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Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group.Janet E Brown *a, Catherine Handforth* a, Juliet E Compstonb, William Cross c, Nigel Parr d, Peter Selby e, Steven Wood a, Claire Ward f, Lawrence Drudge-Coates g, Jennifer S Walsh h, Caroline Mitchell j, Fiona J Collinson k, Robert E Coleman a, Nicholas James l, Roger M Francis m, David Reid n, Eugene McCloskey h.*Joint first authora Academic unit of Clinical Oncology, University of Sheffieldb Department of Medicine, Cambridge Biomedical Campusc Department of Urology, Leeds Teaching Hospitals NHS Trustd Department of Urology, Wirral University Hospitals NHS Foundation Truste Metabolic bone disease, University of Manchesterf Department of Urology, Sheffield Teaching Hospitals Foundation NHS trustg Department of Urology, Kings College Hospital NHS Foundation Trusth Academic Unit of Bone Metabolism, University of Sheffieldj Academic Unit of Primary Medical Care, University of Sheffieldk Leeds Institute of Clinical Trials Research, University of Leedsl Institute of cancer and genomic sciences, University of Birminghamm Institute of cellular medicine, University of Newcastlen Institute of Medical Sciences, University of AberdeenCorresponding Author: Professor Janet E BrownAcademic unit of Clinical Oncology, Broomcross buildingWeston Park Hospital, Whitham Rd, Sheffield S10 2SJ. Tel 0114 226 5202Email: j.e.brown@sheffield.ac.ukConflict of interestLawrence Drudge-Coates has received honoraria from Amgen, AstraZeneca, Ipsen, Ferring, AstellasKeywords: Prostate cancer; skeletal health; osteoporosis; fracture riskWord count: 5,296Take home message: Bone health assessment should be prioritised when men with prostate cancer start long-term ADT. Assessment of bone mineral density and fracture risk identifies those at risk, allows rapid initiation of treatment, and avoids skeletal complications with resulting morbidity and mortality. Abstract Background and objectiveThe incidence of prostate cancer (PC) is increasing alongside the ageing global population, and androgen deprivation therapy (ADT) and other therapies are increasing survival. Consideration of bone health is vital, to reduce the likelihood of fragility fractures and their associated morbidity and mortality. This guidance aims to summarise the evidence for assessment and management of bone health in this population, with specific recommendations for clinical practice.MethodsA systematic literature review was followed by a meeting of key opinion leaders. Input and endorsement was also sought from patient and nursing representatives, and specialist societies. Summary of guidanceADT is associated with significant loss of bone mineral density (BMD). Chemotherapy and abiraterone are used alongside ADT in the metastatic setting, and require significant doses of concomitant corticosteroids. Both ADT and corticosteroids pose a significant challenge to skeletal health, in a population of patients who are likely to have ongoing bone loss related to age and/or comorbid conditions. Current PC guidelines lack specific recommendations regarding supplementation with calcium and vitamin D, the role of fracture assessment and reassessment, intervention thresholds and selection of therapy. All men starting long-term ADT (with our without metastatic bone disease) should receive lifestyle advice regarding their bone health. Calcium and vitamin D intake should be assessed with supplementation if required. All men should have their BMD measured and fracture risk calculated (FRAX) with the need for intervention checked against National Osteoporosis Guideline Group thresholds. Those below the intervention threshold should have BMD and FRAX repeated after 12-18 months. Those above the intervention threshold should be further assessed, with referral to a specialist centre if available, and offered appropriate pharmacological treatment. IntroductionBone health is emerging as one of the most important considerations for men receiving treatment for prostate cancer (PC). Projected to be the commonest cancer by 2030 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/bjc.2011.430","ISSN":"1532-1827","PMID":"22033277","abstract":"BACKGROUND: Projections of cancer incidence are important for planning health services and to provide a baseline for assessing the impact of public health interventions.\n\nMETHODS: Rates estimated from smooth function age-period-cohort modelling of cancer incidence data from Great Britain 1975 to 2007 are extrapolated to 2030 and applied to UK population projections. Prostate and breast cancer projections take into account the effect of screening.\n\nRESULTS: Overall rates of cancer are projected to be stable over the next 20 years, but this masks individual changes. In both sexes, age-standardised rates of cancers of the stomach, larynx, bladder and leukaemia are projected to fall by ≥1% per year, whereas cancers of the lip, mouth and pharynx (ICD-10 C00-C14) and melanoma are projected to increase by ≥1% per year. The growing and aging populations will have a substantial impact: numbers of cancers in men and women are projected to increase by 55% (from 149,169 to 231,026) and 35% (from 148,716 to 200,929), respectively, between 2007 and 2030. The model used yields similar results to those of Nordpred, but is more flexible.\n\nCONCLUSION: Without new initiatives for smoking and obesity reduction, the number of cancers in the United Kingdom will increase substantially reflecting the growing and aging populations.","author":[{"dropping-particle":"","family":"Mistry","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkin","given":"D M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahmad","given":"a S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sasieni","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British journal of cancer","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2011","11","22"]]},"page":"1795-803","publisher":"Nature Publishing Group","title":"Cancer incidence in the United Kingdom: projections to the year 2030.","type":"article-journal","volume":"105"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1, 1 in 8 men will receive a diagnosis of PC in their lifetime. There are more than 400,000 new cases of PC in Europe each year, and the majority of these occur in men aged over 70 years ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","abstract":"Prostate cancer survival statistics (UK)","accessed":{"date-parts":[["2016","4","15"]]},"author":[{"dropping-particle":"","family":"CRUK","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Cancer statistics","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"²","plainTextFormattedCitation":"2","previouslyFormattedCitation":"²"},"properties":{"noteIndex":0},"schema":""}2. Despite the fact that PC is the second leading cause of cancer-related mortality in men ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2016","5","5"]]},"author":[{"dropping-particle":"","family":"CRUK","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Cancer research UK mortality statistics","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"³","plainTextFormattedCitation":"3","previouslyFormattedCitation":"³"},"properties":{"noteIndex":0},"schema":""}3, survival rates have improved considerably over the past four decades as a result of both earlier diagnosis and newer therapies (current 5- year survival is 85% in all patients, compared with 71% in 1980) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","abstract":"Prostate cancer survival statistics (UK)","accessed":{"date-parts":[["2016","4","15"]]},"author":[{"dropping-particle":"","family":"CRUK","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Cancer statistics","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"²","plainTextFormattedCitation":"2","previouslyFormattedCitation":"²"},"properties":{"noteIndex":0},"schema":""}2. Many patients with PC now live with their disease for many years, and consideration of the long-term consequences of treatment is increasingly important. Men with PC are not routinely referred to bone specialists for optimisation of their bone health, despite the fact that cancer treatment induced bone loss (CTIBL) and the resulting increased risk of fragility fractures (many of which require hospitalisation) is a significant issue ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ejca.2012.01.035","ISBN":"0959-8049","ISSN":"09598049","PMID":"22386317","abstract":"Background: Prostate cancer patients have an increased risk of fractures as a consequence of skeletal metastases and osteoporosis induced by endocrine treatment. Data on incidence of fractures and risks in subgroups of men with prostate cancer are sparse. Our aim with this study is to report the risk of fractures among men with prostate cancer in a nationwide population-based study. Patients and methods: We identified 76,600 Swedish men diagnosed with prostate cancer 1997-2006 in the Prostate Cancer Data Base (PCBaSe) Sweden and compared the occurrence of fractures requiring hospitalisation with the Swedish male population. Results: Only men treated with gonadotropin releasing-hormone (GnRH) agonists or orchiectomy had increased incidence and increased relative risk of fractures requiring hospitalisation. Men treated with GnRH agonists had 9.8 and 6.3/1000 person-years higher incidence of any fracture and hip fracture requiring hospitalisation than the general population. The corresponding increases in incidence for men treated with orchiectomy were 16 and 12/1000 person-years, respectively. Men treated with orchiectomy, GnRH agonists, and antiandrogen monotherapy, had SIR for hip fracture of 2.0 (95% Confidence Interval 1.8-2.2), 1.6 (95% CI 1.5-1.8) and 0.9 (95% CI 0.7-1.1), respectively. Men treated with a curative intent (radical prostatectomy or radiotherapy) or managed with surveillance had no increased risk of fractures. Older men had the highest incidence of fractures while younger men had the highest relative risk. Conclusion: Prostate cancer patients treated with GnRH agonists or orchiectomy have significantly increased risk of fractures requiring hospitalisation while patients treated with antiandrogen monotherapy had no increase in such fractures. In absolute terms the excess risk in men treated with GnRH agonists corresponded to almost 10 extra fractures leading to hospitalisation per 1000 patient-years. Effects on bone density should be considered for men on long-term endocrine treatment. Unwarranted use of orchiectomy and GnRH agonists should be avoided. ? 2011 Elsevier Ltd. All rights reserved.","author":[{"dropping-particle":"","family":"Thorstenson","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bratt","given":"Ola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akre","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hellborg","given":"Henrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmberg","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lambe","given":"Mats","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bill-Axelson","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stattin","given":"P?r","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adolfsson","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Cancer","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2012"]]},"page":"1672-1681","title":"Incidence of fractures causing hospitalisation in prostate cancer patients: Results from the population-based PCBaSe Sweden","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴","plainTextFormattedCitation":"4","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}4. Although pathological fractures may occur in men with metastatic bone involvement, fragility fractures outweigh these by approximately 8:1 in all patients?with?PC ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/01.ju.0000059281.67667.97","ISBN":"0022-5347","ISSN":"00225347","PMID":"12686824","abstract":"PURPOSE: Bone loss has been reported in patients with prostate cancer treated with androgen deprivation therapy. We assess fracture risk following bilateral orchiectomy.\\n\\nMATERIALS AND METHODS: Through the Rochester Epidemiology Project we identified 429 Olmsted County, Minnesota men who underwent bilateral orchiectomy in 1956 to 2000, almost all for prostate cancer. Fractures were ascertained from comprehensive medical records and compared with expected numbers based on local incidence rates (standardized incidence ratio, SIR). Potential risk factors were assessed with proportional hazards models.\\n\\nRESULTS: During 1961 person-years of followup 161 men experienced 267 fractures, for a cumulative incidence after 15 years of 40% compared to 19% expected (p <0.001). However, 42 were pathological fractures and 82 were found incidentally on radiological surveys for metastasis. Overall fracture risk was increased (SIR 3.42, 95% CI 2.91-3.99) but was reduced by excluding the pathological and incidental fractures (SIR 2.04, 95% CI 1.66-2.47). The increase was largely accounted for by the moderate trauma fractures of the hip, spine and distal forearm traditionally linked with osteoporosis (SIR 3.50, 95% CI 2.71-4.43). In multivariate analyses risk factors for fractures generally included patient age, inactivity, prior radiological diagnosis of osteoporosis, chemotherapy and use of nonsteroidal antiandrogens, while independent risk factors for the traditional osteoporotic fractures included age, inactivity and diagnosis of osteoporosis.\\n\\nCONCLUSIONS: Fractures are common in men with prostate cancer due to advanced age, occurrence of pathological fractures and enhanced skeletal surveillance but there remains a significant increase in osteoporotic fracture risk following bilateral orchiectomy.","author":[{"dropping-particle":"","family":"Melton","given":"L. Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alothman","given":"Khalid I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khosla","given":"Sundeep","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Achenbach","given":"Sara J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oberg","given":"Ann L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zincke","given":"Horst","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2003"]]},"page":"1747-1750","title":"Fracture risk following bilateral orchiectomy","type":"article-journal","volume":"169"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵","plainTextFormattedCitation":"5","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}5,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0008-543X","PMID":"9028366","abstract":"BACKGROUND Luteinizing hormone-releasing hormone agonists (LHRH-a) have become an established treatment for certain patients with prostate carcinoma. LHRH-a are known to decrease bone mineral density. The purpose of this study was to determine the risk of bone fracture in men receiving LHRH-a for prostate carcinoma. METHODS A retrospective chart review and phone interviews were conducted to determine the incidence of bone fractures occurring in patients receiving LHRH-a for the treatment of prostate carcinoma. Abstracted data included the number of monthly LHRH-a injections, age, clinical stage of disease, sites of metastases, and bone fracture history. RESULTS Twenty of the 224 patients (9%) treated with LHRH-a for prostate carcinoma between 1988 and 1995 at 3 teaching hospitals had at least 1 bone fracture during treatment with LHRH-a. The duration of treatment to the time of fracture ranged from 1 to 96 months (mean, 22.2 months). Seven fractures (32%) were osteoporotic in nature (i.e., vertebral compression fractures or hip fractures after a fall from standing), whereas 8 fractures (36%) were associated with a significant traumatic event (i.e., a motor vehicle accident, boxing, etc.) and 5 were of mixed etiology. Two of 22 fractures (9%) were pathologic. CONCLUSIONS This study demonstrated a 9% fracture incidence in a cohort of patients receiving LHRH-a for prostate carcinoma for up to 96 months. The incidence of osteoporotic fractures was 5%.","author":[{"dropping-particle":"","family":"Townsend","given":"M F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sanders","given":"W H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Northway","given":"R O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graham","given":"S D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"3","issued":{"date-parts":[["1997","2","1"]]},"page":"545-50","title":"Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma.","type":"article-journal","volume":"79"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. This guidance aims to provide non-bone specialists with evidence-based recommendations to support the assessment and management of bone health in men receiving PC treatment. 1.1 MethodologyExpert group and specialist society involvementThis guidance was developed by a group of experts, identified from key opinion leaders in the management of PC and bone disorders, including: medical and clinical oncologists, urologists, endocrinologists, rheumatologists, physicians specialising in metabolic bone disease, general practitioners, uro-oncology nurse specialists and patient representatives. Input and endorsement was also sought from a range of specialist societies during the process of guideline development: the National Osteoporosis Guideline Group (NOGG); National Osteoporosis Society; British Uro-oncology Group; Association of Cancer Physicians; European Association of Urology; European Society for Medical Oncology; Society for Endocrinology; and the British Association of Urological Nurses. Current guidelinesNational and international guidelines lack detailed, specific recommendations for the management of bone health in men receiving treatment for PC. The UK National Institute for Health and Care Excellence (NICE) Clinical Guideline for the management of PC makes general recommendations; that fracture risk is considered for all men receiving ADT and that treatment is offered to all those with osteoporosis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"(NICE)","given":"National Institute for Health and Care Excellence","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2014"]]},"publisher-place":"London, UK","title":"Prostate cancer: diagnosis and management. Clinical guideline 175.","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷","plainTextFormattedCitation":"7","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}7. An updated version is due to be published in 2019, and recommends use of zoledronic acid in men with hormone refractory disease to prevent or reduce the risk of skeletal related events and/or to provide pain relief ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Care","given":"National Institute for Health and","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Excellence","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2019"]]},"number-of-pages":"1-91","title":"Guideline version (Draft) Prostate cancer: diagnosis and management","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸","plainTextFormattedCitation":"8","previouslyFormattedCitation":"⁸"},"properties":{"noteIndex":0},"schema":""}8. However there is no mention of bone health assessment at the time of ADT initiation.Joint European Association of Urology, European Society for Radiotherapy and Oncology and International Society for Geriatric Oncology PC guidelines suggest that BMD assessment is undertaken prior to the initiation of long-term ADT, and that the FRAX? tool should be used to estimate individual fracture risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.eururo.2007.09.002","ISBN":"0471222887","ISSN":"0210-4806","PMID":"19418833","author":[{"dropping-particle":"","family":"Mottet N, Bellmunt J, Briers E, Bolla M, Cornford P","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2016"]]},"number-of-pages":"1-146","title":"EAU-ESTRO-SIOG Guidelines on Prostate Cancer","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹","plainTextFormattedCitation":"9","previouslyFormattedCitation":"⁹"},"properties":{"noteIndex":0},"schema":""}9 . There is no current guidance as to the intervention thresholds that should be used to initiate treatment, or the most appropriate pharmacological therapy. It is often unclear as to who should have overall responsibility for managing bone health in this group of patients, many of whom will be managed in a multi-disciplinary setting across both primary and secondary care. Definition of scopeAn initial meeting of expert group members was held, where the scope of the guidance was defined. To address the need for specific guidance for the management of PC treatment induced bone loss (including intervention thresholds) in a European settingTo summarise the evidence supporting the management of bone health during PC treatment for non-bone specialists (including general practitioners, urologists, oncologists and specialist nurses) involved in the care of patients with PC at risk of cancer treatment-induced bone lossUsing the UK as an exemplar, to sit the PC guidance alongside the NICE- accredited National Osteoporosis Guidance Group Clinical Guideline (2017) for the prevention and treatment of osteoporosis and the NICE guidance for the diagnosis and management of prostate cancer (NICE Clinical Guideline 175)The group recommended that guidance should be available as an electronic download, along with a summary algorithm. Search strategyAn initial systematic literature search was undertaken in 2012 using PubMed and Ovid MEDLINE databases using search terms chosen by the expert group (Appendix 1). The search was limited to articles published in English between January 2000 and March 2012. Randomised controlled trials, observational studies and meta-analyses were included for assessment. The search was repeated in July 2018, and key publications were added by members of the expert group for inclusion.Selection of evidenceFollowing the initial literature search, abstracts were screened for relevance. Assessment of potentially relevant articles was conducted by at least two members of the expert reference group, with any disagreement resolved by consensus after discussion.1.2 Prostate cancer and bone lossProstate cancer treatments associated with bone lossAndrogen deprivation therapyAndrogen deprivation therapy (ADT) is offered to men with PC in several different clinical settings, including; men who present with or progress to metastatic disease (continuous ADT); men who receive radical radiotherapy for localised or locally advanced disease (temporary ADT); and men who progress during a period of watchful waiting who are not fit for radical treatment (palliative continuous