPC9hdXRob3I+PGF1dGhvcj5HdXllciwgUC48
L2F1dGhvcj48YXV0aG9yPkJhcmtlciwgRC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz5NUkMgRW52aXJvbm1lbnRhbCBFcGlkZW1pb2xvZ3kgVW5pdCwgU291
dGhhbXB0b24gR2VuZXJhbCBIb3NwaXRhbCwgU291dGhhbXB0b24sIFVuaXRlZCBLaW5nZG9tPC9h
dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGhlIGVwaWRlbWlvbG9neSBvZiBQYWdldCZhcG9z
O3MgZGlzZWFzZSBpbiBCcml0YWluOiBpcyB0aGUgcHJldmFsZW5jZSBkZWNyZWFzaW5nPzwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5KLiBCb25lIE1pbmVyLiBSZXM8L3NlY29uZGFyeS10aXRsZT48
L3RpdGxlcz48cGFnZXM+MTkyLTE5NzwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+
MjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+SW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3
b3Jkcz48a2V5d29yZD5hPC9rZXl3b3JkPjxrZXl3b3JkPmFnZTwva2V5d29yZD48a2V5d29yZD5B
Z2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQs
ODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5F
cGlkZW1pb2xvZ2ljIE1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpZGVtaW9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48
a2V5d29yZD5HcmVhdCBCcml0YWluPC9rZXl3b3JkPjxrZXl3b3JkPkhlYWQ8L2tleXdvcmQ+PGtl
eXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+THVtYmFyIFZlcnRlYnJhZTwva2V5d29yZD48
a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPm1lbjwva2V5d29yZD48a2V5d29yZD5tZXRo
b2Q8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdl
PC9rZXl3b3JkPjxrZXl3b3JkPk9zdGVpdGlzIERlZm9ybWFuczwva2V5d29yZD48a2V5d29yZD5Q
YWdldDwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3M8L2tleXdvcmQ+PGtleXdvcmQ+UGFn
ZXQmYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UGVsdmlzPC9rZXl3b3JkPjxrZXl3
b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+cmFkaW9ncmFwaHk8L2tleXdvcmQ+PGtl
eXdvcmQ+UmFkaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnNjcmVlbmluZzwva2V5d29yZD48a2V5
d29yZD5TZXggRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5zdXBwb3J0LG5vbi11LnMuZ292JmFw
b3M7dDwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+VW5p
dGVkIFN0YXRlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk5PC95ZWFyPjxw
dWItZGF0ZXM+PGRhdGU+Mi8xOTk5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjQ3
NTg8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5p
aC5nb3YvcHVibWVkLzk5MzM0NzI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+
PC9DaXRlPjxDaXRlPjxBdXRob3I+QnJpdHRvbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
Y051bT4xOTU0MDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTk1NDA8L3JlYy1udW1iZXI+
PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0dDAxcHpl
enF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMTUxOTA3OTU5MiI+MTk1NDA8L2tleT48L2ZvcmVp
Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv
bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyaXR0b24sIEMuPC9hdXRob3I+PGF1dGhvcj5C
cm93biwgUy48L2F1dGhvcj48YXV0aG9yPldhcmQsIEwuPC9hdXRob3I+PGF1dGhvcj5SZWEsIFMu
IEwuPC9hdXRob3I+PGF1dGhvcj5SYXRhamN6YWssIFQuPC9hdXRob3I+PGF1dGhvcj5XYWxzaCwg
Si4gUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBh
cnRtZW50IG9mIEVuZG9jcmlub2xvZ3kgYW5kIERpYWJldGVzLCBTaXIgQ2hhcmxlcyBHYWlyZG5l
ciBIb3NwaXRhbCwgTmVkbGFuZHMsIFdBLCA2MDA5LCBBdXN0cmFsaWEuJiN4RDtOZXVyb2dlbmV0
aWMgRGlzZWFzZXMgTGFib3JhdG9yeSwgSGFycnkgUGVya2lucyBJbnN0aXR1dGUgb2YgTWVkaWNh
bCBSZXNlYXJjaCwgVGhlIFVuaXZlcnNpdHkgb2YgV2VzdGVybiBBdXN0cmFsaWEsIENyYXdsZXks
IFdBLCA2MDA5LCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIEVuZG9jcmlub2xvZ3kgYW5k
IERpYWJldGVzLCBTaXIgQ2hhcmxlcyBHYWlyZG5lciBIb3NwaXRhbCwgTmVkbGFuZHMsIFdBLCA2
MDA5LCBBdXN0cmFsaWEuIGpvaG4ud2Fsc2hAaGVhbHRoLndhLmdvdi5hdS4mI3hEO1NjaG9vbCBv
ZiBNZWRpY2luZSBhbmQgUGhhcm1hY29sb2d5LCBUaGUgVW5pdmVyc2l0eSBvZiBXZXN0ZXJuIEF1
c3RyYWxpYSwgQ3Jhd2xleSwgV0EsIDYwMDksIEF1c3RyYWxpYS4gam9obi53YWxzaEBoZWFsdGgu
d2EuZ292LmF1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBDaGFuZ2luZyBQcmVz
ZW50YXRpb24gb2YgUGFnZXQmYXBvcztzIERpc2Vhc2Ugb2YgQm9uZSBpbiBBdXN0cmFsaWEsIEEg
SGlnaCBQcmV2YWxlbmNlIFJlZ2lvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DYWxjaWYgVGlz
c3VlIEludDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl
PkNhbGNpZmllZCB0aXNzdWUgaW50ZXJuYXRpb25hbDwvZnVsbC10aXRsZT48YWJici0xPkNhbGNp
ZiBUaXNzdWUgSW50PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxwYWdlcz41NjQtNTY5PC9wYWdlcz48
dm9sdW1lPjEwMTwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxlZGl0aW9uPjIwMTcvMDkvMDk8
L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPlBhZ2V0JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmU8
L2tleXdvcmQ+PGtleXdvcmQ+U1FTVE0xL3A2Mjwva2V5d29yZD48a2V5d29yZD5TZWN1bGFyIGNo
YW5nZTwva2V5d29yZD48a2V5d29yZD5TZXZlcml0eTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl
cz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVz
PjwvZGF0ZXM+PGlzYm4+MTQzMi0wODI3IChFbGVjdHJvbmljKSYjeEQ7MDE3MS05NjdYIChMaW5r
aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yODg4NDIxMTwvYWNjZXNzaW9uLW51bT48dXJscz48
cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjg4
ODQyMTE8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt
PjEwLjEwMDcvczAwMjIzLTAxNy0wMzEyLTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj
b3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA (3,23-29). In keeping with this, the prevalence of osteosarcoma in adults (a complication of PDB) has also declined in recent years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5naGFtPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5naGFtPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48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ADDIN EN.CITE.DATA (30,31). Various environmental triggers for PDB have been suggested including dietary calcium or vitamin D deficiency and exposure to environmental toxins PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXJpczwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXJpczwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+PFJl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ADDIN EN.CITE.DATA (32,33), repetitive biomechanical loading or skeletal trauma PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2xvbW9uPC9BdXRob3I+PFllYXI+MTk3OTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2xvbW9uPC9BdXRob3I+PFllYXI+MTk3OTwvWWVhcj48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ADDIN EN.CITE.DATA (34,35) and slow virus infections ADDIN EN.CITE <EndNote><Cite><Author>Rebel</Author><Year>1974</Year><RecNum>7418</RecNum><DisplayText><style face="superscript">(36)</style></DisplayText><record><rec-number>7418</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">7418</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rebel, A.</author><author>Malkani, K.</author><author>Basle, M.</author><author>Bregeon, C.</author><author>Patezour, A.</author><author>Filmon, R.</author></authors></contributors><titles><title>Ultrastructural characteristics of osteoclasts in Paget's disease</title><secondary-title>Rev. Rhum. Mal Osteoartic</secondary-title></titles><pages>767-771</pages><volume>41</volume><number>12</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Biopsy</keyword><keyword>Cell Nucleus</keyword><keyword>Disease</keyword><keyword>etiology</keyword><keyword>France</keyword><keyword>human</keyword><keyword>Ilium</keyword><keyword>inclusion bodies</keyword><keyword>inclusion bodies,viral</keyword><keyword>Microscopy,Electron</keyword><keyword>Osteitis Deformans</keyword><keyword>osteoclast</keyword><keyword>Osteoclasts</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>pathology</keyword><keyword>ultrastructure</keyword></keywords><dates><year>1974</year><pub-dates><date>12/1974</date></pub-dates></dates><label>4928</label><urls><related-urls><url>;(36). The most widely studied environmental factor is slow virus infection and over the years, measles ADDIN EN.CITE <EndNote><Cite><Author>Rebel</Author><Year>1974</Year><RecNum>7418</RecNum><DisplayText><style face="superscript">(36)</style></DisplayText><record><rec-number>7418</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">7418</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rebel, A.</author><author>Malkani, K.</author><author>Basle, M.</author><author>Bregeon, C.</author><author>Patezour, A.</author><author>Filmon, R.</author></authors></contributors><titles><title>Ultrastructural characteristics of osteoclasts in Paget's disease</title><secondary-title>Rev. Rhum. Mal Osteoartic</secondary-title></titles><pages>767-771</pages><volume>41</volume><number>12</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Biopsy</keyword><keyword>Cell Nucleus</keyword><keyword>Disease</keyword><keyword>etiology</keyword><keyword>France</keyword><keyword>human</keyword><keyword>Ilium</keyword><keyword>inclusion bodies</keyword><keyword>inclusion bodies,viral</keyword><keyword>Microscopy,Electron</keyword><keyword>Osteitis Deformans</keyword><keyword>osteoclast</keyword><keyword>Osteoclasts</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>pathology</keyword><keyword>ultrastructure</keyword></keywords><dates><year>1974</year><pub-dates><date>12/1974</date></pub-dates></dates><label>4928</label><urls><related-urls><url>;(36), respiratory syncytial virus ADDIN EN.CITE <EndNote><Cite><Author>Mills</Author><Year>1984</Year><RecNum>6042</RecNum><DisplayText><style face="superscript">(37)</style></DisplayText><record><rec-number>6042</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">6042</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mills, B.G.</author><author>Singer, F.R.</author><author>Weiner, L.P.</author><author>Suffin, S.C.</author><author>Stabile, E.</author><author>Holst, P.</author></authors></contributors><titles><title>Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget's disease of bone</title><secondary-title>Clin Orthop Rel Res</secondary-title></titles><pages>303-311</pages><volume>183</volume><reprint-edition>In File</reprint-edition><keywords><keyword>Antigens</keyword><keyword>bone</keyword><keyword>Disease</keyword><keyword>immunohistology</keyword><keyword>measles</keyword><keyword>measles virus</keyword><keyword>MV</keyword><keyword>osteoclast</keyword><keyword>Osteoclasts</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>paramyxovirus</keyword><keyword>Patients</keyword><keyword>RSV</keyword><keyword>virus</keyword></keywords><dates><year>1984</year><pub-dates><date>1984</date></pub-dates></dates><label>119</label><urls></urls></record></Cite></EndNote>(37) and canine distemper ADDIN EN.CITE <EndNote><Cite><Author>O'Driscoll</Author><Year>1985</Year><RecNum>6561</RecNum><DisplayText><style face="superscript">(38)</style></DisplayText><record><rec-number>6561</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">6561</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>O'Driscoll, J.B.</author><author>Anderson, D.C.</author></authors></contributors><titles><title>Past pets and Paget's disease</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>919-921</pages><volume>2</volume><reprint-edition>In File</reprint-edition><keywords><keyword>CDV</keyword><keyword>Disease</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>paramyxovirus</keyword><keyword>Patients</keyword><keyword>PET</keyword><keyword>pets</keyword></keywords><dates><year>1985</year><pub-dates><date>1985</date></pub-dates></dates><label>109</label><urls></urls></record></Cite></EndNote>(38) have all been implicated and over-expression of measles virus nucleocapsids protein in experimental models have been shown to increase bone remodelling PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZXJhbWFjaGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZXJhbWFjaGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy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ADDIN EN.CITE.DATA (39). Attempts to detect evidence of paramyxovirus nucleic acids and proteins in patient material have yielded conflicting results however PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXR0aGV3czwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXR0aGV3czwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+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ADDIN EN.CITE.DATA (40-47) and serological studies have found no evidence of an enhanced immune response to paramyxoviruses in PDB ADDIN EN.CITE <EndNote><Cite><Author>Visconti</Author><Year>2017</Year><RecNum>17149</RecNum><DisplayText><style face="superscript">(48)</style></DisplayText><record><rec-number>17149</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1498912540">17149</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Visconti, M. R.</author><author>Usategui-Martin, R.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>The Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK.
The Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK. stuart.ralston@ed.ac.uk.</auth-address><titles><title>Antibody Response to Paramyxoviruses in Paget's Disease of Bone</title><secondary-title>Calcif Tissue Int</secondary-title></titles><periodical><full-title>Calcified tissue international</full-title><abbr-1>Calcif Tissue Int</abbr-1></periodical><edition>2017/04/01</edition><keywords><keyword>Distemper</keyword><keyword>Genetic</keyword><keyword>Measles</keyword><keyword>Paget's disease of bone</keyword><keyword>Paramyxovirus</keyword></keywords><dates><year>2017</year><pub-dates><date>Mar 31</date></pub-dates></dates><isbn>1432-0827 (Electronic)
0171-967X (Linking)</isbn><accession-num>28361207</accession-num><urls><related-urls><url>;(48). It has been reported that the nuclear inclusion bodies that were identified in PDB many decades ago and thought to be measles virus nucleocapsids ADDIN EN.CITE <EndNote><Cite><Author>Rebel</Author><Year>1974</Year><RecNum>7418</RecNum><DisplayText><style face="superscript">(36)</style></DisplayText><record><rec-number>7418</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">7418</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rebel, A.</author><author>Malkani, K.</author><author>Basle, M.</author><author>Bregeon, C.</author><author>Patezour, A.</author><author>Filmon, R.</author></authors></contributors><titles><title>Ultrastructural characteristics of osteoclasts in Paget's disease</title><secondary-title>Rev. Rhum. Mal Osteoartic</secondary-title></titles><pages>767-771</pages><volume>41</volume><number>12</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Biopsy</keyword><keyword>Cell Nucleus</keyword><keyword>Disease</keyword><keyword>etiology</keyword><keyword>France</keyword><keyword>human</keyword><keyword>Ilium</keyword><keyword>inclusion bodies</keyword><keyword>inclusion bodies,viral</keyword><keyword>Microscopy,Electron</keyword><keyword>Osteitis Deformans</keyword><keyword>osteoclast</keyword><keyword>Osteoclasts</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>pathology</keyword><keyword>ultrastructure</keyword></keywords><dates><year>1974</year><pub-dates><date>12/1974</date></pub-dates></dates><label>4928</label><urls><related-urls><url>;(36) are morphologically distinct from measles on ultrastructural analysis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWxmcmljaDwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWxmcmljaDwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+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ADDIN EN.CITE.DATA (43). Experimental evidence has been gained to suggest that they may instead be abnormal protein aggregates due to defects in the autophagy pathway ADDIN EN.CITE <EndNote><Cite><Author>Helfrich</Author><Year>2014</Year><RecNum>10212</RecNum><DisplayText><style face="superscript">(49)</style></DisplayText><record><rec-number>10212</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">10212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Helfrich, M.H.</author><author>Hocking, L.J.</author></authors></contributors><titles><title>Genetics and aetiology of Pagetic disorders of Bone</title><secondary-title>Archives Biochem Biophys</secondary-title></titles><pages>172-182</pages><volume>473</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>genetics</keyword><keyword>genetic</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>Disease</keyword><keyword>bone</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>11229</label><urls></urls></record></Cite></EndNote>(49).Many of the clinical features and complications of PDB are thought to be due to the abnormalities of bone remodelling that are characteristic of the disease. The enlarged bones may cause hearing loss, basilar invagination of the skull, obstructive hydrocephalus, spinal canal stenosis and paraplegia. The increased vascularity of bone can result in excessive blood loss should orthopaedic surgery be required. It has been suggested that in some cases, paraplegia may be due to a vascular “steal” phenomenon, rather than direct compression of the spinal cord by bone enlargement ADDIN EN.CITE <EndNote><Cite><Author>Douglas</Author><Year>1981</Year><RecNum>19549</RecNum><DisplayText><style face="superscript">(50)</style></DisplayText><record><rec-number>19549</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1519080583">19549</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Douglas, D. L.</author><author>Duckworth, T.</author><author>Kanis, J. A.</author><author>Jefferson, A. A.</author><author>Martin, T. J.</author><author>Russell, R. G.</author></authors></contributors><titles><title>Spinal cord dysfunction in Paget's disease of bone. Has medical treatment a vascular basis?</title><secondary-title>J Bone Joint Surg Br</secondary-title></titles><periodical><full-title>J Bone Joint Surg Br</full-title></periodical><pages>495-503</pages><volume>63B</volume><number>4</number><edition>1981/01/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Clodronic Acid/therapeutic use</keyword><keyword>Etidronic Acid/therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications/drug therapy</keyword><keyword>Paralysis/etiology</keyword><keyword>Spinal Cord/blood supply</keyword><keyword>Spinal Cord Compression/*etiology/therapy</keyword></keywords><dates><year>1981</year></dates><isbn>0301-620X (Print)
0301-620X (Linking)</isbn><accession-num>6457839</accession-num><urls><related-urls><url>;(50). High output cardiac failure due to increased bone blood flow has been reported but is extremely rare ADDIN EN.CITE <EndNote><Cite><Author>Tuck</Author><Year>2017</Year><RecNum>19877</RecNum><DisplayText><style face="superscript">(51)</style></DisplayText><record><rec-number>19877</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1519249254">19877</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tuck,S.P., Layfield,R., Walker,J.,Mekkayil,B., Francis,R.</author></authors></contributors><titles><title>Adult Paget’s disease of Bone: a review</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology (Oxford)</full-title></periodical><pages>2050-2059</pages><volume>56</volume><number>12</number><section>2050</section><dates><year>2017</year></dates><work-type>Review</work-type><urls></urls></record></Cite></EndNote>(51). The overall frequency with which complications occur in PDB is unknown since it has been estimated that fewer than 10% of patients with x-ray evidence of PDB come to medical attention PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA (2). In those that do present clinically, bone pain is the most common symptom which was reported to occur in 73% of patients in a recent systematic review ADDIN EN.CITE <EndNote><Cite><Author>Tan</Author><Year>2014</Year><RecNum>8906</RecNum><DisplayText><style face="superscript">(52)</style></DisplayText><record><rec-number>8906</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">8906</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tan, A.</author><author>Ralston, S.H.</author></authors></contributors><auth-address>Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK</auth-address><titles><title>Clinical Presentation of Paget's Disease: Evaluation of a Contemporary Cohort and Systematic Review</title><secondary-title>Calcif. Tissue Int</secondary-title></titles><pages>385-392</pages><volume>95</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>analysis</keyword><keyword>AS</keyword><keyword>bone</keyword><keyword>bone pain</keyword><keyword>clinical</keyword><keyword>complications</keyword><keyword>deafness</keyword><keyword>Disease</keyword><keyword>Experimental</keyword><keyword>fracture</keyword><keyword>genetic</keyword><keyword>genetics</keyword><keyword>genomic</keyword><keyword>Medicine</keyword><keyword>molecular</keyword><keyword>morbidity</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>pain</keyword><keyword>Patients</keyword><keyword>PDB</keyword><keyword>Research</keyword><keyword>review</keyword><keyword>Rheumatology</keyword><keyword>therapeutic</keyword><keyword>treatment</keyword><keyword>Western</keyword></keywords><dates><year>2014</year><pub-dates><date>8/27/2014</date></pub-dates></dates><label>10874</label><urls><related-urls><url>;(52). The mechanisms of pain in PDB are incompletely understood. Although pain in some patients is due to increased metabolic activity, there is a weak correlation between the presence of bone pain and metabolic activity in PDB, at least as reflected by total ALP concentrations. For example, in the study of Reid and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVj
TnVtPjE2MzU1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
KDUzKTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE2MzU1PC9yZWMt
bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iemZweGVwcHhldnYwMGdl
dHQwMXB6ZXpxdnhmOXN0ZTBlNTU5IiB0aW1lc3RhbXA9IjE0OTQ3NjM1NzkiPjE2MzU1PC9rZXk+
PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10
eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZWlkLCBJLiBSLjwvYXV0aG9yPjxh
dXRob3I+TmljaG9sc29uLCBHLiBDLjwvYXV0aG9yPjxhdXRob3I+V2VpbnN0ZWluLCBSLiBTLjwv
YXV0aG9yPjxhdXRob3I+SG9za2luZywgRC4gSi48L2F1dGhvcj48YXV0aG9yPkN1bmR5LCBULjwv
YXV0aG9yPjxhdXRob3I+S290b3dpY3osIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5NdXJwaHksIFcu
IEEuLCBKci48L2F1dGhvcj48YXV0aG9yPlllYXAsIFMuPC9hdXRob3I+PGF1dGhvcj5EdWZyZXNu
ZSwgUy48L2F1dGhvcj48YXV0aG9yPkxvbWJhcmRpLCBBLjwvYXV0aG9yPjxhdXRob3I+TXVzbGlu
ZXIsIFQuIEEuPC9hdXRob3I+PGF1dGhvcj5UaG9tcHNvbiwgRC4gRS48L2F1dGhvcj48YXV0aG9y
PllhdGVzLCBBLiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy
ZXNzPkRlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQXVja2xhbmQsIE5ldyBa
ZWFsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJpb2NoZW1pY2FsIGFuZCByYWRp
b2xvZ2ljIGltcHJvdmVtZW50IGluIFBhZ2V0JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmUgdHJlYXRl
ZCB3aXRoIGFsZW5kcm9uYXRlOiBhIHJhbmRvbWl6ZWQsIHBsYWNlYm8tY29udHJvbGxlZCB0cmlh
bDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9k
aWNhbD48cGFnZXM+MzQxLTg8L3BhZ2VzPjx2b2x1bWU+MTAxPC92b2x1bWU+PG51bWJlcj40PC9u
dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkbWluaXN0cmF0aW9uLCBPcmFsPC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+
PGtleXdvcmQ+QWxlbmRyb25hdGUvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2Ug
ZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFsa2FsaW5lIFBob3Nw
aGF0YXNlL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkJpb3BzeTwva2V5d29yZD48a2V5d29yZD5C
b25lIGFuZCBCb25lcy9kaWFnbm9zdGljIGltYWdpbmcvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS9ibG9vZDwva2V5d29yZD48a2V5d29yZD5Db2xsYWdlbi91
cmluZTwva2V5d29yZD48a2V5d29yZD5Db2xsYWdlbiBUeXBlIEk8L2tleXdvcmQ+PGtleXdvcmQ+
RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk
ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+T3N0ZWl0aXMgRGVmb3JtYW5zL2RpYWdub3N0aWMg
aW1hZ2luZy8qZHJ1ZyB0aGVyYXB5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlk
ZXMvdXJpbmU8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3BoYXRlcy9ibG9vZDwva2V5d29yZD48a2V5
d29yZD5SYWRpb2dyYXBoeTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+
MDAwMi05MzQzIChQcmludCkmI3hEOzAwMDItOTM0MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv
bi1udW0+ODg3MzUwMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0
cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg3MzUwMzwvdXJsPjwvcmVsYXRlZC11
cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (53), 22/55 (41.1%) patients with a raised total ALP did not experience bone pain. Similarly, in the PRISM study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE.DATA (54), 635 patients had a raised ALP at the baseline visit but 295 (46.4%) of these individuals did not have bone pain. Aside from pain, many other complications of PDB are recognised. In the systematic review cited previously ADDIN EN.CITE <EndNote><Cite><Author>Tan</Author><Year>2014</Year><RecNum>8906</RecNum><DisplayText><style face="superscript">(52)</style></DisplayText><record><rec-number>8906</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">8906</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tan, A.</author><author>Ralston, S.H.</author></authors></contributors><auth-address>Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK</auth-address><titles><title>Clinical Presentation of Paget's Disease: Evaluation of a Contemporary Cohort and Systematic Review</title><secondary-title>Calcif. Tissue Int</secondary-title></titles><pages>385-392</pages><volume>95</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>analysis</keyword><keyword>AS</keyword><keyword>bone</keyword><keyword>bone pain</keyword><keyword>clinical</keyword><keyword>complications</keyword><keyword>deafness</keyword><keyword>Disease</keyword><keyword>Experimental</keyword><keyword>fracture</keyword><keyword>genetic</keyword><keyword>genetics</keyword><keyword>genomic</keyword><keyword>Medicine</keyword><keyword>molecular</keyword><keyword>morbidity</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>pain</keyword><keyword>Patients</keyword><keyword>PDB</keyword><keyword>Research</keyword><keyword>review</keyword><keyword>Rheumatology</keyword><keyword>therapeutic</keyword><keyword>treatment</keyword><keyword>Western</keyword></keywords><dates><year>2014</year><pub-dates><date>8/27/2014</date></pub-dates></dates><label>10874</label><urls><related-urls><url>;(52) bone deformity was present in 21.5% of patients at first presentation followed by deafness (8.9%) and pathological fracture (8.5%). Osteoarthritis is a common complication of PDB. An analysis of the UK General Practice Research Database in 2002 revealed that patients who have been diagnosed with PDB were more likely to require hip arthroplasty for osteoarthritis compared with age matched controls (odds ratio 3.1, 95% confidence interval 2.4-4.1) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA (2). Osteosarcoma is a rare complication of PDB which affects about 0.3% of patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gU3RhYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA (2). It has a poor prognosis even with aggressive treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdWdnaWVyaTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdWdnaWVyaTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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==
ADDIN EN.CITE.DATA (55). Giant cell tumour (GCT) is a very rare complication in PDB. A systematic review identified 117 cases of GCT associated with PDB that had been reported in the literature worldwide PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5kaW5hPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5kaW5hPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48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ADDIN EN.CITE.DATA (56). In this series there was overrepresentation of people of Italian descent from the region of Campania. A high proportion of patients from this region who have GCT and PDB carry a specific missense mutation in the ZNF678 gene PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXZpc2F0bzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXZpc2F0bzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
PFJlY051bT4xOTkwOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp
cHQiPig1Nyk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xOTkwOTwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2
MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIxNTIwODQ2MjE4Ij4xOTkwOTwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RGl2aXNhdG8sIEcuPC9hdXRo
b3I+PGF1dGhvcj5Gb3JtaWNvbGEsIEQuPC9hdXRob3I+PGF1dGhvcj5Fc3Bvc2l0bywgVC48L2F1
dGhvcj48YXV0aG9yPk1lcmxvdHRpLCBELjwvYXV0aG9yPjxhdXRob3I+UGF6emFnbGlhLCBMLjwv
YXV0aG9yPjxhdXRob3I+RGVsIEZhdHRvcmUsIEEuPC9hdXRob3I+PGF1dGhvcj5TaXJpcywgRS48
L2F1dGhvcj48YXV0aG9yPk9yY2VsLCBQLjwvYXV0aG9yPjxhdXRob3I+QnJvd24sIEouIFAuPC9h
dXRob3I+PGF1dGhvcj5OdXRpLCBSLjwvYXV0aG9yPjxhdXRob3I+U3RyYXp6dWxsbywgUC48L2F1
dGhvcj48YXV0aG9yPkJlbmFzc2ksIE0uIFMuPC9hdXRob3I+PGF1dGhvcj5DYW5jZWxhLCBNLiBM
LjwvYXV0aG9yPjxhdXRob3I+TWljaG91LCBMLjwvYXV0aG9yPjxhdXRob3I+UmVuZGluYSwgRC48
L2F1dGhvcj48YXV0aG9yPkdlbm5hcmksIEwuPC9hdXRob3I+PGF1dGhvcj5HaWFuZnJhbmNlc2Nv
LCBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkluc3Rp
dHV0ZSBvZiBHZW5ldGljcyBhbmQgQmlvcGh5c2ljcyAmcXVvdDtBZHJpYW5vIEJ1enphdGktVHJh
dmVyc28sJnF1b3Q7IE5hdGlvbmFsIFJlc2VhcmNoIENvdW5jaWwgb2YgSXRhbHksIDgwMTMxIE5h
cGxlcywgSXRhbHkuJiN4RDtEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBTdXJnZXJ5IGFuZCBOZXVy
b3NjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFNpZW5hLCBTaWVuYSA1MzEwMCwgSXRhbHkuJiN4RDtM
YWJvcmF0b3J5IG9mIEV4cGVyaW1lbnRhbCBPbmNvbG9neSwgUml6em9saSBPcnRob3BhZWRpYyBJ
bnN0aXR1dGUsIEJvbG9nbmEgNDAxMzYsIEl0YWx5LiYjeEQ7QmFtYmlubyBHZXN1IENoaWxkcmVu
JmFwb3M7cyBIb3NwaXRhbCwgUmVnZW5lcmF0aXZlIE1lZGljaW5lIFVuaXQsIFJvbWUgMDAxNDYs
IEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgQ29sdW1iaWEgVW5pdmVyc2l0eSBN
ZWRpY2FsIENlbnRyZSwgTmV3IFlvcmssIE5ZIDEwMDMyLCBVU0EuJiN4RDtQb2xlIEFwcGFyZWls
IExvY29tb3RldXIsIFNlcnZpY2UgZGUgUmh1bWF0b2xvZ2llIEIsIEhvcGl0YWwgTGFyaWJvaXNp
ZXJlLCBBc3Npc3RhbmNlIFB1YmxpcXVlLUhvcGl0YXV4IGRlIFBhcmlzLCBQYXJpcyA3NTAxMCwg
RnJhbmNlLiYjeEQ7RGl2aXNpb24gb2YgUmhldW1hdG9sb2d5LCBEZXBhcnRtZW50IG9mIE1lZGlj
aW5lLCBVbml2ZXJzaXRlIExhdmFsLCBRdWViZWMsIFFDIDQyMTc4LCBDYW5hZGEuJiN4RDtEZXBh
cnRtZW50IG9mIE1lZGljaW5lIGFuZCBTdXJnZXJ5LCBGZWRlcmljbyBJSSBVbml2ZXJzaXR5LCBO
YXBsZXMgODAxMzEsIEl0YWx5LiYjeEQ7RGVwYXJ0bWVudCBvZiBCaW9tZWRpY2FsIFNjaWVuY2Vz
IGFuZCBNZWRpY2luZSBhbmQgQ2VudHJlIG9mIE1hcmluZSBTY2llbmNlcywgVW5pdmVyc2l0eSBv
ZiBBbGdhcnZlLCBGYXJvIDgwMDUtMTM5LCBQb3J0dWdhbC4mI3hEO0luc3RpdHV0ZSBvZiBHZW5l
dGljcyBhbmQgQmlvcGh5c2ljcyAmcXVvdDtBZHJpYW5vIEJ1enphdGktVHJhdmVyc28sJnF1b3Q7
IE5hdGlvbmFsIFJlc2VhcmNoIENvdW5jaWwgb2YgSXRhbHksIDgwMTMxIE5hcGxlcywgSXRhbHku
IEVsZWN0cm9uaWMgYWRkcmVzczogZmVybmFuZG8uZ2lhbmZyYW5jZXNjb0BpZ2IuY25yLml0Ljwv
YXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlpORjY4NyBNdXRhdGlvbnMgaW4gU2V2ZXJlIFBh
Z2V0IERpc2Vhc2Ugb2YgQm9uZSBBc3NvY2lhdGVkIHdpdGggR2lhbnQgQ2VsbCBUdW1vcjwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIEh1bSBHZW5ldDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogSHVtIEdlbmV0PC9mdWxsLXRpdGxlPjwv
cGVyaW9kaWNhbD48cGFnZXM+Mjc1LTg2PC9wYWdlcz48dm9sdW1lPjk4PC92b2x1bWU+PG51bWJl
cj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMi8wNjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv
cmQ+QW1pbm8gQWNpZCBTZXF1ZW5jZTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk
PjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxrZXl3b3JkPkV4b25zPC9rZXl3b3JkPjxrZXl3b3Jk
PkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Gb3VuZGVyIEVmZmVjdDwva2V5d29yZD48a2V5d29y
ZD4qR2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRpb24sIE5lb3BsYXN0aWM8L2tleXdvcmQ+PGtleXdv
cmQ+R2lhbnQgQ2VsbCBUdW1vcnMvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv
a2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1vbGVjdWxhciBTZXF1ZW5j
ZSBEYXRhPC9rZXl3b3JkPjxrZXl3b3JkPk11dGF0aW9uLCBNaXNzZW5zZTwva2V5d29yZD48a2V5
d29yZD5Pc3RlaXRpcyBEZWZvcm1hbnMvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk9zdGVv
Y2xhc3RzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGVkaWdyZWU8L2tleXdvcmQ+PGtl
eXdvcmQ+VXAtUmVndWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5aZWJyYWZpc2gvZ2VuZXRpY3M8
L2tleXdvcmQ+PGtleXdvcmQ+WmluYyBGaW5nZXJzLypnZW5ldGljczwva2V5d29yZD48L2tleXdv
cmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViIDQ8L2RhdGU+
PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTM3LTY2MDUgKEVsZWN0cm9uaWMpJiN4RDswMDAy
LTkyOTcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2ODQ5MTEwPC9hY2Nlc3Npb24t
bnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292
L3B1Ym1lZC8yNjg0OTExMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0
NzQ2MzY3PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouYWpoZy4y
MDE1LjEyLjAxNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5k
Tm90ZT4A
ADDIN EN.CITE.DATA (57). In Italy the prevalence of GCT complicating PDB is estimated to be about 0.8% (L Gennari, unpublished data) but is likely to be much lower in other countries.Need for the guideline The Paget Association and other supporting organisations identified a need for a new guideline which was evidence based, patient focused and which considered all of the available evidence. This guideline differs previous guidelines published on this subject PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZWxieTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZWxieTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl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==
ADDIN EN.CITE.DATA (58-60) in that we considered both pharmacological and non-pharmacological treatments options, in that we had patient representation on the guideline development group and sought feedback from patients in the peer review process; and in that we have provided information on the key questions used to develop the guideline, as well as details of the search strategy and numbers of publications which were reviewed for each key question. Remit of the guideline The remit of the guideline was to provide patient-centred, evidence-based recommendations for the diagnosis and management of classical PDB in adults. The guideline focused on classical PDB and did not consider the diagnosis or management of rare PDB-like syndromes. We evaluated tools for the diagnosis of PDB and evaluation of disease extent, the effects of bisphosphonates and other drug treatments on various clinical outcomes, the predictors of treatment response and the effects of non-pharmacological treatments. Due to limitations in the evidence base, we were unable to evaluate how well imaging techniques and biochemical tests performed in differentiating PDB from other conditions such as hyperostosis frontalis interna, chronic non-bacterial osteomyelitis and osteosclerotic metastases or in evaluating the clinical role and performance of invasive techniques like bone biopsy in differential diagnosis. That being said, clinical experience indicates that PDB can usually be differentiated quite easily from other conditions by the patient’s clinical characteristics, and the typical appearances of the disease on radiographic and scintigraphic examination as discussed below ADDIN EN.CITE <EndNote><Cite><Author>Ralston</Author><Year>2013</Year><RecNum>7353</RecNum><DisplayText><style face="superscript">(61)</style></DisplayText><record><rec-number>7353</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">7353</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ralston, S.H.</author></authors></contributors><auth-address>Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. stuart.ralston@ed.ac.uk</auth-address><titles><title>Clinical practice. Paget's disease of bone</title><secondary-title>N. Engl. J. Med</secondary-title></titles><pages>644-650</pages><volume>368</volume><number>7</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Aged</keyword><keyword>bone</keyword><keyword>bone density</keyword><keyword>Bone Density Conservation Agents</keyword><keyword>clinical</keyword><keyword>diagnosis</keyword><keyword>diphosphonate</keyword><keyword>Diphosphonates</keyword><keyword>Disease</keyword><keyword>Drug Therapy</keyword><keyword>genetic</keyword><keyword>genetics</keyword><keyword>Humans</keyword><keyword>Lumbar Vertebrae</keyword><keyword>Male</keyword><keyword>Medicine</keyword><keyword>molecular</keyword><keyword>Osteitis Deformans</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>radiography</keyword><keyword>review</keyword><keyword>therapeutic use</keyword><keyword>therapy</keyword><keyword>Western</keyword></keywords><dates><year>2013</year><pub-dates><date>2/14/2013</date></pub-dates></dates><label>10243</label><urls><related-urls><url>;(61)The guideline will be of interest to rheumatologists, endocrinologists, physicians involved in care of older people, orthopaedic surgeons, internal medicine specialists, metabolic medicine specialists, radiologists, general practitioners, specialist nurses, clinical biochemists, rehabilitation specialists, physiotherapists, occupational therapists and pharmacists who are involved in the care of patients with PDB. Patients affected by PDB, their care-givers and other family members may also find the guideline to be of interest.It should be noted that adherence to the recommendations may not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at achieving the same result. The ultimate judgement must be made by the appropriate healthcare professional(s) responsible for clinical decisions regarding a particular clinical procedure or treatment plan. This judgement should only be arrived at following discussion of the options with the patient, covering the diagnostic and treatment choices available. It is advised, however, that significant departures from guidelines should be fully documented in the patient’s medical records at the time the relevant decision is taken.Recommendations within this guideline are based on the best available clinical evidence. Some recommendations may include the prescription of medicines for which they do not have marketing authorisation (a product licence). Medicines may be prescribed outside their product licence in some countries and this can be necessary for a variety of reasons such as if the clinical need cannot be met by licensed medicines. In such cases off label prescribing may be employed provided it is supported by clinical evidence and experience. Methods The Guideline Development Group (GDG) was established in January 2016 by the UK Paget’s Association, the European Calcified Tissues Society and the International Osteoporosis Foundation, which incorporated a multidisciplinary panel of medical practitioners with experience in rheumatology, endocrinology, internal medicine, clinical biochemistry a non-clinical scientist, a specialist nurse and one lay member (a patient with PDB). All members were volunteers and none received payment for their participation The GDG identified six relevant key questions (KQ) (Appendix 1, supplementary material) and used the 2013 update of GRADE methodology () to assess the strength of evidence and to formulate recommendations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbG9uc28tQ29lbGxvPC9BdXRob3I+PFllYXI+MjAxNjwv
WWVhcj48UmVjTnVtPjE5NDQ0PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl
cnNjcmlwdCI+KDYyLTY1KTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVy
PjE5NDQ0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iemZw
eGVwcHhldnYwMGdldHQwMXB6ZXpxdnhmOXN0ZTBlNTU5IiB0aW1lc3RhbXA9IjE1MTg2MzMyMDci
PjE5NDQ0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs
ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BbG9uc28tQ29l
bGxvLCBQLjwvYXV0aG9yPjxhdXRob3I+T3htYW4sIEEuIEQuPC9hdXRob3I+PGF1dGhvcj5Nb2Jl
cmcsIEouPC9hdXRob3I+PGF1dGhvcj5CcmlnbmFyZGVsbG8tUGV0ZXJzZW4sIFIuPC9hdXRob3I+
PGF1dGhvcj5Ba2wsIEUuIEEuPC9hdXRob3I+PGF1dGhvcj5EYXZvbGksIE0uPC9hdXRob3I+PGF1
dGhvcj5UcmV3ZWVrLCBTLjwvYXV0aG9yPjxhdXRob3I+TXVzdGFmYSwgUi4gQS48L2F1dGhvcj48
YXV0aG9yPlZhbmR2aWssIFAuIE8uPC9hdXRob3I+PGF1dGhvcj5NZWVycG9obCwgSi48L2F1dGhv
cj48YXV0aG9yPkd1eWF0dCwgRy4gSC48L2F1dGhvcj48YXV0aG9yPlNjaHVuZW1hbm4sIEguIEou
PC9hdXRob3I+PGF1dGhvcj5HcmFkZSBXb3JraW5nIEdyb3VwPC9hdXRob3I+PC9hdXRob3JzPjwv
Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SWJlcm9hbWVyaWNhbiBDb2NocmFuZSBDZW50cmUs
IENJQkVSRVNQLUlJQiBTYW50IFBhdSwgQmFyY2Vsb25hLCBTcGFpbiBEZXBhcnRtZW50IG9mIENs
aW5pY2FsIEVwaWRlbWlvbG9neSBhbmQgQmlvc3RhdGlzdGljcywgTWNNYXN0ZXIgVW5pdmVyc2l0
eSwgSGFtaWx0b24sIENhbmFkYSBwYWxvbnNvQHNhbnRwYXUuY2F0LiYjeEQ7R2xvYmFsIEhlYWx0
aCBVbml0LCBOb3J3ZWdpYW4gSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIE9zbG8sIE5vcndh
eS4mI3hEO0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgRXBpZGVtaW9sb2d5IGFuZCBCaW9zdGF0aXN0
aWNzLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgQ2FuYWRhIEV2aWRlbmNlIEJhc2Vk
IERlbnRpc3RyeSBVbml0LCBGYWN1bHR5IG9mIERlbnRpc3RyeSwgVW5pdmVyc2lkYWQgZGUgQ2hp
bGUsIFNhbnRpYWdvLCBDaGlsZS4mI3hEO0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgRXBpZGVtaW9s
b2d5IGFuZCBCaW9zdGF0aXN0aWNzLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgQ2Fu
YWRhIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUsIENsaW5pY2FsIEVwaWRlbWlvbG9n
eSBVbml0LCBBbWVyaWNhbiBVbml2ZXJzaXR5IG9mIEJlaXJ1dCBNZWRpY2FsIENlbnRlciwgQmVp
cnV0LCBMZWJhbm9uLiYjeEQ7RGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xvZ3ksIExhemlvIFJlZ2lv
bmFsIEhlYWx0aCBTZXJ2aWNlLCBSb21lLCBJdGFseS4mI3hEO0hlYWx0aCBTZXJ2aWNlcyBSZXNl
YXJjaCBVbml0LCBVbml2ZXJzaXR5IG9mIEFiZXJkZWVuLCBBYmVyZGVlbiwgVUsuJiN4RDtEZXBh
cnRtZW50IG9mIENsaW5pY2FsIEVwaWRlbWlvbG9neSBhbmQgQmlvc3RhdGlzdGljcywgTWNNYXN0
ZXIgVW5pdmVyc2l0eSwgSGFtaWx0b24sIENhbmFkYSBEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBV
bml2ZXJzaXR5IG9mIE1pc3NvdXJpLUthbnNhcyBDaXR5LCBLYW5zYXMgQ2l0eSwgTWlzc291cmks
IFVTQS4mI3hEO0NvY2hyYW5lIEdlcm1hbnksIE1lZGljYWwgQ2VudGVyIC0gVW5pdmVyc2l0eSBv
ZiBGcmVpYnVyZywgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBGcmVpYnVyZywg
R2VybWFueS4mI3hEO0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgRXBpZGVtaW9sb2d5IGFuZCBCaW9z
dGF0aXN0aWNzLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgQ2FuYWRhIERlcGFydG1l
bnQgb2YgTWVkaWNpbmUsIE1jTWFzdGVyIFVuaXZlcnNpdHksIEhhbWlsdG9uLCBDYW5hZGEuPC9h
dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R1JBREUgRXZpZGVuY2UgdG8gRGVjaXNpb24gKEV0
RCkgZnJhbWV3b3JrczogYSBzeXN0ZW1hdGljIGFuZCB0cmFuc3BhcmVudCBhcHByb2FjaCB0byBt
YWtpbmcgd2VsbCBpbmZvcm1lZCBoZWFsdGhjYXJlIGNob2ljZXMuIDI6IENsaW5pY2FsIHByYWN0
aWNlIGd1aWRlbGluZXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Qk1KPC9zZWNvbmRhcnktdGl0
bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Qk1KPC9mdWxsLXRpdGxlPjwvcGVy
aW9kaWNhbD48cGFnZXM+aTIwODk8L3BhZ2VzPjx2b2x1bWU+MzUzPC92b2x1bWU+PGVkaXRpb24+
MjAxNi8wNy8wMjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Q2hvaWNlIEJlaGF2aW9yPC9r
ZXl3b3JkPjxrZXl3b3JkPkNvc3QtQmVuZWZpdCBBbmFseXNpczwva2V5d29yZD48a2V5d29yZD4q
RGVjaXNpb24gTWFraW5nPC9rZXl3b3JkPjxrZXl3b3JkPipFdmlkZW5jZS1CYXNlZCBNZWRpY2lu
ZTwva2V5d29yZD48a2V5d29yZD5IZWFsdGggUGxhbiBJbXBsZW1lbnRhdGlvbi8qbWV0aG9kczwv
a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KlByYWN0aWNlIEd1aWRl
bGluZXMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ3JhbSBEZXZlbG9wbWVudDwva2V5
d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+
SnVuIDMwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc1Ni0xODMzIChFbGVjdHJv
bmljKSYjeEQ7MDk1OS01MzVYIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzM2NTQ5
NDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi
aS5ubG0ubmloLmdvdi9wdWJtZWQvMjczNjU0OTQ8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+
PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMzYvYm1qLmkyMDg5PC9lbGVjdHJvbmljLXJl
c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5BbG9uc28tQ29lbGxvPC9B
dXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVjTnVtPjE5NDQ1PC9SZWNOdW0+PHJlY29yZD48cmVj
LW51bWJlcj4xOTQ0NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGIt
aWQ9InpmcHhlcHB4ZXZ2MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIxNTE4
NjMzMjA3Ij4xOTQ0NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFs
IEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QWxv
bnNvLUNvZWxsbywgUC48L2F1dGhvcj48YXV0aG9yPlNjaHVuZW1hbm4sIEguIEouPC9hdXRob3I+
PGF1dGhvcj5Nb2JlcmcsIEouPC9hdXRob3I+PGF1dGhvcj5CcmlnbmFyZGVsbG8tUGV0ZXJzZW4s
IFIuPC9hdXRob3I+PGF1dGhvcj5Ba2wsIEUuIEEuPC9hdXRob3I+PGF1dGhvcj5EYXZvbGksIE0u
PC9hdXRob3I+PGF1dGhvcj5UcmV3ZWVrLCBTLjwvYXV0aG9yPjxhdXRob3I+TXVzdGFmYSwgUi4g
QS48L2F1dGhvcj48YXV0aG9yPlJhZGEsIEcuPC9hdXRob3I+PGF1dGhvcj5Sb3NlbmJhdW0sIFMu
PC9hdXRob3I+PGF1dGhvcj5Nb3JlbGxpLCBBLjwvYXV0aG9yPjxhdXRob3I+R3V5YXR0LCBHLiBI
LjwvYXV0aG9yPjxhdXRob3I+T3htYW4sIEEuIEQuPC9hdXRob3I+PGF1dGhvcj5HcmFkZSBXb3Jr
aW5nIEdyb3VwPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+
SWJlcm9hbWVyaWNhbiBDb2NocmFuZSBDZW50cmUsIENJQkVSRVNQLUlJQiBTYW50IFBhdSwgQmFy
Y2Vsb25hLCBTcGFpbiBEZXBhcnRtZW50IG9mIENsaW5pY2FsIEVwaWRlbWlvbG9neSBhbmQgQmlv
c3RhdGlzdGljcywgTWNNYXN0ZXIgVW5pdmVyc2l0eSwgSGFtaWx0b24sIENhbmFkYS4mI3hEO0Rl
cGFydG1lbnQgb2YgQ2xpbmljYWwgRXBpZGVtaW9sb2d5IGFuZCBCaW9zdGF0aXN0aWNzLCBNY01h
c3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgQ2FuYWRhIERlcGFydG1lbnQgb2YgTWVkaWNpbmUs
IE1jTWFzdGVyIFVuaXZlcnNpdHksIEhhbWlsdG9uLCBDYW5hZGEuJiN4RDtOb3J3ZWdpYW4gSW5z
dGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIE9zbG8sIE5vcndheS4mI3hEO0RlcGFydG1lbnQgb2Yg
Q2xpbmljYWwgRXBpZGVtaW9sb2d5IGFuZCBCaW9zdGF0aXN0aWNzLCBNY01hc3RlciBVbml2ZXJz
aXR5LCBIYW1pbHRvbiwgQ2FuYWRhIEV2aWRlbmNlIEJhc2VkIERlbnRpc3RyeSBVbml0LCBGYWN1
bHR5IG9mIERlbnRpc3RyeSwgVW5pdmVyc2lkYWQgZGUgQ2hpbGUsIFNhbnRpYWdvLCBDaGlsZS4m
I3hEO0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgRXBpZGVtaW9sb2d5IGFuZCBCaW9zdGF0aXN0aWNz
LCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgQ2FuYWRhIERlcGFydG1lbnQgb2YgSW50
ZXJuYWwgTWVkaWNpbmUsIENsaW5pY2FsIEVwaWRlbWlvbG9neSBVbml0LCBBbWVyaWNhbiBVbml2
ZXJzaXR5IG9mIEJlaXJ1dCBNZWRpY2FsIENlbnRlciwgQmVpcnV0IDExMDcsIDIwMjAsIExlYmFu
b24uJiN4RDtEZXBhcnRtZW50IG9mIEVwaWRlbWlvbG9neSwgTGF6aW8gUmVnaW9uYWwgSGVhbHRo
IFNlcnZpY2UsIFJvbWUsIEl0YWx5LiYjeEQ7SGVhbHRoIFNlcnZpY2VzIFJlc2VhcmNoIFVuaXQs
IFVuaXZlcnNpdHkgb2YgQWJlcmRlZW4sIEFiZXJkZWVuLCBVSy4mI3hEO0RlcGFydG1lbnQgb2Yg
Q2xpbmljYWwgRXBpZGVtaW9sb2d5IGFuZCBCaW9zdGF0aXN0aWNzLCBNY01hc3RlciBVbml2ZXJz
aXR5LCBIYW1pbHRvbiwgQ2FuYWRhIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkg
b2YgTWlzc291cmktS2Fuc2FzIENpdHksIEthbnNhcyBDaXR5LCBNaXNzb3VyaSwgVVNBLCA2NDEx
MC4mI3hEO0V2aWRlbmNlIEJhc2VkIEhlYWx0aCBDYXJlIFByb2dyYW0sIEZhY3VsdHkgb2YgTWVk
aWNpbmUsIFBvbnRpZmljaWEgVW5pdmVyc2lkYWQgQ2F0b2xpY2EgZGUgQ2hpbGUsIFNhbnRpYWdv
LCBDaGlsZSBEZXBhcnRtZW50IG9mIEludGVybmFsIE1lZGljaW5lLCBGYWN1bHR5IG9mIE1lZGlj
aW5lLCBQb250aWZpY2lhIFVuaXZlcnNpZGFkIENhdG9saWNhIGRlIENoaWxlLCBTYW50aWFnbywg
Q2hpbGUgRXBpc3RlbW9uaWtvcyBGb3VuZGF0aW9uLCBTYW50aWFnbywgQ2hpbGUuJiN4RDtOb3J3
ZWdpYW4gSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIE9zbG8sIE5vcndheSBveG1hbkBvbmxp
bmUubm8uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R1JBREUgRXZpZGVuY2UgdG8gRGVj
aXNpb24gKEV0RCkgZnJhbWV3b3JrczogYSBzeXN0ZW1hdGljIGFuZCB0cmFuc3BhcmVudCBhcHBy
b2FjaCB0byBtYWtpbmcgd2VsbCBpbmZvcm1lZCBoZWFsdGhjYXJlIGNob2ljZXMuIDE6IEludHJv
ZHVjdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CTUo8L3NlY29uZGFyeS10aXRsZT48L3Rp
dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5CTUo8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs
PjxwYWdlcz5pMjAxNjwvcGFnZXM+PHZvbHVtZT4zNTM8L3ZvbHVtZT48ZWRpdGlvbj4yMDE2LzA2
LzMwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5DaG9pY2UgQmVoYXZpb3I8L2tleXdvcmQ+
PGtleXdvcmQ+KkRlY2lzaW9uIFN1cHBvcnQgVGVjaG5pcXVlczwva2V5d29yZD48a2V5d29yZD4q
RGVsaXZlcnkgb2YgSGVhbHRoIENhcmU8L2tleXdvcmQ+PGtleXdvcmQ+KkV2aWRlbmNlLUJhc2Vk
IE1lZGljaW5lPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48L2tleXdvcmRzPjxk
YXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVuIDI4PC9kYXRlPjwvcHVi
LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTc1Ni0xODMzIChFbGVjdHJvbmljKSYjeEQ7MDk1OS01MzVY
IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzM1MzQxNzwvYWNjZXNzaW9uLW51bT48
dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt
ZWQvMjczNTM0MTc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy
Y2UtbnVtPjEwLjExMzYvYm1qLmkyMDE2PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29y
ZD48L0NpdGU+PENpdGU+PEF1dGhvcj5BdGtpbnM8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
ZWNOdW0+MzY2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4zNjY8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0dDAxcHplenF2
eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMCI+MzY2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10
eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1
dGhvcnM+PGF1dGhvcj5BdGtpbnMsIEQuPC9hdXRob3I+PGF1dGhvcj5CZXN0LCBELjwvYXV0aG9y
PjxhdXRob3I+QnJpc3MsIFAuQS48L2F1dGhvcj48YXV0aG9yPkVjY2xlcywgTS48L2F1dGhvcj48
YXV0aG9yPkZhbGNrLVl0dGVyLCBZLjwvYXV0aG9yPjxhdXRob3I+RmxvdHRvcnAsIFMuPC9hdXRo
b3I+PGF1dGhvcj5HdXlhdHQsIEcuSC48L2F1dGhvcj48YXV0aG9yPkhhcmJvdXIsIFIuVC48L2F1
dGhvcj48YXV0aG9yPkhhdWdoLCBNLkMuPC9hdXRob3I+PGF1dGhvcj5IZW5yeSwgRC48L2F1dGhv
cj48YXV0aG9yPkhpbGwsIFMuPC9hdXRob3I+PGF1dGhvcj5KYWVzY2hrZSwgUi48L2F1dGhvcj48
YXV0aG9yPkxlbmcsIEcuPC9hdXRob3I+PGF1dGhvcj5MaWJlcmF0aSwgQS48L2F1dGhvcj48YXV0
aG9yPk1hZ3JpbmksIE4uPC9hdXRob3I+PGF1dGhvcj5NYXNvbiwgSi48L2F1dGhvcj48YXV0aG9y
Pk1pZGRsZXRvbiwgUC48L2F1dGhvcj48YXV0aG9yPk1ydWtvd2ljeiwgSi48L2F1dGhvcj48YXV0
aG9yPk8mYXBvcztDb25uZWxsLCBELjwvYXV0aG9yPjxhdXRob3I+T3htYW4sIEEuRC48L2F1dGhv
cj48YXV0aG9yPlBoaWxsaXBzLCBCLjwvYXV0aG9yPjxhdXRob3I+U2NodW5lbWFubiwgSC5KLjwv
YXV0aG9yPjxhdXRob3I+RWRlamVyLCBULjwvYXV0aG9yPjxhdXRob3I+VmFyb25lbiwgSC48L2F1
dGhvcj48YXV0aG9yPlZpc3QsIEcuRS48L2F1dGhvcj48YXV0aG9yPldpbGxpYW1zLCBKLlcuLCBK
ci48L2F1dGhvcj48YXV0aG9yPlphemEsIFMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0
b3JzPjx0aXRsZXM+PHRpdGxlPkdyYWRpbmcgcXVhbGl0eSBvZiBldmlkZW5jZSBhbmQgc3RyZW5n
dGggb2YgcmVjb21tZW5kYXRpb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkJNSjwvc2Vjb25k
YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJNSjwvZnVsbC10aXRs
ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0OTA8L3BhZ2VzPjx2b2x1bWU+MzI4PC92b2x1bWU+PG51
bWJlcj43NDU0PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1l
ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5hPC9rZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9r
ZXl3b3JkPjxrZXl3b3JkPmNvc3Q8L2tleXdvcmQ+PGtleXdvcmQ+Q29zdC1CZW5lZml0IEFuYWx5
c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkV2aWRlbmNlLUJhc2VkIE1lZGljaW5lPC9rZXl3b3JkPjxr
ZXl3b3JkPmd1aWRlbGluZXM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3
b3JkPkp1ZGdtZW50PC9rZXl3b3JkPjxrZXl3b3JkPm1ldGhvZDwva2V5d29yZD48a2V5d29yZD5t
ZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPlByYWN0aWNlIEd1aWRlbGluZXM8L2tleXdvcmQ+PGtl
eXdvcmQ+UHJhY3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5RdWFs
aXR5IEFzc3VyYW5jZSxIZWFsdGggQ2FyZTwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaDwva2V5
d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0PC9rZXl3b3JkPjxrZXl3b3JkPlJpc2s8L2tl
eXdvcmQ+PGtleXdvcmQ+c3RhbmRhcmRzPC9rZXl3b3JkPjxrZXl3b3JkPlN1cHBvcnQ8L2tleXdv
cmQ+PGtleXdvcmQ+VHJhbnNsYXRpb248L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+
MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMTkvMjAwNDwvZGF0ZT48L3B1Yi1kYXRlcz48
L2RhdGVzPjxsYWJlbD4xMDk3ODwvbGFiZWw+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6
Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTUyMDUyOTU8L3VybD48L3JlbGF0ZWQtdXJs
cz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+SHN1PC9BdXRob3I+PFllYXI+
MjAxMTwvWWVhcj48UmVjTnVtPjE5NDUxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xOTQ1
MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4
ZXZ2MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIxNTE4NjMzNzAxIj4xOTQ1
MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3
PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SHN1LCBKLjwvYXV0aG9y
PjxhdXRob3I+QnJvemVrLCBKLiBMLjwvYXV0aG9yPjxhdXRob3I+VGVycmFjY2lhbm8sIEwuPC9h
dXRob3I+PGF1dGhvcj5LcmVpcywgSi48L2F1dGhvcj48YXV0aG9yPkNvbXBhbGF0aSwgRS48L2F1
dGhvcj48YXV0aG9yPlN0ZWluLCBBLiBULjwvYXV0aG9yPjxhdXRob3I+RmlvY2NoaSwgQS48L2F1
dGhvcj48YXV0aG9yPlNjaHVuZW1hbm4sIEguIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp
YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBFcGlkZW1pb2xvZ3kg
YW5kIEJpb3N0YXRpc3RpY3MsIE1jTWFzdGVyIFVuaXZlcnNpdHksIEhhbWlsdG9uLCBPbnRhcmlv
LCBDYW5hZGEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QXBwbGljYXRpb24gb2YgR1JB
REU6IG1ha2luZyBldmlkZW5jZS1iYXNlZCByZWNvbW1lbmRhdGlvbnMgYWJvdXQgZGlhZ25vc3Rp
YyB0ZXN0cyBpbiBjbGluaWNhbCBwcmFjdGljZSBndWlkZWxpbmVzPC90aXRsZT48c2Vjb25kYXJ5
LXRpdGxlPkltcGxlbWVudCBTY2k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh
bD48ZnVsbC10aXRsZT5JbXBsZW1lbnQgU2NpPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn
ZXM+NjI8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxlZGl0aW9uPjIwMTEvMDYvMTU8L2VkaXRp
b24+PGtleXdvcmRzPjxrZXl3b3JkPkRlbHBoaSBUZWNobmlxdWU8L2tleXdvcmQ+PGtleXdvcmQ+
RGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkRpYWdub3N0aWMgVGVzdHMsIFJvdXRpbmUvKnN0
YW5kYXJkczwva2V5d29yZD48a2V5d29yZD5FdmlkZW5jZS1CYXNlZCBNZWRpY2luZS8qbWV0aG9k
czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+UHJhY3RpY2UgR3Vp
ZGVsaW5lcyBhcyBUb3BpYy8qc3RhbmRhcmRzPC9rZXl3b3JkPjxrZXl3b3JkPlByZWRpY3RpdmUg
VmFsdWUgb2YgVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvYmFiaWxpdHk8L2tleXdvcmQ+PGtl
eXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW4gMTA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48
aXNibj4xNzQ4LTU5MDggKEVsZWN0cm9uaWMpJiN4RDsxNzQ4LTU5MDggKExpbmtpbmcpPC9pc2Ju
PjxhY2Nlc3Npb24tbnVtPjIxNjYzNjU1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVy
bHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMTY2MzY1NTwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMzMTI2NzE3PC9jdXN0b20yPjxlbGVj
dHJvbmljLXJlc291cmNlLW51bT4xMC4xMTg2LzE3NDgtNTkwOC02LTYyPC9lbGVjdHJvbmljLXJl
c291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbG9uc28tQ29lbGxvPC9BdXRob3I+PFllYXI+MjAxNjwv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ADDIN EN.CITE.DATA (62-65).A literature search based on each of the KQ was performed according to GRADE recommendations. Search strategies and flow diagrams for each search are provided in the supplementary material (Appendix 2, supplementary material). The initial search was performed in August 2016 supervised by Dr Ruth Wills from the medical communications company International Medical Press (). We incorporated search findings from the 2017 Cochrane review ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66) which focused on bisphosphonate treatment of PDB in March 2017. The search updated in January 2018 but no new papers of relevance to the KQ were identified. We initially searched for systematic reviews that addressed the KQ followed by randomised controlled trials if no systematic reviews were available. If no randomised controlled trials had been performed, we searched for observational studies and case series provided the number of individuals studied was greater than 10. Individual case reports and case series of less than 10 subjects were generally excluded, unless these provided insights into the question that were not addressed by larger studies or clinical trials. The summary of findings tables in these manuscripts were used to grade the quality of evidence. For other interventions and diagnostic tests, the panel conducted their own review by assessing the papers that were relevant to the question and excluding papers that were not. Significant limitations were found when dealing with diagnostic tests for PDB since most studies were performed in patients known to have PDB. Because of this, there were very few reliable studies that could be used to establish the accuracy of different diagnostic tests. The GDG noted that PDB does not have a single gold standard test for diagnosis, since both x-rays and radionuclide bone scans can provide different information that often can be considered diagnostic of PDB.The members of the GDG assessed the quality of the evidence according to the methodology described by the GRADE system. In this system quality of supporting evidence is assessed based on explicit methodological criteria and classified as either: “high” (further research is very unlikely to change our confidence in the estimate of effect), “moderate” (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate), “low” (further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate) or “very low” (any estimate of effect is very uncertain). The method we used for wording of recommendations is shown in Table 1. The GDG considered the quality of evidence, the balance between benefit and harms, patients’ values and preferences and the resources and potential costs involved. For instances where interventions or investigations were recommended (or not recommended) the GDG felt that the benefits clearly outweighed the harms for most people or vice versa. For instances where there was a closer balance between benefits and harm for interventions and investigations the GDG made a conditional recommendation. For conditional recommendations, the GDG felt that that clinicians should discuss with patients and families the relative merits of alternative management options to the intervention to help each patient arrive at a decision consistent with his or her values and preferences. For instances where there was insufficient evidence to support the use of an intervention or investigation for a specific indication, it was agreed that a statement should be made to acknowledge that the intervention or investigation was not recommended. Table 1. Wording of recommendations RecommendationLanguageMeaning for patientsMeaning for cliniciansPositive recommendationThe intervention or investigation is recommendedMost patients would want the intervention or investigation Most patients should receive the intervention or investigation.Negative recommendation The intervention or investigation is not recommended.Most patients would not want the intervention or investigation Most patients should not receive the intervention or investigation.Conditional recommendationThe intervention or investigation may be consideredSome patients would want the recommended intervention or investigation but others would not. Different choices may be applicable to different patients depending on their values and preferences. The clinician should discuss the risks and benefits with the patient before reaching a decision Insufficient evidence The intervention or investigation is not recommendedMost patients would not want the intervention or investigation Most patients should not receive the intervention or investigation.The guideline process was validated in accordance with the Appraisal of Guidelines for Research and Evaluation, using the AGREE reporting check list 2016 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm91d2VyczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
PFJlY051bT4xOTM2ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp
cHQiPig2Nyk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xOTM2ODwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2
MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIxNTE4NjI5NTMzIj4xOTM2ODwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnJvdXdlcnMsIE0uIEMuPC9h
dXRob3I+PGF1dGhvcj5LZXJrdmxpZXQsIEsuPC9hdXRob3I+PGF1dGhvcj5TcGl0aG9mZiwgSy48
L2F1dGhvcj48YXV0aG9yPkFncmVlIE5leHQgU3RlcHMgQ29uc29ydGl1bTwvYXV0aG9yPjwvYXV0
aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk1jTWFzdGVyIFVuaXZlcnNpdHksIERl
cGFydG1lbnQgb2YgT25jb2xvZ3ksIEp1cmF2aW5za2kgSG9zcGl0YWwgYW5kIENhbmNlciBDZW50
cmUsIDEyODAgTWFpbiBTdHJlZXQgV2VzdCwgSGFtaWx0b24sIE9OLCBDYW5hZGEsIEw4UyA0TDgg
bWJyb3V3ZXJAbWNtYXN0ZXIuY2EuJiN4RDtNY01hc3RlciBVbml2ZXJzaXR5LCBEZXBhcnRtZW50
IG9mIE9uY29sb2d5LCBKdXJhdmluc2tpIEhvc3BpdGFsIGFuZCBDYW5jZXIgQ2VudHJlLCAxMjgw
IE1haW4gU3RyZWV0IFdlc3QsIEhhbWlsdG9uLCBPTiwgQ2FuYWRhLCBMOFMgNEw4LjwvYXV0aC1h
ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBBR1JFRSBSZXBvcnRpbmcgQ2hlY2tsaXN0OiBhIHRv
b2wgdG8gaW1wcm92ZSByZXBvcnRpbmcgb2YgY2xpbmljYWwgcHJhY3RpY2UgZ3VpZGVsaW5lczwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5CTUo8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy
aW9kaWNhbD48ZnVsbC10aXRsZT5CTUo8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5p
MTE1MjwvcGFnZXM+PHZvbHVtZT4zNTI8L3ZvbHVtZT48ZWRpdGlvbj4yMDE2LzAzLzEwPC9lZGl0
aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5CaW9tZWRpY2FsIFJlc2VhcmNoLyptZXRob2RzPC9rZXl3
b3JkPjxrZXl3b3JkPipDaGVja2xpc3Q8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk
PjxrZXl3b3JkPlByYWN0aWNlIEd1aWRlbGluZXMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+
UHJhY3RpY2UgUGF0dGVybnMsIFBoeXNpY2lhbnMmYXBvczs8L2tleXdvcmQ+PGtleXdvcmQ+UmVz
ZWFyY2ggRGVzaWduPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTY8L3llYXI+
PHB1Yi1kYXRlcz48ZGF0ZT5NYXIgODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE3
NTYtMTgzMyAoRWxlY3Ryb25pYykmI3hEOzA5NTktNTM1WCAoTGlua2luZyk8L2lzYm4+PGFjY2Vz
c2lvbi1udW0+MjY5NTcxMDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJs
Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI2OTU3MTA0PC91cmw+PC9yZWxh
dGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzUxMTg4NzMgd3d3LmljbWplLm9yZy9jb2lfZGlz
Y2xvc3VyZS5wZGYgKGF2YWlsYWJsZSBvbiByZXF1ZXN0IGZyb20gdGhlIGNvcnJlc3BvbmRpbmcg
YXV0aG9yKSBhbmQgZGVjbGFyZTogc3VwcG9ydCBmcm9tIHRoZSBDYW5hZGlhbiBJbnN0aXR1dGVz
IG9mIEhlYWx0aCBSZXNlYXJjaCBmb3IgdGhpcyBzdWJtaXR0ZWQgd29yazsgbm8gZmluYW5jaWFs
IHJlbGF0aW9uc2hpcHMgd2l0aCBhbnkgb3JnYW5pc2F0aW9ucyB0aGF0IG1pZ2h0IGhhdmUgYW4g
aW50ZXJlc3QgaW4gdGhlIHN1Ym1pdHRlZCB3b3JrIGluIHRoZSBwcmV2aW91cyB0aHJlZSB5ZWFy
czsgYW5kIG5vIG90aGVyIHJlbGF0aW9uc2hpcHMgb3IgYWN0aXZpdGllcyB0aGF0IGNvdWxkIGFw
cGVhciB0byBoYXZlIGluZmx1ZW5jZWQgdGhlIHN1Ym1pdHRlZCB3b3JrLjwvY3VzdG9tMj48ZWxl
Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEzNi9ibWouaTExNTI8L2VsZWN0cm9uaWMtcmVzb3Vy
Y2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm91d2VyczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+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ADDIN EN.CITE.DATA (67). The draft guidelines were sent to several stakeholders and were externally reviewed by the representatives from the American Society of Bone and Mineral Research, the European Calcified Tissues Society, the International Osteoporosis Foundation, the British Geriatrics Society, the Bone Research Society (UK) as well as several patients who are members of the UK Paget’s Association. Several other organisations were invited to comment but did not respond (Appendix 3, supplementary material). The final version of the guideline was revised and updated to take account of the comments that were received. The GDG intends to conduct regular reviews every three years after publication of the guidance, to determine whether the evidence base has progressed significantly enough to alter the current guideline recommendations and require an update.Results and recommendationsIn this section the results of the literature search are summarised, along with the recommendations of the guideline group for each key question that was posed. Diagnosis of Paget’s disease of boneThe following section deals with techniques used for the diagnosis of PDB. A limitation of the studies described in this section is that with one exception PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZWtob2ZmPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZWtob2ZmPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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 EN.CITE.DATA (68) the literature search failed to identify any studies in diagnostic tools were assessed or compared in a population-based setting. Similarly, no studies were identified that addressed the order in which diagnostic tests should be used. In view of this, the present section reports upon the performance of different modalities in evaluating the presence and extent of the disease in patients suspected to have PDB. RadiographsThe radiological features of PDB have been reviewed elsewhere ADDIN EN.CITE <EndNote><Cite><Author>Mirra</Author><Year>1995</Year><RecNum>18838</RecNum><DisplayText><style face="superscript">(69)</style></DisplayText><record><rec-number>18838</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1515623798">18838</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mirra, J. M.</author><author>Brien, E. W.</author><author>Tehranzadeh, J.</author></authors></contributors><auth-address>Orthopaedic Oncology Service, Orthopaedic Hospital, Los Angeles, CA 90007, USA.</auth-address><titles><title>Paget's disease of bone: review with emphasis on radiologic features, Part II</title><secondary-title>Skeletal Radiol</secondary-title></titles><periodical><full-title>Skeletal Radiol</full-title></periodical><pages>173-84</pages><volume>24</volume><number>3</number><edition>1995/04/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Bone Neoplasms/diagnostic imaging/pathology/secondary</keyword><keyword>Bone and Bones/diagnostic imaging/pathology</keyword><keyword>Child</keyword><keyword>Diagnosis, Differential</keyword><keyword>Giant Cell Tumor of Bone/diagnostic imaging/pathology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Middle Aged</keyword><keyword>Neoplasms, Radiation-Induced/diagnostic imaging/pathology</keyword><keyword>Osteitis Deformans/diagnosis/*diagnostic imaging/pathology</keyword><keyword>Radiography</keyword><keyword>Sarcoma/diagnostic imaging/pathology</keyword></keywords><dates><year>1995</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0364-2348 (Print)
0364-2348 (Linking)</isbn><accession-num>7610409</accession-num><urls><related-urls><url>;(69). The disease has characteristic features on x-ray that are summarised in Table 1 and illustrated in Figure 1. Individually, these features are not specific but when they occur in combination, they are usually diagnostic.Table 1. X-ray features of PDBOsteolytic areasCortical thickeningLoss of distinction between cortex and medullaTrabecular thickeningOsteosclerosisBone expansionBone deformityFigure 1. X-ray features of PDBPelvic radiograph from a patient with PDB affecting the upper right femur showing alternating areas of osteolysis and osteosclerosis in the greater and lesser trochanters and femoral neck; loss of distinction between the cortex and medulla in the upper femur; bone expansion and deformity of the affected femur; and a pseudofracture on the lateral aspect of the femur opposite the lesser trochanter.Guanabens and colleagues ADDIN EN.CITE <EndNote><Cite><Author>Guanabens</Author><Year>2012</Year><RecNum>18556</RecNum><DisplayText><style face="superscript">(70)</style></DisplayText><record><rec-number>18556</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513770584">18556</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Guanabens, N.</author><author>Rotes, D.</author><author>Holgado, S.</author><author>Gobbo, M.</author><author>Descalzo, M. A.</author><author>Gorordo, J. M.</author><author>Martinez-Ferrer, M. A.</author><author>Salmoral, A.</author><author>Morales-Piga, A.</author></authors></contributors><auth-address>Department of Rheumatology, Hospital Clinic, CIBERehd, C/Villarroel 170, 08036, Barcelona, Spain. nguanabens@ub.edu</auth-address><titles><title>Implications of a new radiological approach for the assessment of Paget disease</title><secondary-title>Calcif Tissue Int</secondary-title></titles><periodical><full-title>Calcified tissue international</full-title><abbr-1>Calcif Tissue Int</abbr-1></periodical><pages>409-15</pages><volume>91</volume><number>6</number><edition>2012/10/12</edition><keywords><keyword>Aged</keyword><keyword>Bone and Bones/*diagnostic imaging</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*diagnostic imaging/epidemiology</keyword><keyword>Radionuclide Imaging</keyword><keyword>Skull/diagnostic imaging</keyword><keyword>Tibia/diagnostic imaging</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1432-0827 (Electronic)