ADT). These indications are based upon clear evidence from large randomised clinical trials ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(11)70063-8","ISSN":"1470-2045","abstract":"BACKGROUND\nThe TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. \n\nMETHODS\nBetween June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5–7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. \n\nFINDINGS\n802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9–11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57–0·90; p=0·003) and local progression (0·49, 0·33–0·73; p=0·0005), and improved event-free survival (0·63, 0·52–0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46–0·72; p<0·0001) and local progression (0·45, 0·30–0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42–0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60–1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60–1·23; p=0·398), or all-cause mortality (0·84, 0·65–1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31–0·76; p=0·001), pro…","author":[{"dropping-particle":"","family":"Denham","given":"James W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steigler","given":"Allison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamb","given":"David S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Joseph","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turner","given":"Sandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matthews","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Atkinson","given":"Chris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"North","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christie","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spry","given":"Nigel A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tai","given":"Keen-Hun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wynne","given":"Chris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Este","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet Oncology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2011","5","1"]]},"page":"451-459","publisher":"Elsevier","title":"Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰","plainTextFormattedCitation":"10","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}10,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Bolla","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reijke","given":"Theodorus M","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tienhoven","given":"Van","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergh","given":"Alphonsus C M","non-dropping-particle":"Van Den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oddens","given":"Jorg","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Poortmans","given":"Philip M P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gez","given":"Eliahu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kil","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akdas","given":"Atif","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soete","given":"Guy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kariakine","given":"Oleg","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steen-Banasik","given":"Elsbietha M","non-dropping-particle":"Van Der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Musat","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Piérart","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mauer","given":"Murielle E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Collette","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Duration of Androgen Suppression in the Treatment of Prostate Cancer","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹","plainTextFormattedCitation":"11","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}11,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2003.11.023","ISSN":"0732-183X","PMID":"14581419","abstract":"PURPOSE Radiation Therapy Oncology Group (RTOG) Protocol 92-02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. PATIENTS AND METHODS Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. RESULTS The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P =.044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037), the cause of which is not clear. CONCLUSION The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.","author":[{"dropping-particle":"","family":"Hanks","given":"Gerald E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pajak","given":"Thomas F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porter","given":"Arthur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grignon","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brereton","given":"Harmart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Venkatesan","given":"Varagur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horwitz","given":"Eric M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lawton","given":"Colleen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenthal","given":"Seth A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sandler","given":"Howard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shipley","given":"William U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Radiation Therapy Oncology Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issue":"21","issued":{"date-parts":[["2003","11","1"]]},"page":"3972-8","title":"Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02.","type":"article-journal","volume":"21"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²","plainTextFormattedCitation":"12","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}12,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa1212299","author":[{"dropping-particle":"","family":"Hussain","given":"Maha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tangen","given":"Catherine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berry","given":"Donna L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Higano","given":"Celestia S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"David Crawford","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Glenn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilding","given":"George","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prescott","given":"Stephen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanaga Sundaram","given":"Subramanian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jay Small","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ann Dawson","given":"Nancy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Donnelly","given":"Bryan J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Venner","given":"Peter M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaishampayan","given":"Ulka N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schellhammer","given":"Paul F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Quinn","given":"David I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raghavan","given":"Derek","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ely","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moinpour","given":"Carol M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vogelzang","given":"Nicholas J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thompson","given":"Ian M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"N Engl J Med","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"page":"1314-1339","title":"Intermittent versus Continuous Androgen Deprivation in Prostate Cancer","type":"article-journal","volume":"368"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³","plainTextFormattedCitation":"13","previouslyFormattedCitation":"¹³"},"properties":{"noteIndex":0},"schema":""}13. ADT is most commonly achieved by the administration of luteinising hormone releasing hormone (LHRH) agonists (such as goserelin and leuprorelin) and LHRH antagonists (such as degarelix). Antiandrogens (such as bicalutamide) may also be used.Following initiation of ADT, sex steroid levels decrease rapidly and substantially (with the exception of bicalutamide). This reduction in circulating androgens and oestrogens disrupts the bone remodelling balance, stimulates osteoclast activity, decreases osteoclast apoptosis, and increases apoptosis of osteoblasts, all of which lead to net bone loss. Oestrogen decreases bone resorption, and its importance in skeletal homeostasis was highlighted by studies of male patients unable to produce or respond to serum oestrogen, who had both significantly increased bone turnover and incidence of osteopenia. A large randomised controlled trial is currently in progress to determine the safety and efficacy of transcutaneous oestrogen as an alternative to ADT (LHRH agonists) in men with PC: . Evidence suggests that even before ADT is initiated, men with PC may have lower baseline bone mineral density (BMD) than age-matched controls ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"1464-4096","PMID":"14616447","abstract":"OBJECTIVE To examine the incidence of osteoporosis in patients with advanced prostate cancer (using forearm densitometry) before commencing androgen deprivation therapy (ADT), as osteoporotic fractures are more frequent in patients with prostate cancer who have undergone either medical or surgical castration, because of rapid loss of bone mass. PATIENTS AND METHODS In all, 174 patients (mean age 74.6 years, range 46-90) with advanced prostate cancer presented over 2 years. Their forearm bone densitometry values were compared with those from 106 age-matched controls (mean age 74.3 years, range 66-90). RESULTS Of the 174 patients, 73 (42%) were osteoporotic (t score <or=- 2.5) and 65 (37%) were osteopenic (t score - 1 to - 2.4). This compares with a 27% incidence of osteoporosis in the control group (P = 0.022). There were also no significant correlations between prostate specific antigen levels, Gleason score, tumour stage, biochemical markers and the presence or absence of osteoporosis risk factors. CONCLUSION Patients with advanced prostate cancer requiring ADT have a high incidence of osteoporosis before treatment. In addition, osteoporosis in these men cannot be predicted from clinical or biochemical values. Therefore, bone densitometry should be used in all patients with advanced cancer requiring ADT, as the results have implications for the choice of cancer therapy and the prophylaxis for osteoporosis.","author":[{"dropping-particle":"","family":"Hussain","given":"S A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weston","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stephenson","given":"R N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"George","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parr","given":"N J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJU international","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2003","11"]]},"page":"690-4","title":"Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation.","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴","plainTextFormattedCitation":"14","previouslyFormattedCitation":"¹⁴"},"properties":{"noteIndex":0},"schema":""}14 . Prospective studies have found that loss of BMD is most rapid during the first year of ADT (5-10% BMD loss) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Maillefert JF, Sibilia J, Michel F","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-1","issue":"1219-1222","issued":{"date-parts":[["1999"]]},"title":"Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma","type":"article-journal","volume":"161"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁵","plainTextFormattedCitation":"15","previouslyFormattedCitation":"¹⁵"},"properties":{"noteIndex":0},"schema":""}15,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Berruti A, Dogliotti L, Terrone C","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-1","issued":{"date-parts":[["2002"]]},"page":"2361-2367","title":"Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy","type":"article-journal","volume":"167"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁶","plainTextFormattedCitation":"16","previouslyFormattedCitation":"¹⁶"},"properties":{"noteIndex":0},"schema":""}16,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"GnRH). J Clin Endocrinol Metab 1993; 76:288–90.","author":[{"dropping-particle":"","family":"Goldray D, Weisman Y, Jaccard N","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-1","issued":{"date-parts":[["1993"]]},"page":"288-290","title":"Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist decapeptyl (D-Trp6-GnRH)","type":"article-journal","volume":"76"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁷","plainTextFormattedCitation":"17","previouslyFormattedCitation":"¹⁷"},"properties":{"noteIndex":0},"schema":""}17,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Daniell HW, Dunn SR, Ferguson DW","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-1","issued":{"date-parts":[["2000"]]},"page":"181-186","title":"Progressive osteoporosis during androgen deprivation therapy for prostate cancer.","type":"article-journal","volume":"163"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁸","plainTextFormattedCitation":"18","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}18, and is greater than both normal age-related bone loss (0.5-1.0% per annum) and bone loss in postmenopausal women. Bone loss continues, although at a less rapid rate, throughout the duration of ADT. Ongoing CTIBL in men with PC is superimposed upon normal age-related bone loss (more than half of men diagnosed with PC are aged over 70 years). It is more likely that older men will also have risk factors for fragility fracture other than ADT, such as risk of falls and comorbid conditions. In addition to ADT-mediated effects on BMD, evidence suggests that ADT is associated with significant disruption to bone microarchitecture (for example, changes in cortical area and cortical porosity) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2010-0902","ISBN":"1945-7197 (Electronic) 0021-972X (Linking)","ISSN":"1945-7197","PMID":"20881261","abstract":"CONTEXT: Androgen deprivation therapy (ADT) used in the treatment of prostate cancer reduces bone mineral density (BMD) and predisposes to fractures. The structural basis of the BMD deficit and bone fragility is uncertain.\\n\\nOBJECTIVE AND PATIENTS: We investigated changes in bone microarchitecture in 26 men (70.6±6.8 yr) with nonmetastatic prostate cancer during the first year of ADT using the new technique of high-resolution peripheral quantitative computed tomography.\\n\\nDESIGN AND SETTING: We conducted a 12-month prospective observational study in the setting of a tertiary referral center.\\n\\nRESULTS: After 12 months of ADT, total volumetric density decreased by 5.2±5.4% at the distal radius and 4.2±2.7% at the distal tibia (both P<0.001). This was due to a decrease in cortical volumetric BMD (by 11.3±8.6% for radius and 6.0±4.2% for tibia, all P<0.001) and trabecular density (by 3.5±6.0% for radius and 1.5±2.3% for tibia, all P<0.01), after correcting for trabecularization of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (P<0.05). Total testosterone, but not estradiol, levels were independently associated with total and corrected cortical volumetric BMD at the tibia.\\n\\nCONCLUSIONS: Sex steroid deficiency induced by ADT for prostate cancer results in microarchitectural decay. Bone fragility in these men may be more closely linked to testosterone than estradiol deficiency.","author":[{"dropping-particle":"","family":"Hamilton","given":"E J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ghasem-Zadeh","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gianatti","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim-Joon","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bolton","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zebaze","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seeman","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zajac","given":"J D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grossmann","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of clinical endocrinology and metabolism","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2010"]]},"page":"E456-63","title":"Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy.","type":"article-journal","volume":"95"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁹","plainTextFormattedCitation":"19","previouslyFormattedCitation":"¹⁹"},"properties":{"noteIndex":0},"schema":""}19. As microarchitecture is an important determinant of whole bone strength (independent of BMD), this further compromises bone strength in men receiving long-term ADT. In addition to its direct effects on bone, ADT also affects body composition. Adiposity is substantially increased along with a decrease in lean body mass within 3-12 months of ADT initiation ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2013.49.5523","ISBN":"0732-183X","ISSN":"15277755","PMID":"24344218","abstract":"PURPOSE: Androgen-deprivation therapy is a commonly used treatment for men with prostate cancer; however, the adverse effects can be detrimental to patient health and quality of life. Exercise has been proposed as a strategy for ameliorating a range of these treatment-related adverse effects. We conducted a systematic review of the literature regarding the effects of exercise on treatment-related adverse effects in men receiving androgen-deprivation therapy for prostate cancer. METHODS: An online electronic search of the Cochrane Library, EMBASE, MEDLINE, CINAHL, SPORTDiscus, and Health Source databases was performed to identify relevant peer-reviewed articles published between January 1980 and June 2013. Eligible study designs included randomized controlled trials as well as uncontrolled trials with pre- and postintervention data. Information was extracted regarding participant and exercise intervention characteristics as well as the effects of exercise on bone health, body composition, physical performance, cardiometabolic risk, fatigue, and quality of life. RESULTS: Ten studies were included, with exercise interventions involving aerobic and/or resistance training. Exercise training demonstrated benefits in muscular strength, cardiorespiratory fitness, functional task performance, lean body mass, and fatigue, with inconsistent effects observed for adiposity. The impact of exercise on bone health, cardiometabolic risk markers, and quality of life are currently unclear. CONCLUSION: Among patients with prostate cancer treated with androgen-deprivation therapy, appropriately prescribed exercise is safe and may ameliorate a range of treatment-induced adverse effects. Ongoing research of high methodologic quality is required to consolidate and expand on current knowledge and to allow the development of specific evidence-based exercise prescription recommendations.","author":[{"dropping-particle":"","family":"Gardner","given":"Jason R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Livingston","given":"Patricia M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fraser","given":"Steve F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"page":"335-346","title":"Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: A systematic review","type":"article-journal","volume":"32"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁰","plainTextFormattedCitation":"20","previouslyFormattedCitation":"²⁰"},"properties":{"noteIndex":0},"schema":""}20. Sarcopenia, defined as a progressive impairment of muscle function due to loss of skeletal muscle mass, increases the risk of falls, fractures and consequent loss of function or independence ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1046/j.1532-5415.2001.49115.x","ISSN":"00028614","author":[{"dropping-particle":"","family":"Society","given":"American Geriatrics","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Society","given":"Geriatrics","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Of","given":"American Academy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"On Falls Prevention","given":"Orthopaedic Surgeons Panel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Geriatrics Society","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2001","5"]]},"page":"664-672","publisher":"Blackwell Science Inc","title":"Guideline for the Prevention of Falls in Older Persons","type":"article-journal","volume":"49"},"uris":[""]}],"mendeley":{"formattedCitation":"²¹","plainTextFormattedCitation":"21","previouslyFormattedCitation":"²¹"},"properties":{"noteIndex":0},"schema":""}21. ChemotherapyIn the setting of metastatic hormone-sensitive PC, recent evidence has demonstrated a survival benefit when upfront chemotherapy is given alongside ADT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"1163-1177","title":"Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.","type":"article-journal","volume":"387"},"uris":[""]}],"mendeley":{"formattedCitation":"²²","plainTextFormattedCitation":"22","previouslyFormattedCitation":"²²"},"properties":{"noteIndex":0},"schema":""}22 . Therefore, all men in this situation who are fit enough are currently offered six cycles of docetaxel. Corticosteroids are given alongside each cycle of docetaxel to reduce the risk of allergic reaction and to mitigate against some of the adverse effects. These are given as pre-medication (local protocols vary but usually between 30-40mg dexamethasone) and as a daily dose of prednisolone (10mg per day) for 21 days ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"1163-1177","title":"Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.","type":"article-journal","volume":"387"},"uris":[""]}],"mendeley":{"formattedCitation":"²²","plainTextFormattedCitation":"22","previouslyFormattedCitation":"²²"},"properties":{"noteIndex":0},"schema":""}22.Other systemic therapiesAbiraterone acetate is a selective androgen synthesis inhibitor. Inhibition of cytochrome P450 17 alpha-hydroxylase (CYP17A1) blocks androgen production in the testes, adrenals and prostate tumour tissue. As this also blocks the production of glucocorticoids, prednisolone (usual dose 10mg/day) is given together with abiraterone. It is recommended for use in men with metastatic castration resistant prostate cancer (mCRPC)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"The recommendations in this guidance represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, health professionals are expected to take this guidance fully into account, alongside the individual needs, preferences and values of their patients. The application of the recommendations in this guidance are at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Commissioners and/or providers have a responsibility to provide the funding required to enable the guidance to be applied when individual health professionals and their patients wish to use it, in accordance with the NHS Constitution. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. Abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA387)","author":[{"dropping-particle":"","family":"National institute for health and care excellence","given":"UK","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"²³","plainTextFormattedCitation":"23","previouslyFormattedCitation":"²³"},"properties":{"noteIndex":0},"schema":""}23. Abiraterone has also been found to improve survival in men with newly diagnosed hormone sensitive metastatic prostate cancer (compared to ADT alone) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa1702900","ISBN":"0028-4793","ISSN":"0028-4793","PMID":"28578639","abstract":"BackgroundAbiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. MethodsWe randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radi...","author":[{"dropping-particle":"","family":"James","given":"Nicholas D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bono","given":"Johann S.","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spears","given":"Melissa R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clarke","given":"Noel W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mason","given":"Malcolm D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dearnaley","given":"David P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ritchie","given":"Alastair W.S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amos","given":"Claire L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilson","given":"Clare","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Rob J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matheson","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Millman","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Attard","given":"Gerhardt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chowdhury","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cross","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gillessen","given":"Silke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parker","given":"Christopher C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Russell","given":"J. 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We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. ResultsAfter a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not rea...","author":[{"dropping-particle":"","family":"Fizazi","given":"Karim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tran","given":"NamPhuong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fein","given":"Luis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsubara","given":"Nobuaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodriguez-Antolin","given":"Alfredo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alekseev","given":"Boris Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"?zgüro?lu","given":"Mustafa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ye","given":"Dingwei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feyerabend","given":"Susan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Protheroe","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porre","given":"Peter","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kheoh","given":"Thian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Youn C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Todd","given":"Mary B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chi","given":"Kim N.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"352-360","title":"Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer","type":"article-journal","volume":"377"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁵","plainTextFormattedCitation":"25","previouslyFormattedCitation":"²⁵"},"properties":{"noteIndex":0},"schema":""}25. It is currently approved by the United States Food and Drug Administration and the European Medicines Agency, and recommended by both ESMO and EAU for use in this setting ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.eururo.2017.09.029","ISBN":"0302-2838","ISSN":"18737560","PMID":"29103760","abstract":"Addition of docetaxel to androgen deprivation therapy (ADT) was recommended for patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), who are fit enough to receive docetaxel. Two recently published trials showed that the addition of abiraterone acetate plus prednisone to ADT has a clear survival benefit and acceptable overall tolerance, and should be considered as another standard of care for newly diagnosed mHSPC.","author":[{"dropping-particle":"","family":"Mottet","given":"Nicolas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santis","given":"Maria","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Briers","given":"Erik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bourke","given":"Liam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gillessen","given":"Silke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grummet","given":"Jeremy P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lam","given":"Thomas B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Poel","given":"Henk G.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rouvière","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergh","given":"Roderick C.N.","non-dropping-particle":"van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cornford","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"316-321","title":"Updated Guidelines for Metastatic Hormone-sensitive Prostate Cancer: Abiraterone Acetate Combined with Castration Is Another Standard [Figure presented]","type":"article-journal","volume":"73"},"uris":[""]},{"id":"ITEM-2","itemData":{"URL":"","author":[{"dropping-particle":"al","family":"Parker C., Gillessen S.","given":"Heidenreich A. et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-2","issued":{"date-parts":[["2018"]]},"title":"eUpdate – Cancer of the Prostate Treatment Recommendations. This update refers to the Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals Oncology 2015; (Suppl 5): v69-v77.","type":"webpage"},"uris":[""]},{"id":"ITEM-3","itemData":{"URL":"","author":[{"dropping-particle":"","family":"US Food and Drug Administration","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-3","issued":{"date-parts":[["2018"]]},"title":"FDA approves abiraterone acetate in combination with prednisone for high-risk metastatic castration-sensitive prostate cancer","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"^26–28","plainTextFormattedCitation":"26–28","previouslyFormattedCitation":"^26–28"},"properties":{"noteIndex":0},"schema":""}26–28. Enzalutamide is an oral androgen receptor inhibitor that is currently used in men with mCRPC ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Scher HI, Fizazi K, Saad F","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NEJM","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"page":"1187-1197","title":"Increased survival with enzalutamide in prostate cancer after chemotherapy.","type":"article-journal","volume":"367"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁹","plainTextFormattedCitation":"29","previouslyFormattedCitation":"²⁹"},"properties":{"noteIndex":0},"schema":""}29. Unlike abiraterone it does not require concomitant corticosteroids. Recent data suggest that it may have a future role in the management of non-metastatic castration resistant disease ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Hussain M, Fizazi K, Saad F, Rahenborg P, Ferreira U, Ivashchenko P","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"2465-2474","title":"Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer","type":"article-journal","volume":"378"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁰","plainTextFormattedCitation":"30","previouslyFormattedCitation":"³⁰"},"properties":{"noteIndex":0},"schema":""}30.Glucocorticoids and bone lossThe long-term use of glucocorticoids is one of the commonest causes of secondary osteoporosis. In addition to their use with chemotherapy and abiraterone, they may also be used in a palliative setting when all standard treatment options for PC have been used. The underlying pathophysiology involves increased osteoblast and osteocyte apoptosis, and decreased osteoblastogenesis. There is also a transient increase in osteoclast survival and osteoclastogenesis when glucocorticoids are initiated. As a consequence of increased bone resorption, decreased formation and interruption of regulatory pathways, there is an early and rapid loss of BMD and bone quality, and a significantly increased risk of fracture ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jaci.2013.08.040","ISBN":"0091-6749; 1097-6825","ISSN":"00916749","PMID":"24176682","abstract":"Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures. ?? 2013 American Academy of Allergy, Asthma & Immunology.","author":[{"dropping-particle":"","family":"Buehring","given":"Bjoern","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viswanathan","given":"Ravi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Binkley","given":"Neil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Busse","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Allergy and Clinical Immunology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013"]]},"page":"1019-1030","publisher":"Elsevier Ltd","title":"Glucocorticoid-induced osteoporosis: An update on effects and management","type":"article-journal","volume":"132"},"uris":[""]}],"mendeley":{"formattedCitation":"³¹","plainTextFormattedCitation":"31","previouslyFormattedCitation":"³¹"},"properties":{"noteIndex":0},"schema":""}31. The risk of hip and vertebral fractures increases up to 7- and 17- fold respectively when doses equivalent to 10-12mg prednisolone are given for more than 3 months ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jaci.2013.08.040","ISBN":"0091-6749; 1097-6825","ISSN":"00916749","PMID":"24176682","abstract":"Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures. ?? 2013 American Academy of Allergy, Asthma & Immunology.","author":[{"dropping-particle":"","family":"Buehring","given":"Bjoern","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viswanathan","given":"Ravi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Binkley","given":"Neil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Busse","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Allergy and Clinical Immunology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013"]]},"page":"1019-1030","publisher":"Elsevier Ltd","title":"Glucocorticoid-induced osteoporosis: An update on effects and management","type":"article-journal","volume":"132"},"uris":[""]}],"mendeley":{"formattedCitation":"³¹","plainTextFormattedCitation":"31","previouslyFormattedCitation":"³¹"},"properties":{"noteIndex":0},"schema":""}31. The risk of fracture is also increased even when small (2.5-3mg) daily doses are given ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jaci.2013.08.040","ISBN":"0091-6749; 1097-6825","ISSN":"00916749","PMID":"24176682","abstract":"Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures. ?? 2013 American Academy of Allergy, Asthma & Immunology.","author":[{"dropping-particle":"","family":"Buehring","given":"Bjoern","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viswanathan","given":"Ravi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Binkley","given":"Neil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Busse","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Allergy and Clinical Immunology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013"]]},"page":"1019-1030","publisher":"Elsevier Ltd","title":"Glucocorticoid-induced osteoporosis: An update on effects and management","type":"article-journal","volume":"132"},"uris":[""]}],"mendeley":{"formattedCitation":"³¹","plainTextFormattedCitation":"31","previouslyFormattedCitation":"³¹"},"properties":{"noteIndex":0},"schema":""}31. No studies to date have investigated the impact of the combination of docetaxel and glucocorticoids, or other systemic therapies on bone health or risk of fracture in men with PC. 1.4 OsteoporosisBackgroundOsteoporosis is defined as a progressive systemic skeletal disorder, characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Kanis JA, Melton III LJ, Christiansen C, Johnston CC","given":"Khaltaev N","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","id":"ITEM-1","issued":{"date-parts":[["1994"]]},"page":"1137-1141","title":"The diagnosis of osteoporosis","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"³²","plainTextFormattedCitation":"32","previouslyFormattedCitation":"³²"},"properties":{"noteIndex":0},"schema":""}32. The prevalence of osteoporosis increases with age, due to both age-related loss of bone mineral density (BMD) (0.5%-1.0% BMD per year) and the presence of additional factors that accelerate bone loss, such as the menopause, lifestyle factors, presence of comorbid conditions and use of medications that have direct effects on bone. In Europe, there are 22 million women and 5.5 million men living with osteoporosis, which is responsible for 3.5 million fragility fractures per year. The economic burden of both incident and prior fragility fractures has been estimated at €37 billion, with the majority of the costs being accrued in the first year ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s11657-013-0137-0","ISSN":"1862-3522","PMID":"24113838","abstract":"UNLABELLED This report describes epidemiology, burden, and treatment of osteoporosis in each of the 27 countries of the European Union (EU27). INTRODUCTION In 2010, 22 million women and 5.5 million men were estimated to have osteoporosis in the EU; and 3.5 million new fragility fractures were sustained, comprising 620,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures. The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. The aim of this report was to characterize the burden of osteoporosis in each of the EU27 countries in 2010 and beyond. METHODS The data on fracture incidence and costs of fractures in the EU27 were taken from a concurrent publication in this journal (Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden) and country specific information extracted. RESULTS The clinical and economic burden of osteoporotic fractures in 2010 is given for each of the 27 countries of the EU. The costs are expected to increase on average by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. CONCLUSIONS In spite of the high cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by aging populations, the use of pharmacological prevention of osteoporosis has decreased in recent years, suggesting that a change in healthcare policy concerning the disease is warranted.","author":[{"dropping-particle":"","family":"Svedbom","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernlund","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iverg?rd","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Compston","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenmark","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J?nsson","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanis","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"EU Review Panel of IOF","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Osteoporosis","id":"ITEM-1","issue":"1-2","issued":{"date-parts":[["2013","12","11"]]},"page":"137","title":"Osteoporosis in the European Union: a compendium of country-specific reports","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"³³","plainTextFormattedCitation":"33","previouslyFormattedCitation":"³³"},"properties":{"noteIndex":0},"schema":""}33. Fragility fractures arise as a consequence of low energy mechanical forces that would not ordinarily cause fracture (equivalent to a fall from standing height or less), and most commonly affect the proximal femur (hip), vertebrae and distal radius ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/yd.20075","ISSN":"1537-5781","PMID":"24474255","author":[{"dropping-particle":"","family":"National Osteoporosis Guideline Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"January","issued":{"date-parts":[["2016"]]},"number-of-pages":"1-8","title":"Osteoporosis Clinical guideline for prevention and treatment: Executive Summary","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁴","plainTextFormattedCitation":"34","previouslyFormattedCitation":"³⁴"},"properties":{"noteIndex":0},"schema":""}34. More than one in three of adult women and one in five men will sustain one or more fragility fractures in their lifetime ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"8756-3282","PMID":"11728921","abstract":"Records from the General Practice Research Database were used to derive age- and gender-specific fracture incidence rates for England and Wales during the period 1988-1998. In total, 103,052 men and 119,317 women in the sample of 5 million adults sustained a fracture over 10.4 million and 11.2 million person-years (py) of follow-up. Among women, the most frequent fracture sites were the radius/ulna (30.2 cases per 10,000 py) and femur/hip (17.0 per 10,000 py). In men, the most common fracture was that of the carpal bones (26.2 per 10,000 py); the incidence of femur/hip fracture was 5.3 per 10,000 py. Varying patterns of fracture incidence were observed with increasing age; whereas some fractures became more common in later life (vertebral, distal forearm, hip, proximal humerus, rib, clavicle, pelvis), others were more frequent in childhood and young adulthood (tibia, fibula, carpus, foot, ankle). The lifetime risk of any fracture was 53.2% at age 50 years among women, and 20.7% at the same age among men. Whereas fractures of the proximal femur and vertebral body were associated with excess mortality over a 5 year period following fracture diagnosis among both men and women, fractures of the distal forearm were associated with only slight excess mortality in men. This study provides robust estimates of fracture incidence that will assist health-care planning and delivery.","author":[{"dropping-particle":"","family":"Staa","given":"T P","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dennison","given":"E M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leufkens","given":"H G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bone","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2001","12"]]},"page":"517-22","title":"Epidemiology of fractures in England and Wales.","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁵","plainTextFormattedCitation":"35","previouslyFormattedCitation":"³⁵"},"properties":{"noteIndex":0},"schema":""}35. Such fractures are also a major predictor of subsequent fracture, the risk of which increases at least two-fold after a previous fracture, and is partially independent of BMD.Hip fractures are the most serious fragility fracture, and pose a considerable challenge to health and social care provision. They usually occur after a fall from standing, but may also occur spontaneously. There are more than 600,000 new hip fractures in Europe each year ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s11657-013-0136-1","ISSN":"1862-3522","PMID":"24113837","abstract":"UNLABELLED This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). INTRODUCTION Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. METHODS The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010. RESULTS Twenty-two million women and 5.5 million men were estimated to have osteoporosis; and 3.5 million new fragility fractures were sustained, comprising 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. fractures of the pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). The economic burden of incident and prior fragility fractures was estimated at <euro> 37 billion. Incident fractures represented 66?% of this cost, long-term fracture care 29?% and pharmacological prevention 5?%. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25?% in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. CONCLUSIONS In spite of the high social and economic cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by the aging populations, the use of pharmacological interventions to prevent fractures has decreased in recent years, suggesting that a change in healthcare policy is warranted.","author":[{"dropping-particle":"","family":"Hernlund","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svedbom","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iverg?rd","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Compston","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stenmark","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J?nsson","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanis","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Osteoporosis","id":"ITEM-1","issue":"1-2","issued":{"date-parts":[["2013","12","11"]]},"page":"136","title":"Osteoporosis in the European Union: medical management, epidemiology and economic burden","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁶","plainTextFormattedCitation":"36","previouslyFormattedCitation":"³⁶"},"properties":{"noteIndex":0},"schema":""}36, a figure which is projected to increase significantly by 2050 as a result of the ageing population ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Gullberg J, Johnnell O","given":"Kanis JA.