0171-967X (Linking)</isbn><accession-num>23052226</accession-num><urls><related-urls><url>;(70) investigated the issue of how many regions of the skeleton would need to be x-rayed to pick up PDB, based on analysis of plain x-rays and radionuclide bone scans in 208 patients already known to have PDB from a disease registry in Spain. The study showed that as compared with bone scan, an abdominal x-ray (defined as an x-ray which includes the lower ribs and femoral heads) would pick up PDB in 79% of cases; that addition of an x-ray or the skull and facial bones would increase the pickup rate to 89% and the addition of an x-ray of the upper tibiae increased the pickup rate to 93%. The evidence summary and recommendations for the use of x-rays in the diagnosis and assessment of patients with PDB are shown in Table 2. Table 2. Role of x-rays in the diagnosis of PDBRisk-benefit balancePlain x-rays targeted to the abdomen, skull and facial bones and both tibiae are likely to detect 93% of PDB bone lesions compared with 79% for an abdominal x-ray. The benefit to the patient in making a diagnosis from having additional radiographs is likely to outweigh the risk to the patient in terms of the additional radiation exposure.Quality of evidenceVery lowPatient values and preferencesIt’s likely that the majority of patients would be content with having radiographs of three sites as opposed to one to more accurately make a diagnosis of PDBCosts and use of resourcesPlain x-rays are widely available and relatively inexpensiveRecommendationPlain X-rays of the abdomen, tibiae, skull and facial bones are recommended as an initial diagnostic screening test in patients suspected to have PDB on biochemical or clinical grounds.Radionuclide bone scintigraphyRadionuclide bone scintigraphy is widely considered to be a valuable technique for the diagnosis of PDB and assessment of disease extent PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGlyYXppPC9BdXRob3I+PFllYXI+MTk3NDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGlyYXppPC9BdXRob3I+PFllYXI+MTk3NDwvWWVhcj48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ADDIN EN.CITE.DATA (71). Radionuclide bone scanning is performed following intravenous injection of the gamma emitting isotope, Technetium-99m (Tc99m) linked to a bisphosphonate (most commonly as Tc99m-methylene diphosphonate). When PDB involves a bone, the radiolabelled bisphosphonate accumulates in sites where there is high bone remodelling. In PDB, sites of involvement are visualised as a region of intense and homogeneous tracer uptake which in long bones starts at the metaphysis and extends down the shaft. Although many other conditions such as fibrous dysplasia, infections, metastases and arthritis can be associated with increased tracer uptake on bone scans, the appearances in PDB usually allow differentiation from other conditions. In certain sites the scintigraphic features of PDB are highly specific. These are “clover” or “mickey mouse sign” and the “heart sign” when PDB affects the spine PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (72,73). This observation can be of value in the differential diagnosis with vertebral metastases but false positive results have been described ADDIN EN.CITE <EndNote><Cite><Author>Reyes</Author><Year>2008</Year><RecNum>20097</RecNum><DisplayText><style face="superscript">(74)</style></DisplayText><record><rec-number>20097</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1521451978">20097</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reyes, R.</author><author>Peris, P.</author><author>Monegal, A.</author><author>Fuster, D.</author><author>Guanabens, N.</author></authors></contributors><auth-address>Service of Rheumatology, Metabolic Bone Diseases Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain.</auth-address><titles><title>Vertebral "clover" scintigraphic image in a vertebral metastasis misdiagnosed with Paget's disease</title><secondary-title>Clin Rheumatol</secondary-title></titles><periodical><full-title>Clin Rheumatol</full-title></periodical><pages>1585-6</pages><volume>27</volume><number>12</number><edition>2008/09/04</edition><keywords><keyword>Biopsy, Needle</keyword><keyword>Bone Neoplasms/*diagnosis/pathology/secondary</keyword><keyword>Carcinoma, Hepatocellular/*pathology/secondary</keyword><keyword>*Diagnostic Errors</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*pathology</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*diagnosis</keyword><keyword>Radionuclide Imaging</keyword><keyword>Spinal Neoplasms/*pathology/secondary</keyword><keyword>Thoracic Vertebrae/*pathology</keyword></keywords><dates><year>2008</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1434-9949 (Electronic)
0770-3198 (Linking)</isbn><accession-num>18766427</accession-num><urls><related-urls><url>;(74). Several investigators have compared the performance of bone scanning with plain x-rays in the evaluation of PDB. Wellman and colleagues compared the performance of radionuclide bone scans with x-rays in 108 PDB patients ADDIN EN.CITE <EndNote><Cite><Author>Wellman</Author><Year>1977</Year><RecNum>18552</RecNum><DisplayText><style face="superscript">(75)</style></DisplayText><record><rec-number>18552</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513770347">18552</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wellman, H. N.</author><author>Schauwecker, D.</author><author>Robb, J. A.</author><author>Khairi, M. R.</author><author>Johnston, C. C.</author></authors></contributors><titles><title>Skeletal scintimaging and radiography in the diagnosis and management of Paget's disease</title><secondary-title>Clin Orthop Relat Res</secondary-title></titles><periodical><full-title>Clinical orthopaedics and related research</full-title><abbr-1>Clin Orthop Relat Res</abbr-1></periodical><pages>55-62</pages><number>127</number><edition>1977/01/01</edition><keywords><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Diagnosis, Differential</keyword><keyword>Etidronic Acid/therapeutic use</keyword><keyword>Humans</keyword><keyword>Osteitis Deformans/*diagnosis/diagnostic imaging/drug therapy</keyword><keyword>Radiography</keyword><keyword>Radionuclide Imaging</keyword></keywords><dates><year>1977</year></dates><isbn>0009-921X (Print)
0009-921X (Linking)</isbn><accession-num>410575</accession-num><urls><related-urls><url>;(75). They reported that 101 lesions were detected both by x-rays and radionuclide scans; that a further 36 lesions were detected only on radionuclide scan and not by x-ray and that 11 lesions were detected by x-ray only ADDIN EN.CITE <EndNote><Cite><Author>Wellman</Author><Year>1977</Year><RecNum>18552</RecNum><DisplayText><style face="superscript">(75)</style></DisplayText><record><rec-number>18552</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513770347">18552</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wellman, H. N.</author><author>Schauwecker, D.</author><author>Robb, J. A.</author><author>Khairi, M. R.</author><author>Johnston, C. C.</author></authors></contributors><titles><title>Skeletal scintimaging and radiography in the diagnosis and management of Paget's disease</title><secondary-title>Clin Orthop Relat Res</secondary-title></titles><periodical><full-title>Clinical orthopaedics and related research</full-title><abbr-1>Clin Orthop Relat Res</abbr-1></periodical><pages>55-62</pages><number>127</number><edition>1977/01/01</edition><keywords><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Diagnosis, Differential</keyword><keyword>Etidronic Acid/therapeutic use</keyword><keyword>Humans</keyword><keyword>Osteitis Deformans/*diagnosis/diagnostic imaging/drug therapy</keyword><keyword>Radiography</keyword><keyword>Radionuclide Imaging</keyword></keywords><dates><year>1977</year></dates><isbn>0009-921X (Print)
0009-921X (Linking)</isbn><accession-num>410575</accession-num><urls><related-urls><url>;(75). They concluded that radionuclide bone scan was more sensitive than x-ray in detecting sites of involvement but that scan may be negative in sclerotic (“burned out’) lesions. Another study by Meunier and colleagues ADDIN EN.CITE <EndNote><Cite><Author>Meunier</Author><Year>1987</Year><RecNum>18621</RecNum><DisplayText><style face="superscript">(76)</style></DisplayText><record><rec-number>18621</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513951431">18621</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meunier, P. J.</author><author>Salson, C.</author><author>Mathieu, L.</author><author>Chapuy, M. C.</author><author>Delmas, P.</author><author>Alexandre, C.</author><author>Charhon, S.</author></authors></contributors><titles><title>Skeletal distribution and biochemical parameters of Paget's disease</title><secondary-title>Clin Orthop Relat Res</secondary-title></titles><periodical><full-title>Clinical orthopaedics and related research</full-title><abbr-1>Clin Orthop Relat Res</abbr-1></periodical><pages>37-44</pages><number>217</number><edition>1987/04/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Antibodies/analysis</keyword><keyword>Bone and Bones/*diagnostic imaging/metabolism</keyword><keyword>Etidronic Acid</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hydroxyproline/urine</keyword><keyword>Hypocalcemia/blood</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Organotechnetium Compounds</keyword><keyword>Osteitis Deformans/*diagnostic imaging/metabolism</keyword><keyword>Parathyroid Hormone/immunology</keyword><keyword>Radiography</keyword><keyword>Radionuclide Imaging</keyword><keyword>Technetium</keyword></keywords><dates><year>1987</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0009-921X (Print)
0009-921X (Linking)</isbn><accession-num>3103964</accession-num><urls><related-urls><url>;(76) compared the performance of x-rays and radionuclide scans in 170 PDB patients. They reported evidence of increased tracer uptake in 863 sites of which 16 (1.9%) showed changes consistent with osteoarthritis; 6 (0.7%) with changes consistent with bone metastases and 3 (0.35%) with changes consistent with vertebral fractures. Of the 838 sites showing scintigraphic changes consistent with PDB, 727 (86.7%) showed evidence of PDB on x-ray. Of 71 (8.4%) showed changes typical of PDB on bone scan only and in another 23 sites, radiographs were positive and bone scans were negative. The authors reported that of 863 sites detected on bone scan, 30.6% were symptomatic. The authors concluded that bone scans are more sensitive than radiographs at detecting PDB lesions but that bone scans may be negative if the disease is inactive. A further comparative study of 23 patients with PDB showed 127 sites of involvement of which 120 (94.5%) were recognised on scan compared with 94 (74%) on radiological skeletal survey ADDIN EN.CITE <EndNote><Cite><Author>Fogelman</Author><Year>1980</Year><RecNum>18538</RecNum><DisplayText><style face="superscript">(77)</style></DisplayText><record><rec-number>18538</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513769787">18538</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fogelman, I.</author><author>Carr, D.</author></authors></contributors><titles><title>A comparison of bone scanning and radiology in the assessment of patients with symptomatic Paget's disease</title><secondary-title>Eur J Nucl Med</secondary-title></titles><periodical><full-title>Eur J Nucl Med</full-title></periodical><pages>417-21</pages><volume>5</volume><number>5</number><edition>1980/10/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Evaluation Studies as Topic</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*diagnostic imaging</keyword><keyword>Radiography</keyword><keyword>Radionuclide Imaging</keyword></keywords><dates><year>1980</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0340-6997 (Print)
0340-6997 (Linking)</isbn><accession-num>7215363</accession-num><urls><related-urls><url>;(77). Of these, 7 lesions (5.5%) were detected on x-ray only and 33 (25.9%) on bone scan only; lesions were detected by both modalities in 87 (67.5%) sites. When data from these three studies are combined 83.5% of bone lesions in PDB were detected by both x-rays and radionuclide bone scans; 12.8% by bone scan only and 3.7% by x-ray only. The evidence summary and recommendations for the use of radionuclide bone scans in the diagnosis and assessment of patients with PDB are shown in Table 3.Table 3. Role of radionuclide bone scans in the diagnosis of PDBRisk-benefit balanceRadionuclide bone scans are more sensitive than radiographs at detecting bone lesions in PDB but radiographic evidence of PDB may be observed in about 3.7% of sites when the bone scan is negative. However, the majority of sites detected by imaging may be asymptomatic. Quality of evidenceVery lowPatient values and preferencesIt is likely that many patients may not object to having a bone scan in addition to targeted radiographs to fully assess the extent of PDB.Costs and use of resourcesRadionuclide bone scans are widely available but are more expensive than plain x-raysRecommendationRadionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of the metabolically active disease in patients with PDB.Magnetic resonance imaging and computed tomographyThere have been few studies on the role of magnetic resonance imaging (MRI) and computerised tomography (CT) in the diagnosis of PDB. Roberts and colleagues compared the appearances of magnetic resonance (MR) imaging, computed tomography (CT) and plain radiographs in 13 patients with PDB ADDIN EN.CITE <EndNote><Cite><Author>Roberts</Author><Year>1989</Year><RecNum>4</RecNum><DisplayText><style face="superscript">(78)</style></DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="r0rd2ss0rtfdxyefxw5vrx2xtpdwv5adzfdz" timestamp="1518793726">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roberts, M. C.</author><author>Kressel, H. Y.</author><author>Fallon, M. D.</author><author>Zlatkin, M. B.</author><author>Dalinka, M. K.</author></authors></contributors><auth-address>Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.</auth-address><titles><title>Paget disease: MR imaging findings</title><secondary-title>Radiology</secondary-title><alt-title>Radiology</alt-title></titles><pages>341-5</pages><volume>173</volume><number>2</number><edition>1989/11/01</edition><keywords><keyword>Aged</keyword><keyword>Bone and Bones/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Osteitis Deformans/complications/*diagnosis</keyword></keywords><dates><year>1989</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0033-8419 (Print)
0033-8419</isbn><accession-num>2798865</accession-num><urls></urls><electronic-resource-num>10.1148/radiology.173.2.2798865</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(78). The MRI findings and CT findings were consistent with the abnormalities seen in plain radiographs. Another study compared CT appearances of the skull in 10 patients with PDB with those in 10 patients with fibrous dysplasia of the skull PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZWhyYW56YWRlaDwvQXV0aG9yPjxZZWFyPjE5OTg8L1ll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZWhyYW56YWRlaDwvQXV0aG9yPjxZZWFyPjE5OTg8L1ll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ADDIN EN.CITE.DATA (79). The author identified 10 differentiating features including a ground glass appearance (favouring FD), symmetric cranial involvement (PDB), thick cortices (PDB) and involvement of the sinuses, sphenoid, orbit and nasal cavity (all favouring FD).Although the use of MR imaging and CT imaging is not generally indicated for the diagnosis of PDB, clinical experience indicates that MR and/or CT imaging is very useful for the investigation of several complications of PDB including basilar invagination, spinal stenosis and osteosarcoma ADDIN EN.CITE <EndNote><Cite><Author>Roberts</Author><Year>1989</Year><RecNum>97</RecNum><DisplayText><style face="superscript">(78)</style></DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="p2ezp0v5vpr0xpept9apfatsez25d5vzw0t0" timestamp="1514925482">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roberts, M. C.</author><author>Kressel, H. Y.</author><author>Fallon, M. D.</author><author>Zlatkin, M. B.</author><author>Dalinka, M. K.</author></authors></contributors><auth-address>Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.</auth-address><titles><title>Paget disease: MR imaging findings</title><secondary-title>Radiology</secondary-title><alt-title>Radiology</alt-title></titles><periodical><full-title>Radiology</full-title><abbr-1>Radiology</abbr-1></periodical><alt-periodical><full-title>Radiology</full-title><abbr-1>Radiology</abbr-1></alt-periodical><pages>341-5</pages><volume>173</volume><number>2</number><edition>1989/11/01</edition><keywords><keyword>Aged</keyword><keyword>Bone and Bones/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Osteitis Deformans/complications/*diagnosis</keyword></keywords><dates><year>1989</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0033-8419 (Print)
0033-8419</isbn><accession-num>2798865</accession-num><urls></urls><electronic-resource-num>10.1148/radiology.173.2.2798865</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(78). The evidence summary and recommendations for the use of MRI scans and CT scans in the diagnosis and assessment of patients with PDB are shown in Table 4.Table 4. Role of MRI and CT scanning in the diagnosis of PDBRisk-benefit balanceThe radiation exposure with CT scans is higher than plain x-rays or radionuclide bone scans but MRI scans do not involve radiation exposureQuality of evidenceVery low.Patient values and preferencesPatients with claustrophobia may prefer to avoid MRI.Costs and use of resourcesBoth CT scans and MRI scans are considerably more expensive than plain x-rays or radionuclide bone scans.RecommendationThere was insufficient evidence to recommend MRI or CT imaging for the diagnosis of PDB and neither technique is recommended for this purpose. These imaging techniques are recommended for the assessment of disease complications.Biochemical markersThe elevations in bone remodelling that are characteristic of active PBD can be detected clinically by measurement of biochemical markers of bone turnover in blood and urine samples. It should be noted however that elevations in markers of bone turnover occur in many disease states and cannot be used in isolation for the diagnosis of PDB. The most widely used biochemical marker for the diagnosis of PDB is serum total alkaline phosphatase (ALP) which is usually performed as part of liver function tests in a routine biochemistry screen. A population-based study by Eekhof PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZWtob2ZmPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZWtob2ZmPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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 EN.CITE.DATA (68) specifically looked at the performance of ALP in detecting PDB in participants of the Rotterdam study in Holland. The researchers selected 73 individuals from a cohort of 4406 subjects who had an elevated total ALP with normal transaminases and matched these subjects with 6 controls who had a normal total ALP. They found that the relative risk for PDB (based on radiographs of the hands, spine, pelvis and knees) in the presence of a raised total ALP activity was 10.9 [95% CI, 4.8 to 24.9] in men and women older than 55 years of age PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZWtob2ZmPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FZWtob2ZmPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48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ADDIN EN.CITE.DATA (80). This is the only study that has addressed the accuracy of any biochemical marker for the diagnosis of PDB. It showed that the sensitivity of total ALP was 57.7%, 95% CI 38.9-74.5; specificity 88.9%, 95% CI 85.9-91.3; positive likelihood ratio 5.19. 95% CI 3.45-7.82; and negative likelihood ratio 0.48, 95% CI 0.30-0.75). It should be noted that the calculated sensitivity may be an underestimate because radiographic assessment of PDB in the study didn’t include the skull and some patients with PDB of this site could have been missed. It’s also important to emphasise that of 26 patients with radiological features of PDB, only 11 (42%) had elevated total ALP concentrations. The performance of various biochemical markers of bone turnover in patients with PDB was studied by Alvarez in 51 patients who had not received treatment in the previous 6 months. This showed that of the markers studied, procollagen type I N-terminal propeptide (PINP) showed the highest proportion of increased values among bone formation markers when compared with BALP and total ALP (94%, 82% and 76%, respectively)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbHZhcmV6PC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbHZhcmV6PC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48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==
ADDIN EN.CITE.DATA (81). In the same study urinary cross-linked N-terminal telopeptide of type I collagen (uNTX) values were increased in 96% of patients with PDB compared with urinary pyridinoline (uPYD) (69%), urinary deoxypyridinoline (uDPD) (71%) and urinary cross-linked beta C-terminal telopeptide of type I collagen (uβCTX) (65%). Osteocalcin (OC) was increased in only 34% of patients. Another study by the same group of researchers evaluated with total ALP and bone alkaline phosphatase (BALP) in a series of 59 patients with PDB who had been untreated for at least 6 months, along with various other markers including the carboxy-terminal propeptide of type I collagen (PICP), tartrate resistant acid phosphatase (TRAP), telopeptide carboxyterminal propeptide of type I collagen (ICTP), urinary pyridinoline (PYD) and deoxypyridinoline D-PYR) and hydroxyproline (HYP). Total ALP values were elevated in 74.5% of patients, but BALP was elevated in 90%. The best performing resorption marker was D-PYD which was elevated in 73%. Of the 15 subjects with normal total ALP, serum BALP was increased in 60%. Woitge and colleagues reported that uNTX values were increased in 94% of a small series of 18 PDB patients as compared with 64% for serum cross-linked beta C-terminal telopeptide of type I collagen (sβCTX) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb2l0Z2U8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb2l0Z2U8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (82). In the same study total ALP was increase in 100% of cases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb2l0Z2U8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb2l0Z2U8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (82). The role of biochemical markers in predicting disease extent was evaluated in a systematic review by Al-Nofal and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbCBOb2ZhbDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
PFJlY051bT4xODYzNTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3Jp
cHQiPig4Myk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xODYzNTwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2
MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIxNTE0MDM4NjYwIj4xODYzNTwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QWwgTm9mYWwsIEEuIEEuPC9h
dXRob3I+PGF1dGhvcj5BbHRheWFyLCBPLjwvYXV0aG9yPjxhdXRob3I+QmVuS2hhZHJhLCBLLjwv
YXV0aG9yPjxhdXRob3I+UWFzaW0gQWdoYSwgTy4gUS48L2F1dGhvcj48YXV0aG9yPkFzaSwgTi48
L2F1dGhvcj48YXV0aG9yPk5hYmhhbiwgTS48L2F1dGhvcj48YXV0aG9yPlByb2tvcCwgTC4gSi48
L2F1dGhvcj48YXV0aG9yPlRlYmJlbiwgUC48L2F1dGhvcj48YXV0aG9yPk11cmFkLCBNLiBILjwv
YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9m
IFBlZGlhdHJpYyBFbmRvY3Jpbm9sb2d5LCBNYXlvIENsaW5pYywgUm9jaGVzdGVyLCBNTiwgVVNB
LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJvbmUgdHVybm92ZXIgbWFya2VycyBpbiBQ
YWdldCZhcG9zO3MgZGlzZWFzZSBvZiB0aGUgYm9uZTogQSBTeXN0ZW1hdGljIHJldmlldyBhbmQg
bWV0YS1hbmFseXNpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Pc3Rlb3Bvcm9zIEludDwvc2Vj
b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk9zdGVvcG9yb3Np
cyBpbnRlcm5hdGlvbmFsIDogYSBqb3VybmFsIGVzdGFibGlzaGVkIGFzIHJlc3VsdCBvZiBjb29w
ZXJhdGlvbiBiZXR3ZWVuIHRoZSBFdXJvcGVhbiBGb3VuZGF0aW9uIGZvciBPc3Rlb3Bvcm9zaXMg
YW5kIHRoZSBOYXRpb25hbCBPc3Rlb3Bvcm9zaXMgRm91bmRhdGlvbiBvZiB0aGUgVVNBPC9mdWxs
LXRpdGxlPjxhYmJyLTE+T3N0ZW9wb3JvcyBJbnQ8L2FiYnItMT48L3BlcmlvZGljYWw+PHBhZ2Vz
PjE4NzUtOTE8L3BhZ2VzPjx2b2x1bWU+MjY8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48ZWRp
dGlvbj4yMDE1LzA2LzA0PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbGthbGluZSBQaG9z
cGhhdGFzZS9ibG9vZDwva2V5d29yZD48a2V5d29yZD5CaW9tYXJrZXJzL2Jsb29kPC9rZXl3b3Jk
PjxrZXl3b3JkPkJvbmUgRGVuc2l0eSBDb25zZXJ2YXRpb24gQWdlbnRzL3BoYXJtYWNvbG9neS8q
dGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkJvbmUgUmVtb2RlbGluZy8qZHJ1ZyBl
ZmZlY3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGlwaG9zcGhvbmF0ZXMvcGhhcm1h
Y29sb2d5L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+T3N0ZWl0aXMgRGVmb3JtYW5zLypkaWFnbm9zaXMvZGlhZ25vc3RpYyBpbWFnaW5n
LypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+UmFkaW9udWNsaWRlIEltYWdpbmc8L2tl
eXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRl
Pkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE0MzMtMjk2NSAoRWxlY3Ryb25p
YykmI3hEOzA5MzctOTQxWCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYwMzc3OTE8
L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmku
bmxtLm5paC5nb3YvcHVibWVkLzI2MDM3NzkxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl
bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDA3L3MwMDE5OC0wMTUtMzA5NS0wPC9lbGVjdHJv
bmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbCBOb2ZhbDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+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ADDIN EN.CITE.DATA (83). This study synthesised data from 17 observational studies and 1 randomized trial in patients with PDB. The markers included were serum total ALP, BSALP, uNTX, uβCTX, sβCTX and PINP. In treatment na?ve patients, circulating concentrations of all markers were found to be highly significantly associated with extent of PDB as determined by radionuclide bone scintigraphy. The correlation between marker concentrations and disease extent for individual markers were; BSALP = 0.750 [95% CI 0.621-0.839]; PINP = 0.756 [95% CI 0.692-0.809]; total ALP = 0.617 [95% CI 0.518-0.700], sβCTX = 0.583 [95% CI 0.324-0.761]; uβCTX = 0.589 [95% CI 0.332-0.765]; and uNTX = 0.796 [95% CI 0.702-0.862]. The p-value for differences between the individual markers was not significant (p=0.083). The evidence summary and recommendations for the use of biochemical markers in the diagnosis and assessment of patients with PDB are shown in Table 5.Table 5. Role of biochemical markers in the diagnosis of PDBRisk-benefit balanceThe risk of having to provide blood or urine samples for diagnosis is minimal and outweighed by the benefit of making a correct diagnosis Quality of evidenceVery low. Patient values and preferencesMost patients are unlikely to be concerned about providing a blood or urine sample Costs and use of resourcesSerum total ALP is widely available and considerably cheaper that other biochemical markers that have been assessed in PDBRecommendationSerum total ALP is recommended as a first line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. If total ALP values are normal and clinical suspicion of metabolically active PDB is high, measurement of BALP, PINP or uNTX may be considered to screen for metabolically active disease. Effects of drug treatment in Paget’s diseaseThis section focuses on drug treatment for PDB and the effects of treatment on complications and clinical features of the disease. Two broad categories of drug treatment are commonly used in patients with PDB. Specific anti-Pagetic treatment involves the use osteoclast inhibitors to reduce the elevations in bone turnover that are characteristic of active disease, whereas other treatments such as analgesics, non-steroidal anti-inflammatory drugs and anti-neuropathic agents are used for symptom control PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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 EN.CITE.DATA (54,84). We have mainly focused on the use of bisphosphonates which are currently considered to be the treatment of choice for PDB and which are the only agents that have been evaluated in randomised controlled trials ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66). Through the literature review we identified studies of several osteoclast inhibitors that had been employed at some point in the treatment of PDB including glucagon ADDIN EN.CITE <EndNote><Cite><Author>Condon</Author><Year>1971</Year><RecNum>19230</RecNum><DisplayText><style face="superscript">(85)</style></DisplayText><record><rec-number>19230</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1517673493">19230</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Condon, J. R.</author></authors></contributors><titles><title>Glucagon in the treatment of Paget's disease of bone</title><secondary-title>Br Med J</secondary-title></titles><periodical><full-title>Br Med J</full-title></periodical><pages>719-21</pages><volume>4</volume><number>5789</number><edition>1971/12/18</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Resorption/prevention & control</keyword><keyword>Bone and Bones/enzymology</keyword><keyword>Calcification, Physiologic</keyword><keyword>Calcitonin/secretion</keyword><keyword>Calcium/urine</keyword><keyword>Female</keyword><keyword>Glucagon/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Hydroxyproline/urine</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*drug therapy</keyword><keyword>Pyrophosphatases/metabolism</keyword></keywords><dates><year>1971</year><pub-dates><date>Dec 18</date></pub-dates></dates><isbn>0007-1447 (Print)
0007-1447 (Linking)</isbn><accession-num>5129617</accession-num><urls><related-urls><url>;(85), mithramycin ADDIN EN.CITE <EndNote><Cite><Author>Heath</Author><Year>1981</Year><RecNum>18945</RecNum><DisplayText><style face="superscript">(86)</style></DisplayText><record><rec-number>18945</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1515864723">18945</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heath, D. A.</author></authors></contributors><titles><title>The role of mithramycin in the management of Paget's disease</title><secondary-title>Metab Bone Dis Relat Res</secondary-title></titles><periodical><full-title>Metabolic bone disease & related research</full-title><abbr-1>Metab Bone Dis Relat Res</abbr-1></periodical><pages>343-5</pages><volume>3</volume><number>4-5</number><edition>1981/01/01</edition><keywords><keyword>Humans</keyword><keyword>Osteitis Deformans/*drug therapy/metabolism</keyword><keyword>Plicamycin/adverse effects/*therapeutic use</keyword></keywords><dates><year>1981</year></dates><isbn>0221-8747 (Print)
0221-8747 (Linking)</isbn><accession-num>6220192</accession-num><urls><related-urls><url>;(86), actinomycin D ADDIN EN.CITE <EndNote><Cite><Author>Fennelly</Author><Year>1971</Year><RecNum>18940</RecNum><DisplayText><style face="superscript">(87)</style></DisplayText><record><rec-number>18940</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1515864449">18940</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fennelly, J. J.</author><author>Groarke, J. F.</author></authors></contributors><titles><title>Effect of actinomycin D on Paget's disease of bone</title><secondary-title>Br Med J</secondary-title></titles><periodical><full-title>Br Med J</full-title></periodical><pages>423-6</pages><volume>1</volume><number>5746</number><edition>1971/02/20</edition><keywords><keyword>Aged</keyword><keyword>Alanine Transaminase/blood</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Aspartate Aminotransferases/blood</keyword><keyword>Calcium/blood/urine</keyword><keyword>Dactinomycin/adverse effects/*therapeutic use</keyword><keyword>Depression/chemically induced</keyword><keyword>Humans</keyword></keywords><dates><year>1971</year><pub-dates><date>Feb 20</date></pub-dates></dates><isbn>0007-1447 (Print)
0007-1447 (Linking)</isbn><accession-num>5101343</accession-num><urls><related-urls><url>;(87) and gallium nitrate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NrbWFuPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NrbWFuPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48
UmVjTnVtPjgxNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi
Pig4OCk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj44MTQ8L3JlYy1u
dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0
dDAxcHplenF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMCI+ODE0PC9rZXk+PC9mb3JlaWduLWtl
eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli
dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Cb2NrbWFuLCBSLlMuPC9hdXRob3I+PGF1dGhvcj5XaWxo
ZWxtLCBGLjwvYXV0aG9yPjxhdXRob3I+U2lyaXMsIEUuUy48L2F1dGhvcj48YXV0aG9yPlNpbmdl
ciwgRi48L2F1dGhvcj48YXV0aG9yPkNoYXVzbWVyLCBBLjwvYXV0aG9yPjxhdXRob3I+Qml0dG9u
LCBSLjwvYXV0aG9yPjxhdXRob3I+S290bGVyLCBKLjwvYXV0aG9yPjxhdXRob3I+Qm9zY28sIEIu
Si48L2F1dGhvcj48YXV0aG9yPkV5cmUsIEQuUi48L2F1dGhvcj48YXV0aG9yPkxldmVuc29uLCBE
LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BIG11bHRp
Y2VudGVyIHRyaWFsIG9mIGxvdyBkb3NlIGdhbGxpdW0gbml0cmF0ZSBpbiBwYXRpZW50cyB3aXRo
IGFkdmFuY2VkIFBhZ2V0JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmU8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+Sm91cm5hbCBvZiBDbGluaWNhbCBFbmRvY3Jpbm9sb2d5ICZhbXA7IE1ldGFib2xpc208
L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+NTk1LTYwMjwvcGFnZXM+PHZvbHVtZT44
MDwvdm9sdW1lPjxudW1iZXI+MjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8
L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+NDk8L2tleXdvcmQ+PGtleXdvcmQ+
YTwva2V5d29yZD48a2V5d29yZD5hY3Rpdml0eTwva2V5d29yZD48a2V5d29yZD5BZG1pbmlzdHJh
dGlvbjwva2V5d29yZD48a2V5d29yZD5hbGthbGluZSBwaG9zcGhhdGFzZTwva2V5d29yZD48a2V5
d29yZD5ib25lPC9rZXl3b3JkPjxrZXl3b3JkPmJvbmUgdHVybm92ZXI8L2tleXdvcmQ+PGtleXdv
cmQ+Y29sbGFnZW48L2tleXdvcmQ+PGtleXdvcmQ+Y3Jvc3MgbGlua3M8L2tleXdvcmQ+PGtleXdv
cmQ+Y3Jvc3MtbGlua3M8L2tleXdvcmQ+PGtleXdvcmQ+Y3Jvc3NsaW5rczwva2V5d29yZD48a2V5
d29yZD5EaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRydWc8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1
Z3M8L2tleXdvcmQ+PGtleXdvcmQ+RmFzdGluZzwva2V5d29yZD48a2V5d29yZD5HYWxsaXVtPC9r
ZXl3b3JkPjxrZXl3b3JkPmdhbGxpdW0gbml0cmF0ZTwva2V5d29yZD48a2V5d29yZD5IeWRyb3h5
cHJvbGluZTwva2V5d29yZD48a2V5d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3b3JkPk1lZGljaW5l
PC9rZXl3b3JkPjxrZXl3b3JkPk5ldyBZb3JrPC9rZXl3b3JkPjxrZXl3b3JkPm5pdHJhdGU8L2tl
eXdvcmQ+PGtleXdvcmQ+UGFnZXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3
b3JkPjxrZXl3b3JkPlBhZ2V0JmFwb3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0
JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aWVudHM8L2tleXdv
cmQ+PGtleXdvcmQ+cGhvc3BoYXRhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UXVhbGl0eSBvZiBMaWZl
PC9rZXl3b3JkPjxrZXl3b3JkPnNlcnVtPC9rZXl3b3JkPjxrZXl3b3JkPnN1cmdlcnk8L2tleXdv
cmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD50cmlhbDwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4xOTk1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTk5NSBGZWI8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+MjMxMDwvbGFiZWw+PHVybHM+PC91cmxz
PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA (88). These were not considered further since the guideline group felt they were of historical interest and were evaluated in uncontrolled studies with no comparator. Similarly, supportive treatments such as non-steroidal anti-inflammatory drugs, anti-neuropathic agents and analgesics are widely used for pain control in patients with PDB and in the PRISM study at least one of these agents was used by all patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE.DATA (54). We did not identify any trials in which the effectiveness of these agents was investigated specifically in PDB. The effects of denosumab PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (89) and calcitonin ADDIN EN.CITE <EndNote><Cite><Author>Kanis</Author><Year>1975</Year><RecNum>18991</RecNum><DisplayText><style face="superscript">(90)</style></DisplayText><record><rec-number>18991</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1515865119">18991</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kanis, J. A.</author><author>Fitzpatrick, K.</author><author>Strong, J. A.</author></authors></contributors><titles><title>Treatment of Paget's disease of bone with porcine calcitonin: clinical and metabolic responses</title><secondary-title>Q J Med</secondary-title></titles><periodical><full-title>The Quarterly journal of medicine</full-title><abbr-1>Q J Med</abbr-1></periodical><pages>399-413</pages><volume>44</volume><number>175</number><edition>1975/07/01</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Regeneration/drug effects</keyword><keyword>Calcitonin/*therapeutic use</keyword><keyword>Calcium/metabolism</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnesium/metabolism</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Nitrogen/metabolism</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology/metabolism</keyword><keyword>Parathyroid Hormone/secretion</keyword><keyword>Phosphates/metabolism</keyword><keyword>Potassium/metabolism</keyword><keyword>Sodium/metabolism</keyword></keywords><dates><year>1975</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0033-5622 (Print)
0033-5622 (Linking)</isbn><accession-num>1101286</accession-num><urls><related-urls><url>;(90) in PDB were also reviewed and are discussed separately within this article. Bone PainBone pain in PDB is a complex symptom which is can be associated with increased bone turnover but which may also occur in patients without increased metabolic activity. This section focuses on the effects of bisphosphonates in the treatment of bone pain. Although other drugs such as analgesics, non-steroidal anti-inflammatory drugs and anti-neuropathic agents are often used in the management of bone pain associated with PDB, these agents haven’t been investigated in controlled clinical trials. Calcitonin and denosumab have also been reported to improve bone pain in PDB but are discussed separately since neither has been investigated in randomised trials. A meta-analysis of placebo controlled studies with various bisphosphonates ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66) involving a total of 418 subjects showed that these drugs were effective at reducing bone pain compared with placebo such that the proportion of patients who achieved any reduction in bone pain was 45% vs 23%; RR 1.97 95% confidence interval (CI) 1.29 to 3.01; NNT 5 (95% CI 2 to 15). It should be noted that all but one of these trials PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (53) involved etidronate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWxzdG9uPC9BdXRob3I+PFllYXI+MTk4NzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWxzdG9uPC9BdXRob3I+PFllYXI+MTk4NzwvWWVhcj48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ADDIN EN.CITE.DATA (91-93) or tiludronate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFzZXI8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFzZXI8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS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 EN.CITE.DATA (94-96) which are no longer in widespread use. A randomised open label trial involving 89 subjects ADDIN EN.CITE <EndNote><Cite><Author>Merlotti</Author><Year>2007</Year><RecNum>16347</RecNum><DisplayText><style face="superscript">(97)</style></DisplayText><record><rec-number>16347</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1494698901">16347</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Merlotti, D.</author><author>Gennari, L.</author><author>Martini, G.</author><author>Valleggi, F.</author><author>De Paola, V.</author><author>Avanzati, A.</author><author>Nuti, R.</author></authors></contributors><auth-address>Department of Internal Medicine, Endocrine, Metabolic Sciences, and Biochemistry, University of Siena, Siena, Italy. merlotti4@unisi.it</auth-address><titles><title>Comparison of different intravenous bisphosphonate regimens for Paget's disease of bone</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>1510-7</pages><volume>22</volume><number>10</number><keywords><keyword>Aged</keyword><keyword>Diphosphonates/*administration & dosage/adverse effects/*therapeutic use</keyword><keyword>Drug-Related Side Effects and Adverse Reactions</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Imidazoles/administration & dosage/adverse effects/therapeutic use</keyword><keyword>Injections, Intravenous</keyword><keyword>Male</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology/pathology</keyword><keyword>Pain/drug therapy/pathology</keyword><keyword>Quality of Life</keyword><keyword>Time Factors</keyword></keywords><dates><year>2007</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0884-0431 (Print)
0884-0431 (Linking)</isbn><accession-num>17605632</accession-num><urls><related-urls><url>;(97) showed that a single intravenous infusion of 4mg zoledronic acid was more likely to give pain relief than 30mg intravenous pamidronate when given on 2 consecutive days every 3 months (relative risk (RR) = 1.30, 95% CI 1.10-1.53, number needed to treat = 5, 95% CI 3-11). A randomised open label trial comparing intravenous pamidronate 60mg intravenously every three months with oral alendronic acid 40mg daily in 3-month blocks reported no difference in bone pain between the treatments although the paper did not include detailed information on this outcome PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWxzaDwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWxzaDwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl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ADDIN EN.CITE.DATA (98). Another randomised double blind study involving 357 patients published by Reid and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj
TnVtPjc1MzQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4o
OTkpPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NzUzNDwvcmVjLW51
bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBnZXR0
MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIwIj43NTM0PC9rZXk+PC9mb3JlaWduLWtl
eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli
dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZWlkLCBJLlIuPC9hdXRob3I+PGF1dGhvcj5NaWxsZXIs
IFAuPC9hdXRob3I+PGF1dGhvcj5MeWxlcywgSy48L2F1dGhvcj48YXV0aG9yPkZyYXNlciwgVy48
L2F1dGhvcj48YXV0aG9yPkJyb3duLCBKLlAuPC9hdXRob3I+PGF1dGhvcj5TYWlkaSwgWS48L2F1
dGhvcj48YXV0aG9yPk1lc2VuYnJpbmssIFAuPC9hdXRob3I+PGF1dGhvcj5TdSwgRy48L2F1dGhv
cj48YXV0aG9yPlBhaywgSi48L2F1dGhvcj48YXV0aG9yPlplbGVuYWthcywgSy48L2F1dGhvcj48
YXV0aG9yPkx1Y2hpLCBNLjwvYXV0aG9yPjxhdXRob3I+UmljaGFyZHNvbiwgUC48L2F1dGhvcj48
YXV0aG9yPkhvc2tpbmcsIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo
LWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBBdWNrbGFuZCwg
QXVja2xhbmQsIE5ldyBaZWFsYW5kLiBpLnJlaWRAYXVja2xhbmQuYWMubno8L2F1dGgtYWRkcmVz
cz48dGl0bGVzPjx0aXRsZT5Db21wYXJpc29uIG9mIGEgc2luZ2xlIGluZnVzaW9uIG9mIHpvbGVk
cm9uaWMgYWNpZCB3aXRoIHJpc2Vkcm9uYXRlIGZvciBQYWdldCZhcG9zO3MgZGlzZWFzZTwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5OLiBFbmdsLiBKLiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3Rp
dGxlcz48cGFnZXM+ODk4LTkwODwvcGFnZXM+PHZvbHVtZT4zNTM8L3ZvbHVtZT48bnVtYmVyPjk8
L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtl
eXdvcmRzPjxrZXl3b3JkPmE8L2tleXdvcmQ+PGtleXdvcmQ+YWNpZDwva2V5d29yZD48a2V5d29y
ZD5hbGthbGluZSBwaG9zcGhhdGFzZTwva2V5d29yZD48a2V5d29yZD5BUzwva2V5d29yZD48a2V5
d29yZD5iaXNwaG9zcGhvbmF0ZTwva2V5d29yZD48a2V5d29yZD5iaXNwaG9zcGhvbmF0ZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+Ym9uZSB0dXJub3Zlcjwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkhlYWx0aDwva2V5d29yZD48a2V5d29yZD5pbmZ1c2lvbjwva2V5d29y
ZD48a2V5d29yZD5JbnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5tYXJrZXI8L2tleXdvcmQ+
PGtleXdvcmQ+bWFya2Vyczwva2V5d29yZD48a2V5d29yZD5NZWRpY2luZTwva2V5d29yZD48a2V5
d29yZD5tZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5O
ZXcgWmVhbGFuZDwva2V5d29yZD48a2V5d29yZD5ORVctWkVBTEFORDwva2V5d29yZD48a2V5d29y
ZD5vcmFsPC9rZXl3b3JkPjxrZXl3b3JkPm91dGNvbWU8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQ8
L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0JmFw
b3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPnBhaW48L2tleXdvcmQ+PGtleXdvcmQ+UGF0
aWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGhvc3BoYXRhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UXVh
bGl0eSBvZiBMaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2Vkcm9uYXRlPC9rZXl3b3JkPjxrZXl3
b3JkPnRoZXJhcGV1dGljPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv
cmQ+dHJlYXRtZW50PC9rZXl3b3JkPjxrZXl3b3JkPnRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPnpv
bGVkcm9uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPnpvbGVkcm9uaWMgYWNpZDwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OS8xLzIwMDU8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+NzI4NzwvbGFiZWw+PHVybHM+PHJlbGF0
ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTYxMzU4MzQ8
L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE.DATA (99) showed that zoledronic acid given as a single dose of 5mg intravenously was more likely to give pain relief than risedronate sodium 30mg daily orally for 2 months (RR = 1.36, 95% CI 1.06-1.74, number needed to treat = 7, 95% CI 4-24).An insight into the durability of the response of pain with different bisphosphonates comes from an extension of the Reid study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE.DATA (99) which compared the effects of a single dose of zoledronic acid 5mg with a single 2-month course of risedronate sodium 30mg daily PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (100). The extension study focused on a subgroup of 267 individuals in whom total ALP values were normal at the end of the core study. Clinical relapse, as defined by recurrence of bone pain occurred in 14/152 (9.2%) of patients in the zoledronic acid group, compared with 29/115 (25.2%) of the risedronate sodium group. It should be noted that the rate of clinical relapse was more than 10 times greater than the rate of biochemical relapse in the zoledronic acid group (0.7%) and was about 25% greater than the rate of biochemical relapse in the risedronate sodium group (20%). This indicates that biochemical relapse of PDB and clinical relapse as defined by the recurrence of pain are distinct entities. The evidence summary and recommendations for the use of bisphosphonates to treat bone pain in PDB are shown in Table 6.Table 6. Effect of bisphosphonate treatment on bone painRisk-benefit balanceBisphosphonates improve bone pain in PDB compared with placebo and comparative studies within bisphosphonates have shown that zoledronic acid is more likely to give an improvement than pamidronate and risedronate sodium. These bisphosphonates have a generally favourable adverse effect profile. In addition, most patients required other pain-relieving medications such as analgesics and non-steroidal anti-inflammatory drugs for pain control. Quality of evidenceModerate Patient values and preferencesMost patients that have bone pain are likely to favour the potential benefits of bisphosphonates with or without other analgesics considering their generally favourable adverse event profile. Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which need to be considered.RecommendationBisphosphonates are recommended for the treatment of bone pain associated with Paget’s disease. Zoledronic acid is recommended as the bisphosphonate most likely to give a favourable pain response. Health related quality of lifeNo information was available from randomised trials with which to evaluate the effects of bisphosphonates on health-related quality of life compared with placebo. A comparison of zoledronic acid with risedronate sodium PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj
TnVtPjc1MzQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4o
OTkpPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NzUzNDwvcmVjLW51
bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBnZXR0
MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIwIj43NTM0PC9rZXk+PC9mb3JlaWduLWtl
eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli
dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZWlkLCBJLlIuPC9hdXRob3I+PGF1dGhvcj5NaWxsZXIs
IFAuPC9hdXRob3I+PGF1dGhvcj5MeWxlcywgSy48L2F1dGhvcj48YXV0aG9yPkZyYXNlciwgVy48
L2F1dGhvcj48YXV0aG9yPkJyb3duLCBKLlAuPC9hdXRob3I+PGF1dGhvcj5TYWlkaSwgWS48L2F1
dGhvcj48YXV0aG9yPk1lc2VuYnJpbmssIFAuPC9hdXRob3I+PGF1dGhvcj5TdSwgRy48L2F1dGhv
cj48YXV0aG9yPlBhaywgSi48L2F1dGhvcj48YXV0aG9yPlplbGVuYWthcywgSy48L2F1dGhvcj48
YXV0aG9yPkx1Y2hpLCBNLjwvYXV0aG9yPjxhdXRob3I+UmljaGFyZHNvbiwgUC48L2F1dGhvcj48
YXV0aG9yPkhvc2tpbmcsIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo
LWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBBdWNrbGFuZCwg
QXVja2xhbmQsIE5ldyBaZWFsYW5kLiBpLnJlaWRAYXVja2xhbmQuYWMubno8L2F1dGgtYWRkcmVz
cz48dGl0bGVzPjx0aXRsZT5Db21wYXJpc29uIG9mIGEgc2luZ2xlIGluZnVzaW9uIG9mIHpvbGVk
cm9uaWMgYWNpZCB3aXRoIHJpc2Vkcm9uYXRlIGZvciBQYWdldCZhcG9zO3MgZGlzZWFzZTwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5OLiBFbmdsLiBKLiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3Rp
dGxlcz48cGFnZXM+ODk4LTkwODwvcGFnZXM+PHZvbHVtZT4zNTM8L3ZvbHVtZT48bnVtYmVyPjk8
L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtl
eXdvcmRzPjxrZXl3b3JkPmE8L2tleXdvcmQ+PGtleXdvcmQ+YWNpZDwva2V5d29yZD48a2V5d29y
ZD5hbGthbGluZSBwaG9zcGhhdGFzZTwva2V5d29yZD48a2V5d29yZD5BUzwva2V5d29yZD48a2V5
d29yZD5iaXNwaG9zcGhvbmF0ZTwva2V5d29yZD48a2V5d29yZD5iaXNwaG9zcGhvbmF0ZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+Ym9uZSB0dXJub3Zlcjwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkhlYWx0aDwva2V5d29yZD48a2V5d29yZD5pbmZ1c2lvbjwva2V5d29y
ZD48a2V5d29yZD5JbnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5tYXJrZXI8L2tleXdvcmQ+
PGtleXdvcmQ+bWFya2Vyczwva2V5d29yZD48a2V5d29yZD5NZWRpY2luZTwva2V5d29yZD48a2V5
d29yZD5tZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5O
ZXcgWmVhbGFuZDwva2V5d29yZD48a2V5d29yZD5ORVctWkVBTEFORDwva2V5d29yZD48a2V5d29y
ZD5vcmFsPC9rZXl3b3JkPjxrZXl3b3JkPm91dGNvbWU8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQ8
L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0JmFw
b3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPnBhaW48L2tleXdvcmQ+PGtleXdvcmQ+UGF0
aWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGhvc3BoYXRhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UXVh
bGl0eSBvZiBMaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2Vkcm9uYXRlPC9rZXl3b3JkPjxrZXl3
b3JkPnRoZXJhcGV1dGljPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv
cmQ+dHJlYXRtZW50PC9rZXl3b3JkPjxrZXl3b3JkPnRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPnpv
bGVkcm9uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPnpvbGVkcm9uaWMgYWNpZDwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OS8xLzIwMDU8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+NzI4NzwvbGFiZWw+PHVybHM+PHJlbGF0
ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTYxMzU4MzQ8
L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (99) showed that the average physical component summary score of SF-36 improved to a greater extent in the zoledronic acid group, although the absolute difference was about 2 points which is below the 5-point threshold that is considered clinically significant PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE.DATA (99). When the SF36 physical summary score data were analysed by multivariate testing taking baseline scores into account the authors reported a nominally significant difference (p=0.04) favouring zoledronic acid, but this was not adjusted for multiple comparisons. When the data were expressed as the proportion of patients whose SF36 physical summary score improved following treatment the difference favoured zoledronic acid (RR = 1.30, 95% CI 1.18-1.42) ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66). In an extension of the same study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (100) the mean change from baseline SF36 summary score favoured zoledronic acid (mean difference 3.8, 95% CI 3.12-4.49). However, this analysis was not intention to treat, and was based on a selected group of patients who had normal total ALP values at the end of the core study.The evidence summary and recommendations for the use of bisphosphonates to improve quality of life in PDB are shown in Table 7.Table 7. Effect of bisphosphonate treatment on health-related quality of lifeRisk-benefit balanceWe found no evidence to evaluate the effects of bisphosphonates on quality of life compared with placebo. We found evidence that zoledronic acid improved some aspects of quality of life more than risedronate sodium but the differences were below the threshold that is considered clinically significant. Quality of evidenceVery lowPatient values and preferencesQuality of life is important to patients. If treatment strategies could be identified that offered a significant improvement in quality of life, it is likely that they would be favoured by patients.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which need to be considered.RecommendationThere is insufficient evidence that bisphosphonate therapy improves quality of life to a clinically meaningful extent in PDB and they are not recommended for this indication.Prevention of fracturesFractures in patients with PDB can be divided into two categories; those that occur in affected bone (pathological fractures) and those that occur in unaffected bone. The vast majority of pathological fractures in PDB affect the femur or tibia. The literature review revealed that there was insufficient evidence to evaluate the effects of bisphosphonates on incident fractures of either category when compared to placebo. A Cochrane review ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66) of placebo-controlled trials reported that information on fracture was only available in 356 participants and the reports did not distinguish pathological fractures from fractures in unaffected bone. In these studies, the rate of fractures in the placebo group was 0/79 (0%) vs. 4/277 % (1.4%) in the bisphosphonate group, RR = 0.89 (95% CI 0.18 to 4.31). There was no data on which to evaluate the effects of different individual bisphosphonates on incident fractures or to evaluate the effects of bisphosphonates on fractures in bone affected by PDB.The evidence summary and recommendations for the use of bisphosphonates to prevent fractures in PDB are shown in Table 8.Table 8. Effect of bisphosphonates treatment on fracture preventionRisk-benefit balanceThe effects of bisphosphonates on prevention of fractures in PDB have not been adequately studied. Quality of evidenceVery lowPatient values and preferencesPrevention of fractures is valued by patients with PDB. If treatment strategies could be identified that were effective in preventing fractures, it is likely that they would be favoured by patients.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which need to be considered.RecommendationThere is insufficient evidence that bisphosphonate therapy prevents fractures in PDB and they are not recommended for this indication.Progression of osteoarthritis There was no evidence upon which to evaluate the effects of bisphosphonates on progression of osteoarthritis compared with placebo; and no evidence to evaluate the effects of individual bisphosphonates compared with one another on progression of osteoarthritis. The evidence summary and recommendations for the use of bisphosphonates to prevent progression of osteoarthritis in PDB are shown in Table 9.Table 9. Effect of bisphosphonate treatment on progression of osteoarthritisRisk-benefit balanceThe effects of bisphosphonates on progression of osteoarthritis have not been adequately studied. Quality of evidenceVery lowPatient values and preferencesPrevention of osteoarthritis is likely to be valued by patients with PDB. If treatment strategies could be identified that were effective in preventing progression of osteoarthritis, it is likely that they would be favoured by patients.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which may need to be considered.RecommendationThere is insufficient evidence that bisphosphonate therapy prevents progression of osteoarthritis in PDB and they are not recommended for this indication.Progression of hearing lossThe effects of treatment on hearing loss is considered separately from neurological symptoms for two reasons; the first is that it has been for studied separately and the second is that in many cases deafness is not due to nerve compression but is a conductive deafness possibly related to abnormalities in the temporal bone ADDIN EN.CITE <EndNote><Cite><Author>Monsell</Author><Year>1995</Year><RecNum>6155</RecNum><DisplayText><style face="superscript">(101)</style></DisplayText><record><rec-number>6155</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">6155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Monsell, E.M.</author><author>Bone, H.G.</author><author>Cody, D.D.</author><author>Jacobson, G.P.</author><author>Newman, C.W.</author><author>Patel, S.C.</author><author>Divine, G.W.</author></authors></contributors><titles><title>Hearing loss in Paget's disease of bone: evidence of auditory nerve integrity</title><secondary-title>American Journal of Otology</secondary-title></titles><pages>27-33</pages><volume>16</volume><number>1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>analysis</keyword><keyword>AS</keyword><keyword>Audiometry</keyword><keyword>bone</keyword><keyword>Disease</keyword><keyword>Ear</keyword><keyword>function</keyword><keyword>hearing</keyword><keyword>Hearing Loss</keyword><keyword>Mi</keyword><keyword>Neck</keyword><keyword>NO</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>Skull</keyword><keyword>Support</keyword><keyword>surgery</keyword><keyword>Temporal Bone</keyword><keyword>Tomography</keyword></keywords><dates><year>1995</year><pub-dates><date>1995 Jan</date></pub-dates></dates><label>2275</label><urls></urls></record></Cite></EndNote>(101). There was no evidence from randomised trials upon which to evaluate the effects of bisphosphonates compared with placebo; no evidence to compare the effects of individual bisphosphonates; and no evidence to compare the effects of other treatments with bisphosphonates or other treatments with placebo. We identified one observational study of 25 PDB patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25hdGg8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25hdGg8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (102) in which the effects of tiludronate (400mg daily for 3 months; n=15) or pamidronate (30mg IV for 6 days; n=10) on hearing loss were studied in patients with PDB of the skull. Audiometry demonstrated sensorineural hearing loss in 12 patients, conductive hearing loss in 4 and a mixed pattern in 6 patients. The authors reported no significant change in hearing thresholds after 12 months overall, although they commented that there was a non-significant (7.5db) increase in hearing thresholds in the high frequency region in those with sensorineural loss PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25hdGg8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25hdGg8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (102). The evidence summary and recommendations for the use of bisphosphonates to prevent progression of hearing loss in PDB are shown in Table 10.Table 10. Effect of bisphosphonate treatment on progression of hearing lossRisk-benefit balanceThe effects of bisphosphonates on progression of hearing loss have not been adequately studied. Quality of evidenceVery lowPatient values and preferencesPrevention of progression of hearing loss is likely to be valued by patients with PDB. If treatment strategies could be identified that were effective in preventing progression of hearing loss, it is likely that they would be favoured by patients.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which may need to be considered.RecommendationThere is insufficient evidence that bisphosphonate therapy prevents progression of hearing loss in PDB and they are not recommended for this indication.Blood loss during elective orthopaedic surgeryThere was no evidence from randomised trials upon which to evaluate the effects of: bisphosphonates compared with placebo, the effects of individual bisphosphonates, or the effects of other treatments on operative blood loss during elective surgery. Some information was available from observational studies on the relation between having received anti-Pagetic treatment and operative blood loss. Wegryzn reviewed the outcome of 39 cementless hip replacements in a series of 32 patients undergoing surgery in a French centre between 1992 and 2006 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWdyenluPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
UmVjTnVtPjE2Mzc1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlw
dCI+KDEwMyk8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xNjM3NTwv
cmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2
MDBnZXR0MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIxNDk0ODUxNjQ5Ij4xNjM3NTwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2Vncnp5biwgSi48L2F1dGhv
cj48YXV0aG9yPlBpYmFyb3QsIFYuPC9hdXRob3I+PGF1dGhvcj5DaGFwdXJsYXQsIFIuPC9hdXRo
b3I+PGF1dGhvcj5DYXJyZXQsIEouIFAuPC9hdXRob3I+PGF1dGhvcj5CZWp1aS1IdWd1ZXMsIEou
PC9hdXRob3I+PGF1dGhvcj5HdXllbiwgTy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE9ydGhvcGVkaWMgU3VyZ2VyeSAtIFBhdmls
bG9uIFQsIEhvcGl0YWwgRWRvdWFyZCBIZXJyaW90LCBMeW9uLCBGcmFuY2UuIGp1bGllbi53ZWdy
enluQGNodS1seW9uLmZyPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2VtZW50bGVzcyB0
b3RhbCBoaXAgYXJ0aHJvcGxhc3R5IGluIFBhZ2V0JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmU6IGEg
cmV0cm9zcGVjdGl2ZSByZXZpZXc8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SW50IE9ydGhvcDwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkludCBPcnRo
b3A8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTAzLTk8L3BhZ2VzPjx2b2x1bWU+
MzQ8L3ZvbHVtZT48bnVtYmVyPjg8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWN0aXZpdGll
cyBvZiBEYWlseSBMaXZpbmc8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29y
ZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BcnRocm9wbGFzdHksIFJlcGxh
Y2VtZW50LCBIaXAvKm1ldGhvZHMvcmVoYWJpbGl0YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Qm9u
ZSBEZW5zaXR5IENvbnNlcnZhdGlvbiBBZ2VudHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr
ZXl3b3JkPkNlbWVudGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRpcGhvc3Bob25hdGVzL3RoZXJh
cGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5EdXJhcGF0aXRlPC9rZXl3b3JkPjxrZXl3b3Jk
PkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZWFsdGggU3RhdHVzIEluZGljYXRvcnM8L2tleXdv
cmQ+PGtleXdvcmQ+SGlwIEpvaW50L3BoeXNpb3BhdGhvbG9neS8qc3VyZ2VyeTwva2V5d29yZD48
a2V5d29yZD5IaXAgUHJvc3RoZXNpczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5
d29yZD5Pc3RlaXRpcyBEZWZvcm1hbnMvKnN1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+KlBvc3Rv
cGVyYXRpdmUgQ29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5QcmVvcGVyYXRpdmUgQ2Fy
ZTwva2V5d29yZD48a2V5d29yZD5Qcm9zdGhlc2lzIEZhaWx1cmUvZHJ1ZyBlZmZlY3RzPC9rZXl3
b3JkPjxrZXl3b3JkPlJhbmdlIG9mIE1vdGlvbiwgQXJ0aWN1bGFyPC9rZXl3b3JkPjxrZXl3b3Jk
PlJlb3BlcmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5
d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl
cz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVz
PjwvZGF0ZXM+PGlzYm4+MTQzMi01MTk1IChFbGVjdHJvbmljKSYjeEQ7MDM0MS0yNjk1IChMaW5r
aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTY2OTc2MjwvYWNjZXNzaW9uLW51bT48dXJscz48
cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTk2
Njk3NjI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DMjk4OTA3MTwvY3Vz
dG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwNy9zMDAyNjQtMDA5LTA4NTMtNzwv
ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWdyenluPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48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=
ADDIN EN.CITE.DATA (103). All patients received intravenous pamidronate prior to surgery and 31/39 (79%) of hip replacements had been performed in patients with a normal total ALP at the time of surgery. The average blood loss was 744ml (range 250-2000ml) which the authors commented was greater than in patients undergoing similar procedures that did not have PDB (range 200-450ml). Gabel ADDIN EN.CITE <EndNote><Cite><Author>Gabel</Author><Year>1991</Year><RecNum>18587</RecNum><DisplayText><style face="superscript">(104)</style></DisplayText><record><rec-number>18587</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513770885">18587</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gabel, G. T.</author><author>Rand, J. A.</author><author>Sim, F. H.</author></authors></contributors><auth-address>Department of Orthopedics, Mayo Clinic, Rochester, Minnesota 55905.</auth-address><titles><title>Total knee arthroplasty for osteoarthrosis in patients who have Paget disease of bone at the knee</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>The Journal of bone and joint surgery American volume</full-title><abbr-1>J Bone Joint Surg Am</abbr-1></periodical><pages>739-44</pages><volume>73</volume><number>5</number><edition>1991/06/01</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Female</keyword><keyword>Femur</keyword><keyword>Humans</keyword><keyword>Intraoperative Complications</keyword><keyword>Knee Joint/diagnostic imaging/*surgery</keyword><keyword>*Knee Prosthesis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications</keyword><keyword>Osteoarthritis/complications/diagnostic imaging/*surgery</keyword><keyword>Postoperative Complications</keyword><keyword>Radiography</keyword><keyword>Range of Motion, Articular</keyword><keyword>Retrospective Studies</keyword><keyword>Tibia</keyword></keywords><dates><year>1991</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0021-9355 (Print)
0021-9355 (Linking)</isbn><accession-num>2045399</accession-num><urls><related-urls><url>;(104) studied blood loss in 13 patients who had 16 total knee replacements (TKR) at a single US centre between 1974-1986. The average blood loss was 481ml (range 100-2000) and the authors commented that there was no difference between blood loss in patients who had previous treatment with either calcitonin or etidronate or those who did not have treatment. Similar findings were reported by Lee in 21 TKR from 20 patients referred to a US centre between 1978 and 1999 ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2005</Year><RecNum>18616</RecNum><DisplayText><style face="superscript">(105)</style></DisplayText><record><rec-number>18616</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513771046">18616</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, G. C.</author><author>Sanchez-Sotelo, J.</author><author>Berry, D. J.</author></authors></contributors><auth-address>Department of Orthopaedic Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA.</auth-address><titles><title>Total knee arthroplasty in patients with Paget's disease of bone at the knee</title><secondary-title>J Arthroplasty</secondary-title></titles><periodical><full-title>J Arthroplasty</full-title></periodical><pages>689-93</pages><volume>20</volume><number>6</number><edition>2005/09/06</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Arthroplasty, Replacement, Knee</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>In Vitro Techniques</keyword><keyword>*Knee Joint</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*surgery</keyword><keyword>Postoperative Complications</keyword><keyword>Reoperation</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2005</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0883-5403 (Print)
0883-5403 (Linking)</isbn><accession-num>16139702</accession-num><urls><related-urls><url>;(105). Blood loss was estimated as 300ml (range 100-600ml) but the authors found no difference between blood loss in patients who had or had not received pre-operative treatment with etidronate (278ml vs. 315ml, p=0.32) ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2005</Year><RecNum>18616</RecNum><DisplayText><style face="superscript">(105)</style></DisplayText><record><rec-number>18616</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513771046">18616</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, G. C.</author><author>Sanchez-Sotelo, J.</author><author>Berry, D. J.</author></authors></contributors><auth-address>Department of Orthopaedic Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA.</auth-address><titles><title>Total knee arthroplasty in patients with Paget's disease of bone at the knee</title><secondary-title>J Arthroplasty</secondary-title></titles><periodical><full-title>J Arthroplasty</full-title></periodical><pages>689-93</pages><volume>20</volume><number>6</number><edition>2005/09/06</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Arthroplasty, Replacement, Knee</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>In Vitro Techniques</keyword><keyword>*Knee Joint</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*surgery</keyword><keyword>Postoperative Complications</keyword><keyword>Reoperation</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2005</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0883-5403 (Print)
0883-5403 (Linking)</isbn><accession-num>16139702</accession-num><urls><related-urls><url>;(105). A systematic review conducted by Jorge-Mora and colleagues reviewed the effects of anti-Pagetic therapy on blood loss and other outcomes after elective spinal surgery in 17 case reports PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3JnZS1Nb3JhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3JnZS1Nb3JhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE.DATA (106). The most common indications for surgery were spinal cord compression (n=8), spinal stenosis (n=6) and back pain (n=3). Bisphosphonate was given prior to the surgery in 7 patients, but the type of bisphosphonate used and the dose were not recorded. Bleeding was noted as a complication in 0/7 patients given bisphosphonate and 4/10 patients not given bisphosphonate (p=0.22, Fishers exact test). Parvizi and colleagues reported upon the influence of treatment on blood loss during osteotomy in 22 PDB patients ADDIN EN.CITE <EndNote><Cite><Author>Parvizi</Author><Year>2003</Year><RecNum>18618</RecNum><DisplayText><style face="superscript">(107)</style></DisplayText><record><rec-number>18618</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513771237">18618</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parvizi, J.</author><author>Frankle, M. A.</author><author>Tiegs, R. D.</author><author>Sim, F. H.</author></authors></contributors><auth-address>Department of Orthopedics and Endocrinology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.</auth-address><titles><title>Corrective osteotomy for deformity in Paget disease</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>The Journal of bone and joint surgery American volume</full-title><abbr-1>J Bone Joint Surg Am</abbr-1></periodical><pages>697-702</pages><volume>85-A</volume><number>4</number><edition>2003/04/04</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Blood Loss, Surgical</keyword><keyword>Case-Control Studies</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Fracture Fixation/*methods</keyword><keyword>Fracture Healing/*physiology</keyword><keyword>Humans</keyword><keyword>Leg Bones/surgery</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/physiopathology/*surgery</keyword><keyword>*Osteotomy</keyword><keyword>Pain Measurement</keyword><keyword>Radius/surgery</keyword><keyword>Treatment Outcome</keyword><keyword>Wound Healing/physiology</keyword></keywords><dates><year>2003</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0021-9355 (Print)