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issued":{"date-parts":[["1997"]]},"page":"407-413","title":"World-wide projections for hip fracture.","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁷","plainTextFormattedCitation":"37","previouslyFormattedCitation":"³⁷"},"properties":{"noteIndex":0},"schema":""}37. In the United Kingdom, hip fractures account for almost 70,000 unplanned hospital admissions and 20% of orthopaedic bed occupancy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"This product may be of interest to members of the public and other stakeholders to make local and national comparisons of hospital activity in relation to admitted patient care. We are the trusted source of authoritative data and information relating to health and care.","author":[{"dropping-particle":"","family":"Health and social care information centre","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Hospital Episode Statistics: Admitted patient care 2012-2013","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38. They are an important cause of morbidity, often resulting in significant pain, disability and loss of independence. More than 50% of patients will be unable to live independently following discharge from hospital, and only 30% will fully recover. The association between hip fracture and mortality is well established, with around one third of patients dying within 12 months ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MLR.0000000000000383","ISSN":"0025-7079","author":[{"dropping-particle":"","family":"Neuburger","given":"Jenny","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Currie","given":"Colin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wakeman","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsang","given":"Carmen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Plant","given":"Fay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stavola","given":"Bianca","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cromwell","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meulen","given":"Jan","non-dropping-particle":"van der","parse-names":false,"suffix":""}],"container-title":"Medical Care","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2015","8"]]},"page":"686-691","title":"The Impact of a National Clinician-led Audit Initiative on Care and Mortality after Hip Fracture in England","type":"article-journal","volume":"53"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁹","plainTextFormattedCitation":"39","previouslyFormattedCitation":"³⁹"},"properties":{"noteIndex":0},"schema":""}39. Mortality following hip fracture is significantly higher in men ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1059/0003-4819-152-6-201003160-00008","abstract":"Background-Although an increased risk for death after hip fracture is well established, whether this excess mortality persists over time is unclear.","author":[{"dropping-particle":"","family":"Haentjens","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Magaziner","given":"Jay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Colón-Emeric","given":"Cathleen S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vanderschueren","given":"Dirk","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milisen","given":"Koen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velkeniers","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boonen","given":"Steven","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2010"]]},"title":"Meta-analysis: Excess Mortality After Hip Fracture Among Older Women and Men","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00198-016-3787-0","abstract":"One-year mortality following a fracture was greater for men compared to women, varied markedly between regions in England with the lowest rates in the London region, and was higher among black women compared to white women. The excess in mortality did not change during the study period. Introduction-Fractures are associated with increased mortality. With the shift towards an increasingly elderly demography, and so increasing numbers of fractures, the impact of such events on mortality is of key public health importance. Therefore, we aimed to present up to date mortality rates following fracture in England.","author":[{"dropping-particle":"","family":"Klop","given":"Corinne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Staa","given":"Tjeerd P","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Cyrus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harvey","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vries","given":"Frank","non-dropping-particle":"De","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["0"]]},"title":"The epidemiology of mortality after fracture in England: variation by age, sex, time, geographic location and ethnicity","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"^40,41","plainTextFormattedCitation":"40,41","previouslyFormattedCitation":"^40,41"},"properties":{"noteIndex":0},"schema":""}40,41. Other common and important sites of fragility fracture are the vertebrae and upper limb ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"al","family":"Svedbom A","given":"et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"557-566","title":"Quality of life for up to 18 months after low-energy hip, vertebral, and distal forearm fractures-results from the ICUROS.","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42. Vertebral fractures are frequently under-diagnosed, and often detected incidentally or as a result of investigations following another type of fracture. Vertebral fractures cause pain, limited activity, height loss and respiratory compromise, and are associated with increased mortality. Upper limb fractures are less likely to result in hospitalisation, but are often associated with considerable impact on ability to self care (degree of impact depends on whether the dominant side is fractured), increased carer burden, lasting impact on acivities of daily living, and chronic pain. Definition and diagnosisThe World Health Organization (WHO) definition of osteoporosis, launched in 1994, is based upon bone mineral density (BMD). Fracture risk increases progressively with decreasing BMD, with approximately a twofold increase in risk with each standard deviation (SD) decrease in BMD ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1359/JBMR.050304","ISSN":"08840431","PMID":"15940371","abstract":"UNLABELLED The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of approximately 39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score. INTRODUCTION The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value. MATERIALS AND METHODS We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients. RESULTS BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value. CONCLUSIONS We conclude that BMD is…","author":[{"dropping-particle":"","family":"Johnell","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanis","given":"John A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oden","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Helena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laet","given":"Chris","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Delmas","given":"Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eisman","given":"John A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fujiwara","given":"Seiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kroger","given":"Heikki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellstrom","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meunier","given":"Pierre J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melton","given":"L Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Neill","given":"Terry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pols","given":"Huibert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reeve","given":"Jonathan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silman","given":"Alan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tenenhouse","given":"Alan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Bone and Mineral Research","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2005","3","7"]]},"page":"1185-1194","title":"Predictive Value of BMD for Hip and Other Fractures","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴³","plainTextFormattedCitation":"43","previouslyFormattedCitation":"⁴³"},"properties":{"noteIndex":0},"schema":""}43, ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0959-8138","PMID":"8634613","abstract":"OBJECTIVE To determine the ability of measurements of bone density in women to predict later fractures. DESIGN Meta-analysis of prospective cohort studies published between 1985 and end of 1994 with a baseline measurement of bone density in women and subsequent follow up for fractures. For comparative purposes, we also reviewed case control studies of hip fractures published between 1990 and 1994. SUBJECTS Eleven separate study populations with about 90,000 person years of observation time and over 2000 fractures. MAIN OUTCOME MEASURES Relative risk of fracture for a decrease in bone mineral density of one standard deviation below age adjusted mean. RESULTS All measuring sites had similar predictive abilities (relative risk 1.5 (95% confidence interval 1.4 to 1.6)) for decrease in bone mineral density except for measurement at spine for predicting vertebral fractures (relative risk 2.3 (1.9 to 2.8)) and measurement at hip for hip fractures (2.6 (2.0 to 3.5)). These results are in accordance with results of case-control studies. Predictive ability of decrease in bone mass was roughly similar to (or, for hip or spine measurements, better than) that of a 1 SD increase in blood pressure for stroke and better than a 1 SD increase in serum cholesterol concentration for cardiovascular disease. CONCLUSIONS Measurements of bone mineral density can predict fracture risk but cannot identify individuals who will have a fracture. We do not recommend a programme of screening menopausal women for osteoporosis by measuring bone density.","author":[{"dropping-particle":"","family":"Marshall","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnell","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wedel","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMJ (Clinical research ed.)","id":"ITEM-1","issue":"7041","issued":{"date-parts":[["1996","5","18"]]},"page":"1254-9","title":"Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.","type":"article-journal","volume":"312"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁴","plainTextFormattedCitation":"44","previouslyFormattedCitation":"⁴⁴"},"properties":{"noteIndex":0},"schema":""}44. Using dual energy X-ray absorptiometry (DXA), a T-score of 2.5 SD or more below the mean value for young healthy adults is diagnostic of osteoporosis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Kanis JA, Melton III LJ, Christiansen C, Johnston CC","given":"Khaltaev N","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","id":"ITEM-1","issued":{"date-parts":[["1994"]]},"page":"1137-1141","title":"The diagnosis of osteoporosis","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"³²","plainTextFormattedCitation":"32","previouslyFormattedCitation":"³²"},"properties":{"noteIndex":0},"schema":""}32. The proximal femur (total hip or femoral neck) is an important site to assess, due to its higher predictive risk for fracture, and relatively low prevalence of degenerative change (which artificially increases BMD measurements at the spine) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.bone.2007.11.001","ISSN":"87563282","PMID":"18180210","abstract":"In 1994, the World Health Organization published diagnostic criteria for osteoporosis. Since then, many new technologies have been developed for the measurement of bone mineral at multiple skeletal sites. The information provided by each assessment will describe the clinical characteristics, fracture risk and epidemiology of osteoporosis differently. Against this background, there is a need for a reference standard for describing osteoporosis. In the absence of a true gold standard, this paper proposes that the reference standard should be based on bone mineral density (BMD) measurement made at the femoral neck with dual-energy X-ray absorptiometry (DXA). This site has been the most extensively validated, and provides a gradient of fracture risk as high as or higher than that of many other techniques. The recommended reference range is the NHANES III reference database for femoral neck measurements in women aged 20-29 years. A similar cut-off value for femoral neck BMD that is used to define osteoporosis in women can be used for the diagnosis of osteoporosis in men - namely, a value for BMD 2.5 SD or more below the average for young adult women. The adoption of DXA as a reference standard provides a platform on which the performance characteristics of less well established and new methodologies can be compared.","author":[{"dropping-particle":"","family":"Kanis","given":"John A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Helena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oden","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melton","given":"L. Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khaltaev","given":"Nikolai","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bone","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2008","3"]]},"page":"467-475","title":"A reference standard for the description of osteoporosis","type":"article-journal","volume":"42"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁵","plainTextFormattedCitation":"45","previouslyFormattedCitation":"⁴⁵"},"properties":{"noteIndex":0},"schema":""}45. BMD should also be measured in the lumbar spine (L1-L4) in all patientsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"Official Positions of the International Society for Clinical Densitometry","author":[{"dropping-particle":"","family":"Baim","given":"Sanford","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bilezikian","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blank","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bouxsein","given":"Mary L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carey","given":"John J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jankowski","given":"Lawrence G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kent","given":"Kyla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Genant","given":"Harry K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kado","given":"Deborah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheung","given":"Angela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindsey","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chapurlat","given":"Roland","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pawel","given":"Szulc","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"ISCD Position Paper","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"1 - 21.","title":"Official Positions 2015 ISCD Combined Adult and Pediatric.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁶","plainTextFormattedCitation":"46","previouslyFormattedCitation":"⁴⁶"},"properties":{"noteIndex":0},"schema":""}46. However, its accuracy may be impaired in older patients by the presence of degenerative disc disease, osteophytes and aortic calcification, all of which may artefactually increase BMD. DXA has the advantage that it is widely available and uses low dose radiation, however, it cannot be used in isolation to predict those at high risk of fracture, due to important limitations. BMD testing is highly specific but has low sensitivity for fracture prediction; many individuals who sustain a fracture are subsequently found to have non-osteoporotic BMD. Most fragility fractures will therefore occur in those who do not have osteoporosis as defined by a T-score ≤-2.5 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0098-7484","PMID":"11735756","abstract":"CONTEXT Large segments of the population at risk for osteoporosis and fracture have not been evaluated, and the usefulness of peripheral measurements for short-term prediction of fracture risk is uncertain. OBJECTIVES To describe the occurrence of low bone mineral density (BMD) in postmenopausal women, its risk factors, and fracture incidence during short-term follow-up. DESIGN The National Osteoporosis Risk Assessment, a longitudinal observational study initiated September 1997 to March 1999, with approximately 12 months of subsequent follow-up. SETTING AND PARTICIPANTS A total of 200 160 ambulatory postmenopausal women aged 50 years or older with no previous osteoporosis diagnosis, derived from 4236 primary care practices in 34 states. MAIN OUTCOME MEASURES Baseline BMD T scores, obtained from peripheral bone densitometry performed at the heel, finger, or forearm; risk factors for low BMD, derived from questionnaire responses; and clinical fracture rates at 12-month follow-up. RESULTS Using World Health Organization criteria, 39.6% had osteopenia (T score of -1 to -2.49) and 7.2% had osteoporosis (T score </=-2.5). Age, personal or family history of fracture, Asian or Hispanic heritage, smoking, and cortisone use were associated with significantly increased likelihood of osteoporosis; higher body mass index, African American heritage, estrogen or diuretic use, exercise, and alcohol consumption significantly decreased the likelihood. Among the 163 979 participants with follow-up information, osteoporosis was associated with a fracture rate approximately 4 times that of normal BMD (rate ratio, 4.03; 95% confidence interval [CI], 3.59-4.53) and osteopenia was associated with a 1.8-fold higher rate (95% CI, 1.49-2.18). CONCLUSIONS Almost half of this population had previously undetected low BMD, including 7% with osteoporosis. Peripheral BMD results were highly predictive of fracture risk. Given the economic and social costs of osteoporotic fractures, strategies to identify and manage osteoporosis in the primary care setting need to be established and implemented.","author":[{"dropping-particle":"","family":"Siris","given":"E S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"P D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barrett-Connor","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Faulkner","given":"K G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wehren","given":"L E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abbott","given":"T A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"M L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santora","given":"A C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sherwood","given":"L M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2001","12","12"]]},"page":"2815-22","title":"Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment.","type":"article-journal","volume":"286"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁷","plainTextFormattedCitation":"47","previouslyFormattedCitation":"⁴⁷"},"properties":{"noteIndex":0},"schema":""}47. Several other factors that are BMD-independent may also contribute to the risk of fracture. These include; age, sex, increased risk of falls, previous fracture, family history of fracture, and other lifestyle factors. Fracture risk assessment tools such as FRAX? and QFracture have been developed, which integrate these variables with other information in order to determine risk of fracture. 1.5 Management of CTIBL in prostate cancerPatient and clinician educationCurrent evidence suggests that men with PC receiving ADT often lack basic osteoporosis knowledge and do not actively seek to take measures to optimise their bone health ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Nadler M, Alibhai S, Catton P, Catton C, To MJ","given":"Jones JM","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJU International","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2013"]]},"page":"1301-1309","title":"Osteoporosis knowledge, health beliefs, and healthy bone behaviours in patients on androgen-deprivation therapy (ADT) for prostate cancer.","type":"article-journal","volume":"118"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁸","plainTextFormattedCitation":"48","previouslyFormattedCitation":"⁴⁸"},"properties":{"noteIndex":0},"schema":""}48 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1177/1557988315615956","ISSN":"1557-9883","abstract":"This descriptive study aimed to (a) determine the extent of osteoporosis knowledge, perceived health beliefs, and self-efficacy with bone healthy behaviors in men with prostate cancer and survivors and (b) identify how dietary bone healthy behaviors are associated with these psychobehavioral and psychosocial factors. Three different questionnaires were used to measure osteoporosis knowledge, health beliefs, and self-efficacy in a group of men with prostate cancer and survivors. Bone health was assessed via dual-energy X-ray absorptiometry and calcium intake using a diet history. The prevalence of osteoporosis and low bone mass was high at over 70%. Participants had inadequate osteoporosis knowledge with a mean score of 43.3% (SD = 18%) on the Facts on Osteoporosis Quiz. Participants scored low on the subscale measuring barriers to exercise (median = 11; interquartile range [IQR] = 6.5), indicating minimal barriers to exercise participation, and the subscale measuring the benefits of exercise scored the hi...","author":[{"dropping-particle":"","family":"Lassemillante","given":"Annie-Claude M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Skinner","given":"Tina L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hooper","given":"John D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prins","given":"John B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wright","given":"Olivia R. L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Men's Health","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017","1"]]},"page":"13-23","publisher":"SAGE PublicationsSage CA: Los Angeles, CA","title":"Osteoporosis-Related Health Behaviors in Men With Prostate Cancer and Survivors","type":"article-journal","volume":"11"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁹","plainTextFormattedCitation":"49","previouslyFormattedCitation":"⁴⁹"},"properties":{"noteIndex":0},"schema":""}49. Provision of individualised, patient-centred information can improve knowledge and engagement with appropriate lifestyle modifications ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Nadler M, Alibhai S, Catton P, Catton C, To MJ","given":"Jones JM","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJU International","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2013"]]},"page":"1301-1309","title":"Osteoporosis knowledge, health beliefs, and healthy bone behaviours in patients on androgen-deprivation therapy (ADT) for prostate cancer.","type":"article-journal","volume":"118"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁸","plainTextFormattedCitation":"48","previouslyFormattedCitation":"⁴⁸"},"properties":{"noteIndex":0},"schema":""}48. Published surveys of urologists and clinical oncologists have found that clinicians lack confidence in providing self-management advice to patients to optimise bone health, and do not feel able to effectively manage men who are identified as having abnormal BMD ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Damji AN, Bies K, Alibhai SMH","given":"Jones JM","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015"]]},"page":"951-959","title":"Bone health management in men undergoing ADT: examining enablers and barriers to care","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁰","plainTextFormattedCitation":"50","previouslyFormattedCitation":"⁵⁰"},"properties":{"noteIndex":0},"schema":""}50,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Ellsworth P, Providence RI, Carithers G","given":"et al. Dipaulo R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-1","issue":"4Supp","issued":{"date-parts":[["2011"]]},"page":"e290","title":"Educational needs of urologists on bone health in prostate cancer","type":"article-journal","volume":"185"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵¹","plainTextFormattedCitation":"51","previouslyFormattedCitation":"⁵¹"},"properties":{"noteIndex":0},"schema":""}51 . Lifestyle factorsBoth smoking and excessive alcohol intake reduce the BMD of men with PC, and should be avoided ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Agarwal","given":"M. M. et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issued":{"date-parts":[["2005"]]},"page":"2042-2052","title":"Factors affecting bone mineral density in patients with prostate carcinoma before and after orchidectomy","type":"article-journal","volume":"103"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵²","plainTextFormattedCitation":"52","previouslyFormattedCitation":"⁵²"},"properties":{"noteIndex":0},"schema":""}52. It has been demonstrated that exercise improves muscular strength, cardiorespiratory fitness, lean body mass, fatigue, and quality of life in men receiving treatment for PC ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.29406","ISSN":"0008543X","author":[{"dropping-particle":"","family":"Buffart","given":"Laurien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newton","given":"Robert U.