0021-9355 (Linking)</isbn><accession-num>12672847</accession-num><urls><related-urls><url>;(107). Calcitonin was given to 6 patients and pamidronate to 3 patients prior to surgery. The authors commented that excessive bleeding was observed in all cases but did not define what was meant by excessive bleeding. They also commented that medical treatment significantly reduced intraoperative blood loss and that estimated blood loss was higher in patients with active disease but no data on blood loss or disease activity in these subgroups were provided.The evidence summary and recommendations for the use of bisphosphonates to prevent or reduce blood loss during elective orthopaedic surgery are shown in Table 11.Table 11. Effect of bisphosphonate treatment on blood loss during elective orthopaedic surgery Risk-benefit balanceThe data on blood loss in patients who have and have not had bisphosphonate treatment prior to elective orthopaedic or spinal surgery are conflicting and difficult to interpret. Quality of evidenceVery lowPatient values and preferencesPrevention of blood loss during surgery is likely to be valued by patients with PDB. If treatment strategies could be identified that were effective in preventing blood loss during elective orthopaedic surgery, it is likely that they would be favoured by patients.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which may need to be considered.RecommendationThere is insufficient evidence that bisphosphonate therapy reduces perioperative blood loss during elective orthopaedic surgery and they are not recommended for this indication.Bone deformityThere was no evidence from randomized trials upon which to evaluate the effects of: bisphosphonates compared with placebo, the effects of individual bisphosphonates, or the effects of other treatments on the prevention or treatment of bone deformity. One case series of 9 PDB patients with facial deformity was identified ADDIN EN.CITE <EndNote><Cite><Author>Bickerstaff</Author><Year>1990</Year><RecNum>19927</RecNum><DisplayText><style face="superscript">(108)</style></DisplayText><record><rec-number>19927</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1520859864">19927</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bickerstaff, D. R.</author><author>Douglas, D. L.</author><author>Burke, P. H.</author><author>O'Doherty, D. P.</author><author>Kanis, J. A.</author></authors></contributors><auth-address>University of Sheffield Medical School, England.</auth-address><titles><title>Improvement in the deformity of the face in Paget's disease treated with diphosphonates</title><secondary-title>J Bone Joint Surg Br</secondary-title></titles><periodical><full-title>J Bone Joint Surg Br</full-title></periodical><pages>132-6</pages><volume>72</volume><number>1</number><edition>1990/01/01</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Cephalometry</keyword><keyword>Clodronic Acid/*therapeutic use</keyword><keyword>Diphosphonates/*therapeutic use</keyword><keyword>Etidronic Acid/*therapeutic use</keyword><keyword>Face/*pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/drug therapy/enzymology/*pathology</keyword><keyword>Photogrammetry</keyword><keyword>Skull/pathology</keyword></keywords><dates><year>1990</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0301-620X (Print)
0301-620X (Linking)</isbn><accession-num>2137127</accession-num><urls><related-urls><url>;(108). Each of these patients was treated with etidronate or clodronate for between 1 and 6 years and facial deformity was measured using a stereophotogrammetric technique. Based on this analysis the authors reported that facial deformity (as reflected by a derived measure of facial or skull volume) improved in 7/8 cases. The evidence summary and recommendations for the use of bisphosphonates to prevent progression of bone deformity in PDB are shown in Table 12.Table 12. Effect of bisphosphonate treatment on bone deformity Risk-benefit balanceThe effects of bisphosphonates on bone deformity have not been adequately studied. Quality of evidenceVery lowPatient values and preferencesBone deformity is of concern to patients. If treatment strategies could be identified that were effective in preventing bone deformity, it is likely that they would be favoured by patients.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which may need to be considered.RecommendationThere is insufficient evidence that bisphosphonates can prevent or treat bone deformity in PDB and they are not recommended for this indication.Neurological symptomsThis section concerns the effect of treatment on neurological symptoms other than deafness which was considered earlier. No randomised comparative trials were identified in which the effects of bisphosphonates or other treatments have been evaluated in respect to neurological symptoms. We identified two case series of patients which addressed this issue. Chen and colleagues described the response to treatment with salmon or porcine calcitonin given subcutaneously in 49 PDB patients with neurological symptoms treated between 1969 and 1973 at a single referral centre in the USA ADDIN EN.CITE <EndNote><Cite><Author>Chen</Author><Year>1979</Year><RecNum>19883</RecNum><DisplayText><style face="superscript">(109)</style></DisplayText><record><rec-number>19883</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1519408830">19883</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chen, J. R.</author><author>Rhee, R. S.</author><author>Wallach, S.</author><author>Avramides, A.</author><author>Flores, A.</author></authors></contributors><titles><title>Neurologic disturbances in Paget disease of bone: response to calcitonin</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>448-57</pages><volume>29</volume><number>4</number><edition>1979/04/01</edition><keywords><keyword>Aged</keyword><keyword>Brain Stem</keyword><keyword>Calcitonin/*therapeutic use</keyword><keyword>Cranial Nerves</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myelography</keyword><keyword>*Neurologic Manifestations</keyword><keyword>Osteitis Deformans/*complications/drug therapy</keyword><keyword>Peripheral Nervous System Diseases/etiology</keyword><keyword>Spinal Cord Compression/etiology</keyword><keyword>Spinal Cord Diseases/etiology</keyword><keyword>Spinal Nerve Roots</keyword><keyword>Spinal Nerves</keyword></keywords><dates><year>1979</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0028-3878 (Print)
0028-3878 (Linking)</isbn><accession-num>220561</accession-num><urls><related-urls><url>;(109). The starting dose was 100 IU by subcutaneous injection, although subsequently the dose was reduced in some patients to 50 IU 3 times weekly. Treatment was continued for between 7 and 31 months (average 23 months). The indication for treatment in 10 patients was cranial nerve lesions (other than lesions of the 8th cranial nerve), spinal nerve root dysfunction in 15, spinal cord problems in 6 and miscellaneous neurological problems in 8. The authors reported objective improvement in 40% of patients with a cranial nerve lesion responded to treatment, as compared with 33% with spinal nerve problems, 50% with spinal cord symptoms and 0% with miscellaneous problems. In another case series from the UK, Douglas reported the results of treatment with calcitonin, etidronate or clodronate in 8 patients with neurological dysfunction due to Paget’s disease of the spine ADDIN EN.CITE <EndNote><Cite><Author>Douglas</Author><Year>1981</Year><RecNum>19549</RecNum><DisplayText><style face="superscript">(50)</style></DisplayText><record><rec-number>19549</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1519080583">19549</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Douglas, D. L.</author><author>Duckworth, T.</author><author>Kanis, J. A.</author><author>Jefferson, A. A.</author><author>Martin, T. J.</author><author>Russell, R. G.</author></authors></contributors><titles><title>Spinal cord dysfunction in Paget's disease of bone. Has medical treatment a vascular basis?</title><secondary-title>J Bone Joint Surg Br</secondary-title></titles><periodical><full-title>J Bone Joint Surg Br</full-title></periodical><pages>495-503</pages><volume>63B</volume><number>4</number><edition>1981/01/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Clodronic Acid/therapeutic use</keyword><keyword>Etidronic Acid/therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications/drug therapy</keyword><keyword>Paralysis/etiology</keyword><keyword>Spinal Cord/blood supply</keyword><keyword>Spinal Cord Compression/*etiology/therapy</keyword></keywords><dates><year>1981</year></dates><isbn>0301-620X (Print)
0301-620X (Linking)</isbn><accession-num>6457839</accession-num><urls><related-urls><url>;(50). Seven of the 8 patients were treated with calcitonin 100 IU daily and all improved neurologically. One patient treated with clodronate also improved. In 3 patients whose symptoms recurred despite treatment with calcitonin there was a response to etidronate or clodronate. Douglas also reviewed the results of medical treatment of spinal dysfunction from other published case reports with calcitonin at that time ADDIN EN.CITE <EndNote><Cite><Author>Douglas</Author><Year>1981</Year><RecNum>19549</RecNum><DisplayText><style face="superscript">(50)</style></DisplayText><record><rec-number>19549</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1519080583">19549</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Douglas, D. L.</author><author>Duckworth, T.</author><author>Kanis, J. A.</author><author>Jefferson, A. A.</author><author>Martin, T. J.</author><author>Russell, R. G.</author></authors></contributors><titles><title>Spinal cord dysfunction in Paget's disease of bone. Has medical treatment a vascular basis?</title><secondary-title>J Bone Joint Surg Br</secondary-title></titles><periodical><full-title>J Bone Joint Surg Br</full-title></periodical><pages>495-503</pages><volume>63B</volume><number>4</number><edition>1981/01/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Clodronic Acid/therapeutic use</keyword><keyword>Etidronic Acid/therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications/drug therapy</keyword><keyword>Paralysis/etiology</keyword><keyword>Spinal Cord/blood supply</keyword><keyword>Spinal Cord Compression/*etiology/therapy</keyword></keywords><dates><year>1981</year></dates><isbn>0301-620X (Print)
0301-620X (Linking)</isbn><accession-num>6457839</accession-num><urls><related-urls><url>;(50) and identified 13 additional patients that had been treated with calcitonin for spinal cord dysfunction whose symptoms had improved following therapy. The evidence summary and recommendations for the use of calcitonin and bisphosphonates in the treatment of neurological symptoms in PDB are shown in Table 13.Table 13. Effect of calcitonin and bisphosphonates on neurological symptomsRisk-benefit balanceMost experience in the medical treatment of spinal cord dysfunction in PDB comes from case series of patients treated with calcitonin and clinical benefit from treatment has been reported in a proportion of treated patients. Similar benefit has been noted in a small number of patients treated with bisphosphonates. Quality of evidenceVery lowPatient values and preferencesSpinal cord dysfunction and the symptoms associated with this complication is of major concern to patients. Treatment strategies that are effective in preventing spinal cord dysfunction are likely to be favoured by patients.Costs and use of resourcesCalcitonin is a relatively expensive treatment which needs to be administered by injection. Bisphosphonates are inexpensive but have been little studied in this situation. Intravenous bisphosphonate therapy involves additional support costs and costs in terms of patient time attending for the infusion which may need to be considered.RecommendationA trial of calcitonin treatment may be considered as part of the treatment package in patients with PDB who have evidence of neurological dysfunction. Bisphosphonate treatment may also be considered although there are few studies to support the use of bisphosphonates in this situation. Treatment of increased metabolic activity in asymptomatic patientsBisphosphonates are highly efficacious at reducing the elevations in bone turnover that are characteristic of active PDB (see section 4.4). Here we focus on the effects of treatment on serum total ALP since it the most commonly used biochemical marker of metabolic activity in PDB and has served as the primary outcome measure in clinical trials where bisphosphonates have been compared with placebo and with other bisphosphonates. In a Cochrane review ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66) it was noted that bisphosphonates achieved a 50.1% (95% CI 32.5 to 67.7) greater reduction in total ALP (592 participants) than placebo and the relative risk (RR) of bisphosphonates normalizing total ALP was 9.96 (95% CI 3.74 to 26.58). In the same review, a comparison of nitrogen-containing bisphosphonates with non-nitrogen containing bisphosphonates showed that nitrogen containing bisphosphonates were more effective at normalising total ALP than non-nitrogen containing bisphosphonates (212 participants), RR 4.3 95% CI 2.72 to 6.79, NNT 2 95% CI 1 to 4. Within the nitrogen containing bisphosphonates, zoledronic acid was more efficacious at reducing total ALP than pamidronate (90 participants) or risedronate sodium (347 participants); RR 2.57 95% CI 1.79 to 3.70, NNT 2 95% CI 1 to 3 and RR 1.53 95% CI 1.33 to 1.76, NNT 3 95% CI 3 to 5 respectively. The duration of effect of different bisphosphonates on serum total ALP concentrations has also been studied. A randomised trial comparing oral risedronate sodium 30mg daily for 2 months with oral etidronate 400mg daily for 6 months showed that total ALP values remained suppressed in 53% of the risedronate sodium group compared with 14% of the etidronate group ADDIN EN.CITE <EndNote><Cite><Author>Miller</Author><Year>1999</Year><RecNum>6020</RecNum><DisplayText><style face="superscript">(110)</style></DisplayText><record><rec-number>6020</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">6020</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Miller, P.D.</author><author>Brown, J.P</author><author>Siris, E.S.</author><author>Hoseyni, M.S.</author><author>Axelrod, D.W.</author><author>Bekker, P.J.</author></authors></contributors><titles><title>A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group</title><secondary-title>American Journal of Medicine</secondary-title></titles><pages>513-520</pages><volume>106</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>alkaline phosphatase</keyword><keyword>bisphosphonates</keyword><keyword>bone</keyword><keyword>deoxypyridinoline</keyword><keyword>Disease</keyword><keyword>Drug</keyword><keyword>drugs</keyword><keyword>etidronate</keyword><keyword>method</keyword><keyword>methods</keyword><keyword>north america</keyword><keyword>oral</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>pain</keyword><keyword>Patients</keyword><keyword>phosphatase</keyword><keyword>Remission</keyword><keyword>risedronate</keyword><keyword>serum</keyword><keyword>therapy</keyword><keyword>treatment</keyword></keywords><dates><year>1999</year><pub-dates><date>1999</date></pub-dates></dates><label>3033</label><urls><related-urls><url><style face="underline" font="default" size="100%">;(110). In a long-term extension of the HORIZON Paget’s study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (100) 88% of patients treated with a single dose of 5mg zoledronic acid intravenously still had a normal serum total ALP after 5 years follow-up as compared with 47% of patients treated with oral risedronate sodium. It should be noted that the attrition rate in this study was high and that only patients with normal ALP at the end of the core study were eligible to be enrolled into the extension.Although many clinical trials of bisphosphonates have enrolled patients on the basis that serum total ALP values are elevated (whether or not symptoms were present), we found no clinical trials or observational studies that specifically addressed the issue of whether treatment of asymptomatic patients with bisphosphonates that have metabolically active PDB was of benefit in preventing complications of the disease. Of some relevance to the issue of treating asymptomatic patients is the fact that bisphosphonates can promote healing of lytic lesions at least in the short term. In one observational study of PDB patients treated with pamidronate, healing of lytic lesions was demonstrated in some cases at 6 months, but longer-term follow-up of these patients after 2 years showed progression of lytic lesions once again even though biochemical markers of bone turnover were normal at this point PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXR0ZXJpZGdlPC9BdXRob3I+PFllYXI+MTk5NjwvWWVh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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXR0ZXJpZGdlPC9BdXRob3I+PFllYXI+MTk5NjwvWWVh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==
ADDIN EN.CITE.DATA (111). The effects of bisphosphonates on lytic lesions have been studied in two randomised controlled trials. One examined the effects of alendronic acid 40mg daily for 6 months in 55 PDB patients in comparison with placebo. The average age was about 70 years; 19% had previously been treated with anti-Pagetic mediation and 32 (58%) had bone pain thought to be due to PDB at baseline. The authors reported healing of lytic lesions in 11/23 (47.8%) patients treated with alendronic acid and no change in 12/23 (52.1%) patients. Corresponding values in placebo treated patient were 1/23 healed no change in 22/23 patients (95.6 %). Bone biopsies were obtained through Paget’s bone in four alendronic acid treated patients and 9 placebo treated patents. Histomorphometry showed lower bone turnover in the alendronic acid treated cases. Another randomised trial compared the effects of alendronate 40mg daily for 6 months with etidronate 400mg daily for 6 months in 89 PDB patients of average age about 70 years. showed that lesions improved in 32.4% of the ALN group whereas 8.8% showed worsening. The corresponding proportions in the etidronate group were 26.5% and 14.7%, respectively, a difference that was not significant. The issue of giving bisphosphonates with the aim of suppressing bone turnover in established PDB was addressed by the PRISM trial which is discussed in more detail later. The GDG noted that risks and benefits of giving prophylactic zoledronic acid to asymptomatic people at risk of developing PDB was being addressed by the ZiPP study (EUDRACT 2008-005667-34) which is due to report in 2020. The evidence summary and recommendations for the use of bisphosphonates with the primary aim of supressing bone turnover symptoms in asymptomatic patients with PDB are shown in Table 14.Table 14. Effects of bisphosphonate treatment on asymptomatic patients with increased metabolic activity.Risk-benefit balanceBisphosphonates are highly effective at reducing metabolic activity in PDB as reflected by concentrations of total ALP and other biochemical markers of bone turnover. Improvements in lytic lesions have also been reported in short term studies. The clinical benefit of giving bisphosphonates in asymptomatic patients with the primary aim of supressing metabolic activity is unknown.Quality of evidenceHighPatient values and preferencesPatients with PDB who have elevated concentrations of total ALP or other biochemical markers of bone turnover in the absence of symptoms may or may not derive clinical benefit from treatment. Some patients may favour treatment whereas others may not in view of the potential risk of adverse effects and uncertain benefit.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs and costs in terms of patient time attending for the infusion which need to be considered.RecommendationBisphosphonate therapy may be considered to suppress metabolic activity in PDB but the clinical benefit is uncertain. Within this class of drugs, nitrogen containing bisphosphonates are more effective than non-nitrogen containing bisphosphonates and within the bisphosphonates, zoledronic acid is most efficacious. Neoplastic transformation There was no evidence from randomised trials upon which to evaluate the effects of bisphosphonates compared with placebo; the effects of individual bisphosphonates; or the effects of other treatments on the prevention of osteosarcoma or GCT. Similarly, no observational studies were identified which evaluated the effects of treatment on neoplastic transformation. The evidence summary and recommendations for the use of bisphosphonates with aim of preventing neoplastic transformation in PDB are shown in Table 15.Table 15. Effect of treatment on neoplastic transformationRisk-benefit balanceThe effects of bisphosphonates on the prevention of neoplastic transformation in PDB have not been adequately studied. Quality of evidenceVery lowPatient values and preferencesPrevention of neoplastic transformation is likely to be highly valued by patients with PDB. Treatment strategies that are effective in preventing neoplastic transformation would most likely be favoured by patientsCosts and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs which need to be considered.RecommendationThere is insufficient evidence to show that bisphosphonates prevent neoplastic transformation in PDB and they are not recommended for this indication.Adverse eventsThis section evaluates the adverse events that have been reported with bisphosphonate treatment with an emphasis of those of relevance to the treatment of PDB. Atypical femoral fractures, uveitis, osteonecrosis or the jaw, hypocalcaemia and impaired renal function are recognized to be rare adverse effects of bisphosphonates. A recent Cochrane review ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66) evaluated the frequency of rare adverse events in PDB patients treated with bisphosphonates by reviewing the websites of the Food and Drugs Agency (FDA), the Medicines and Healthcare products regulatory Agency (MHRA), the European Medicines Agency (EMA) and the Australian Regulatory Agency (AARB). The estimated frequency of osteonecrosis of the jaw (ONJ) in people with PDB receiving oral bisphosphonates was estimated as between 0.0004% and 0.06% which is much lower than in osteoporosis. There is no clear evidence regarding the risk of ONJ following use of intravenous bisphosphonates for PDB although one case was reported in the PRISM-EZ study in a patient who received intensive bisphosphonate therapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (112). Atypical femoral fractures (AFF) are thought to be a class effect of bisphosphonates as of 2017, the EMA had received only one report of an AFF in a patient with PDB. The authors of the Cochrane review speculated that the infrequent occurrence of ONJ and AFF in PDB might be related to the fact that patients tend to have intermittent or short-term courses for treatment of the disease. In a recent Cochrane review ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66) no statistically significant difference was found in adverse effects with oral bisphosphonates compared with placebo (6 studies, 678 participants, Risk difference 0.11, 95% CI 0.00 to 0.22). Similarly, the risk of discontinuation due to adverse events was similar as compared with placebo (517 participants); RR 1.01 95% CI 0.38 to 2.69. It should be noted that these comparisons predominantly involved non-nitrogen containing oral bisphosphonates. Zoledronic acid was found to have an increased risk of adverse effects when compared with placebo: RR 2.57 95% CI 1.21-5.44. The most common adverse event in studies with zoledronic acid was a transient flu-like illness PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj
TnVtPjc1MzQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4o
OTkpPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NzUzNDwvcmVjLW51
bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InpmcHhlcHB4ZXZ2MDBnZXR0
MDFwemV6cXZ4ZjlzdGUwZTU1OSIgdGltZXN0YW1wPSIwIj43NTM0PC9rZXk+PC9mb3JlaWduLWtl
eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli
dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZWlkLCBJLlIuPC9hdXRob3I+PGF1dGhvcj5NaWxsZXIs
IFAuPC9hdXRob3I+PGF1dGhvcj5MeWxlcywgSy48L2F1dGhvcj48YXV0aG9yPkZyYXNlciwgVy48
L2F1dGhvcj48YXV0aG9yPkJyb3duLCBKLlAuPC9hdXRob3I+PGF1dGhvcj5TYWlkaSwgWS48L2F1
dGhvcj48YXV0aG9yPk1lc2VuYnJpbmssIFAuPC9hdXRob3I+PGF1dGhvcj5TdSwgRy48L2F1dGhv
cj48YXV0aG9yPlBhaywgSi48L2F1dGhvcj48YXV0aG9yPlplbGVuYWthcywgSy48L2F1dGhvcj48
YXV0aG9yPkx1Y2hpLCBNLjwvYXV0aG9yPjxhdXRob3I+UmljaGFyZHNvbiwgUC48L2F1dGhvcj48
YXV0aG9yPkhvc2tpbmcsIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo
LWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBBdWNrbGFuZCwg
QXVja2xhbmQsIE5ldyBaZWFsYW5kLiBpLnJlaWRAYXVja2xhbmQuYWMubno8L2F1dGgtYWRkcmVz
cz48dGl0bGVzPjx0aXRsZT5Db21wYXJpc29uIG9mIGEgc2luZ2xlIGluZnVzaW9uIG9mIHpvbGVk
cm9uaWMgYWNpZCB3aXRoIHJpc2Vkcm9uYXRlIGZvciBQYWdldCZhcG9zO3MgZGlzZWFzZTwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5OLiBFbmdsLiBKLiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3Rp
dGxlcz48cGFnZXM+ODk4LTkwODwvcGFnZXM+PHZvbHVtZT4zNTM8L3ZvbHVtZT48bnVtYmVyPjk8
L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtl
eXdvcmRzPjxrZXl3b3JkPmE8L2tleXdvcmQ+PGtleXdvcmQ+YWNpZDwva2V5d29yZD48a2V5d29y
ZD5hbGthbGluZSBwaG9zcGhhdGFzZTwva2V5d29yZD48a2V5d29yZD5BUzwva2V5d29yZD48a2V5
d29yZD5iaXNwaG9zcGhvbmF0ZTwva2V5d29yZD48a2V5d29yZD5iaXNwaG9zcGhvbmF0ZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+Ym9uZSB0dXJub3Zlcjwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkhlYWx0aDwva2V5d29yZD48a2V5d29yZD5pbmZ1c2lvbjwva2V5d29y
ZD48a2V5d29yZD5JbnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5tYXJrZXI8L2tleXdvcmQ+
PGtleXdvcmQ+bWFya2Vyczwva2V5d29yZD48a2V5d29yZD5NZWRpY2luZTwva2V5d29yZD48a2V5
d29yZD5tZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5d29yZD5O
ZXcgWmVhbGFuZDwva2V5d29yZD48a2V5d29yZD5ORVctWkVBTEFORDwva2V5d29yZD48a2V5d29y
ZD5vcmFsPC9rZXl3b3JkPjxrZXl3b3JkPm91dGNvbWU8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQ8
L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzPC9rZXl3b3JkPjxrZXl3b3JkPlBhZ2V0JmFw
b3M7cyBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPnBhaW48L2tleXdvcmQ+PGtleXdvcmQ+UGF0
aWVudHM8L2tleXdvcmQ+PGtleXdvcmQ+cGhvc3BoYXRhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UXVh
bGl0eSBvZiBMaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2Vkcm9uYXRlPC9rZXl3b3JkPjxrZXl3
b3JkPnRoZXJhcGV1dGljPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdv
cmQ+dHJlYXRtZW50PC9rZXl3b3JkPjxrZXl3b3JkPnRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPnpv
bGVkcm9uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPnpvbGVkcm9uaWMgYWNpZDwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OS8xLzIwMDU8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+NzI4NzwvbGFiZWw+PHVybHM+PHJlbGF0
ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTYxMzU4MzQ8
L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (99). The prevalence and severity of this adverse effect has not been studied in detail in PDB but in osteoporosis it was estimated to occur in 42.5% of patients; of these episodes 46% were considered to be mild by the investigator, 45% moderate and 10% severe PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj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 EN.CITE.DATA (113). There is good evidence that the flu-like symptoms are milder after second and subsequent infusions of zoledronic acid as compared with the first infusion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
TnVtPjc1Mzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4o
MTEzKTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjc1Mzk8L3JlYy1u
dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0
dDAxcHplenF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMCI+NzUzOTwva2V5PjwvZm9yZWlnbi1r
ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp
YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UmVpZCwgSS5SLjwvYXV0aG9yPjxhdXRob3I+R2FtYmxl
LCBHLkQuPC9hdXRob3I+PGF1dGhvcj5NZXNlbmJyaW5rLCBQLjwvYXV0aG9yPjxhdXRob3I+TGFr
YXRvcywgUC48L2F1dGhvcj48YXV0aG9yPkJsYWNrLCBELk0uPC9hdXRob3I+PC9hdXRob3JzPjwv
Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgRmFjdWx0
eSBvZiBNZWRpY2FsIGFuZCBIZWFsdGggU2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgQXVja2xhbmQs
IFByaXZhdGUgQmFnIDkyMDE5LCAxMTQyIEF1Y2tsYW5kLCBOZXcgWmVhbGFuZC4gaS5yZWlkQGF1
Y2tsYW5kLmFjLm56PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2hhcmFjdGVyaXphdGlv
biBvZiBhbmQgcmlzayBmYWN0b3JzIGZvciB0aGUgYWN1dGUtcGhhc2UgcmVzcG9uc2UgYWZ0ZXIg
em9sZWRyb25pYyBhY2lkPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkouIENsaW4uIEVuZG9jcmlu
b2wuIE1ldGFiPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjQzODAtNDM4NzwvcGFn
ZXM+PHZvbHVtZT45NTwvdm9sdW1lPjxudW1iZXI+OTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+
Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+YTwva2V5d29y
ZD48a2V5d29yZD5hY2lkPC9rZXl3b3JkPjxrZXl3b3JkPmFjdXRlIHBoYXNlIHJlc3BvbnNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkFjdXRlLVBoYXNlIFJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmFk
dmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFn
ZWQsODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tleXdvcmQ+PGtleXdv
cmQ+QVM8L2tleXdvcmQ+PGtleXdvcmQ+YmlzcGhvc3Bob25hdGU8L2tleXdvcmQ+PGtleXdvcmQ+
YmlzcGhvc3Bob25hdGVzPC9rZXl3b3JkPjxrZXl3b3JkPmJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+
Ym9uZSBkZW5zaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkJvbmUgRGVuc2l0eSBDb25zZXJ2YXRpb24g
QWdlbnRzPC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1pY2FsbHkgaW5kdWNlZDwva2V5d29yZD48a2V5
d29yZD5jbGFzc2lmaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5kaWFiZXRlczwva2V5d29yZD48
a2V5d29yZD5EaWFycmhlYTwva2V5d29yZD48a2V5d29yZD5kaXBob3NwaG9uYXRlPC9rZXl3b3Jk
PjxrZXl3b3JkPkRpcGhvc3Bob25hdGVzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWc8L2tleXdvcmQ+
PGtleXdvcmQ+RHJ1ZyBUaGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgVG94aWNpdHk8L2tl
eXdvcmQ+PGtleXdvcmQ+RWRlbWE8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpZGVtaW9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkV5ZTwva2V5d29yZD48a2V5
d29yZD5GYXRpZ3VlPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5G
ZXZlcjwva2V5d29yZD48a2V5d29yZD5IZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r
ZXl3b3JkPjxrZXl3b3JkPkltaWRhem9sZXM8L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5vbG9neTwv
a2V5d29yZD48a2V5d29yZD5JbmNpZGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9u
PC9rZXl3b3JkPjxrZXl3b3JkPmluZnVzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkludHJhdmVub3Vz
PC9rZXl3b3JkPjxrZXl3b3JkPk1lZGljaW5lPC9rZXl3b3JkPjxrZXl3b3JkPk11bHRpY2VudGVy
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+TmV3IFplYWxhbmQ8L2tleXdvcmQ+PGtleXdvcmQ+
TkVXLVpFQUxBTkQ8L2tleXdvcmQ+PGtleXdvcmQ+b3JhbDwva2V5d29yZD48a2V5d29yZD5vc3Rl
b3Bvcm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+T3N0ZW9wb3Jvc2lzLFBvc3RtZW5vcGF1c2FsPC9r
ZXl3b3JkPjxrZXl3b3JkPm91dGNvbWU8L2tleXdvcmQ+PGtleXdvcmQ+cGFpbjwva2V5d29yZD48
a2V5d29yZD5QYXRpZW50czwva2V5d29yZD48a2V5d29yZD5SaXNrPC9rZXl3b3JkPjxrZXl3b3Jk
PnJpc2sgZmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5
d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UaW1lIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+
dHJlYXRtZW50PC9rZXl3b3JkPjxrZXl3b3JkPnRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPlZvbWl0
aW5nPC9rZXl3b3JkPjxrZXl3b3JkPnpvbGVkcm9uaWMgYWNpZDwva2V5d29yZD48L2tleXdvcmRz
PjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OS8yMDEwPC9kYXRlPjwv
cHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjk5MTQ8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+
PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIwNTU0NzA4PC91cmw+PC9y
ZWxhdGVkLXVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA (113). The evidence summary and recommendations with regard to adverse effects of bisphosphonate treatment are shown in Table 16.Table 16. Adverse events of bisphosphonate treatmentRisk-benefit balanceSerious adverse events with bisphosphonates are rare. In PDB oral bisphosphonates have a similar adverse event profile as placebo but that a transient flu like illness occurs commonly with zoledronic acid. Usually this is of mild to moderate severity but can be severe in some patients.Quality of evidenceVery lowPatient values and preferencesAdverse events are of concern to patients and a proportion of individuals may decline treatment because of the risk of adverse events.Costs and use of resourcesBisphosphonates are inexpensive but intravenous therapy involves additional support costs which may need to be considered.RecommendationWe recommend that patients undergoing treatment with bisphosphonates for PDB are informed about their favourable adverse event profile. We also recommend that patients are advised that a transient flu like illness occurs commonly with intravenous zoledronic acid.Treatment strategy in Paget’s diseaseThis section focuses on randomised trials which have compared different treatment strategies in PDB. Only three studies were identified which directly addressed this issue. These were the PRISM study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE.DATA (54) and its extension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (112) and the study of intravenous versus intramuscular neridronate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJsb3R0aTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJsb3R0aTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (114). All three studies concerned the use of bisphosphonates.Treatment of increased metabolic activity or symptoms?The Paget’s Disease, Randomised Trial of Intensive versus Symptomatic Management (PRISM) study compared the effects of a treat to target strategy aimed at normalising total ALP as compared with a strategy aimed at controlling symptoms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+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ADDIN EN.CITE.DATA (54) in 1324 patients with PDB. The average age of participants at entry to the study was about 74 years with an average disease duration of 8 years. About 70% of patients had previously been treated with bisphosphonates; about 47% had elevated total ALP values at baseline, and 46% had bone pain thought to be caused by PDB. There was a poor correlation between presence of bone pain thought to be due to PDB and an elevated ALP value however PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nc3RvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+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ADDIN EN.CITE.DATA (84). Participants randomised to receive “intensive” bisphosphonate treatment (n=661) were prescribed bisphosphonates with the aim of maintaining or suppressing total ALP values to within the reference range irrespective of whether bone pain was present. Risedronate sodium was the bisphosphonate of first choice but any licensed bisphosphonate could be used. In the symptomatic group (n=663) the therapeutic goal was to control bone pain. This was initially attempted using analgesics but if the response was inadequate non-nitrogen containing bisphosphonates or calcitonin were used first followed by nitrogen-containing bisphosphonates if necessary. The primary endpoint was clinical fracture. Secondary endpoints included fractures through Pagetic bone; orthopaedic procedures, quality of life assessed by SF36, HAQ and EQ5D, bone pain, bone deformity, progression of hearing loss in patients with skull involvement assessed by audiometry and adverse events. PRISM was an event driven study, which was stopped when 95 clinical fractures occurred. The average duration or follow up was 3 years with a range of 2 – 4 years.The PRISM-extension with zoledronic acid study (PRISM-EZ) employed the same strategy as in PRISM but zoledronic acid was used as the treatment of first choice in the intensive arm PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO
dW0+MTkzMDk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4o
MTEyKTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE5MzA5PC9yZWMt
bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iemZweGVwcHhldnYwMGdl
dHQwMXB6ZXpxdnhmOXN0ZTBlNTU5IiB0aW1lc3RhbXA9IjE1MTgwNDE5MzgiPjE5MzA5PC9rZXk+
PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10
eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5UYW4sIEEuPC9hdXRob3I+PGF1dGhv
cj5Hb29kbWFuLCBLLjwvYXV0aG9yPjxhdXRob3I+V2Fsa2VyLCBBLjwvYXV0aG9yPjxhdXRob3I+
SHVkc29uLCBKLjwvYXV0aG9yPjxhdXRob3I+TWFjTGVubmFuLCBHLiBTLjwvYXV0aG9yPjxhdXRo
b3I+U2VsYnksIFAuIEwuPC9hdXRob3I+PGF1dGhvcj5GcmFzZXIsIFcuIEQuPC9hdXRob3I+PGF1
dGhvcj5SYWxzdG9uLCBTLiBILjwvYXV0aG9yPjxhdXRob3I+UHJpc20tRXogVHJpYWwgR3JvdXA8
L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5DZW50cmUgZm9y
IEdlbm9taWMgYW5kIEV4cGVyaW1lbnRhbCBNZWRpY2luZSwgTVJDIEluc3RpdHV0ZSBvZiBHZW5l
dGljcyBhbmQgTW9sZWN1bGFyIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIEVkaW5idXJnaCwgV2Vz
dGVybiBHZW5lcmFsIEhvc3BpdGFsLCBFZGluYnVyZ2ggRUg0IDJYVSwgVUsuJiN4RDtFZGluYnVy
Z2ggQ2xpbmljYWwgVHJpYWxzIFVuaXQsIFVuaXZlcnNpdHkgb2YgRWRpbmJ1cmdoLCBXZXN0ZXJu
IEdlbmVyYWwgSG9zcGl0YWwsIEVkaW5idXJnaCwgRUg0IDJYVSwgVUsuJiN4RDtIZWFsdGggU2Vy
dmljZXMgUmVzZWFyY2ggVW5pdCwgVW5pdmVyc2l0eSBvZiBBYmVyZGVlbiwgQWJlcmRlZW4sIFVL
LiYjeEQ7SW5zdGl0dXRlIG9mIEh1bWFuIERldmVsb3BtZW50LCBGYWN1bHR5IG9mIE1lZGljYWwg
YW5kIEh1bWFuIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIE1hbmNoZXN0ZXIsIE1hbmNoZXN0ZXIs
IFVLLiYjeEQ7TWFuY2hlc3RlciBSb3lhbCBJbmZpcm1hcnksIENlbnRyYWwgTWFuY2hlc3RlciBV
bml2ZXJzaXR5IEhvc3BpdGFscyBOSFMgRm91bmRhdGlvbiBUcnVzdCwgTWFuY2hlc3RlciBBY2Fk
ZW1pYyBIZWFsdGggU2NpZW5jZSBDZW50cmUsIE1hbmNoZXN0ZXIsIFVLLiYjeEQ7RGVwYXJ0bWVu
dCBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBFYXN0IEFuZ2xpYSwgTm9yd2ljaCwgVUsuPC9h
dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TG9uZy1UZXJtIFJhbmRvbWl6ZWQgVHJpYWwgb2Yg
SW50ZW5zaXZlIFZlcnN1cyBTeW1wdG9tYXRpYyBNYW5hZ2VtZW50IGluIFBhZ2V0JmFwb3M7cyBE
aXNlYXNlIG9mIEJvbmU6IFRoZSBQUklTTS1FWiBTdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRs
ZT5KIEJvbmUgTWluZXIgUmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+
PGZ1bGwtdGl0bGU+SiBCb25lIE1pbmVyIFJlczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh
Z2VzPjExNjUtMTE3MzwvcGFnZXM+PHZvbHVtZT4zMjwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVy
PjxlZGl0aW9uPjIwMTcvMDIvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkJpc3Bob3Nw
aG9uYXRlczwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCB0cmlhbDwva2V5d29yZD48a2V5d29y
ZD5QYWdldCZhcG9zO3MgZGlzZWFzZSBvZiBib25lPC9rZXl3b3JkPjxrZXl3b3JkPlF1YWxpdHkg
b2YgbGlmZTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48
ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1k
YXRlcz48L2RhdGVzPjxpc2JuPjE1MjMtNDY4MSAoRWxlY3Ryb25pYykmI3hEOzA4ODQtMDQzMSAo
TGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgxNzYzODY8L2FjY2Vzc2lvbi1udW0+PHVy
bHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVk
LzI4MTc2Mzg2PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNl
LW51bT4xMC4xMDAyL2pibXIuMzA2NjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+
PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (112). Patients within PRISM-EZ maintained the same treatment allocation as they had been randomised to in PRISM. The PRISM-EZ study followed 270 patients in the intensive group and 232 in the symptomatic group providing an average total duration of 7.3 years follow-up since the beginning of the PRISM study. The primary and secondary endpoints were the same in PRISM-EZ as in PRISM, except that patients did not undergo audiometry in the extension.FracturesThe number of clinical fractures in the intensive and symptomatic PRISM treatment arms were similar. In the intensive group 46/661 (7.0%) participants had clinical fractures, compared with 49/663 (7.3%) in the symptomatic group (RR= 0.94 (95% CI) 0.64-1.39). Fractures through Pagetic bone occurred in 8/661 (1.2%) of the intensive group and 13/663 (2.0%) of the symptomatic group (RR = 0.62 (95% CI, 0.22-1.60). In the PRISM-EZ trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (115), 22/270 (8.1%) of participants in the intensive group had clinical fractures compared with 12/232 (5.2%) in the symptomatic group (RR = 1.84, 95% CI 0.76-4.44). Fractures through Pagetic bone occurred in 5/270 (1.9%) in the intensive group versus 2/232 (0.9%) in the symptomatic group (RR = 2.15 (95% CI) 0.42 to 10.96).Orthopaedic surgeryIn the PRISM study the number of patients undergoing orthopedic surgery in the intensive treatment group was 48/661 (7.2%) and 55/663 (8.2%) in the symptomatic group (RR= 0.88 (95% CI) 0.60-1.27). Of the 103 procedures performed, 73.7% were joint replacements for osteoarthritis. In the PRISM-EZ study, 15/270 (5.5%) of patients in the intensive group underwent orthopaedic surgery compared with 7/232 (3.0%) patients in the symptomatic group (RR = 1.84 95% CI 0.76-4.44). Joint replacements were also the most common orthopaedic procedure in PRISM-EZ and were more commonly required in the intensive group 11/270 (4.1%) vs 4/232 (1.7%).Health related quality of lifeThe PRISM study showed no significant difference in health-related quality of life between the treatment groups at any time point using various tools including SF36, EQ5D and HAQ. Within the PRISM-EZ study, small differences in some aspects of quality of life were observed between the treatment groups at some time points but the differences were below the 5-point threshold that is considered clinically significant and were not consistently observed at different time points. Bone painThe PRISM study showed no difference between treatment groups in the proportion of patients with bone pain at 2 years (311/422 (73.7%) vs 295/423 (69.7%), p=0.20) or bone pain thought by the clinician to be due to PDB (96/311) (30.8%) versus 78/295, (26.4%), p=0.22). In the PRISM-EZ study, there were no differences in bone pain or bone pain thought by the clinician to be due to PDB except at 2 years where the standardized mean difference, calculated by propensity scoring showed 1.3% fewer patients with bone pain (95% CI 0.3-2.3) in the intensive treatment group. Progression of deafnessThe PRISM study showed no significant difference between treatment groups in progression of hearing loss, as determined by audiometry and the proportion of patients using a hearing aid over an average of three years follow up. Audiometry showed that the mean (±SD) change in hearing threshold was +1.8±14.6 in the left ear in the intensive group compared with 0±12.6 in the symptomatic group (mean, 95% CI difference = 1.8, -3.4 to 7.0). Corresponding values in the right ear were 2.5 ± 5.7 vs 2.1 ± 9.4 (mean, 95% CI difference = 0.5, -2.5 to 3.3). At the baseline visit of PRISM, 151/663 (22.9%) of the symptomatic group and 144/661 (21.9%) of the intensive group used a hearing aid. The proportion of hearing aid users increased to a similar extent in both groups such that by the end of study 133/486 (27.3%) of the symptomatic group used a hearing aid compared with 134/505 (26.5%) of the intensive group.Adverse eventsIn the PRISM study the numbers of adverse events and serious adverse events in the two treatment groups was similar. In the PRISM-EZ study the number of patients with adverse events in the intensive group was 226/270 (83.7%) compared with 196.232 (84.5%) in the symptomatic group (RR= 0.99, 95% CI 0.92-1.08). The number of serious adverse events in the two treatment groups was 87/270 (32.2%) versus 66/232 (28.4%) (RR 1.28, 95% CI 0.96-1.72). Alkaline phosphataseIn the PRISM study, serum concentrations of total ALP were significantly lower in the intensive group from 4 months onward. At the end of the study 78.8% of the intensive group had a total ALP within the reference range compared with 61.2% of the symptomatic group (p<0.001). In the PRISM-EZ study, total ALP values were lower at baseline and throughout the study in the intensive group. By the end of study total ALP values were within the reference range in 85.3% of the intensive group versus 70.3% of the symptomatic group (P<0.001).The evidence summary and recommendations with regard to employing a strategy of supressing bone turnover as the primary therapeutic goal in PDB as opposed to treating symptoms is shown in Table 17.Table 17. Treating symptoms or increased metabolic activity in PDBRisk-benefit balanceA strategy of intensive bisphosphonate therapy aimed at maintaining total ALP concentrations within the reference range performed similarly to a strategy of treatment with bisphosphonates and other drugs which aimed to control symptoms, with respect to the occurrence of clinical fractures, fractures through Pagetic bone, requirement for orthopaedic surgery, quality of life, bone pain and progression of progression of hearing loss. Quality of evidenceModeratePatient values and preferencesPrevention of fractures and orthopaedic procedures, and improvements in bone pain, quality of life and prevention of progressive hearing loss are all highly valued by patients. Costs and use of resourcesBisphosphonates are inexpensive drugs but intravenous therapy may involve additional support costs which may need to be considered. More frequent courses of therapy increase health care costs and resources as compared with less frequent courses of treatment.RecommendationTreatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalising total ALP in PDB.Route of administration of bisphosphonatesThe literature review identified several studies in which different modes of administration of bisphosphonates for the treatment of PDB were investigated, but the only randomised trial was by Merlotti and colleagues with neridronate, a nitrogen containing bisphosphonate licensed in Italy for PDB PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJsb3R0aTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJsb3R0aTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (114). The study group comprised 57 patients with active PDB as defined by a serum total ALP value above the upper limit of the reference range. All patients were reported to have bone pain prior to treatment. Participants were randomised to receive intravenous neridronate (100mg iv on two consecutive days) or intramuscular neridronate (25mg once weekly for 8 weeks). The primary endpoint was normalisation of total ALP. Secondary endpoints included bone pain and the time taken until ALP normalised. Normalization of ALP levels at 6 months was achieved in 24/27 patients (88.9%) in the intravenous group and 26/29 patients (89.6%) in the intramuscular group. Longer term follow-up at 36 months, revealed that normal total ALP values were maintained in 13/27 (48.1%) and 13/29 (44.8%) of patients in the intravenous and intramuscular groups respectively. Pain had improved or disappeared in 21/27 (77%) of patients given intravenous therapy at 6 months compared with 19/29 (65.5%) given intramuscular therapy a difference that was not significant (chi-square 1.02, p=0.30). Adverse effects in the two treatment groups were similar. The authors concluded that both routes of administration gave equivalent therapeutic responses but commented that the intramuscular route was slightly more expensive (115 versus 90 euros). The evidence summary and recommendations with regard to administering neridronate intravenously as opposed to intramuscularly is shown in Table 18.Table 18. Route of administration of the bisphosphonate neridronate in PDBRisk-benefit balanceInformation from randomised trials is only available for the comparison of intravenous and intramuscular modes of administration of neridronate. Both routes of administration were found to give similar results in terms of suppression of ALP and control of bone pain.Quality of evidenceLowPatient values and preferencesImprovements in bone pain are valued by patients. Some patients might prefer two infusions as opposed to 8 intramuscular injections, although the intramuscular route could be preferred in patients with poor venous access. Costs and use of resourcesNeridronate is inexpensive with little differences between regimens. Nursing support costs may be higher with intramuscular therapy but day patient facilities and other support costs may be higher with intravenous therapy.RecommendationFor patients with metabolically active PDB with bone pain treated with neridronate, either the intravenous or intramuscular route can be recommended. CalcitoninCalcitonin was one of the first osteoclast inhibitors to be used in the treatment of PDB. No randomised trials were identified in which the effects of calcitonin were compared with placebo or with other osteoclast inhibitors. One of the largest case series of patients treated with calcitonin was published by Martin and colleagues who reported on the response to porcine calcitonin 80 MRC units daily in a case series of 38 patients with active PDB who received 44 courses of treatment by daily injection for periods of between 6 weeks and 18 months ADDIN EN.CITE <EndNote><Cite><Author>Martin</Author><Year>1977</Year><RecNum>19555</RecNum><DisplayText><style face="superscript">(116)</style></DisplayText><record><rec-number>19555</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1519080583">19555</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martin, T. J.</author><author>Jerums, G.</author><author>Melick, R. A.</author><author>Xipell, J. M.</author><author>Arnott, R.</author></authors></contributors><titles><title>Clinical, biochemical and histological observations on the effect of porcine calcitonin in Paget's disease of bone</title><secondary-title>Aust N Z J Med</secondary-title></titles><periodical><full-title>Australian and New Zealand journal of medicine</full-title><abbr-1>Aust N Z J Med</abbr-1></periodical><pages>36-43</pages><volume>7</volume><number>1</number><edition>1977/02/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Animals</keyword><keyword>Bone and Bones/pathology</keyword><keyword>Calcitonin/*therapeutic use</keyword><keyword>Cell Count</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*drug therapy/metabolism/pathology</keyword><keyword>Osteoclasts</keyword><keyword>Swine</keyword></keywords><dates><year>1977</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0004-8291 (Print)
0004-8291 (Linking)</isbn><accession-num>266891</accession-num><urls><related-urls><url>;(116). Bone pain improved in 32/38 (81.8%) patients following treatment, although the method of assessing bone pain was not described. Serum total ALP concentrations also decreased from a mean (SEM) of 899 (145) U/L to 579 (130) U/L (p<0.001). The reference range for total ALP wasn’t provided and so it was impossible to determine in what proportion of patients total ALP values had fallen to within the reference range. Six patients (15.7%) were reported to have adverse effects, the most common of which were nausea and diarrhoea. In one patient (2.6%) treatment was stopped because of adverse effects and in one (2.6%) the dose was reduced because of adverse effects. Since these early reports, long term calcitonin therapy for osteoporosis has been associated with an increased risk of certain cancers. We identified one randomised trial of 44 patients with active PDB that had bone pain inadequately unresponsive to analgesia who were randomised to receive oral etidronate in a dose of 400mg daily for 6 months or oral etidronate 400mg daily plus calcitonin, 100 IU three times weekly by subcutaneous injection ADDIN EN.CITE <EndNote><Cite><Author>O'Donoghue</Author><Year>1987</Year><RecNum>16349</RecNum><DisplayText><style face="superscript">(117)</style></DisplayText><record><rec-number>16349</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1494699833">16349</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>O'Donoghue, D. J.</author><author>Hosking, D. J.</author></authors></contributors><auth-address>Department of Medicine, University Hospital, Nottingham, UK.</auth-address><titles><title>Biochemical response to combination of disodium etidronate with calcitonin in Paget's disease</title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>219-25</pages><volume>8</volume><number>4</number><keywords><keyword>Alkaline Phosphatase/*blood</keyword><keyword>Calcitonin/*therapeutic use</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Etidronic Acid/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Hydroxyproline/*urine</keyword><keyword>Osteitis Deformans/blood/*drug therapy/enzymology/urine</keyword></keywords><dates><year>1987</year></dates><isbn>8756-3282 (Print)
1873-2763 (Linking)</isbn><accession-num>3128315</accession-num><urls><related-urls><url>;(117). The response of biochemical markers of bone turnover in these patients was compared to a group of historical controls with PDB who had been treated with calcitonin alone at the same dose. In the historical controls treated with calcitonin, total ALP decreased from an average of 1261 U/L before treatment to 595 U/L 6 months after treatment (53% reduction, p<0.001). Corresponding values for the etidronate group were 1228U/L to 539 U/L (56% reduction, p<0.001) and for the etidronate plus calcitonin group 1448U/L to 428U/L (71% reduction, p<0.001). The combination of etidronate plus calcitonin was more effective at decreasing total ALP than etidronate alone (p<0.002). The authors did not specifically comment on the effects of these agents on bone pain in the results section. Calcitonin has been studied in case series of patients with neurological dysfunction associated with PDB and treatment has been associated with clinical benefit. The results of these studies are summarised in section 5.9. The evidence summary and recommendations with regard to the use of calcitonin in the treatment of PDB is shown in Table 19.Table 19. Effects of calcitonin on bone pain and metabolic activity in PDB.Risk-benefit balanceCalcitonin improves bone pain in PDB and decreases total ALP concentrations. Long term administration of calcitonin has been associated with an increased risk of cancerQuality of evidenceVery lowPatient values and preferencesImprovements in bone pain are highly valued by patients. Adverse events may be observed with calcitonin and the need for repeated injections at frequent intervals may be considered a barrier by some patients. Costs and use of resourcesCalcitonin is considerably more expensive than bisphosphonates.RecommendationCalcitonin may be considered for the short-term treatment of bone pain in PDB where bisphosphonates are contraindicated.DenosumabThere have been two case reports in the use of denosumab 60mg by subcutaneous injection every 6 months in PDB in patients where bisphosphonates were poorly tolerated or contraindicated. In both cases denosumab resulted in a decrease in total ALP concentrations and an improvement of bone pain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (89,118). Three open label trials have been conducted to study the effects of denosumab in the treatment of GCT but PDB was an exclusion in two of these studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5VZWRhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
TnVtPjE5OTI5PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
KDExOSwxMjApPC9zdHlsZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTk5Mjk8
L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2
djAwZ2V0dDAxcHplenF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMTUyMDg3NDg3MSI+MTk5Mjk8
L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv
cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlVlZGEsIFQuPC9hdXRob3I+
PGF1dGhvcj5Nb3Jpb2thLCBILjwvYXV0aG9yPjxhdXRob3I+TmlzaGlkYSwgWS48L2F1dGhvcj48
YXV0aG9yPktha3VuYWdhLCBTLjwvYXV0aG9yPjxhdXRob3I+VHN1Y2hpeWEsIEguPC9hdXRob3I+
PGF1dGhvcj5NYXRzdW1vdG8sIFkuPC9hdXRob3I+PGF1dGhvcj5Bc2FtaSwgWS48L2F1dGhvcj48
YXV0aG9yPklub3VlLCBULjwvYXV0aG9yPjxhdXRob3I+WW9uZWRhLCBULjwvYXV0aG9yPjwvYXV0
aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgT3J0aG9wYWVk
aWMgU3VyZ2VyeSwgT3Nha2EgTmF0aW9uYWwgSG9zcGl0YWwsIE9zYWthIHVlZGF0QG9uaC5nby5q
cC4mI3hEO0RlcGFydG1lbnQgb2YgT3J0aG9wYWVkaWMgU3VyZ2VyeSwgU2Nob29sIG9mIE1lZGlj
aW5lLCBLZWlvIFVuaXZlcnNpdHksIFRva3lvLiYjeEQ7RGVwYXJ0bWVudCBvZiBPcnRob3BhZWRp
YyBTdXJnZXJ5LCBOYWdveWEgVW5pdmVyc2l0eSBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNpbmUs
IE5hZ295YS4mI3hEO0RlcGFydG1lbnQgb2YgT3J0aG9wYWVkaWMgU3VyZ2VyeSwgT3Nha2EgTmF0
aW9uYWwgSG9zcGl0YWwsIE9zYWthLiYjeEQ7RGVwYXJ0bWVudCBvZiBPcnRob3BhZWRpYyBTdXJn
ZXJ5LCBHcmFkdWF0ZSBTY2hvb2wgb2YgTWVkaWNhbCBTY2llbmNlLCBLYW5hemF3YSBVbml2ZXJz
aXR5LCBLYW5hemF3YS4mI3hEO0RlcGFydG1lbnQgb2YgT3J0aG9wYWVkaWMgU3VyZ2VyeSwgR3Jh
ZHVhdGUgU2Nob29sIG9mIE1lZGljYWwgU2NpZW5jZXMsIEt5dXNodSBVbml2ZXJzaXR5LCBGdWt1
b2thLiYjeEQ7RGFpaWNoaSBTYW5reW8gQ28uLCBMdGQsIFRva3lvLCBKYXBhbi4mI3hEO0Rpdmlz
aW9uIG9mIEhlbWF0b2xvZ3kvT25jb2xvZ3ksIEluZGlhbmEgVW5pdmVyc2l0eSBTY2hvb2wgb2Yg
TWVkaWNpbmUsIEluZGlhbmFwb2xpcywgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
Pk9iamVjdGl2ZSB0dW1vciByZXNwb25zZSB0byBkZW5vc3VtYWIgaW4gcGF0aWVudHMgd2l0aCBn
aWFudCBjZWxsIHR1bW9yIG9mIGJvbmU6IGEgbXVsdGljZW50ZXIgcGhhc2UgSUkgdHJpYWw8L3Rp
dGxlPjxzZWNvbmRhcnktdGl0bGU+QW5uIE9uY29sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+
PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIE9uY29sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh
bD48cGFnZXM+MjE0OS01NDwvcGFnZXM+PHZvbHVtZT4yNjwvdm9sdW1lPjxudW1iZXI+MTA8L251
bWJlcj48ZWRpdGlvbj4yMDE1LzA3LzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9s
ZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tl
eXdvcmQ+PGtleXdvcmQ+Qm9uZSBEZW5zaXR5IENvbnNlcnZhdGlvbiBBZ2VudHMvKnRoZXJhcGV1
dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5Cb25lIE5lb3BsYXNtcy8qZHJ1ZyB0aGVyYXB5L3Bh
dGhvbG9neTwva2V5d29yZD48a2V5d29yZD5EZW5vc3VtYWIvKnRoZXJhcGV1dGljIHVzZTwva2V5
d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rm9sbG93LVVwIFN0dWRpZXM8
L2tleXdvcmQ+PGtleXdvcmQ+R2lhbnQgQ2VsbCBUdW1vciBvZiBCb25lLypkcnVnIHRoZXJhcHkv
cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5lb3BsYXNt
IFJlY3VycmVuY2UsIExvY2FsLypkcnVnIHRoZXJhcHkvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3
b3JkPk5lb3BsYXNtIFN0YWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3Jk
PjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+WW91bmcgQWR1
bHQ8L2tleXdvcmQ+PGtleXdvcmQ+UmFua2w8L2tleXdvcmQ+PGtleXdvcmQ+ZGVub3N1bWFiPC9r
ZXl3b3JkPjxrZXl3b3JkPmdpYW50IGNlbGwgdHVtb3Igb2YgYm9uZTwva2V5d29yZD48a2V5d29y
ZD5vYmplY3RpdmUgdHVtb3IgcmVzcG9uc2U8L2tleXdvcmQ+PGtleXdvcmQ+cHJpbWFyeSBib25l
IHR1bW9yPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT5PY3Q8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTY5LTgwNDEg
KEVsZWN0cm9uaWMpJiN4RDswOTIzLTc1MzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt
PjI2MjA1Mzk1PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov
L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNjIwNTM5NTwvdXJsPjwvcmVsYXRlZC11cmxz
PjwvdXJscz48Y3VzdG9tMj5QTUM0NTc2OTA5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNl
LW51bT4xMC4xMDkzL2Fubm9uYy9tZHYzMDc8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVj
b3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkNoYXdsYTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT4xOTkzMTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTk5MzE8L3JlYy1udW1i
ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6ZnB4ZXBweGV2djAwZ2V0dDAx
cHplenF2eGY5c3RlMGU1NTkiIHRpbWVzdGFtcD0iMTUyMDg3NDkwOCI+MTk5MzE8L2tleT48L2Zv
cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+
PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNoYXdsYSwgUy48L2F1dGhvcj48YXV0aG9y
PkhlbnNoYXcsIFIuPC9hdXRob3I+PGF1dGhvcj5TZWVnZXIsIEwuPC9hdXRob3I+PGF1dGhvcj5D
aG95LCBFLjwvYXV0aG9yPjxhdXRob3I+QmxheSwgSi4gWS48L2F1dGhvcj48YXV0aG9yPkZlcnJh
cmksIFMuPC9hdXRob3I+PGF1dGhvcj5Lcm9lcCwgSi48L2F1dGhvcj48YXV0aG9yPkdyaW1lciwg
Ui48L2F1dGhvcj48YXV0aG9yPlJlaWNoYXJkdCwgUC48L2F1dGhvcj48YXV0aG9yPlJ1dGtvd3Nr
aSwgUC48L2F1dGhvcj48YXV0aG9yPlNjaHVldHplLCBTLjwvYXV0aG9yPjxhdXRob3I+U2t1Yml0
eiwgSy48L2F1dGhvcj48YXV0aG9yPlN0YWRkb24sIEEuPC9hdXRob3I+PGF1dGhvcj5UaG9tYXMs
IEQuPC9hdXRob3I+PGF1dGhvcj5RaWFuLCBZLjwvYXV0aG9yPjxhdXRob3I+SmFjb2JzLCBJLjwv
YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNhcmNvbWEgT25j
b2xvZ3kgQ2VudGVyLCBTYW50YSBNb25pY2EsIENBIDkwNDAzLCBVU0EuIHNhbnRjaGF3bGFAc2Fy
Y29tYW9uY29sb2d5LmNvbTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNhZmV0eSBhbmQg
ZWZmaWNhY3kgb2YgZGVub3N1bWFiIGZvciBhZHVsdHMgYW5kIHNrZWxldGFsbHkgbWF0dXJlIGFk
b2xlc2NlbnRzIHdpdGggZ2lhbnQgY2VsbCB0dW1vdXIgb2YgYm9uZTogaW50ZXJpbSBhbmFseXNp
cyBvZiBhbiBvcGVuLWxhYmVsLCBwYXJhbGxlbC1ncm91cCwgcGhhc2UgMiBzdHVkeTwvdGl0bGU+
PHNlY29uZGFyeS10aXRsZT5MYW5jZXQgT25jb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48
cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgT25jb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp
Y2FsPjxwYWdlcz45MDEtODwvcGFnZXM+PHZvbHVtZT4xNDwvdm9sdW1lPjxudW1iZXI+OTwvbnVt
YmVyPjxlZGl0aW9uPjIwMTMvMDcvMjM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xl
c2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGll
cywgTW9ub2Nsb25hbCwgSHVtYW5pemVkLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv
cmQ+Qm9uZSBOZW9wbGFzbXMvKmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Db2hvcnQg
U3R1ZGllczwva2V5d29yZD48a2V5d29yZD5EZW5vc3VtYWI8L2tleXdvcmQ+PGtleXdvcmQ+RmVt
YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3Jk
PkdpYW50IENlbGwgVHVtb3Igb2YgQm9uZS8qZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnRlcm5hdGlvbmFsIEFnZW5jaWVzPC9rZXl3b3Jk
PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl
eXdvcmQ+TmVvcGxhc20gUmVjdXJyZW5jZSwgTG9jYWwvY2hlbWljYWxseSBpbmR1Y2VkLypkaWFn
bm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+UHJvZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5n
IEFkdWx0PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc0LTU0ODgg
KEVsZWN0cm9uaWMpJiN4RDsxNDcwLTIwNDUgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt
PjIzODY3MjExPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczov
L3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzg2NzIxMTwvdXJsPjwvcmVsYXRlZC11cmxz
PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9TMTQ3MC0yMDQ1KDEzKTcw
Mjc3LTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5VZWRhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (119,120) and in the third, no information on co-existing PDB was available PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9tYXM8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9tYXM8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (121). The posology in this situation is an initial loading dose of 120mg denosumab subcutaneously two weekly followed by 120mg 4 weekly thereafter. Of three case reports where denosumab was given to PDB patients with non-resectable GCT, the treatment improved bone pain and reduced tumour size PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3NzbzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3NzbzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE.DATA (122-124). The evidence summary and recommendations with regard to the use of denosumab in the treatment of PDB and GCT associated with PDB is shown in Table 20.Table 20. Role of denosumab in Paget’s disease Risk-benefit balanceFrom the evidence available, denosumab may be efficacious treating pain and reducing tumour size in GCT complicating PDB. There is little evidence supporting its use in PDB Quality of evidenceVery lowPatient values and preferencesImprovements in bone pain are highly valued by patients. Patients may be dissuaded by the need for repeated injections and risk of adverse events. Costs and use of resourcesDenosumab is considerably more expensive than bisphosphonates and involves repeated injections administered by a health care professional.RecommendationDenosumab may be considered for the treatment of GCT complicating PDB when the tumour is non-resectable. There is insufficient evidence to support the use of denosumab in the treatment of PDB and it is not recommended for this indication.Predicting the response to treatment in Paget’s diseaseA large number of observational studies and clinical trials been conducted in which biochemical markers of bone turnover have been measured before and after administration of various bisphosphonates in PDB. Indeed, most clinical trials of bisphosphonate therapy in PDB have used serum total ALP as the primary endpoint for efficacy ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66). These studies have consistently shown that total ALP values and other biochemical markers of bone turnover are decreased by bisphosphonate therapy. It has been shown that the decrease is greater with nitrogen-containing bisphosphonates as opposed to non-nitrogen containing bisphosphonates; and that within the bisphosphonates, zoledronic acid is most effective at reducing total ALP ADDIN EN.CITE <EndNote><Cite><Author>Corral-Gudino</Author><Year>2017</Year><RecNum>19254</RecNum><DisplayText><style face="superscript">(66)</style></DisplayText><record><rec-number>19254</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1518033746">19254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corral-Gudino, L.</author><author>Tan, A. J.</author><author>Del Pino-Montes, J.</author><author>Ralston, S. H.</author></authors></contributors><auth-address>Internal Medicine Department, Hospital el Bierzo, Gerencia de Asistencia Sanitaria del Bierzo, SACYL, IBSAL, RETICEF, c/Medicos Sin fronteras, 7, Ponferrada, Leon, Spain, 24411.</auth-address><titles><title>Bisphosphonates for Paget's disease of bone in adults</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004956</pages><volume>12</volume><edition>2017/12/02</edition><keywords><keyword>Aged</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone Density Conservation Agents/adverse effects/*therapeutic use</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates/adverse effects/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Musculoskeletal Pain/drug therapy</keyword><keyword>Osteitis Deformans/*drug therapy/enzymology</keyword><keyword>Patient Dropouts/statistics & numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>29192423</accession-num><urls><related-urls><url>;(66). Predicting the response of bone lesions Al Nofal and colleagues conducted a systematic review and meta-analysis of studies that compared changes in marker concentrations following bisphosphonate therapy with disease extent as assessed by quantitative radionuclide scintigraphy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbCBOb2ZhbDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbCBOb2ZhbDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+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ADDIN EN.CITE.DATA (83). Decreases in bone ALP concentrations following treatment have been observed following treatment with various bisphosphonates. However, in a meta-analysis, bone ALP was a weak predictor of scintigraphic indices of disease extent following treatment (r=0.24, 95% CI 0.004-0.457). Total ALP performed better than bone ALP but with confidence intervals that overlapped (r=0.427, 95% CI 0.256-0.573), whereas PINP was the strongest predictor of the bone formation markers assessed (r=0.704, 95% CI 0.559-0.808). The bone resorption markers sβCTX, uNTX and sNTX also significantly predicted lesion extent assessed by scintigraphy after bisphosphonate treatment with values of 0.563, 95% CI 0.297-0.748 for uβCTX; 0.639 95% CI for sβCTX 0.401-0.796; and 0.674, 95% CI 0.518-0.787 for uNTX. The evidence summary and recommendations with regard to the use of biochemical markers in predicting the response of bone lesions to bisphosphonate treatment in PDB is shown in Table 21.Table 21. Predicting response of bone lesions to bisphosphonate treatment Risk-benefit balanceBiochemical markers of bone turnover can be easily assessed by analysis of blood or urine samples and several markers of bone turnover are associated with scintigraphic extent of bone lesions following bisphosphonate therapy Quality of evidenceVery lowPatient values and preferencesPatients may value undergoing biochemical tests to predict the extent of PDB and response of bone lesions to bisphosphonates. Costs and use of resourcesThe strongest predictor was PINP, but the confidence intervals overlapped with sβCTX, uNTX and sNTX. These markers performed better than total ALP but are more expensive and not widely available. RecommendationMeasurement of PINP is recommended to predict lesion extent, as defined by scintigraphy, following bisphosphonate therapy.Predicting the response of bone painBoudreau examined the relation between changes in bone pain in a series of 24 patients with PDB undergoing treatment with etidronate, mithramycin or calcitonin in relation to bone scan appearances and changes in total ALP. They concluded that changes in blood flow as visualised on bone scan were the most reliable predictor of response of pain, although changes in total ALP and changes in bone scan static images following treatment also were associated with the response of pain ADDIN EN.CITE <EndNote><Cite><Author>Boudreau</Author><Year>1983</Year><RecNum>18877</RecNum><DisplayText><style face="superscript">(125)</style></DisplayText><record><rec-number>18877</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1515774125">18877</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boudreau, R. J.</author><author>Lisbona, R.</author><author>Hadjipavlou, A.</author></authors></contributors><titles><title>Observations on serial radionuclide blood-flow studies in Paget's disease: concise communication</title><secondary-title>J Nucl Med</secondary-title></titles><periodical><full-title>J Nucl Med</full-title></periodical><pages>880-5</pages><volume>24</volume><number>10</number><edition>1983/10/01</edition><keywords><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bone and Bones/*blood supply/diagnostic imaging</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Diphosphonates</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Etidronic Acid/therapeutic use</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Hyperemia/diagnostic imaging</keyword><keyword>Osteitis Deformans/*diagnostic imaging/drug therapy/physiopathology</keyword><keyword>Plicamycin/therapeutic use</keyword><keyword>Radionuclide Imaging</keyword><keyword>Regional Blood Flow</keyword><keyword>Technetium</keyword><keyword>Technetium Tc 99m Medronate</keyword></keywords><dates><year>1983</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0161-5505 (Print)
0161-5505 (Linking)</isbn><accession-num>6225840</accession-num><urls><related-urls><url>;(125). This study is of limited relevance to modern day treatment of PDB in view of the agents employed. A randomised placebo-controlled trial of alendronic acid performed by Reid and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVj
TnVtPjE2MzU1PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
KDUzKTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE2MzU1PC9yZWMt
bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iemZweGVwcHhldnYwMGdl
dHQwMXB6ZXpxdnhmOXN0ZTBlNTU5IiB0aW1lc3RhbXA9IjE0OTQ3NjM1NzkiPjE2MzU1PC9rZXk+
PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10
eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5SZWlkLCBJLiBSLjwvYXV0aG9yPjxh
dXRob3I+TmljaG9sc29uLCBHLiBDLjwvYXV0aG9yPjxhdXRob3I+V2VpbnN0ZWluLCBSLiBTLjwv
YXV0aG9yPjxhdXRob3I+SG9za2luZywgRC4gSi48L2F1dGhvcj48YXV0aG9yPkN1bmR5LCBULjwv
YXV0aG9yPjxhdXRob3I+S290b3dpY3osIE0uIEEuPC9hdXRob3I+PGF1dGhvcj5NdXJwaHksIFcu
IEEuLCBKci48L2F1dGhvcj48YXV0aG9yPlllYXAsIFMuPC9hdXRob3I+PGF1dGhvcj5EdWZyZXNu
ZSwgUy48L2F1dGhvcj48YXV0aG9yPkxvbWJhcmRpLCBBLjwvYXV0aG9yPjxhdXRob3I+TXVzbGlu
ZXIsIFQuIEEuPC9hdXRob3I+PGF1dGhvcj5UaG9tcHNvbiwgRC4gRS48L2F1dGhvcj48YXV0aG9y
PllhdGVzLCBBLiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy
ZXNzPkRlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgQXVja2xhbmQsIE5ldyBa
ZWFsYW5kLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJpb2NoZW1pY2FsIGFuZCByYWRp
b2xvZ2ljIGltcHJvdmVtZW50IGluIFBhZ2V0JmFwb3M7cyBkaXNlYXNlIG9mIGJvbmUgdHJlYXRl
ZCB3aXRoIGFsZW5kcm9uYXRlOiBhIHJhbmRvbWl6ZWQsIHBsYWNlYm8tY29udHJvbGxlZCB0cmlh
bDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9k
aWNhbD48cGFnZXM+MzQxLTg8L3BhZ2VzPjx2b2x1bWU+MTAxPC92b2x1bWU+PG51bWJlcj40PC9u
dW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkbWluaXN0cmF0aW9uLCBPcmFsPC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+
PGtleXdvcmQ+QWxlbmRyb25hdGUvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2Ug
ZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFsa2FsaW5lIFBob3Nw
aGF0YXNlL2Jsb29kPC9rZXl3b3JkPjxrZXl3b3JkPkJpb3BzeTwva2V5d29yZD48a2V5d29yZD5C
b25lIGFuZCBCb25lcy9kaWFnbm9zdGljIGltYWdpbmcvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS9ibG9vZDwva2V5d29yZD48a2V5d29yZD5Db2xsYWdlbi91
cmluZTwva2V5d29yZD48a2V5d29yZD5Db2xsYWdlbiBUeXBlIEk8L2tleXdvcmQ+PGtleXdvcmQ+
RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk
ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+T3N0ZWl0aXMgRGVmb3JtYW5zL2RpYWdub3N0aWMg
aW1hZ2luZy8qZHJ1ZyB0aGVyYXB5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UGVwdGlk
ZXMvdXJpbmU8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3BoYXRlcy9ibG9vZDwva2V5d29yZD48a2V5
d29yZD5SYWRpb2dyYXBoeTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+
MDAwMi05MzQzIChQcmludCkmI3hEOzAwMDItOTM0MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lv
bi1udW0+ODg3MzUwMzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0
cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvODg3MzUwMzwvdXJsPjwvcmVsYXRlZC11
cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlkPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (53) demonstrated that the response of bone pain correlated poorly with reductions in serum total ALP and urinary NTX. At baseline, all patients had total ALP values at least twice the upper limit of normal and 32/55 (58%) had pain thought to be due to PDB. Following treatment, serum total ALP and uNTX values decreased by 78% and 86% respectively, in the alendronic acid group but did not change significantly in the placebo group. Pain scores decreased by a mean (± SD) of -0.7 ± 0.5 in the placebo and -1.4 ± 0.3 in the alendronic acid group a difference that was not significant (p=0.4). A randomised trial by Siris and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXJpczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
Y051bT44NDI4PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
KDEyNik8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj44NDI4PC9yZWMt
bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iemZweGVwcHhldnYwMGdl
dHQwMXB6ZXpxdnhmOXN0ZTBlNTU5IiB0aW1lc3RhbXA9IjAiPjg0Mjg8L2tleT48L2ZvcmVpZ24t
a2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRy
aWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNpcmlzLCBFLlMuPC9hdXRob3I+PGF1dGhvcj5XZWlu
c3RlaW4sIFIuUy48L2F1dGhvcj48YXV0aG9yPkFsdG1hbiwgUi48L2F1dGhvcj48YXV0aG9yPkNv
bnRlLCBKLk0uPC9hdXRob3I+PGF1dGhvcj5GYXZ1cywgTS48L2F1dGhvcj48YXV0aG9yPkxvbWJh
cmRpLCBBLjwvYXV0aG9yPjxhdXRob3I+THlsZXMsIEsuPC9hdXRob3I+PGF1dGhvcj5NY0lsd2Fp
biwgSC48L2F1dGhvcj48YXV0aG9yPk11cnBoeSwgVy5BLiwgSnIuPC9hdXRob3I+PGF1dGhvcj5S
ZWRhLCBDLjwvYXV0aG9yPjxhdXRob3I+UnVkZSwgUi48L2F1dGhvcj48YXV0aG9yPlNldG9uLCBN
LjwvYXV0aG9yPjxhdXRob3I+VGllZ3MsIFIuPC9hdXRob3I+PGF1dGhvcj5UaG9tcHNvbiwgRC48
L2F1dGhvcj48YXV0aG9yPlR1Y2NpLCBKLlIuPC9hdXRob3I+PGF1dGhvcj5ZYXRlcywgQS5KLjwv
YXV0aG9yPjxhdXRob3I+WmltZXJpbmcsIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0
b3JzPjx0aXRsZXM+PHRpdGxlPkNvbXBhcmF0aXZlIHN0dWR5IG9mIGFsZW5kcm9uYXRlIHZlcnN1
cyBldGlkcm9uYXRlIGZvciB0aGUgdHJlYXRtZW50IG9mIFBhZ2V0JmFwb3M7cyBkaXNlYXNlIG9m
IGJvbmU8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Sm91cm5hbCBvZiBDbGluaWNhbCBFbmRvY3Jp
bm9sb2d5ICZhbXA7IE1ldGFib2xpc208L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGFnZXM+
OTYxLTk2NzwvcGFnZXM+PHZvbHVtZT44MTwvdm9sdW1lPjxudW1iZXI+MzwvbnVtYmVyPjxyZXBy
aW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdv
cmQ+NDA8L2tleXdvcmQ+PGtleXdvcmQ+NDM8L2tleXdvcmQ+PGtleXdvcmQ+YTwva2V5d29yZD48
a2V5d29yZD5BYm5vcm1hbGl0aWVzPC9rZXl3b3JkPjxrZXl3b3JkPmFjaWQ8L2tleXdvcmQ+PGtl
eXdvcmQ+QWNpZHM8L2tleXdvcmQ+PGtleXdvcmQ+QWN0aXZlPC9rZXl3b3JkPjxrZXl3b3JkPkFk
bWluaXN0cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmFsZW5kcm9uYXRlPC9rZXl3b3JkPjxrZXl3
b3JkPmFsa2FsaW5lIHBob3NwaGF0YXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFtaW5vIEFjaWQ8L2tl
eXdvcmQ+PGtleXdvcmQ+QW1pbm8gQWNpZHM8L2tleXdvcmQ+PGtleXdvcmQ+YW5hbHlzaXM8L2tl
eXdvcmQ+PGtleXdvcmQ+QmlvcHN5PC9rZXl3b3JkPjxrZXl3b3JkPmJpc3Bob3NwaG9uYXRlPC9r
ZXl3b3JkPjxrZXl3b3JkPmJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+Ym9uZSByZXNvcnB0aW9uPC9r
ZXl3b3JkPjxrZXl3b3JkPmJvbmUgdHVybm92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+Y2FsY2l1bTwv
a2V5d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5kZW94
eXB5cmlkaW5vbGluZTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3Jk
PmV0aWRyb25hdGU8L2tleXdvcmQ+PGtleXdvcmQ+RXRpZHJvbmF0ZSBEaXNvZGl1bTwva2V5d29y
ZD48a2V5d29yZD5oaXN0b21vcnBob21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPk1lZGljaW5lPC9r
ZXl3b3JkPjxrZXl3b3JkPk5ldyBZb3JrPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxr
ZXl3b3JkPm9yYWw8L2tleXdvcmQ+PGtleXdvcmQ+b3N0ZW9jbGFzdDwva2V5d29yZD48a2V5d29y
ZD5vc3Rlb2x5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPm9zdGVvbWFsYWNpYTwva2V5d29yZD48a2V5
d29yZD5QYWdldDwva2V5d29yZD48a2V5d29yZD5QYWdldCZhcG9zO3M8L2tleXdvcmQ+PGtleXdv
cmQ+UGFnZXQmYXBvcztzIGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+UGFnZXQmYXBvcztzIGRp
c2Vhc2Ugb2YgYm9uZTwva2V5d29yZD48a2V5d29yZD5wYWluPC9rZXl3b3JkPjxrZXl3b3JkPlBh
dGllbnRzPC9rZXl3b3JkPjxrZXl3b3JkPnBob3NwaGF0YXNlPC9rZXl3b3JkPjxrZXl3b3JkPnBo
b3NwaGF0ZTwva2V5d29yZD48a2V5d29yZD5QaG9zcGhhdGVzPC9rZXl3b3JkPjxrZXl3b3JkPlBo
eXNpY2lhbnM8L2tleXdvcmQ+PGtleXdvcmQ+cmVzb3JwdGlvbjwva2V5d29yZD48a2V5d29yZD5T
YWZldHk8L2tleXdvcmQ+PGtleXdvcmQ+c2VydW08L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFwZXV0
aWM8L2tleXdvcmQ+PGtleXdvcmQ+dHJlYXRtZW50PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz
Pjx5ZWFyPjE5OTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk2IE1hcjwvZGF0ZT48L3B1Yi1k
YXRlcz48L2RhdGVzPjxsYWJlbD4yMjczPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9D
aXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXJpczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl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ADDIN EN.CITE.DATA (126) compared biochemical responses with responses of bone pain in PDB patients randomised to etidronate or risedronate sodium. All patients were required to have a total ALP value at least twice the upper limit of the reference range at baseline. At 6 months, ALP had decreased by 63.4% in the risedronate sodium group and 17% in the etidronate group (p<0.001). The investigators reported that change in pain scores adjusted for analgesic use at 6 months showed no significant difference between groups (p=0.07). In another randomized comparative trial of oral risedronate sodium 30mg daily for 2 months and oral etidronate 400mg daily for 6 months ADDIN EN.CITE <EndNote><Cite><Author>Miller</Author><Year>1999</Year><RecNum>6020</RecNum><DisplayText><style face="superscript">(110)</style></DisplayText><record><rec-number>6020</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="0">6020</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Miller, P.D.</author><author>Brown, J.P</author><author>Siris, E.S.</author><author>Hoseyni, M.S.</author><author>Axelrod, D.W.</author><author>Bekker, P.J.</author></authors></contributors><titles><title>A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group</title><secondary-title>American Journal of Medicine</secondary-title></titles><pages>513-520</pages><volume>106</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>alkaline phosphatase</keyword><keyword>bisphosphonates</keyword><keyword>bone</keyword><keyword>deoxypyridinoline</keyword><keyword>Disease</keyword><keyword>Drug</keyword><keyword>drugs</keyword><keyword>etidronate</keyword><keyword>method</keyword><keyword>methods</keyword><keyword>north america</keyword><keyword>oral</keyword><keyword>Paget</keyword><keyword>Paget's</keyword><keyword>Paget's disease</keyword><keyword>Paget's disease of bone</keyword><keyword>pain</keyword><keyword>Patients</keyword><keyword>phosphatase</keyword><keyword>Remission</keyword><keyword>risedronate</keyword><keyword>serum</keyword><keyword>therapy</keyword><keyword>treatment</keyword></keywords><dates><year>1999</year><pub-dates><date>1999</date></pub-dates></dates><label>3033</label><urls><related-urls><url><style face="underline" font="default" size="100%">;(110), risedronate sodium normalised total ALP in 73% of subjects at 6 months compared with 15% with etidronate (p<0.001). In this study pain scores (assessed by SF36) at 6 months reduced by about 3 points in the etidronate group (not significant) and 10 points in the risedronate sodium group (p<0.01). The difference in pain scores between the groups (estimated by the 95% confidence intervals displayed on the graphs) was not significant.The evidence summary and recommendations with regard to the use of biochemical markers in predicting the response of bone lesions to bisphosphonate treatment in PDB is shown in Table 22.Table 22. Predicting response of bone pain to bisphosphonate treatment Risk-benefit balanceBiochemical markers of bone turnover can be easily assessed by analysis of blood or urine samples, but these markers are poorly associated with response of bone pain to osteoclast inhibitors in PDB Quality of evidenceVery lowPatient values and preferencesPatients would value a test that could accurately predict the response of bone pain to bisphosphonate therapy. Costs and use of resourcesTotal ALP is an inexpensive marker. Other specialised markers are considerably more expensive and not widely available. RecommendationMeasurement of biochemical markers of bone turnover are not recommended a means of predicting the response of bone pain to osteoclast inhibitors in PDB.Predicting the response of other outcomesThere was no evidence upon which to identify predictors of change in quality of life, progression of deafness, fractures, bone deformity or requirement for orthopedic surgery Effects of non-pharmacological treatments in Paget’s diseaseNo randomised trials were identified which investigated the effects of non-pharmacological treatments in PDB. The literature review identified several observational studies and case reports concerning the role of orthopaedic surgery in PDB. Of these we only considered series where the sample size was 10 or greater. No studies were identified which specifically investigated the role of physiotherapy, occupational therapy or other non-pharmacological interventions in the management of Paget’s disease. Surgical management of fractures No randomised trials were identified with regard to the treatment of fractures in PDB but the outcomes of surgical treatment have been reported in several observational studies, which for the most part, have been performed several decades ago.Nicholas and colleagues evaluated clinical outcome of 23 PDB patients with fractures of the femur through affected bone referred to a specialist centre for treatment ADDIN EN.CITE <EndNote><Cite><Author>Nicholas</Author><Year>1965</Year><RecNum>19002</RecNum><DisplayText><style face="superscript">(127)</style></DisplayText><record><rec-number>19002</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1516228595">19002</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nicholas, J. A.</author><author>Killoran, P.</author></authors></contributors><titles><title>Fracture of the Femur in Patients with Paget's Disease; Results of Treatment in Twenty-Three Cases</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>The Journal of bone and joint surgery American volume</full-title><abbr-1>J Bone Joint Surg Am</abbr-1></periodical><pages>450-61</pages><volume>47</volume><edition>1965/04/01</edition><keywords><keyword>*Femoral Fractures</keyword><keyword>*Femoral Neck Fractures</keyword><keyword>*Femur</keyword><keyword>*Fracture Fixation</keyword><keyword>*Fractures, Bone</keyword><keyword>*Geriatrics</keyword><keyword>Humans</keyword><keyword>*Osteitis Deformans</keyword><keyword>*Osteosarcoma</keyword><keyword>*Radiography</keyword><keyword>*Sarcoma</keyword><keyword>*Surgical Procedures, Operative</keyword><keyword>*Sarcoma, osteogenic</keyword><keyword>*Surgery, operative</keyword></keywords><dates><year>1965</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0021-9355 (Print)
0021-9355 (Linking)</isbn><accession-num>14275165</accession-num><urls><related-urls><url>;(127). Various methods of treatment were used including traction, intramedullary nails and plating. Only 11/23 (47.8%) patients were felt to have a satisfactory outcome. Verinder evaluated clinical outcome of 89 fractures through affected bone in 67 patients with PDB who were treated over a 15 year period in a single UK centre ADDIN EN.CITE <EndNote><Cite><Author>Verinder</Author><Year>1979</Year><RecNum>19004</RecNum><DisplayText><style face="superscript">(128)</style></DisplayText><record><rec-number>19004</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1516228649">19004</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Verinder, D. G.</author><author>Burke, J.</author></authors></contributors><titles><title>The management of fractures in Paget's disease of bone</title><secondary-title>Injury</secondary-title></titles><periodical><full-title>Injury</full-title><abbr-1>Injury</abbr-1></periodical><pages>276-80</pages><volume>10</volume><number>4</number><edition>1979/05/01</edition><keywords><keyword>Aged</keyword><keyword>Calcitonin/therapeutic use</keyword><keyword>Female</keyword><keyword>Femoral Fractures/complications/therapy</keyword><keyword>Femoral Neoplasms/complications</keyword><keyword>Fractures, Bone/complications/prevention & control/*therapy</keyword><keyword>Fractures, Ununited/complications</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications</keyword><keyword>Osteosarcoma/complications</keyword><keyword>Tibial Fractures/complications/therapy</keyword><keyword>Time Factors</keyword></keywords><dates><year>1979</year><pub-dates><date>May</date></pub-dates></dates><isbn>0020-1383 (Print)
0020-1383 (Linking)</isbn><accession-num>289630</accession-num><urls><related-urls><url>;(128). The femur was affected in 57/89 (64%) cases and the tibia in 22/89 (24.7%) and 10/89 (11.2%) in other sites. Various techniques were used including joint replacement, internal fixation, traction and long leg plaster. Most healed satisfactorily but non-union occurred in 8/11 (72.2%) of patients with femoral neck fractures. Grundy ADDIN EN.CITE <EndNote><Cite><Author>Grundy</Author><Year>1970</Year><RecNum>19008</RecNum><DisplayText><style face="superscript">(129)</style></DisplayText><record><rec-number>19008</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1516228760">19008</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grundy, M.</author></authors></contributors><titles><title>Fractures of the femur in Paget's disease of bone. Their etiology and treatment</title><secondary-title>J Bone Joint Surg Br</secondary-title></titles><periodical><full-title>J Bone Joint Surg Br</full-title></periodical><pages>252-63</pages><volume>52</volume><number>2</number><edition>1970/05/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Female</keyword><keyword>Femoral Fractures/*etiology</keyword><keyword>Femoral Neck Fractures/therapy</keyword><keyword>Fractures, Spontaneous/diagnostic imaging/surgery/*therapy</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications</keyword><keyword>Osteotomy</keyword><keyword>Radiography</keyword><keyword>Traction</keyword></keywords><dates><year>1970</year><pub-dates><date>May</date></pub-dates></dates><isbn>0301-620X (Print)
0301-620X (Linking)</isbn><accession-num>5445406</accession-num><urls><related-urls><url>;(129) evaluated the clinical outcome in 63 low trauma femoral fractures through affected bone in 48 patients presenting to a UK centre over a 16-year period. Various methods of management were used including traction, plating and intramedullary nails. Most fractures healed satisfactorily but non-union occurred in 11/11 (100%) of femoral neck fractures. Bradley and Nade reviewed the outcome of 107 fractures of the femur through affected bone in 93 patients with Paget’s disease over a 25-year period from a centre in New Zealand ADDIN EN.CITE <EndNote><Cite><Author>Bradley</Author><Year>1992</Year><RecNum>19006</RecNum><DisplayText><style face="superscript">(130)</style></DisplayText><record><rec-number>19006</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1516228691">19006</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bradley, C. M.</author><author>Nade, S.</author></authors></contributors><auth-address>Department of Surgery, Westmead Hospital, New South Wales, Australia.</auth-address><titles><title>Outcome after fractures of the femur in Paget's disease</title><secondary-title>Aust N Z J Surg</secondary-title></titles><periodical><full-title>The Australian and New Zealand journal of surgery</full-title><abbr-1>Aust N Z J Surg</abbr-1></periodical><pages>39-44</pages><volume>62</volume><number>1</number><edition>1992/01/01</edition><keywords><keyword>Aged</keyword><keyword>Female</keyword><keyword>Femoral Fractures/etiology/*surgery</keyword><keyword>Femoral Neck Fractures/etiology/surgery</keyword><keyword>Follow-Up Studies</keyword><keyword>Fracture Fixation, Internal</keyword><keyword>Hip Fractures/etiology/surgery</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1992</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0004-8682 (Print)
0004-8682 (Linking)</isbn><accession-num>1731736</accession-num><urls><related-urls><url>;(130). The authors categorized subjects into those in whom the surgery was successful and those in whom it was not (which they termed failure). Failure was defined to be present if there was non-union if the implant failed or if revision surgery was required. Femoral neck fractures had a high rate of failure (11/18 cases, 61.1%) as did subtrochanteric fractures (17/36; 47.2%) whereas failure was rare for fractures of the mid-shaft (1/24; 4.1%). Bidner and Finnegan ADDIN EN.CITE <EndNote><Cite><Author>Bidner</Author><Year>1989</Year><RecNum>16395</RecNum><DisplayText><style face="superscript">(131)</style></DisplayText><record><rec-number>16395</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1494851650">16395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bidner, S.</author><author>Finnegan, M.</author></authors></contributors><auth-address>Division of Orthopedic Surgery, Ottawa General Hospital, Ontario, Canada.</auth-address><titles><title>Femoral fractures in Paget's disease</title><secondary-title>J Orthop Trauma</secondary-title></titles><periodical><full-title>Journal of orthopaedic trauma</full-title><abbr-1>J Orthop Trauma</abbr-1></periodical><pages>317-22</pages><volume>3</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Calcium/blood</keyword><keyword>Female</keyword><keyword>Femoral Fractures/diagnostic imaging/*etiology/therapy</keyword><keyword>Hip Fractures/diagnostic imaging/*etiology/therapy</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/blood/*complications</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Wound Healing</keyword></keywords><dates><year>1989</year></dates><isbn>0890-5339 (Print)
0890-5339 (Linking)</isbn><accession-num>2600700</accession-num><urls><related-urls><url>;(131) reviewed the outcome of 35 femoral fractures occurring through affected bone over an 8-year period in a Canadian centre. Various methods of internal fixation were used. The authors commented that the results were generally satisfactory but that with subtrochanteric fractures, non-union occurred in 3/10 (30%) of cases.The evidence summary and recommendations with regard surgical management of fractures in PDB is shown in Table 23.Table 23. Surgical management of fractures in PDBRisk-benefit balanceThe most commonly affected sites for fracture through Pagetic bone are the femur and tibia. Surgery may be technically difficult. Healing occurs normally in many patients, but the clinical outcome in proximal femoral fractures is poor. The benefit of fracture fixation in terms of pain relief and mobilisation is likely to outweigh the risks of surgeryQuality of evidenceVery lowPatient values and preferencesPatients highly value a positive clinical outcome following fracture fixation. Costs and use of resourcesThe treatment costs for fracture fixation have not been evaluated but are likely to be similar to those in patients without PDB.RecommendationSurgery is recommended for fixation of fractures through affected bone in PDB but the clinical outcome in femoral neck and subtrochanteric fractures is poor. There is insufficient information to recommend one type of surgical treatment over another. Total Hip Replacement surgeryWe identified three case series of total hip replacements for osteoarthritis in patients with PDB. McDonald reviewed the outcome of cemented total hip replacements for osteoarthritis in 80 patients undergoing 91 hip replacements treated at a US referral centre between 1969 and 1982 ADDIN EN.CITE <EndNote><Cite><Author>McDonald</Author><Year>1987</Year><RecNum>19022</RecNum><DisplayText><style face="superscript">(132)</style></DisplayText><record><rec-number>19022</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1516229129">19022</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McDonald, D. J.</author><author>Sim, F. H.</author></authors></contributors><titles><title>Total hip arthroplasty in Paget's disease. A follow-up note</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>The Journal of bone and joint surgery American volume</full-title><abbr-1>J Bone Joint Surg Am</abbr-1></periodical><pages>766-72</pages><volume>69</volume><number>5</number><edition>1987/06/01</edition><keywords><keyword>Aged</keyword><keyword>Evaluation Studies as Topic</keyword><keyword>Female</keyword><keyword>Hip Joint/diagnostic imaging/*surgery</keyword><keyword>*Hip Prosthesis</keyword><keyword>Humans</keyword><keyword>Joint Instability/diagnosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/diagnostic imaging/*surgery</keyword><keyword>Postoperative Complications/diagnosis</keyword><keyword>Prosthesis Failure</keyword><keyword>Radiography</keyword></keywords><dates><year>1987</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0021-9355 (Print)
0021-9355 (Linking)</isbn><accession-num>3597478</accession-num><urls><related-urls><url>;(132). The femur was involved in 12 cases (13.2%), the acetabulum in 43 cases (47.3%) and both sites in 36 cases (39.6%). Heterotopic ossification was observed following surgery in 34/91 hips (37%) which the authors commented was much higher than expected in patients without PDB (4.7%). Radiographic evidence of prosthetic loosening was observed in 38/91 hips (41.7%) No association was observed between total ALP levels at the time of surgery or pre-operative drug treatment with etidronate or calcitonin and the incidence of aseptic loosening. Revision was required in 14/91 hips (15.3%). The authors compared the likelihood of requiring revision for aseptic loosening in the PDB group with a series of 7222 patients without PDB undergoing hip replacement at the same centre. There was no difference for up to 10 years but subsequently requirement for revision was greater in the PDB subjects (approximately 40% compared with 5%, p<0.001). The authors commented that the results of surgery were good or excellent in 74% of hips replaced. Wegryzn reviewed the clinical outcome of 39 cementless hip replacements in 32 patients undergoing surgery in a French centre between 1992 and 2006 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWdyenluPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWdyenluPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48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=
ADDIN EN.CITE.DATA (103). Heterotopic ossification occurred post-operatively in 22/39 hips (56%) and prosthetic loosening in 6/39 hips (15.3%). No patient had required revision surgery at the time of the review which occurred on average 133.5 months (range 97-194 months) after surgery. Overall outcome (assessed by Harris hip score) was reported to excellent in 27 patients (84%) and fair in 5 (18%).Parvizi PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJ2aXppPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJ2aXppPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48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==
ADDIN EN.CITE.DATA (133) reviewed clinical outcome in 18 patients undergoing 19 uncemented total hip replacements in a US referral centre between 1975 and 1996. In 18/19 (94%) of cases the serum total ALP was normal at the time of surgery. The outcome as assessed by Harris hip score was excellent in 16 cases (84.2%) and fair or good in 3 (15.8%). Heterotopic ossification occurred in 6 hips (31.5%) and aseptic loosening in 2 hips (10.5%). None of the patients had required revision surgery after an average follow up of 7.15 years (range 2-15). Total Knee Replacement surgeryTwo case series of total knee replacement were identified. Gabel ADDIN EN.CITE <EndNote><Cite><Author>Gabel</Author><Year>1991</Year><RecNum>18587</RecNum><DisplayText><style face="superscript">(104)</style></DisplayText><record><rec-number>18587</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513770885">18587</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gabel, G. T.</author><author>Rand, J. A.</author><author>Sim, F. H.</author></authors></contributors><auth-address>Department of Orthopedics, Mayo Clinic, Rochester, Minnesota 55905.</auth-address><titles><title>Total knee arthroplasty for osteoarthrosis in patients who have Paget disease of bone at the knee</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>The Journal of bone and joint surgery American volume</full-title><abbr-1>J Bone Joint Surg Am</abbr-1></periodical><pages>739-44</pages><volume>73</volume><number>5</number><edition>1991/06/01</edition><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Female</keyword><keyword>Femur</keyword><keyword>Humans</keyword><keyword>Intraoperative Complications</keyword><keyword>Knee Joint/diagnostic imaging/*surgery</keyword><keyword>*Knee Prosthesis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications</keyword><keyword>Osteoarthritis/complications/diagnostic imaging/*surgery</keyword><keyword>Postoperative Complications</keyword><keyword>Radiography</keyword><keyword>Range of Motion, Articular</keyword><keyword>Retrospective Studies</keyword><keyword>Tibia</keyword></keywords><dates><year>1991</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0021-9355 (Print)
0021-9355 (Linking)</isbn><accession-num>2045399</accession-num><urls><related-urls><url>;(104) reviewed the outcome of total knee replacement (TKR) in 13 patients who had 16 joint replacements referred to a single US centre between 1974-1986. Radiographic loosening was observed in two cases and one patient required revision surgery. The authors noted a functional improvement following surgery with a mean pre-operative score of 33 points compared with 86 points postoperatively. They concluded that knee replacement was an effective procedure in patients with PDB. Lee reviewed the outcome of TKR in 21 knees from 20 patients with PDB undergoing treatment at a US centre between 1978 and 1999 (87). One patient required revision surgery for aseptic loosening after an interval of 10 years. The authors reported that all patients were satisfied with the procedures and felt that it had improved their quality of life.The evidence summary and recommendations with regard to arthroplasty in the management of osteoarthritis in PDB is shown in Table 24.Table 24. Total knee and hip replacement for osteoarthritis in PDBRisk-benefit balanceTotal knee replacement (TKR) and hip replacement (THR) for osteoarthritis can be performed successfully in many patients with PDB with good results, although more data are available for THR. Heterotopic calcification occurs in a high proportion of patients undergoing THR and the risk of aseptic loosening may be slightly higher than in non-Pagetic patients. The benefit of surgery is likely to outweigh the risks in most casesQuality of evidenceVery lowPatient values and preferencesPatients highly value the symptom relief and improvement in quality of life that a hip replacement may offer.Costs and use of resourcesThe treatment costs for TKR and THR in PDB are likely to be similar to patients without PDB and this is recognised to be a cost-effective option for patients with advanced osteoarthritis RecommendationTotal hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient evidence to recommend one type of surgical approach over another for either site. OsteotomyOsteotomy is a recognised strategy for correction of bone deformity and improvement of pain in PDB. We failed to identify any studies in which osteotomy was compared with other treatment modalities and so the GDG was unable make recommendations on the role of this technique be used as opposed to other surgical approaches. Parvizi ADDIN EN.CITE <EndNote><Cite><Author>Parvizi</Author><Year>2003</Year><RecNum>18618</RecNum><DisplayText><style face="superscript">(107)</style></DisplayText><record><rec-number>18618</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513771237">18618</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parvizi, J.</author><author>Frankle, M. A.</author><author>Tiegs, R. D.</author><author>Sim, F. H.</author></authors></contributors><auth-address>Department of Orthopedics and Endocrinology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.</auth-address><titles><title>Corrective osteotomy for deformity in Paget disease</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>The Journal of bone and joint surgery American volume</full-title><abbr-1>J Bone Joint Surg Am</abbr-1></periodical><pages>697-702</pages><volume>85-A</volume><number>4</number><edition>2003/04/04</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Blood Loss, Surgical</keyword><keyword>Case-Control Studies</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Fracture Fixation/*methods</keyword><keyword>Fracture Healing/*physiology</keyword><keyword>Humans</keyword><keyword>Leg Bones/surgery</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/physiopathology/*surgery</keyword><keyword>*Osteotomy</keyword><keyword>Pain Measurement</keyword><keyword>Radius/surgery</keyword><keyword>Treatment Outcome</keyword><keyword>Wound Healing/physiology</keyword></keywords><dates><year>2003</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0021-9355 (Print)