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chinapaw","given":"Mai J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taaffe","given":"Dennis R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spry","given":"Nigel A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Denham","given":"James W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Joseph","given":"David J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lamb","given":"David S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brug","given":"Johannes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galv?o","given":"Daniel A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"16","issued":{"date-parts":[["2015","8","15"]]},"page":"2821-2830","title":"The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer","type":"article-journal","volume":"121"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵³","plainTextFormattedCitation":"53","previouslyFormattedCitation":"⁵³"},"properties":{"noteIndex":0},"schema":""}53, ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2013.49.5523","ISBN":"0732-183X","ISSN":"15277755","PMID":"24344218","abstract":"PURPOSE: Androgen-deprivation therapy is a commonly used treatment for men with prostate cancer; however, the adverse effects can be detrimental to patient health and quality of life. Exercise has been proposed as a strategy for ameliorating a range of these treatment-related adverse effects. We conducted a systematic review of the literature regarding the effects of exercise on treatment-related adverse effects in men receiving androgen-deprivation therapy for prostate cancer. METHODS: An online electronic search of the Cochrane Library, EMBASE, MEDLINE, CINAHL, SPORTDiscus, and Health Source databases was performed to identify relevant peer-reviewed articles published between January 1980 and June 2013. Eligible study designs included randomized controlled trials as well as uncontrolled trials with pre- and postintervention data. Information was extracted regarding participant and exercise intervention characteristics as well as the effects of exercise on bone health, body composition, physical performance, cardiometabolic risk, fatigue, and quality of life. RESULTS: Ten studies were included, with exercise interventions involving aerobic and/or resistance training. Exercise training demonstrated benefits in muscular strength, cardiorespiratory fitness, functional task performance, lean body mass, and fatigue, with inconsistent effects observed for adiposity. The impact of exercise on bone health, cardiometabolic risk markers, and quality of life are currently unclear. CONCLUSION: Among patients with prostate cancer treated with androgen-deprivation therapy, appropriately prescribed exercise is safe and may ameliorate a range of treatment-induced adverse effects. Ongoing research of high methodologic quality is required to consolidate and expand on current knowledge and to allow the development of specific evidence-based exercise prescription recommendations.","author":[{"dropping-particle":"","family":"Gardner","given":"Jason R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Livingston","given":"Patricia M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fraser","given":"Steve F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"page":"335-346","title":"Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: A systematic review","type":"article-journal","volume":"32"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁰","plainTextFormattedCitation":"20","previouslyFormattedCitation":"²⁰"},"properties":{"noteIndex":0},"schema":""}20. The UK National Institute for Health and Care Excellence (NICE) Clinical Guideline 175 for PC recommends that all men starting or having ADT should be offered supervised resistance and aerobic exercise at least twice a week for 12 weeks ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"(NICE)","given":"National Institute for Health and Care Excellence","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2014"]]},"publisher-place":"London, UK","title":"Prostate cancer: diagnosis and management. Clinical guideline 175.","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷","plainTextFormattedCitation":"7","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}7.The role of calcium and vitamin D Daily calcium intake (DCI) is inadequate in the majority of older men with PC ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"al","family":"Planas","given":"J et","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJU International","id":"ITEM-1","issued":{"date-parts":[["2007"]]},"page":"812-815","title":"The relationship between daily calcium intake and bone mineral density in men with prostate cancer.","type":"article-journal","volume":"99"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁴","plainTextFormattedCitation":"54","previouslyFormattedCitation":"⁵⁴"},"properties":{"noteIndex":0},"schema":""}54. The NOGG recommends a DCI between 700 and 1200mg, achieved where possible through dietary intake but supplements may also be used should this not be possible. DCI may be calculated using an online tool such . Vitamin D deficiency (serum 25-hydroxyvitamin D (25-OHD) level <25 nmol/L)) affects more than a quarter of older men, with up to three quarters found to have insufficiency (25-50 nmol/L) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2008-1784","ISSN":"0021-972X","PMID":"19174492","abstract":"CONTEXT: Vitamin D deficiency is not adequately evaluated in older men. OBJECTIVE: The aim of the study was to determine the prevalence of vitamin D deficiency and identify risk factors for its occurrence. DESIGN AND SETTING: We conducted a cross-sectional evaluation of 1606 older men in the general community who were enrolled in the Osteoporotic Fractures in Men Study. PARTICIPANTS: A randomly selected subcohort of a large population of men from six U.S. communities participated in the study. MAIN OUTCOME MEASURES: Serum concentrations of 25-hydroxyvitamin D(2) 25(OH)D(2) and 25(OH)D(3) were measured using mass spectrometry. RESULTS: Deficiency 25(OH)D 80 yr old, did not engage in lawn/garden work, and had a body mass index greater than 25 kg/m(2) and vitamin D intake below 400 IU/d, the prevalence of vitamin D deficiency was 86%. 25(OH)D(2) levels were present in a small fraction of men and accounted for a low proportion of total 25(OH)D levels. The use of vitamin D supplements was reported by 58% of men, but supplement use had a small effect on total 25(OH)D levels and, despite supplement use, low levels remained frequent. CONCLUSIONS: Vitamin D deficiency is common in older men and is especially prevalent in obese, sedentary men living at higher latitudes. Use of vitamin D supplements at levels reported here did not result in adequate vitamin D nutrition.","author":[{"dropping-particle":"","family":"Orwoll","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielson","given":"Carrie M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marshall","given":"Lynn M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lambert","given":"Lori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holton","given":"Kathleen F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoffman","given":"Andrew R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barrett-Connor","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shikany","given":"James M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dam","given":"Tien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cauley","given":"Jane A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2009"]]},"page":"1214-1222","title":"Vitamin D Deficiency in Older Men","type":"article-journal","volume":"94"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁵","plainTextFormattedCitation":"55","previouslyFormattedCitation":"⁵⁵"},"properties":{"noteIndex":0},"schema":""}55. In combination with calcium, vitamin D supplements are associated with a small reduction in hip and non-vertebral fractures in older men ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(07)61342-7","ISSN":"01406736","PMID":"17720017","abstract":"BACKGROUND Whether calcium supplementation can reduce osteoporotic fractures is uncertain. We did a meta-analysis to include all the randomised trials in which calcium, or calcium in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss. METHODS We identified 29 randomised trials (n=63 897) using electronic databases, supplemented by a hand-search of reference lists, review articles, and conference abstracts. All randomised trials that recruited people aged 50 years or older were eligible. The main outcomes were fractures of all types and percentage change of bone-mineral density from baseline. Data were pooled by use of a random-effect model. FINDINGS In trials that reported fracture as an outcome (17 trials, n=52 625), treatment was associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83-0.95; p=0.0004). In trials that reported bone-mineral density as an outcome (23 trials, n=41 419), the treatment was associated with a reduced rate of bone loss of 0.54% (0.35-0.73; p<0.0001) at the hip and 1.19% (0.76-1.61%; p<0.0001) in the spine. The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high (p<0.0001). The treatment effect was better with calcium doses of 1200 mg or more than with doses less than 1200 mg (0.80 vs 0.94; p=0.006), and with vitamin D doses of 800 IU or more than with doses less than 800 IU (0.84 vs 0.87; p=0.03). INTERPRETATION Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older. For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation).","author":[{"dropping-particle":"","family":"Tang","given":"Benjamin MP","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eslick","given":"Guy D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nowson","given":"Caryl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Caroline","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bensoussan","given":"Alan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet","id":"ITEM-1","issue":"9588","issued":{"date-parts":[["2007","8","25"]]},"page":"657-666","title":"Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis","type":"article-journal","volume":"370"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/14651858.CD000227.pub4","ISSN":"14651858","PMID":"24729336","abstract":"BACKGROUND Vitamin D and related compounds have been used to prevent osteoporotic fractures in older people. This is the third update of a Cochrane review first published in 1996. OBJECTIVES To determine the effects of vitamin D or related compounds, with or without calcium, for preventing fractures in post-menopausal women and older men. SEARCH METHODS We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2012), the Cochrane Central Register of Controlled Trials (2012, Issue 12), MEDLINE (1966 to November Week 3 2012), EMBASE (1980 to 2012 Week 50), CINAHL (1982 to December 2012), BIOSIS (1985 to 3 January 2013), Current Controlled Trials (December 2012) and reference lists of articles. SELECTION CRITERIA Randomised or quasi-randomised trials that compared vitamin D or related compounds, alone or with calcium, against placebo, no intervention or calcium alone, and that reported fracture outcomes in older people. The primary outcome was hip fracture. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial risk of selection bias and aspects of methodological quality, and extracted data. Data were pooled, where possible, using the fixed-effect model, or the random-effects model when heterogeneity between studies appeared substantial. MAIN RESULTS We included 53 trials with a total of 91,791 participants. Thirty-one trials, with sample sizes ranging from 70 to 36,282 participants, examined vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures in community, nursing home or hospital inpatient populations. Twelve of these 31 trials had participants with a mean or median age of 80 years or over.Another group of 22 smaller trials examined calcitriol or alfacalcidol (1-alphahydroxyvitamin D3), mostly with participants who had established osteoporosis. These trials were carried out in the setting of institutional referral clinics or hospitals.In the assessment of risk of bias for random sequence generation, 21 trials (40%) were deemed to be at low risk, 28 trials (53%) at unclear risk and four trials at high risk (8%). For allocation concealment, 22 trials were at low risk (42%), 29 trials were at unclear risk (55%) and two trials were at high risk (4%).There is high quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; risk ratio (RR) 1.12, 95% confidence inter…","author":[{"dropping-particle":"","family":"Avenell","given":"Alison","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mak","given":"Jenson CS","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Connell","given":"Dianne","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cochrane Database of Systematic Reviews","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014","4","14"]]},"page":"CD000227","title":"Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁷","plainTextFormattedCitation":"57","previouslyFormattedCitation":"⁵⁷"},"properties":{"noteIndex":0},"schema":""}57, and may also reduce the risk of falls ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Bischoff–Ferrari HA, Dawson–Hughes B, Willett WC","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JAMA - Journal of the American Medical Association","id":"ITEM-1","issued":{"date-parts":[["2004"]]},"page":"1999-2006","title":"Effect of vitamin D on falls: a meta-analysis.","type":"article-journal","volume":"291"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁸","plainTextFormattedCitation":"58","previouslyFormattedCitation":"⁵⁸"},"properties":{"noteIndex":0},"schema":""}58. NOGG recommends vitamin D supplementation with 800IU daily in all men aged over 50 at increased risk of fracture ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"National Osteoporosis Guideline Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2017"]]},"number-of-pages":"1-36","publisher-place":"Sheffield","title":"NOGG 2017: Clinical guideline for the prevention and treatment of osteoporosis shef.ac.uk/NOGG 1 NOGG 2017: Clinical guideline for the prevention and treatment of osteoporosis","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁹","plainTextFormattedCitation":"59","previouslyFormattedCitation":"⁵⁹"},"properties":{"noteIndex":0},"schema":""}59. No studies have specifically examined the effect of calcium and/or vitamin D supplementation upon loss of BMD associated with ADT. However, studies of various bone targeted agents in men with PC have used calcium and vitamin D supplementation in both treatment and control arms ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa0809003","ISSN":"0028-4793","PMID":"19671656","abstract":"BACKGROUND Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. METHODS In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures. RESULTS At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups. CONCLUSIONS Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. ( number, NCT00089674.)","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egerdie","given":"Blair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toriz","given":"Narciso Hernández","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tammela","given":"Teuvo L.J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Fred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heracek","given":"Jiri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szwedowski","given":"Maciej","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ke","given":"Chunlei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kupic","given":"Amy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leder","given":"Benjamin Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goessl","given":"Carsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Denosumab HALT Prostate Cancer Study Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2009","8","20"]]},"page":"745-755","title":"Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer","type":"article-journal","volume":"361"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁰","plainTextFormattedCitation":"60","previouslyFormattedCitation":"⁶⁰"},"properties":{"noteIndex":0},"schema":""}60 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa010845","ISSN":"0028-4793","PMID":"11575286","abstract":"BACKGROUND: Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist. METHODS: In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study. RESULTS: In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02). CONCLUSIONS: Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.","author":[{"dropping-particle":"","family":"Smith","given":"M R R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGovern","given":"F J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zietman","given":"A L L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fallon","given":"M A A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayden","given":"D L L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoenfeld","given":"D A A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kantoff","given":"P W W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finkelstein","given":"J S S","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England journal of medicine","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2001"]]},"page":"948-55","title":"Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.","type":"article-journal","volume":"345"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61 . Currently recommended doses of calcium and vitamin D were found to be insufficient to prevent bone loss associated with ADT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1634/theoncologist.2012-0432","ISBN":"4032109257","PMID":"23429739","author":[{"dropping-particle":"","family":"Datta M","given":"Schwartz GG.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Oncologist","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"page":"1171–1179","title":"Calcium and Vitamin D Supplementation During Androgen Deprivation Therapy for Prostate Cancer: A Critical Review","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶²","plainTextFormattedCitation":"62","previouslyFormattedCitation":"⁶²"},"properties":{"noteIndex":0},"schema":""}62. No subsequent trials have sought to determine the safety or efficacy of using higher doses in this population. Bone targeted agentsBisphosphonatesSeveral randomised studies have investigated the ability of bisphosphonates to reduce BMD loss associated with ADT. (Table 1) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa010845","ISSN":"0028-4793","PMID":"11575286","abstract":"BACKGROUND Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist. METHODS In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study. RESULTS In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02). CONCLUSIONS Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGovern","given":"Francis J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zietman","given":"Anthony L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fallon","given":"Mary Anne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayden","given":"Douglas L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoenfeld","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kantoff","given":"Philip W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finkelstein","given":"Joel S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2001","9","27"]]},"page":"948-955","title":"Pamidronate to Prevent Bone Loss during Androgen-Deprivation Therapy for Prostate Cancer","type":"article-journal","volume":"345"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISSN":"0008-543X","PMID":"11745221","abstract":"BACKGROUND Prostate carcinoma therapy with combined androgen blockade may result in high bone-turnover with significant bone loss. This study was undertaken to evaluate the antiosteoporotic efficacy of intravenous pamidronate in a double blind, randomized, placebo-controlled, crossover study. METHODS Twenty-one consecutive men with metastatic prostate carcinoma who were receiving combined androgen blockade with a long-acting gonadotropin-releasing hormone agonist (gosarelin acetate) and an androgen antagonist (flutamide or bicalutamide) were evaluated at baseline and at 6 and 12 months after therapy. They were randomly assigned to receive a single intravenous infusion of 500 mL of normal saline solution diluted with either pamidronate (90 mg) or placebo at baseline and with a crossover at 6 months. Lumbar-spine bone-mineral densities (BMDs) were measured by spinal quantitative computed tomography (QCT), femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA), and markers of bone turnover were measured by noninvasive methods. Data on 10 men with localized prostate carcinoma who were treated with radiotherapy alone, over the same period, was collected for comparison studies. RESULTS The mean age of the men was 75.1 years +/- 1.6 years. One man withdrew from the study because of deteriorating health, and two died from metastatic disease within the first 6 months. Combined androgen blockade normalized serum prostate-specific antigen activities (from an initial mean value of 86.2 ng/mL +/- 10.1 ng/mL) and maintained serum free testosterone concentrations in