0021-9355 (Linking)</isbn><accession-num>12672847</accession-num><urls><related-urls><url>;(107) reviewed the outcome of 25 osteotomies in 22 patients with Paget’s disease referred to a single US centre. The indication for osteotomy was pain secondary to OA in 20 limbs, stress fractures in three and deformity in two. The most common site was the tibia (n=16) followed by the femur (n=8) and radius (n=1). Healing occurred in the vast majority of procedures (23 out of 25), with an average time to union of 6 months, but this was significantly longer in metaphyseal (average 240 days, range 120-360) than diaphyseal osteotomies (average 150 days, range 60-360). Two patients had delayed union. Patient satisfaction was reported as excellent or good in 12 patients (60%), fair in 6 (30%) and poor in 2 (10%). Roper and colleagues ADDIN EN.CITE <EndNote><Cite><Author>Roper</Author><Year>1971</Year><RecNum>18558</RecNum><DisplayText><style face="superscript">(134)</style></DisplayText><record><rec-number>18558</rec-number><foreign-keys><key app="EN" db-id="zfpxeppxevv00gett01pzezqvxf9ste0e559" timestamp="1513770703">18558</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roper, B. A.</author></authors></contributors><titles><title>Paget's disease at the hip with osteoarthrosis: results of intertrochanteric osteotomy</title><secondary-title>J Bone Joint Surg Br</secondary-title></titles><periodical><full-title>J Bone Joint Surg Br</full-title></periodical><pages>660-2</pages><volume>53</volume><number>4</number><edition>1971/11/01</edition><keywords><keyword>Female</keyword><keyword>Femur/surgery</keyword><keyword>Hip/diagnostic imaging/*surgery</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteitis Deformans/*complications/diagnostic imaging/surgery</keyword><keyword>Osteoarthritis/*complications/diagnostic imaging/surgery</keyword><keyword>*Osteotomy</keyword><keyword>Radiography</keyword></keywords><dates><year>1971</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0301-620X (Print)
0301-620X (Linking)</isbn><accession-num>5131817</accession-num><urls><related-urls><url>;(134) reviewed the results of osteotomy of the intertrochanteric region of femur in 14 patients treated at a single UK centre. The indication for treatment was pain associated with OA of the hip joint in all cases. The authors reported that functional improvement had occurred in 12/13 (92.3%) patients and pain improved in 11/13 (84.6%) although details of the method of assessment of pain and function were not provided. The evidence summary and recommendations with regard to osteotomy in the management of osteoarthritis in PDB is shown in Table 25.Table 25. Osteotomy Risk-benefit balanceOsteotomy can be performed successfully with good results in many patients with PDB of the femur and tibia with good results. The benefit of surgery is likely to outweigh the risks in most casesQuality of evidenceVery lowPatient values and preferencesPatients highly value the symptom relief that osteotomy may provide in osteoarthritis.Costs and use of resourcesThe treatment costs for osteotomy are likely to be lower than those of a total joint replacement.RecommendationOsteotomy may be considered for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate, but there is insufficient evidence to make a recommendation on when this technique should be used as opposed to other surgical procedures such as arthroplasty.Spinal surgeryJorge-Mora and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3JnZS1Nb3JhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3JnZS1Nb3JhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE.DATA (106) conducted a systematic review of patients undergoing surgical treatment of the spine in Paget’s disease and identified 17 studies all of which described single case reports. The commonest indication for surgery was spinal cord compression (n=8) spinal stenosis (n=6) and low back pain. The most common procedure as laminectomy (n-12) although this was sometimes combined with other surgical procedures. Improvement (full or partial) was noted to occur in 14/17 cases.The evidence summary and recommendations with regard spine surgery in the management of PDB is shown in Table 26.Table 26. Spinal surgery in PDB Risk-benefit balanceSpine surgery can be performed successfully with good results in patients with PDB. The benefit of surgery is likely to outweigh the risks in most casesQuality of evidenceVery lowPatient values and preferencesPatients highly value the symptom relief and improvement in neurological symptoms that spine surgery may provide.Costs and use of resourcesThe treatment costs for spine surgery are considerable but in many cases the procedure may be cost effective RecommendationSpine surgery may be considered for patients with PDB who develop spinal stenosis and spinal cord compression.SummaryThis guideline is the result of a comprehensive systematic review on the diagnosis and management of PDB which considered both pharmacological and non-pharmacological treatment options. A summary of the recommendations made are shown in Table 27. Table 27. Summary of recommendationsRecommendationConditionalRecommendationInsufficient evidence Diagnosis of PDBX-raysX-rays of abdomen, skull, facial bone and tibia recommendedRadionuclide bone scansTo fully determine extent of metabolically active diseaseMRI and CTNot recommended for diagnosis May be considered to evaluate complicationsALPFirst line biochemical test for metabolically active PDB in combination with LFTPINP, BALP, NTXSecond line tests when suspicion of metabolically active disease is high and ALP is normalBisphosphonate treatmentBone painRecommended for the treatment of bone painQuality of lifeInsufficient evidence; treatment not recommendedFracture preventionInsufficient evidence; treatment not recommendedProgression of osteoarthritisInsufficient evidence; treatment not recommendedProgression of hearing lossInsufficient evidence; treatment not recommendedBlood loss during elective Orthopaedic surgeryInsufficient evidence; treatment not recommendedBone deformityInsufficient evidence; treatment not recommendedNeurological symptoms Calcitonin or bisphosphonates may be considered as part of the treatment package Asymptomatic patients with increased metabolic activityBisphosphonates may be considered, but clinical benefit unclear.Neoplastic transformationInsufficient evidence; treatment not recommendedAdverse effects of bisphosphonatesPatients can be reassured about the favourable adverse event profileTreatment strategySymptomatic or intensive bisphosphonate treatment Treatment goal should be to control bone pain rather than normalise ALPRoute of neridronate administrationIntravenous and intramuscular both recommended Other treatmentsCalcitonin for bone pain May be considered for short term treatment of bone pain Denosumab for treatment of PDB Insufficient evidence; treatment not recommendedDenosumab for giant cell tumourMay be considered for treatment of giant cell tumour which is unresectablePredicting response to treatment Predicting response of bone lesionsMeasurement of PINP recommended to predict lesion extent defined by scintigraphy following treatmentPredicting response of painMeasurement of biochemical markers is not recommended as a means of predicting response of bone painNon-pharmacological treatmentsFracture fixationSurgery is recommended for fixation of fractures through Pagetic boneHip or knee arthroplastyRecommended for patients with PDB who with OA where medical treatment is inadequateOsteotomyMay be considered or patients with PDB with OA where medical treatment is inadequateA graphical summary of the recommendations for diagnosis and assessment of PDB is shown in Figure 2 and for the management of PDB in Figure 3.Figure 2. Diagnosis and monitoring of Paget’s diseaseAbbreviations: ALP - total alkaline phosphatase, BALP - Bone Specific Alkaline Phosphatase, PINP - procollagen type I N-terminal propeptide, uNTX - urinary cross-linked N-terminal telopeptide of type I collagen.Figure 3. Management of Paget’s diseaseAlthough we have made recommendations in twelve areas and conditional recommendations in five, the GDG noted that for several outcomes of clinical importance to patients there was insufficient evidence to answer the questions posed in this guideline due to the fact that most clinical trials in PDB had been short term and focused on biochemical markers are the primary outcome, rather than patient-reported outcome measures. Accordingly, the GDG felt that further research into PDB is warranted and identified the following topics as areas where research would be warranted (Table 29)Table 29. Clinical questions to be prioritised or further research in PDBRisk and benefits of treating asymptomatic patients with PDBEffects of treatment on complications.Role of genetic profiling in the diagnosis of PDB and prediction of complicationsClinical outcome of joint replacement surgery and osteotomy in the modern eraClinical outcome following fracture fixation in the modern eraEffects of non-pharmacological treatments other than surgeryReferences ADDIN EN.REFLIST 1.Davie M, Davies M, Francis R, Fraser W, Hosking D, Tansley R. Paget's disease of bone: a review of 889 patients. Bone. 5/1999 1999;24(5 Suppl):11S-2S.2.van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C. Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res. 3/2002 2002;17(3):465-71.3.Corral-Gudino L, Borao-Cengotita-Bengoa M, Del Pino-Montes J, Ralston SH. Epidemiology of Paget's disease of bone: A systematic review and meta-analysis of secular changes. Bone. 8/2013 2013;55(2):347-52.4.Mays S. Archaeological skeletons support a northwest European origin for Paget's disease of bone. J Bone Miner Res. 8/2010 2010;25(8):1839-41.5.Meunier PJ, Coindre JM, Edouard CM, Arlot ME. Bone histomorphometry in Paget's disease. Quantitative and dynamic analysis of pagetic and nonpagetic bone tissue. Arthritis Rheum. 10/1980 1980;23(10):1095-103.6.Sofaer JA, Holloway SM, Emery AE. A family study of Paget's disease of bone. J Epidemiol Community Health. 1983 1983;37:226-31.7.Siris ES, Ottman R, Flaster E, Kelsey JL. Familial aggregation of Paget's disease of bone. J Bone Miner Res. 1991 1991;6:495-500.8.Morales-Piga AA, Rey-Rey JS, Corres-Gonzalez J, Garcia-Sagredo JM, Lopez-Abente G. Frequency and characteristics of familial aggregation of Paget's disease of bone. J Bone Miner Res. 1995 1995;10:663-70.9.Morissette J, Laurin N, Brown JP. Sequestosome 1: Mutation Frequencies, Haplotypes, and Phenotypes in Familial Paget's Disease of Bone. J Bone Miner Res. 12/2006 2006;21 Suppl 2:38-44.10.Hocking L, Slee F, Haslam SI, Cundy T, Nicholson G, van Hul W, et al. Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q. Bone. 2000;26(6):577-80.11.Laurin N, Brown JP, Morissette J, Raymond V. Recurrent Mutation of the Gene Encoding sequestosome 1 (SQSTM1/p62) in Paget Disease of Bone. Am J Hum Genet. 6/2002 2002;70(6):1582-8.12.Hocking LJ, Lucas GJA, Daroszewska A, Mangion J, Olavesen M, Nicholson GC, et al. Domain specific mutations in Sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet. 2002 2002;11(22):2735-9.13.Moscat J, Diaz-Meco MT. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 6/12/2009 2009;137(6):1001-4.14.Hocking LJ, Lucas GJA, Daroszewska A, Cundy T, Nicholson GC, Donath J, et al. Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis and structural consequences. J Bone Miner Res. 2004 2004;19(7):1122-7.15.Beyens G, Van HE, Van DK, Fransen E, Devogelaer JP, Vanhoenacker F, et al. Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease. Calcif Tissue Int. 8/2004 2004;75(2):144-52.16.Jin W, Chang M, Paul EM, Babu G, Lee AJ, Reiley W, et al. Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest. 4/1/2008 2008;118(5):1858-66.17.Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 1/2000 2000;24(1):45-8.18.Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, et al. Osteoprotegerin deficiency and juvenile Paget's disease. N Engl J Med. 7/18/2002 2002;347(3):175-84.19.Divisato G, Formicola D, Esposito T, Merlotti D, Pazzaglia L, Del FA, et al. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor. Am J Hum Genet. 2/4/2016 2016;98(2):275-86.20.Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 3/28/2013 2013;495(7442):467-73.21.Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 4/2004 2004;36(4):377-81.22.Albagha OME, Wani S, Visconti MR, Alonso N, Goodman K, Cundy T, et al. Genome-wide association identifies three new susceptibility loci for Paget's disease of bone. Nat Genet. 5/2/2011 2011;43(7):685-9.23.Bolland MJ, Tong PC, Naot D, Callon KE, Wattie DJ, Gamble GD, et al. Delayed Development of Paget's Disease in Offspring Inheriting SQSTM1 Mutations. J Bone Miner Res. 3/2007 2007;22(3):411-5.24.Cundy HR, Gamble G, Wattie D, Rutland M, Cundy T. Paget's disease of bone in New Zealand: continued decline in disease severity. Calcif Tissue Int. 11/2004 2004;75(5):358-64.25.Doyle T, Gunn J, Anderson G, Gill M, Cundy T. Paget's disease in New Zealand: evidence for declining prevalence. Bone. 11/2002 2002;31(5):616-9.26.Poor G, Donath J, Fornet B, Cooper C. Epidemiology of Paget's disease in Europe: the prevalence is decreasing. J Bone Miner Res. 10/2006 2006;21(10):1545-9.27.Corral-Gudino L, Garcia-Aparicio J, Sanchez-Gonzalez MD, Miron-Canelo JA, Blanco JF, Ralston SH, et al. Secular changes in Paget's disease: contrasting changes in the number of new referrals and in disease severity in two neighboring regions of Spain. Osteoporos Int. 2/2013 2013;24(2):443-50.28.Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D. The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J Bone Miner Res. 2/1999 1999;14(2):192-7.29.Britton C, Brown S, Ward L, Rea SL, Ratajczak T, Walsh JP. The Changing Presentation of Paget's Disease of Bone in Australia, A High Prevalence Region. Calcif Tissue Int. Dec 2017;101(6):564-9. Epub 2017/09/09.30.Mangham DC, Davie MW, Grimer RJ. Sarcoma arising in Paget's disease of bone: declining incidence and increasing age at presentation. Bone. 3/2009 2009;44(3):431-6.31.Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. Apr 1 2009;115(7):1531-43. Epub 2009/02/07.32.Siris ES. Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin Arth Rheum. 1994 1994;23(4):222-5.33.Lever JH. Paget's disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone. 9/2002 2002;31(3):434-6.34.Solomon LR. Billiard-player's fingers: an unusual case of Paget's disease of bone. British Medical Journal. 4/7/1979 1979;1(6168):931.35.Hamdy R. Trauma and Paget's disease of bone. Br Med J. Jun 02 1979;1(6176):1487. Epub 1979/06/02.36.Rebel A, Malkani K, Basle M, Bregeon C, Patezour A, Filmon R. Ultrastructural characteristics of osteoclasts in Paget's disease. Rev Rhum Mal Osteoartic. 12/1974 1974;41(12):767-71.37.Mills BG, Singer FR, Weiner LP, Suffin SC, Stabile E, Holst P. Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget's disease of bone. Clin Orthop Rel Res. 1984 1984;183:303-11.38.O'Driscoll JB, Anderson DC. Past pets and Paget's disease. Lancet. 1985 1985;2:919-21.39.Teramachi J, Nagata Y, Mohammad K, Inagaki Y, Ohata Y, Guise T, et al. Measles virus nucleocapsid protein increases osteoblast differentiation in Paget's disease. J Clin Invest. 3/1/2016 2016;126(3):1012-22.40.Matthews BG, Afzal MA, Minor PD, Bava U, Callon KE, Pitto RP, et al. Failure to detect measles virus RNA in bone cells from patients with Paget's disease. J Clin Endocrinol Metab. 1/29/2008 2008;93:1398-401.41.Matthews D, Fry L, Powles A, Weissenbach J, Williamson R. Confirmation of genetic heterogeneity in familial psoriasis. J Med Genet. Jul 1995;32(7):546-8.42.Ralston SH, Afzal MA, Helfrich MH, Fraser WD, Gallagher JA, Mee A, et al. Multicenter blinded analysis of RT-PCR detection methods for paramyxoviruses in relation to Paget's disease of bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007;22(4):569-77.43.Helfrich MH, Hobson RP, Grabowski PS, Zurbriggen A, Cosby SL, Dickson GR, et al. A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies in UK patients. J Bone Miner Res. 12/2000 2000;15(12):2315-29.44.Gordon MT, Mee AP, Anderson DC, Sharpe PT. Canine distemper transcripts sequenced from pagetic bone. Bone Miner. 1992 1992;19:159-74.45.Reddy SV, Singer FR, Mallette L, Roodman GD. Detection of measles virus nucleocapsid transcripts in circulating blood cells from patients with Paget disease. J Bone Miner Res. 1996 1996;11:1602-7.46.Ooi CG, Walsh CA, Gallagher JA, Fraser WD. Absence of measles virus and canine distemper virus transcripts in long- term bone marrow cultures from patients with Paget's disease of bone. Bone. 9/2000 2000;27(3):417-21.47.Birch MA, Taylor W, Fraser WD, Ralston SH, Hart CA, Gallagher JA. Absence of paramyxovirus RNA in cultures of pagetic bone cells and in pagetic bone. J Bone Miner Res. 1/1994 1994;9(1):11-6.48.Visconti MR, Usategui-Martin R, Ralston SH. Antibody Response to Paramyxoviruses in Paget's Disease of Bone. Calcif Tissue Int. Mar 31 2017. Epub 2017/04/01.49.Helfrich MH, Hocking LJ. Genetics and aetiology of Pagetic disorders of Bone. Archives Biochem Biophys. 2014 2014;473:172-82.50.Douglas DL, Duckworth T, Kanis JA, Jefferson AA, Martin TJ, Russell RG. Spinal cord dysfunction in Paget's disease of bone. Has medical treatment a vascular basis? J Bone Joint Surg Br. 1981;63B(4):495-503. Epub 1981/01/01.51.Tuck SP, Layfield,R., Walker,J.,Mekkayil,B., Francis,R. Adult Paget’s disease of Bone: a review. Rheumatology (Oxford). Review 2017;56(12):2050-9.52.Tan A, Ralston SH. Clinical Presentation of Paget's Disease: Evaluation of a Contemporary Cohort and Systematic Review. Calcif Tissue Int. 8/27/2014 2014;95(5):385-92.53.Reid IR, Nicholson GC, Weinstein RS, Hosking DJ, Cundy T, Kotowicz MA, et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med. Oct 1996;101(4):341-8.54.Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby PL, Ralston SH. Randomised Trial of Intensive Bisphosphonate Treatment Versus Symptomatic Management in Paget's Disease of Bone. J Bone Miner Res. 2/1/2010 2010;25:20-31.55.Ruggieri P, Calabro T, Montalti M, Mercuri M. The role of surgery and adjuvants to survival in Pagetic osteosarcoma. Clin Orthop Relat Res. Nov 2010;468(11):2962-8. Epub 2010/07/24.56.Rendina D, De Filippo G, Ralston SH, Merlotti D, Gianfrancesco F, Esposito T, et al. Clinical characteristics and evolution of giant cell tumor occurring in Paget's disease of bone. J Bone Miner Res. Feb 2015;30(2):257-63. Epub 2014/09/10.57.Divisato G, Formicola D, Esposito T, Merlotti D, Pazzaglia L, Del Fattore A, et al. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor. Am J Hum Genet. Feb 4 2016;98(2):275-86. Epub 2016/02/06.58.Selby PL, Davie MW, Ralston SH, Stone MD. Guidelines on the management of Paget's disease of bone. Bone. 9/2002 2002;31(3):366-73.59.Takata S, Hashimoto J, Nakatsuka K, Yoshimura N, Yoh K, Ohno I, et al. Guidelines for diagnosis and management of Paget's disease of bone in Japan. J Bone Miner Metab. 2006 2006;24(5):359-67.60.Singer FR, Bone HG, 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, et al. Paget's disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. Dec 2014;99(12):4408-22.61.Ralston SH. Clinical practice. Paget's disease of bone. N Engl J Med. 2/14/2013 2013;368(7):644-50.62.Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. Jun 30 2016;353:i2089. Epub 2016/07/02.63.Alonso-Coello P, Schunemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. Jun 28 2016;353:i2016. Epub 2016/06/30.64.Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ. 6/19/2004 2004;328(7454):1490.65.Hsu J, Brozek JL, Terracciano L, Kreis J, Compalati E, Stein AT, et al. Application of GRADE: making evidence-based recommendations about diagnostic tests in clinical practice guidelines. Implement Sci. Jun 10 2011;6:62. Epub 2011/06/15.66.Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH. Bisphosphonates for Paget's disease of bone in adults. Cochrane Database Syst Rev. Dec 1 2017;12:CD004956. Epub 2017/12/02.67.Brouwers MC, Kerkvliet K, Spithoff K, Consortium ANS. The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines. BMJ. Mar 8 2016;352:i1152. Epub 2016/03/10.68.Eekhoff ME, van der KM, Kroon HM, Cooper C, Hofman A, Pols HA, et al. Paget's disease of bone in The Netherlands: a population-based radiological and biochemical survey--the Rotterdam Study. J Bone Miner Res. 4/2004 2004;19(4):566-70.69.Mirra JM, Brien EW, Tehranzadeh J. Paget's disease of bone: review with emphasis on radiologic features, Part II. Skeletal Radiol. Apr 1995;24(3):173-84. Epub 1995/04/01.70.Guanabens N, Rotes D, Holgado S, Gobbo M, Descalzo MA, Gorordo JM, et al. Implications of a new radiological approach for the assessment of Paget disease. Calcif Tissue Int. Dec 2012;91(6):409-15. Epub 2012/10/12.71.Shirazi PH, Ryan WG, Fordham EW. Bone scanning in evaluation of Paget's disease of bone. CRC Crit Rev Clin Radiol Nucl Med. Oct 1974;5(4):523-58. Epub 1974/10/01.72.Kim CK, Estrada WN, Lorberboym M, Pandit N, Religioso DG, Alavi A. The 'mouse face' appearance of the vertebrae in Paget's disease. Clinical nuclear medicine. Feb 1997;22(2):104-8. Epub 1997/02/01.73.Rotes-Sala D, Monfort J, Solano A, Miralles E, Vila J, Carbonell J. The clover and heart signs in vertebral scintigraphic images are highly specific of Paget's disease of bone. Bone. Apr 2004;34(4):605-8. Epub 2004/03/31.74.Reyes R, Peris P, Monegal A, Fuster D, Guanabens N. Vertebral "clover" scintigraphic image in a vertebral metastasis misdiagnosed with Paget's disease. Clin Rheumatol. Dec 2008;27(12):1585-6. Epub 2008/09/04.75.Wellman HN, Schauwecker D, Robb JA, Khairi MR, Johnston CC. Skeletal scintimaging and radiography in the diagnosis and management of Paget's disease. Clin Orthop Relat Res. 1977(127):55-62. Epub 1977/01/01.76.Meunier PJ, Salson C, Mathieu L, Chapuy MC, Delmas P, Alexandre C, et al. Skeletal distribution and biochemical parameters of Paget's disease. Clin Orthop Relat Res. Apr 1987(217):37-44. Epub 1987/04/01.77.Fogelman I, Carr D. A comparison of bone scanning and radiology in the assessment of patients with symptomatic Paget's disease. Eur J Nucl Med. Oct 1980;5(5):417-21. Epub 1980/10/01.78.Roberts MC, Kressel HY, Fallon MD, Zlatkin MB, Dalinka MK. Paget disease: MR imaging findings. Radiology. Nov 1989;173(2):341-5. Epub 1989/11/01.79.Tehranzadeh J, Fung Y, Donohue M, Anavim A, Pribram HW. Computed tomography of Paget disease of the skull versus fibrous dysplasia. Skeletal Radiol. Dec 1998;27(12):664-72. Epub 1999/01/28.80.Eekhoff ME, van der Klift M, Kroon HM, Cooper C, Hofman A, Pols HA, et al. Paget's disease of bone in The Netherlands: a population-based radiological and biochemical survey--the Rotterdam Study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. Apr 2004;19(4):566-70. Epub 2004/03/10.81.Alvarez L, Peris P, Pons F, Guanabens N, Herranz R, Monegal A, et al. Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget's disease activity. Arthritis Rheum. Mar 1997;40(3):461-8. Epub 1997/03/01.82.Woitge HW, Pecherstorfer M, Li Y, Keck AV, Horn E, Ziegler R, et al. Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res. May 1999;14(5):792-801. Epub 1999/05/13.83.Al Nofal AA, Altayar O, BenKhadra K, Qasim Agha OQ, Asi N, Nabhan M, et al. Bone turnover markers in Paget's disease of the bone: A Systematic review and meta-analysis. Osteoporos Int. Jul 2015;26(7):1875-91. Epub 2015/06/04.84.Langston AL, Campbell MK, Fraser WD, Maclennan G, Selby P, Ralston SH. Clinical Determinants of Quality of Life in Paget's Disease of Bone. Calcif Tissue Int. 1/2007 2007;80(1):1-9.85.Condon JR. Glucagon in the treatment of Paget's disease of bone. Br Med J. Dec 18 1971;4(5789):719-21. Epub 1971/12/18.86.Heath DA. The role of mithramycin in the management of Paget's disease. Metab Bone Dis Relat Res. 1981;3(4-5):343-5. Epub 1981/01/01.87.Fennelly JJ, Groarke JF. Effect of actinomycin D on Paget's disease of bone. Br Med J. Feb 20 1971;1(5746):423-6. Epub 1971/02/20.88.Bockman RS, Wilhelm F, Siris ES, Singer F, Chausmer A, Bitton R, et al. A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone. Journal of Clinical Endocrinology & Metabolism. 1995 Feb 1995;80(2):595-602.89.Reid IR, Sharma S, Kalluru R, Eagleton C. Treatment of Paget's Disease of Bone with Denosumab: Case Report and Literature Review. Calcif Tissue Int. Sep 2016;99(3):322-5. Epub 2016/05/20.90.Kanis JA, Fitzpatrick K, Strong JA. Treatment of Paget's disease of bone with porcine calcitonin: clinical and metabolic responses. Q J Med. Jul 1975;44(175):399-413. Epub 1975/07/01.91.Ralston SH, Boyce BF, Cowan RA, Fogelman I, Smith ML, Jenkins AS, et al. The effect of one alpha hydroxyvitamin D3 on the mineralisation defect in disodium etidronate treated Paget's disease - a double-blind randomised study. Journal of Bone and Mineral Research. 1987 1987;2:5-12.92.Altman RD, Johnston CC, Khairi MR, Wellman H, Serafini AN, Sankey RR. Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans). N Engl J Med. 1973 Dec 27 1973;289(26):1379-84.93.Canfield R, Rosner W, Skinner J, McWhorter J, Resnick L, Feldman F, et al. Diphosphonate therapy of paget's disease of bone. Journal of Clinical Endocrinology & Metabolism. 1977 Jan 1977;44(1):96-106.94.Fraser WD, Stamp TC, Creek RA, Sawyer JP, Picot C. A double-blind, multicentre, placebo-controlled study of tiludronate in Paget's disease of bone. Postgrad Med J. 1997 Aug 1997;73(862):496-502.95.McClung MR, Tou CK, Goldstein NH, Picot C. Tiludronate therapy for Paget's disease of bone [published erratum appears in Bone 1996 Mar;18(3):292]. Bone. 1995 Nov 1995;17(5 Suppl):493S-6S.96.Reginster JY, Colson F, Morlock G, Combe B, Ethgen D, Geusens P. Evaluation of the efficacy and safety of oral tiludronate in Paget's disease of bone. A double-blind, multiple-dosage, placebo-controlled study. Arthritis & Rheumatism. 8/1992 1992;35(8):967-74.97.Merlotti D, Gennari L, Martini G, Valleggi F, De Paola V, Avanzati A, et al. Comparison of different intravenous bisphosphonate regimens for Paget's disease of bone. J Bone Miner Res. Oct 2007;22(10):1510-7.98.Walsh JP, Ward LC, Stewart GO, Will RK, Criddle RA, Prince RL, et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone. Bone. 4/2004 2004;34(4):747-54.99.Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med. 9/1/2005 2005;353(9):898-908.100.Reid IR, Lyles K, Su G, Brown JP, Walsh JP, del Pino-Montes J, et al. A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res. Sep 2011;26(9):2261-70.101.Monsell EM, Bone HG, Cody DD, Jacobson GP, Newman CW, Patel SC, et al. Hearing loss in Paget's disease of bone: evidence of auditory nerve integrity. American Journal of Otology. 1995 Jan 1995;16(1):27-33.102.Donath J, Krasznai M, Fornet B, Gergely P, Jr., Poor G. Effect of bisphosphonate treatment in patients with Paget's disease of the skull. Rheumatology (Oxford). 1/2004 2004;43(1):89-94.103.Wegrzyn J, Pibarot V, Chapurlat R, Carret JP, Bejui-Hugues J, Guyen O. Cementless total hip arthroplasty in Paget's disease of bone: a retrospective review. Int Orthop. Dec 2010;34(8):1103-9.104.Gabel GT, Rand JA, Sim FH. Total knee arthroplasty for osteoarthrosis in patients who have Paget disease of bone at the knee. J Bone Joint Surg Am. Jun 1991;73(5):739-44. Epub 1991/06/01.105.Lee GC, Sanchez-Sotelo J, Berry DJ. Total knee arthroplasty in patients with Paget's disease of bone at the knee. J Arthroplasty. Sep 2005;20(6):689-93. Epub 2005/09/06.106.Jorge-Mora A, Amhaz-Escanlar S, Lois-Iglesias A, Leborans-Eiris S, Pino-Minguez J. Surgical treatment in spine Paget's disease: a systematic review. Eur J Orthop Surg Traumatol. Jan 2016;26(1):27-30. Epub 2015/07/02.107.Parvizi J, Frankle MA, Tiegs RD, Sim FH. Corrective osteotomy for deformity in Paget disease. J Bone Joint Surg Am. Apr 2003;85-A(4):697-702. Epub 2003/04/04.108.Bickerstaff DR, Douglas DL, Burke PH, O'Doherty DP, Kanis JA. Improvement in the deformity of the face in Paget's disease treated with diphosphonates. J Bone Joint Surg Br. Jan 1990;72(1):132-6. Epub 1990/01/01.109.Chen JR, Rhee RS, Wallach S, Avramides A, Flores A. Neurologic disturbances in Paget disease of bone: response to calcitonin. Neurology. Apr 1979;29(4):448-57. Epub 1979/04/01.110.Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group. American Journal of Medicine. 1999 1999;106:513-20.111.Gutteridge DH, Retallack RW, Ward LC, Stuckey BG, Stewart GO, Prince, et al. Clinical, biochemical, hematologic, and radiographic responses in Paget's disease following intravenous pamidronate disodium: a 2-year study. Bone. 1996 Oct 1996;19(4):387-94.112.Tan A, Goodman K, Walker A, Hudson J, MacLennan GS, Selby PL, et al. Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study. J Bone Miner Res. Jun 2017;32(6):1165-73. Epub 2017/02/09.113.Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab. 9/2010 2010;95(9):4380-7.114.Merlotti D, Rendina D, Gennari L, Mossetti G, Gianfrancesco F, Martini G, et al. Comparison of intravenous and intramuscular neridronate regimens for the treatment of Paget disease of bone. J Bone Miner Res. Mar 2011;26(3):512-8.115.Tan A, Goodman K, Walker A, Hudson J, MacLennan GS, Selby PL, et al. Long-Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM-EZ Study. J Bone Miner Res. Feb 08 2017.116.Martin TJ, Jerums G, Melick RA, Xipell JM, Arnott R. Clinical, biochemical and histological observations on the effect of porcine calcitonin in Paget's disease of bone. Aust N Z J Med. Feb 1977;7(1):36-43. Epub 1977/02/01.117.O'Donoghue DJ, Hosking DJ. Biochemical response to combination of disodium etidronate with calcitonin in Paget's disease. Bone. 1987;8(4):219-25.118.Schwarz P, Rasmussen AQ, Kvist TM, Andersen UB, Jorgensen NR. Paget's disease of the bone after treatment with Denosumab: a case report. Bone. May 2012;50(5):1023-5. Epub 2012/05/16.119.Ueda T, Morioka H, Nishida Y, Kakunaga S, Tsuchiya H, Matsumoto Y, et al. Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial. Ann Oncol. Oct 2015;26(10):2149-54. Epub 2015/07/25.120.Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. Aug 2013;14(9):901-8. Epub 2013/07/23.121.Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 3/2010 2010;11(3):275-80.122.Cosso R, Nuzzo V, Zuccoli A, Brandi ML, Falchetti A. Giant cell tumor in a case of Paget's disease of bone: an aggressive benign tumor exhibiting a quick response to an innovative therapeutic agent. Clin Cases Miner Bone Metab. May 2010;7(2):145-52. Epub 2010/05/01.123.Verma V, Puri A, Shah S, Rekhi B, Gulia A. Giant Cell Tumor Developing in Paget's Disease of Bone: A Case Report with Review of Literature. J Orthop Case Rep. Sep-Oct 2016;6(4):103-7. Epub 2017/02/07.124.Tanaka T, Slavin J, McLachlan SA, Choong P. Anti-osteoclastic agent, denosumab, for a giant cell tumor of the bone with concurrent Paget's disease: A case report. Oncol Lett. Apr 2017;13(4):2105-8. Epub 2017/04/30.125.Boudreau RJ, Lisbona R, Hadjipavlou A. Observations on serial radionuclide blood-flow studies in Paget's disease: concise communication. J Nucl Med. Oct 1983;24(10):880-5. Epub 1983/10/01.126.Siris ES, Weinstein RS, Altman R, Conte JM, Favus M, Lombardi A, et al. Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. Journal of Clinical Endocrinology & Metabolism. 1996 Mar 1996;81(3):961-7.127.Nicholas JA, Killoran P. Fracture of the Femur in Patients with Paget's Disease; Results of Treatment in Twenty-Three Cases. J Bone Joint Surg Am. Apr 1965;47:450-61. Epub 1965/04/01.128.Verinder DG, Burke J. The management of fractures in Paget's disease of bone. Injury. May 1979;10(4):276-80. Epub 1979/05/01.129.Grundy M. Fractures of the femur in Paget's disease of bone. Their etiology and treatment. J Bone Joint Surg Br. May 1970;52(2):252-63. Epub 1970/05/01.130.Bradley CM, Nade S. Outcome after fractures of the femur in Paget's disease. Aust N Z J Surg. Jan 1992;62(1):39-44. Epub 1992/01/01.131.Bidner S, Finnegan M. Femoral fractures in Paget's disease. J Orthop Trauma. 1989;3(4):317-22.132.McDonald DJ, Sim FH. Total hip arthroplasty in Paget's disease. A follow-up note. J Bone Joint Surg Am. Jun 1987;69(5):766-72. Epub 1987/06/01.133.Parvizi J, Schall DM, Lewallen DG, Sim FH. Outcome of uncemented hip arthroplasty components in patients with Paget's disease. Clin Orthop Relat Res. Oct 2002(403):127-34. Epub 2002/10/03.134.Roper BA. Paget's disease at the hip with osteoarthrosis: results of intertrochanteric osteotomy. J Bone Joint Surg Br. Nov 1971;53(4):660-2. Epub 1971/11/01.AcknowledgementsDevelopment of the guideline was supported by unrestricted educational grants from the International Osteoporosis Foundation, the European Calcified Tissues Society and the Paget’s Association. Development of the guideline was also supported in part by a grant to SHR from the European Commission (Paget Advance 787720). The authors wish to acknowledge the assistance of Cara Steiger (International Medical Press) who assisted with the literature search and screening of papers for the literature review and representatives of the Professional Practice Committee of the ASBMR for critical review of the guideline when it was in in draft form. Conflicts of interest. Dr. Zillikens reports personal fees from Amgen, Eli Lilly, Shire, and Kyowa Kirin, outside the submitted work; Professor Guanabens reports personal fees from Amgen, UCB, Eli Lilly and Alexion outside the submitted work. Dr. Javaid reports personal fees from Amgen outside the submitted work. Mr. Simpson, Professor Russell, Dr. Tuck, and Professor Francis, report that they are trustees of the Paget’s Association. Ms. Wilkinson reports that she is an employee of the Paget’s Association. Professor Cooper reports that he is President of the International Osteoporosis Foundation. Dr. Wills reports that she is an employee of International Medical Press. Professor Ralston reports receiving research grants to his institution from Eli Lilly, Amgen, UCB outside the submitted work and having received consultancy fees on behalf of his institution from Novartis, outside the submitted work. The other authors report no conflicts of interestAuthor contributionsLiterature reviewThe literature review was performed by RW, with additional contributions from SHR, LCG and SPT. Writing groupThe first complete draft of the guideline was written by SHR. The first draft of Section 1 was written by LCG and SHR; Section 2 by SHR and LCG; Section 3 by RL and SHR, Section 4 by NG and MKJ, Section 5 by SHR and LCG, Section 6 by SHR, LCG and TON; Section 7 by SHR, Section 8 by RL and SHR; and section 9 by ST, RMF, DW and SHR. The infographic summaries were prepared by LCG. All members of the writing group contributed to revising the draft guideline for intellectual content. All authors approved the final version of the guideline. ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.