the hypogonadal range (< 2.2 pmol/L) in all men throughout the study. Treatment with pamidronate resulted in a 7.8% +/- 1.5% increase in mean lumbar spine QCT from 79.4 mg/cm(3) (95% confidence interval [CI], 64-94 mg/cm(3)) to 85.6 mg/cm(3) (95% CI, 70-101 mg/cm(3)) (P = 0.0005) and a 2% +/- 0.9% increase in mean total femoral neck DXA from 0.98 g/cm(2) (95% CI, 0.90 -1.05 g/cm(2)) to 1.0 mg/cm(2) (95% CI, 0.91-1.08 g/cm(2)) (P = 0.02). Conversely, treatment with placebo, resulted in a 5.7% +/- 1.6% decrease in mean lumbar spine QCT and a 2.3% +/- 0.7% decrease in mean total femoral neck DXA (P = 0.0001 and P = 0.0007 for the comparison of percentage change between the pamidronate and placebo treatments). After pamidronate therapy, serum bone Gla-protein concentrations decreased by 16.8% +/- 5.9%, and urinary deoxypyridinoline excretion rates decreased by 18.5% +/- 12.8% (P < 0.01 respe…","author":[{"dropping-particle":"","family":"Diamond","given":"T H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Winters","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Souza","given":"P","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersley","given":"J H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lynch","given":"W J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bryant","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2001","9","15"]]},"page":"1444-50","title":"The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study.","type":"article-journal","volume":"92"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1097/01.ju.0000063820.94994.95","ISSN":"00225347","author":[{"dropping-particle":"","family":"SMITH","given":"MATTHEW R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"EASTHAM","given":"JAMES","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"GLEASON","given":"DONALD M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"SHASHA","given":"DANIEL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"TCHEKMEDYIAN","given":"SIMON","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ZINNER","given":"NORMAN","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Urology","id":"ITEM-3","issue":"6","issued":{"date-parts":[["2003"]]},"page":"2008-2012","title":"Randomized Controlled Trial of Zoledronic Acid to Prevent Bone Loss in Men Receiving Androgen Deprivation Therapy for Nonmetastatic Prostate Cancer","type":"article-journal","volume":"169"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1016/j.eururo.2005.01.012","ISBN":"0302-2838","ISSN":"03022838","PMID":"15826746","abstract":"Objective: Androgen-deprivation therapy (ADT) is the usual treatment for locally advanced or metastatic prostate cancer. Osteoporosis is a common complication of ADT. The aim of our study was to evaluate the efficacy of neridronate, a relatively new bisphosphonate to prevent bone loss during androgen ablation. Methods: Sixty patients with prostate cancer and osteoporosis were enrolled and randomly assigned to 2 different treatment regimes: group A (30 patients) treated with maximum androgenic blockage (MAB), and group B (30 patients) treated with bicalutamide 150 mg. Each group was divided in 2 subgroups A1-A2 and B1-B2. All patients received calcium and cholecalciferol supplements (500 mg of elemental calcium and 400 IU cholecalciferol) daily. The A2 and B2 subgroups were also treated with neridronate (25 mg intramuscular monthly). Lumbar and femoral bone mineral density (BMD) was evaluated by dualenergy X-ray absorptiometry (DXA), both at baseline and after one year of treatment. Deoxypyridinoline (DPD) and bone-alkaline phosphatase (B-ALP) were determined at the beginning, midstudy and at the end. Results: Patients treated only with calcium and cholecalciferol (A1, B1 subgroups) showed a marked bone loss after 6, and 12 months, with increased levels of DPD and BALP, compared to baseline values. Patients treated with neridronate (A2 et B2 subgroups) showed unchanged levels of these markers. After one year of treatment, lumbar and total hip BMD decreased significantly in patients treated only with calcium and cholecalciferol (A1 subgroup: -4.9% and -1.9% respectively). BMD did not change significantly at any site in patients treated also with neridronate (A2 subgroup: +1% and +0.8% respectively). Lumbar and total hip BMD did not change significantly (-1.5% and -1% respectively) in B1 subgroup. In B2 subgroup an important increase in lumbar spine and the total hip BMD was shown (+2.5% and 1.6% respectively). No relevant side effects were recorded during our study. Conclusion: In conclusion, neridronate is an effective and safe treatment in preventing bone loss in men receiving ADT for prostate cancer. ? 2005 Elsevier B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Magno","given":"Carlo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anastasi","given":"Giuseppina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morabito","given":"Nunziata","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaudio","given":"Agostino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maisano","given":"Domenica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franchina","given":"Fabio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galì","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisina","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melloni","given":"Darwin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-4","issue":"5","issued":{"date-parts":[["2005"]]},"page":"575-580","title":"Preventing bone loss during androgen deprivation therapy for prostate cancer: Early experience with neridronate","type":"article-journal","volume":"47"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.juro.2006.04.078","ISBN":"0022-5347 (Print)\\r0022-5347 (Linking)","ISSN":"00225347","PMID":"16890673","abstract":"PURPOSE: Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. MATERIALS AND METHODS: Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. RESULTS: The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p <0.0001) and 6.7% (p <0.0001), respectively. The effects of zoledronic acid on bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p <0.0001) and were increased in the placebo group (p <0.0001 and p = 0.004, respectively). CONCLUSIONS: Zoledronic acid increased bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.","author":[{"dropping-particle":"","family":"Ryan","given":"Christopher W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huo","given":"Dezheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demers","given":"Laurence M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beer","given":"Tomasz M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Lacerna","given":"Leo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of urology","id":"ITEM-5","issue":"3","issued":{"date-parts":[["2006"]]},"page":"972-978; discussion 978","title":"Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.","type":"article-journal","volume":"176"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1111/j.1464-410X.2007.06853.x","ISBN":"1464-4096 (Print)\\r1464-4096 (Linking)","ISSN":"14644096","PMID":"17552955","abstract":"To report a randomized, placebo-controlled study of treatment with zoledronic acid every 3 months in patients with hormone-sensitive prostate cancer, both with and without bone metastases, to assess the effect on bone mineral density (BMD) and markers of bone turnover.","author":[{"dropping-particle":"","family":"Ryan","given":"Christopher W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huo","given":"Dezheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bylow","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demers","given":"Laurence M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stadler","given":"Walter M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henderson","given":"Tara O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vogelzang","given":"Nicholas J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJU International","id":"ITEM-6","issue":"1","issued":{"date-parts":[["2007"]]},"page":"70-75","title":"Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid","type":"article-journal","volume":"100"},"uris":[""]},{"id":"ITEM-7","itemData":{"DOI":"10.1016/j.eururo.2012.09.007","ISBN":"1873-7560 (Electronic)\\r0302-2838 (Linking)","ISSN":"03022838","PMID":"23040208","abstract":"Background: Androgen-deprivation therapy (ADT) induces loss of bone mineral density (BMD) and increases the risk of fractures in patients with prostate cancer (PCa). We sought to determine whether a weekly dose of alendronate, an oral bisphosphonate, could reduce this unwanted side-effect. Objective: To assess whether once-weekly oral alendronate therapy would maintain or improve BMD in men initiating ADT for localised PCa. Design, setting, and participants: A multicentre, double-blind, randomised, placebo-controlled study, we included hormonally na?ve PCa patients initiating ADT with leuprolide acetate 30 mg intramuscularly every 4 mo. Intervention: Patients were randomised to receive either oral alendronate 70 mg once weekly or placebo for 1 yr. Both groups received daily calcium 1 g and vitamin D 400 international units. Outcome measurements and statistical analysis: Changes in BMD (at the lumbar spine [LS] and total hip [TH]) and bone markers. Results and limitations: One hundred ninety-one subjects were enrolled, and 186 were randomised between alendronate (n = 84) and placebo (n = 102). The alendronate group demonstrated a mean spine BMD increase of 1.7% compared with -1.9% in the placebo group (p < 0.0001). Alendronate also increased the BMD at the hip (percent change: 0.7%) compared to placebo (-1.6%). Median urinary N-terminal crosslinking telopeptide of type I collagen (Ntx) values decreased by 3.5% in the alendronate group and increased by 16.5% in the placebo arm, even after adjusting for centre (p = 0.510) and baseline urinary Ntx (p < 0.0001). Bone-specific alkaline phosphatase (BSAP) decreased a median of 2.25% in the alendronate group and increased a median of 3.12% in the placebo arm, regardless of centre or baseline BSAP or other covariates (p < 0.0001). The safety and tolerability profile was similar for the two treatment groups. Conclusions: Although the study was closed early because of slow accrual, it showed that weekly oral alendronate prevented bone loss and increased bone mass in addition to decreasing bone turnover in patients initiating ADT for localised PCa, with few related side-effects. ? 2012 Published by Elsevier B.V. on behalf of European Association of Urology.","author":[{"dropping-particle":"","family":"Klotz","given":"Laurence H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McNeill","given":"Irene Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kebabdjian","given":"Marlene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Liying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chin","given":"Joseph L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-7","issue":"5","issued":{"date-parts":[["2013"]]},"page":"927-935","title":"A phase 3, double-blind, randomised, parallel-group, placebo-controlled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: The cancer and osteoporosis research with alendronate and leupr","type":"article-journal","volume":"63"},"uris":[""]},{"id":"ITEM-8","itemData":{"author":[{"dropping-particle":"","family":"Choo R, Lukka H, Cheung P","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Radiation Oncology, Biology, Physics","id":"ITEM-8","issued":{"date-parts":[["2013"]]},"page":"1239-1245","title":"Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy.","type":"article-journal","volume":"85"},"uris":[""]},{"id":"ITEM-9","itemData":{"ISSN":"1539-3704","PMID":"17371886","abstract":"BACKGROUND Androgen deprivation therapy (ADT) in men with prostate cancer is associated with bone loss and fractures. OBJECTIVE To determine whether once-weekly oral bisphosphonate can prevent bone loss and reduce bone turnover in men receiving ADT. DESIGN Randomized, double-blind, placebo-controlled, partial crossover trial. First-year, preplanned analysis of a 2-group, parallel-design phase. SETTING University medical center. PATIENTS 112 men with nonmetastatic prostate cancer receiving ADT. INTERVENTION Alendronate, 70 mg once weekly, or placebo. All patients received calcium and vitamin D supplementation. MEASUREMENTS Bone mineral density of the spine and hip and markers of bone resorption and formation. RESULTS At baseline, 39% of men had osteoporosis and 52% had low bone mass. In men treated with alendronate, bone mineral density increased over 1 year by 3.7% (95% CI, 2.8% to 4.6%; P < 0.001) at the spine and 1.6% (CI, 0.4% to 2.8%; P = 0.008) at the femoral neck. Men in the placebo group had losses of 1.4% (CI, -2.7% to - 0.03%; P = 0.045) at the spine and 0.7% (CI, -1.5% to 0.01%; P = 0.081) at the femoral neck. At 12 months, the difference between the 2 groups was 5.1 percentage points (CI, 3.5 to 6.7 percentage points; P < 0.001) at the spine and was 2.3 percentage points (CI, 1.0 to 3.7 percentage points; P < 0.001) at the femoral neck. Bone turnover statistically significantly decreased with active therapy compared with placebo. The groups did not differ in adverse events. LIMITATIONS The study was short (1 year) and was not powered to detect differences in the frequency of fractures. CONCLUSIONS Bone loss that occurred with ADT was prevented and improved with once-weekly oral alendronate. Because most men have low bone mass or osteoporosis, physicians should assess their patients' bone density and provide preventive and therapeutic measures as appropriate. registration number: NCT00048841.","author":[{"dropping-particle":"","family":"Greenspan","given":"Susan L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Joel B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trump","given":"Donald L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resnick","given":"Neil M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of internal medicine","id":"ITEM-9","issue":"6","issued":{"date-parts":[["2007","3","20"]]},"page":"416-24","title":"Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial.","type":"article-journal","volume":"146"},"uris":[""]},{"id":"ITEM-10","itemData":{"DOI":"10.1200/JCO.2007.15.1233","ISBN":"1527-7755 (Electronic)","ISSN":"0732183X","PMID":"18802155","abstract":"PurposeAndrogen-deprivation therapy (ADT) for prostate cancer is associated with bone loss and osteoporotic fractures. Our objective was to examine changes in bone density and turnover with sustained, discontinued, or delayed oral bisphosphonate therapy in men receiving ADT. Patients and MethodsA total of 112 men with nonmetastatic prostate cancer receiving ADT were randomly assigned to alendronate 70 mg once weekly or placebo in a double-blind, partial-crossover trial with a second random assignment at year 2 for those who initially received active therapy. Outcomes included bone mineral density and bone turnover markers. ResultsMen initially randomly assigned to alendronate and randomly reassigned at year 2 to continue had additional bone density gains at the spine (mean, 2.3% {+/-} 0.7) and hip (mean, 1.3% {+/-} 0.5%; both P < .01); those randomly assigned to placebo in year 2 maintained density at the spine and hip but lost (mean, -1.9% {+/-} 0.6%; P < .01) at the forearm. Patients randomly assigned to begin alendronate in year 2 experienced improvements in bone mass at the spine and hip, but experienced less of an increase compared with those who initiated alendronate at baseline. Men receiving alendronate for 2 years experienced a mean 6.7% ({+/-} 1.2%) increase at the spine and a 3.2% ({+/-} 1.5%) at the hip (both P < .05). Bone turnover remained suppressed. ConclusionAmong men with nonmetastatic prostate cancer receiving ADT, once-weekly alendronate improves bone density and decreases turnover. A second year of alendronate provides additional skeletal benefit, whereas discontinuation results in bone loss and increased bone turnover. Delay in bisphosphonate therapy appears detrimental to bone health.","author":[{"dropping-particle":"","family":"Greenspan","given":"Susan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Joel B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trump","given":"Donald L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wagner","given":"Julie M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Megan E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perera","given":"Subashan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resnick","given":"Neil M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-10","issue":"27","issued":{"date-parts":[["2008"]]},"page":"4426-4434","title":"Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy","type":"article-journal","volume":"26"},"uris":[""]},{"id":"ITEM-11","itemData":{"DOI":"10.1200/JCO.2006.07.3361","ISBN":"1527-7755 (Electronic)","ISSN":"0732183X","PMID":"17369566","abstract":"PURPOSE: Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.\\n\\nPATIENTS AND METHODS: In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than -2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.\\n\\nRESULTS: Mean (+/- SE) BMD of the posteroanterior lumbar spine decreased by 3.1% +/- 1.0% in men assigned to placebo and increased by 4.0% +/- 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% +/- 0.7% in men assigned to placebo and increased by 0.7% +/- 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.\\n\\nCONCLUSION: In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.","author":[{"dropping-particle":"","family":"Michaelson","given":"M. Dror","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"Donald S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Hang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGovern","given":"Francis J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kantoff","given":"Philip W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fallon","given":"Mary Anne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finkelstein","given":"Joel S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-11","issue":"9","issued":{"date-parts":[["2007"]]},"page":"1038-1042","title":"Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer","type":"article-journal","volume":"25"},"uris":[""]},{"id":"ITEM-12","itemData":{"DOI":"10.1016/j.juro.2009.07.046","ISBN":"0022-5347","ISSN":"00225347","PMID":"19758618","abstract":"Purpose: Androgen deprivation therapy for prostate cancer is associated with osteoporosis and increased fracture risk. Previous studies of zoledronic acid demonstrated bone loss prevention in patients initiating androgen deprivation therapy. There are limited data on patients on prolonged androgen deprivation therapy or in Veterans Affairs patients with multiple risk factors for osteoporosis. Methods: We randomized 93 patients with M0 prostate cancer in this placebo controlled trial in the Veterans Affairs health care system. Preplanned strata included 50 patients on androgen deprivation therapy for less than 1 year (stratum 1) and 43 on androgen deprivation therapy for greater than 1 year (stratum 2). In each stratum patients were randomized to 4 mg zoledronic acid intravenously every 3 months for 4 treatments or intravenous placebo. The primary end point was the percent change in bone mineral density at the lumbar spine at 12 months. Results: Age, race, body mass index and osteoporosis risk factors were similar for the 2 treatments. Most patients were former smokers, had moderate alcohol intake, were not on calcium/vitamin D supplements and were relatively sedentary at baseline. In stratum 1 spine bone mineral density increased 5.95% in the zoledronic acid arm and decreased 3.23% in the placebo arm (p = 0.0044). In stratum 2 spine bone mineral density increased 6.08% in the zoledronic acid arm and only increased 1.57% in the placebo arm (p = 0.0005). Treatment was well tolerated with minimal impact on renal function. Conclusions: Zoledronic acid improved bone mineral density in patients with M0 prostate cancer on androgen deprivation therapy for 1 year or less, or greater than 1 year. This finding indicates that bisphosphonate therapy remains effective when initiated later in the course of androgen deprivation therapy and is efficacious in Veterans Affairs patients with multiple risk factors for osteoporosis. ? 2009 American Urological Association.","author":[{"dropping-particle":"","family":"Bhoopalam","given":"Nirmala","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Campbell","given":"Steven C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moritz","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Broderick","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iyer","given":"Padmini","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arcenas","given":"Anthony G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Veldhuizen","given":"Peter J.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedman","given":"Nicholas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reda","given":"Domenic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Stuart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garewal","given":"Harinder","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-12","issue":"5","issued":{"date-parts":[["2009"]]},"page":"2257-2264","publisher":"Elsevier Inc.","title":"Intravenous Zoledronic Acid to Prevent Osteoporosis in a Veteran Population With Multiple Risk Factors for Bone Loss on Androgen Deprivation Therapy","type":"article-journal","volume":"182"},"uris":[""]}],"mendeley":{"formattedCitation":"^63–74","plainTextFormattedCitation":"63–74","previouslyFormattedCitation":"^63–74"},"properties":{"noteIndex":0},"schema":""}63–74. Bisphosphonates including pamidronate sodium, neridronic acid, risedronate sodium, zoledronic acid and alendronate have been shown to be effective in the prevention of BMD loss at the lumbar spine (LS), femoral neck and total hip. The largest and most recent study included 186 men with locally advanced PC randomised to receive alendronate or placebo ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.eururo.2012.09.007","ISBN":"1873-7560 (Electronic)\\r0302-2838 (Linking)","ISSN":"03022838","PMID":"23040208","abstract":"Background: Androgen-deprivation therapy (ADT) induces loss of bone mineral density (BMD) and increases the risk of fractures in patients with prostate cancer (PCa). We sought to determine whether a weekly dose of alendronate, an oral bisphosphonate, could reduce this unwanted side-effect. Objective: To assess whether once-weekly oral alendronate therapy would maintain or improve BMD in men initiating ADT for localised PCa. Design, setting, and participants: A multicentre, double-blind, randomised, placebo-controlled study, we included hormonally na?ve PCa patients initiating ADT with leuprolide acetate 30 mg intramuscularly every 4 mo. Intervention: Patients were randomised to receive either oral alendronate 70 mg once weekly or placebo for 1 yr. Both groups received daily calcium 1 g and vitamin D 400 international units. Outcome measurements and statistical analysis: Changes in BMD (at the lumbar spine [LS] and total hip [TH]) and bone markers. Results and limitations: One hundred ninety-one subjects were enrolled, and 186 were randomised between alendronate (n = 84) and placebo (n = 102). The alendronate group demonstrated a mean spine BMD increase of 1.7% compared with -1.9% in the placebo group (p < 0.0001). Alendronate also increased the BMD at the hip (percent change: 0.7%) compared to placebo (-1.6%). Median urinary N-terminal crosslinking telopeptide of type I collagen (Ntx) values decreased by 3.5% in the alendronate group and increased by 16.5% in the placebo arm, even after adjusting for centre (p = 0.510) and baseline urinary Ntx (p < 0.0001). Bone-specific alkaline phosphatase (BSAP) decreased a median of 2.25% in the alendronate group and increased a median of 3.12% in the placebo arm, regardless of centre or baseline BSAP or other covariates (p < 0.0001). The safety and tolerability profile was similar for the two treatment groups. Conclusions: Although the study was closed early because of slow accrual, it showed that weekly oral alendronate prevented bone loss and increased bone mass in addition to decreasing bone turnover in patients initiating ADT for localised PCa, with few related side-effects. ? 2012 Published by Elsevier B.V. on behalf of European Association of Urology.","author":[{"dropping-particle":"","family":"Klotz","given":"Laurence H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McNeill","given":"Irene Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kebabdjian","given":"Marlene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Liying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chin","given":"Joseph L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013"]]},"page":"927-935","title":"A phase 3, double-blind, randomised, parallel-group, placebo-controlled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: The cancer and osteoporosis research with alendronate and leupr","type":"article-journal","volume":"63"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷¹","plainTextFormattedCitation":"71","previouslyFormattedCitation":"⁷¹"},"properties":{"noteIndex":0},"schema":""}71. The mean change in LS BMD was +1.7% in the alendronate group and -1.9% with placebo (p<0.0001), with a significant reduction in biomarkers of bone turnover (BTM) in those receiving bisphosphonates, and a similar rate of adverse events. However, published studies to date have had important limitations including; small patient numbers, heterogeneous populations, variation in type and frequency of bisphosphonate administration, and varying follow-up schedules. No study has been sufficiently powered to detect differences in fracture incidence alone. Only one non-randomised study has sought to compare efficacy of different bisphosphonates ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1442-2042.2006.01721.x","ISSN":"0919-8172","PMID":"17470161","abstract":"To establish whether androgen deprivation therapy (ADT) promotes osteoporosis and osteopenia","author":[{"dropping-particle":"","family":"Rodrigues","given":"Paulo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hering","given":"Flavio O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruna","given":"Paulo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meller","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Afonso","given":"Yuri","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International journal of urology : official journal of the Japanese Urological Association","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2007"]]},"page":"317-20","title":"Comparative study of the protective effect of different intravenous bisphosphonates on the decrease in bone mineral density in patients submitted to radical prostatectomy undergoing androgen deprivation therapy. A prospective open-label controlled study.","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁵","plainTextFormattedCitation":"75","previouslyFormattedCitation":"⁷⁵"},"properties":{"noteIndex":0},"schema":""}75. A meta-analysis of 15 randomised studies including 2,634 patients receiving ADT for PC sought to determine the fracture rate, changes in BMD, incidence of osteoporosis, and adverse events associated with bisphosphonate use ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/pcan.2011.4","ISBN":"1365-7852","ISSN":"1476-5608","PMID":"21894175","abstract":"The objective of this study was to clarify the role of bisphosphonates in the treatment of osteoporosis in patients with prostate adenocarcinoma under androgen deprivation therapy (ADT). The Medline, EMBASE, Cancerlit and the American Society of Clinical Oncology abstract databases were searched for published randomized, placebo-controlled trials evaluating the usage of bisphosphonates in patients with prostate cancer (PC) under ADT. The outcomes assessed were fracture, osteoporosis, incidence of adverse events and changes in bone mineral density (BMD) during treatment. A total of 15 articles (2634 participants) were included in the meta-analysis. Treatment with bisphosphonates showed a substantial effect in preventing fractures (risk ratio (RR), 0.80; P = 0.005) and osteoporosis (RR, 0.39; P <0.00001). Zoledronic acid showed the best number needed to treat (NTT), compared with placebo, in relation to fractures and osteoporosis (NNT = 14.9 and NNT = 2.68, respectively). The between-group difference (bisphosphonates vs placebo) in the lumbar spine and femoral neck BMD were 5.18 ± 3.38% and 2.35 ± 1.16%, respectively. This benefit of bone loss prevention could be reached without major side effects (cardiovascular or gastrointestinal events). Bisphosphonates are effective in preventing bone loss in patients with PC who are under ADT.","author":[{"dropping-particle":"","family":"Serpa Neto","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tobias-Machado","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Esteves","given":"M a P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Senra","given":"M D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wroclawski","given":"M L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fonseca","given":"F L a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reis","given":"R B","non-dropping-particle":"Dos","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pompeo","given":"a C L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giglio","given":"a D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Prostate cancer and prostatic diseases","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2012"]]},"page":"36-44","publisher":"Nature Publishing Group","title":"Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis.","type":"article-journal","volume":"15"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁶","plainTextFormattedCitation":"76","previouslyFormattedCitation":"⁷⁶"},"properties":{"noteIndex":0},"schema":""}76. Treatment with bisphosphonate had a substantial effect in both fracture prevention (RR 0.8, 95% CI 0.69 to 0.94, p=0.005) and osteoporosis reduction (RR 0.39, 95% CI 0.28 to 0.55 for total analysis, p<0.00001). Most studies that compared zoledronic acid with placebo used a 4mg dose administered 3 monthly. However, the usual recommended dose is 5mg annually for the treatment of osteoporosis that is not related to ADT, and the optimal dosing schedule is unclear. There were no significant increases in major adverse events associated with bisphosphonate treatment, which the authors concluded was safe and effective in the prevention of CTIBL in men with PC receiving ADT.Although evidence suggests that bisphosphonates may have a role in the preservation of BMD in men receiving ADT for PC, no bisphosphonate is currently approved for this purpose. Large, prospective randomised studies are required to determine which bisphosphonate has greatest efficacy and cost-efficacy in the prevention of CTIBL, optimal dosing schedules, and detection of differences in fracture risk reduction.DenosumabA placebo-controlled trial of denosumab in 1,468 men receiving ADT for non-metastatic PC found that 60mg denosumab administered subcutaneously every 6 months increased LS BMD by 5.6% after 24 months, whereas treatment with placebo was associated with a 1.0% reduction (p<0.001) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.juro.2009.08.048","ISBN":"1527-3792 (Electronic)\r0022-5347 (Linking)","ISSN":"1527-3792","PMID":"19836774","abstract":"PURPOSE: In a recently completed 3-year, randomized, double-blind study, denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappaB ligand, significantly increased bone mineral density and decreased new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. We conducted subgroup analyses to evaluate the relationships between subject characteristics and the effects of denosumab on bone mineral density at multiple skeletal sites.\\n\\nMATERIALS AND METHODS: A total of 1,468 subjects were randomized 1:1 to receive 60 mg subcutaneous denosumab every 6 months or placebo for 36 months. In these analyses we evaluated the effects of denosumab on bone mineral density at the lumbar spine, total hip and distal 1/3 radius (substudy of 309 subjects) during 36 months in specific subgroups according to age, duration and type of prior androgen deprivation therapy, bone mineral density T score, weight, body mass index, bone turnover marker levels and prevalent vertebral fractures.\\n\\nRESULTS: After 36 months denosumab significantly increased bone mineral density of the lumbar spine, total hip and distal 1/3 radius by 7.9%, 5.7% and 6.9%, respectively, compared with placebo (p <0.0001 for each comparison). Denosumab significantly increased bone mineral density to a degree similar to that observed in the overall analysis for every subgroup including older men as well as those with prevalent fractures, lower baseline bone mineral density, and higher serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b. Mean increases in bone mineral density at each skeletal site were greatest for men with the highest levels of serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b.\\n\\nCONCLUSIONS: Denosumab significantly and consistently increased bone mineral density at all skeletal sites and in every subgroup, including men at greatest risk for bone loss and fractures.","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Fred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egerdie","given":"Blair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szwedowski","given":"Maciej","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tammela","given":"Teuvo L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ke","given":"Chunlei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leder","given":"Benjamin Z","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goessl","given":"Carsten","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of urology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2009"]]},"page":"2670-5","publisher":"Elsevier Inc.","title":"Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.","type":"article-journal","volume":"182"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁷","plainTextFormattedCitation":"77","previouslyFormattedCitation":"⁷⁷"},"properties":{"noteIndex":0},"schema":""}77. Denosumab was also associated with a reduced incidence of new vertebral fractures after 36 months (1.5% with denosumab versus 3.9% with placebo; RR 0.38; 95% CI 0.19–0.78) and a non-significant decrease in fracture incidence at any site. Further subgroup analysis reported that denosumab was associated with significant and consistent increases in BMD at all sites, and in every subgroup analysed (including older men, longer ADT duration, lower baseline T scores, biomarkers of bone turnover, and prevalent vertebral fractures) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.juro.2009.08.048","ISBN":"1527-3792 (Electronic)\r0022-5347 (Linking)","ISSN":"1527-3792","PMID":"19836774","abstract":"PURPOSE: In a recently completed 3-year, randomized, double-blind study, denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappaB ligand, significantly increased bone mineral density and decreased new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. We conducted subgroup analyses to evaluate the relationships between subject characteristics and the effects of denosumab on bone mineral density at multiple skeletal sites.\\n\\nMATERIALS AND METHODS: A total of 1,468 subjects were randomized 1:1 to receive 60 mg subcutaneous denosumab every 6 months or placebo for 36 months. In these analyses we evaluated the effects of denosumab on bone mineral density at the lumbar spine, total hip and distal 1/3 radius (substudy of 309 subjects) during 36 months in specific subgroups according to age, duration and type of prior androgen deprivation therapy, bone mineral density T score, weight, body mass index, bone turnover marker levels and prevalent vertebral fractures.\\n\\nRESULTS: After 36 months denosumab significantly increased bone mineral density of the lumbar spine, total hip and distal 1/3 radius by 7.9%, 5.7% and 6.9%, respectively, compared with placebo (p <0.0001 for each comparison). Denosumab significantly increased bone mineral density to a degree similar to that observed in the overall analysis for every subgroup including older men as well as those with prevalent fractures, lower baseline bone mineral density, and higher serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b. Mean increases in bone mineral density at each skeletal site were greatest for men with the highest levels of serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b.\\n\\nCONCLUSIONS: Denosumab significantly and consistently increased bone mineral density at all skeletal sites and in every subgroup, including men at greatest risk for bone loss and fractures.","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Fred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egerdie","given":"Blair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szwedowski","given":"Maciej","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tammela","given":"Teuvo L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ke","given":"Chunlei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leder","given":"Benjamin Z","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goessl","given":"Carsten","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of urology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2009"]]},"page":"2670-5","publisher":"Elsevier Inc.","title":"Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.","type":"article-journal","volume":"182"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁷","plainTextFormattedCitation":"77","previouslyFormattedCitation":"⁷⁷"},"properties":{"noteIndex":0},"schema":""}77. Patients that received denosumab also experienced a significant suppression of BTM compared with placebo ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jbmr.492","ISSN":"1523-4681","PMID":"21898590","abstract":"Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (<? 70 years versus ≥? 70 years), prior duration of ADT (≤? 6 months versus > 6 months), and baseline BTM (≤? median versus >? median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was -90% in the denosumab group and -3% in the placebo group (p? <? 0.0001). The median change in TRAP-5b levels at month 1 was -55% in the denosumab group and -3% in the placebo group (p?<? 0.0001). The maximal median change in P1NP was -64% in the denosumab group and -11% in the placebo group, (p ?<? 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Fred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egerdie","given":"Blair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sieber","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tammela","given":"Teuvo Lj","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leder","given":"Benjamin Z","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ke","given":"Chunlei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goessl","given":"Carsten","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2011","12"]]},"page":"2827-33","publisher":"NIH Public Access","title":"Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer.","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁸","plainTextFormattedCitation":"78","previouslyFormattedCitation":"⁷⁸"},"properties":{"noteIndex":0},"schema":""}78. A randomised study in 234 men with PC receiving ADT and a T score <-1.0 compared denosumab with weekly alendronic acid for 2 years ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.11138/ccmbm/2016.13.3.195","ISSN":"1724-8914","PMID":"28228781","abstract":"INTRODUCTION Osteoporosis is a complication of androgen deprivation therapy (ADT) in men with prostate carcinoma. The best defense against osteoporosis in prostate cancer is to identify patients with a high risk for fracture during the first clinical visit, select an effective anti-osteoporosis agent, and advise the patient to change his lifestyle and diet to prevent further bone loss. New agents include denosumab, a human monoclonal antibody that inhibits the RANK ligand (RANKL). RANKL promotes the formation, activity, and survival of osteoclasts and, thus, supports the breakdown of bone. PURPOSE This is a multicenter, randomized, double-blind prospective study on use of denosumab versus alendronate in the therapy of secondary osteoporosis related to ADT in prostate cancer patients in three European countries (Italy, France, Switzerland). PATIENTS AND METHODS In this 24-month observation study we enrolled 234 patients with diagnosis of osteoporosis underwent ADT for prostate cancer. All patients aged ≥55 years and had a dual-energy X-ray absorptiometry (DEXA) T-score <-1.0 (hip or spine, measured within last 2 years) and ≥ 1 fragility fracture. Patients were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months or alendronate (70 mg weekly) for 2 years. All patient received supplemental vitamin D (600 IU per day) and supplemental calcium to maintain a calcium intake of 1200 mg per day. Effectiveness of therapy in both groups (denosumab group and alendronate group) was assessed by changes in bone turnover markers (BTMs), Bone Mineral Density (BMD), fracture incidence, Visual Analogue Scale (VAS) score for back pain, and Short Form-8 (SF-8TM) health survey score for health-related quality of life (HRQoL). Percent changes from baseline in BTMs and BMD were assessed using the paired t test; a P-value 0.05). Mean changes in BMD at final follow-up differed significantly between two groups. BMD changes at the lumbar spine at 24 months were 5.6% with denosumab vs -1.1% with alendronate (P<0.001). New vertebral fractures developed in fewer patients in the denosumab group than in the alendronate group during the 24-month period, although this difference was not significant (P=0.10). Back pain significantly (P<0.001) improved from baseline at all time points during the study in both study groups. SF-8 health survey scores significantly improved following treatment with both drugs. Incidence of adverse drug reactions were similar in both g…","author":[{"dropping-particle":"","family":"Doria","given":"Carlo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leali","given":"Paolo Tranquilli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solla","given":"Federico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maestretti","given":"Gianluca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balsano","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scarpa","given":"Robero Mario","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2016"]]},"page":"195-199","publisher":"CIC Edizioni Internazionali","title":"Denosumab is really effective in the treatment of osteoporosis secondary to hypogonadism in prostate carcinoma patients? A prospective randomized multicenter international study.","type":"article-journal","volume":"13"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁹","plainTextFormattedCitation":"79","previouslyFormattedCitation":"⁷⁹"},"properties":{"noteIndex":0},"schema":""}79. Denosumab was superior in terms of improved LS BMD after 2 years (+5.6% in denosumab group vs -1.1% with alendronic acid, p<0.001). Incidence of vertebral fractures, pain reduction and adverse events were similar. On the basis of these results, denosumab has been authorised by the European Medicines Authority for use in the prevention of CTIBL associated with ADT. Bisphosphonates and denosumab are associated with similar adverse effects, the most serious of which is osteonecrosis of the jaw (ONJ). Studies of denosumab in men with both metastatic PC and non-metastatic CRPC have reported an ONJ incidence of 5% or less ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0140-6736(11)61226-9","abstract":"Background-Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition may prevent bone metastases. This phase 3 study evaluated denosumab, a fully human anti-RANKL monoclonal antibody, to","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Fred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Coleman","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Neal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fizazi","given":"Karim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tombal","given":"Bertrand","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Kurt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sieber","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karsh","given":"Lawrence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dami?o","given":"Ronaldo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tammela","given":"Teuvo L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egerdie","given":"Blair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Poppel","given":"Hendrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chin","given":"Joseph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morote","given":"Juan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gómez-Veiga","given":"Francisco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borkowski","given":"Tomasz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ye","given":"Zhishen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kupic","given":"Amy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dansey","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goessl","given":"Carsten","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Denosumab and Bone Metastasis-Free Survival in Men With Castration-Resistant Prostate Cancer: Results of a Global Phase 3, Randomised, Placebo-Controlled Trial","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁰","plainTextFormattedCitation":"80","previouslyFormattedCitation":"⁸⁰"},"properties":{"noteIndex":0},"schema":""}80,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"Lancet 377:813–822","author":[{"dropping-particle":"","family":"Fizazi K, Carducci M, Smith M, Damia?o R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R","given":"Goessl C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"page":"813-822","title":"Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study","type":"article-journal","volume":"377"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸¹","plainTextFormattedCitation":"81","previouslyFormattedCitation":"⁸¹"},"properties":{"noteIndex":0},"schema":""}81. Similarly, the frequency of ONJ with bisphosphonate use in men with PC is 1-2% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"Lancet 377:813–822","author":[{"dropping-particle":"","family":"Fizazi K, Carducci M, Smith M, Damia?o R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R","given":"Goessl C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Lancet","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"page":"813-822","title":"Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study","type":"article-journal","volume":"377"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸¹","plainTextFormattedCitation":"81","previouslyFormattedCitation":"⁸¹"},"properties":{"noteIndex":0},"schema":""}81,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/14651858.CD006250","ISSN":"1469-493X","PMID":"17054286","abstract":"BACKGROUND Prostate cancer is the most common cancer in men in many western countries. It is characterized by its propensity for bone metastases which occur in more than 80% of patients with advanced disease. Patients are at risk of complications including pain, hypercalcaemia, bone fracture and spinal cord compression. Hormonal treatment is the mainstay of treatment for these patients but most of them will then become hormone refractory. Bisphosphonates act by inhibiting osteoclast activities and are a potential therapeutic option for metastatic prostate cancer. In addition, they have been shown to reduce pain in patients with bone metastases as a consequence of multiple myeloma. Early uncontrolled studies of bisphosphonates in metastatic prostate cancer patients have shown encouraging results. OBJECTIVES The objective of this review was to determine the effectiveness of bisphosphonates in relieving pain in patients with bone metastases from prostate cancer. SEARCH STRATEGY Studies were identified by electronic search of bibliographic databases including MEDLINE, EMBASE, CancerLit and the Cochrane Controlled Trials Register. Handsearching included Proceedings of American Society of Clinical Oncology and reference lists of all eligible trials identified. SELECTION CRITERIA Randomised controlled studies comparing the effectiveness of bisphosphonates with placebo or open control for pain relief in patients with bone metastases from prostate cancer. DATA COLLECTION AND ANALYSIS Data were extracted from eligible studies and included study design, participants, interventions and outcomes. Comparable data were pooled together for meta-analysis with intention-to-treat principle. Outcomes included pain response, analgesic consumption, skeletal events (including pathological fractures, spinal cord compression, bone radiotherapy, bone surgery), prostate cancer death, disease progression, radiological response, PSA response, adverse events, performance status, quality of life and comparisons between different routes, doses and types of bisphosphonates. MAIN RESULTS One thousand nine hundred and fifty-five patients from ten studies were included in this review. The pain response rates were 27.9% and 21.1% for the treatment group and the control group, respectively, with an absolute risk difference of 6.8%. The OR for pain response was 1.54 (95% CI 0.97 to 2.44, P = 0.07), showing a trend of improved pain relief in the bisphosphonate group, although this was not sta…","author":[{"dropping-particle":"","family":"Macherey S, Monsef I, Jahn F, Jordan K, Yuen KK, Heidenreich A","given":"Skoetz N","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Cochrane database of systematic reviews","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2006"]]},"page":"CD006250","title":"Bisphosphonates for advanced prostate cancer.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸²","plainTextFormattedCitation":"82","previouslyFormattedCitation":"⁸²"},"properties":{"noteIndex":0},"schema":""}82. These are based on doses used in metastatic bone disease (4mg zoledronic acid or 120mg denosumab every 4 weeks). The incidence of ONJ in the osteoporosis patient population is significantly less, estimated at between 0.001% and 0.01% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jbmr.2405","ISSN":"08840431","PMID":"25414052","abstract":"This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser the…","author":[{"dropping-particle":"","family":"Khan","given":"Aliya A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Archie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanley","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Felsenberg","given":"Dieter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCauley","given":"Laurie K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Ryan","given":"Felice","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reid","given":"Ian R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruggiero","given":"Salvatore L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taguchi","given":"Akira","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tetradis","given":"Sotirios","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watts","given":"Nelson B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brandi","given":"Maria Luisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peters","given":"Edmund","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guise","given":"Teresa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eastell","given":"Richard","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheung","given":"Angela M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morin","given":"Suzanne N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Masri","given":"Basel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Cyrus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morgan","given":"Sarah L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Obermayer-Pietsch","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Langdahl","given":"Bente L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dabagh","given":"Rana","non-dropping-particle":"Al","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davison","given":"K. Shawn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kendler","given":"David L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sándor","given":"George K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Josse","given":"Robert G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhandari","given":"Mohit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rabbany","given":"Mohamed","non-dropping-particle":"El","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pierroz","given":"Dominique D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sulimani","given":"Riad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunders","given":"Deborah P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"Jacques P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Compston","given":"Juliet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"International Task Force on Osteonecrosis of the Jaw","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Bone and Mineral Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015","1"]]},"page":"3-23","title":"Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸³","plainTextFormattedCitation":"83","previouslyFormattedCitation":"⁸³"},"properties":{"noteIndex":0},"schema":""}83. Both denosumab and bisphosphonates are also associated with an increased risk of hypocalcaemia. When denosumab is given twice yearly to men with PC on ADT, the incidence of hypocalcaemia is reported as less than 1% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa0809003","ISSN":"0028-4793","PMID":"19671656","abstract":"BACKGROUND Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. METHODS In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures. RESULTS At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups. CONCLUSIONS Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. ( number, NCT00089674.)","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Egerdie","given":"Blair","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toriz","given":"Narciso Hernández","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tammela","given":"Teuvo L.J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Fred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heracek","given":"Jiri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szwedowski","given":"Maciej","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ke","given":"Chunlei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kupic","given":"Amy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leder","given":"Benjamin Z.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goessl","given":"Carsten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Denosumab HALT Prostate Cancer Study Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2009","8","20"]]},"page":"745-755","title":"Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer","type":"article-journal","volume":"361"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁰","plainTextFormattedCitation":"60","previouslyFormattedCitation":"⁶⁰"},"properties":{"noteIndex":0},"schema":""}60.Other pharmacological treatments for osteoporosis (including the selective oestrogen receptor modulators raloxifene and toremifene) are not currently recommended to prevent bone loss in men with PC receiving ADT. Teriparatide (recombinant PTH) is contraindicated in patients with metastatic bone disease and in those who have received prior radiotherapy.-7200907484110Abbreviations: PC: prostate cancer; BM: bone metastasis; MAB: maximum androgen blockade; ADT: androgen deprivation; LS: lumbar spine; BMD: bone mineral density; OP: osteoporosis00Abbreviations: PC: prostate cancer; BM: bone metastasis; MAB: maximum androgen blockade; ADT: androgen deprivation; LS: lumbar spine; BMD: bone mineral density; OP: osteoporosisTable 1: Randomised studies of the effect of bisphosphonates in men receiving ADT for PCYearStudy populationNStudy groupsFollow-upKey findings2001ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa010845","ISSN":"0028-4793","PMID":"11575286","abstract":"BACKGROUND Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist. METHODS In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study. RESULTS In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02). CONCLUSIONS Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.","author":[{"dropping-particle":"","family":"Smith","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGovern","given":"Francis J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zietman","given":"Anthony L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fallon","given":"Mary Anne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayden","given":"Douglas L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoenfeld","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kantoff","given":"Philip W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finkelstein","given":"Joel S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"13","issued":{"date-parts":[["2001","9","27"]]},"page":"948-955","title":"Pamidronate to Prevent Bone Loss during Androgen-Deprivation Therapy for Prostate Cancer","type":"article-journal","volume":"345"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶³","plainTextFormattedCitation":"63","previouslyFormattedCitation":"⁶³"},"properties":{"noteIndex":0},"schema":""}63Locally advanced or recurrent PC47Pamidronate + ADT vs ADT only48 weeksNo significant BMD change in pamidronate groupSignificant loss of BMD at LS and hip in ADT only group (-3.3% and -1.8%, p<0.001)2001ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0008-543X","PMID":"11745221","abstract":"BACKGROUND Prostate carcinoma therapy with combined androgen blockade may result in high bone-turnover with significant bone loss. This study was undertaken to evaluate the antiosteoporotic efficacy of intravenous pamidronate in a double blind, randomized, placebo-controlled, crossover study. METHODS Twenty-one consecutive men with metastatic prostate carcinoma who were receiving combined androgen blockade with a long-acting gonadotropin-releasing hormone agonist (gosarelin acetate) and an androgen antagonist (flutamide or bicalutamide) were evaluated at baseline and at 6 and 12 months after therapy. They were randomly assigned to receive a single intravenous infusion of 500 mL of normal saline solution diluted with either pamidronate (90 mg) or placebo at baseline and with a crossover at 6 months. Lumbar-spine bone-mineral densities (BMDs) were measured by spinal quantitative computed tomography (QCT), femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA), and markers of bone turnover were measured by noninvasive methods. Data on 10 men with localized prostate carcinoma who were treated with radiotherapy alone, over the same period, was collected for comparison studies. RESULTS The mean age of the men was 75.1 years +/- 1.6 years. One man withdrew from the study because of deteriorating health, and two died from metastatic disease within the first 6 months. Combined androgen blockade normalized serum prostate-specific antigen activities (from an initial mean value of 86.2 ng/mL +/- 10.1 ng/mL) and maintained serum free testosterone concentrations in the hypogonadal range (< 2.2 pmol/L) in all men throughout the study. Treatment with pamidronate resulted in a 7.8% +/- 1.5% increase in mean lumbar spine QCT from 79.4 mg/cm(3) (95% confidence interval [CI], 64-94 mg/cm(3)) to 85.6 mg/cm(3) (95% CI, 70-101 mg/cm(3)) (P = 0.0005) and a 2% +/- 0.9% increase in mean total femoral neck DXA from 0.98 g/cm(2) (95% CI, 0.90 -1.05 g/cm(2)) to 1.0 mg/cm(2) (95% CI, 0.91-1.08 g/cm(2)) (P = 0.02). Conversely, treatment with placebo, resulted in a 5.7% +/- 1.6% decrease in mean lumbar spine QCT and a 2.3% +/- 0.7% decrease in mean total femoral neck DXA (P = 0.0001 and P = 0.0007 for the comparison of percentage change between the pamidronate and placebo treatments). After pamidronate therapy, serum bone Gla-protein concentrations decreased by 16.8% +/- 5.9%, and urinary deoxypyridinoline excretion rates decreased by 18.5% +/- 12.8% (P < 0.01 respe…","author":[{"dropping-particle":"","family":"Diamond","given":"T H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Winters","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Souza","given":"P","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersley","given":"J H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lynch","given":"W J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bryant","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2001","9","15"]]},"page":"1444-50","title":"The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study.","type":"article-journal","volume":"92"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁴","plainTextFormattedCitation":"64","previouslyFormattedCitation":"⁶⁴"},"properties":{"noteIndex":0},"schema":""}64Metastatic PC21MAB + pamidronate vs MAB12 monthsSignificant increase in LS (+7.8% vs -5.7% p=0.0001) and femoral neck (+2.0% vs -2.3% p=0.0007) BMD in pamidronate group compared to MAB group 2003ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/01.ju.0000063820.94994.95","ISSN":"00225347","author":[{"dropping-particle":"","family":"SMITH","given":"MATTHEW R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"EASTHAM","given":"JAMES","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"GLEASON","given":"DONALD M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"SHASHA","given":"DANIEL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"TCHEKMEDYIAN","given":"SIMON","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"ZINNER","given":"NORMAN","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Urology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2003"]]},"page":"2008-2012","title":"Randomized Controlled Trial of Zoledronic Acid to Prevent Bone Loss in Men Receiving Androgen Deprivation Therapy for Nonmetastatic Prostate Cancer","type":"article-journal","volume":"169"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁷","plainTextFormattedCitation":"67","previouslyFormattedCitation":"⁶⁷"},"properties":{"noteIndex":0},"schema":""}67Non-metastatic PC106Zoledronic acid + ADT vs ADT12 monthsZoledronic acid associated with increased LS BMD compared to ADT alone (5.6% Vs -2.2%, p<0.001)2005ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.eururo.2005.01.012","ISBN":"0302-2838","ISSN":"03022838","PMID":"15826746","abstract":"Objective: Androgen-deprivation therapy (ADT) is the usual treatment for locally advanced or metastatic prostate cancer. Osteoporosis is a common complication of ADT. The aim of our study was to evaluate the efficacy of neridronate, a relatively new bisphosphonate to prevent bone loss during androgen ablation. Methods: Sixty patients with prostate cancer and osteoporosis were enrolled and randomly assigned to 2 different treatment regimes: group A (30 patients) treated with maximum androgenic blockage (MAB), and group B (30 patients) treated with bicalutamide 150 mg. Each group was divided in 2 subgroups A1-A2 and B1-B2. All patients received calcium and cholecalciferol supplements (500 mg of elemental calcium and 400 IU cholecalciferol) daily. The A2 and B2 subgroups were also treated with neridronate (25 mg intramuscular monthly). Lumbar and femoral bone mineral density (BMD) was evaluated by dualenergy X-ray absorptiometry (DXA), both at baseline and after one year of treatment. Deoxypyridinoline (DPD) and bone-alkaline phosphatase (B-ALP) were determined at the beginning, midstudy and at the end. Results: Patients treated only with calcium and cholecalciferol (A1, B1 subgroups) showed a marked bone loss after 6, and 12 months, with increased levels of DPD and BALP, compared to baseline values. Patients treated with neridronate (A2 et B2 subgroups) showed unchanged levels of these markers. After one year of treatment, lumbar and total hip BMD decreased significantly in patients treated only with calcium and cholecalciferol (A1 subgroup: -4.9% and -1.9% respectively). BMD did not change significantly at any site in patients treated also with neridronate (A2 subgroup: +1% and +0.8% respectively). Lumbar and total hip BMD did not change significantly (-1.5% and -1% respectively) in B1 subgroup. In B2 subgroup an important increase in lumbar spine and the total hip BMD was shown (+2.5% and 1.6% respectively). No relevant side effects were recorded during our study. Conclusion: In conclusion, neridronate is an effective and safe treatment in preventing bone loss in men receiving ADT for prostate cancer. ? 2005 Elsevier B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Magno","given":"Carlo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Anastasi","given":"Giuseppina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morabito","given":"Nunziata","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaudio","given":"Agostino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maisano","given":"Domenica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franchina","given":"Fabio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galì","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisina","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Melloni","given":"Darwin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2005"]]},"page":"575-580","title":"Preventing bone loss during androgen deprivation therapy for prostate cancer: Early experience with neridronate","type":"article-journal","volume":"47"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁸","plainTextFormattedCitation":"68","previouslyFormattedCitation":"⁶⁸"},"properties":{"noteIndex":0},"schema":""}68Locally advanced PC, OP at baseline60MAB vsMAB + neridronic acid vs bicalutamide vs bicalutamide + neridronic acid12 monthsMAB group experienced significant BMD loss at LS and hip (-4.9% and -1.9%; p=0.002 and 0.004 respectively)No BMD change in the MAB and neridronic acid groupNon-significant BMD loss in bicalutamide groupBMD increase at LS (+2.5%; p<0.05) and hip (+1.6%; p<0.05) in bicalutamide + neridronic acid group2006 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.juro.2006.04.078","ISBN":"0022-5347 (Print)\\r0022-5347 (Linking)","ISSN":"00225347","PMID":"16890673","abstract":"PURPOSE: Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. MATERIALS AND METHODS: Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. RESULTS: The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p <0.0001) and 6.7% (p <0.0001), respectively. The effects of zoledronic acid on bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p <0.0001) and were increased in the placebo group (p <0.0001 and p = 0.004, respectively). CONCLUSIONS: Zoledronic acid increased bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.","author":[{"dropping-particle":"","family":"Ryan","given":"Christopher W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huo","given":"Dezheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demers","given":"Laurence M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beer","given":"Tomasz M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Lacerna","given":"Leo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of urology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2006"]]},"page":"972-978; discussion 978","title":"Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.","type":"article-journal","volume":"176"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁹","plainTextFormattedCitation":"69","previouslyFormattedCitation":"⁶⁹"},"properties":{"noteIndex":0},"schema":""}69Non metastatic PC and received ADT < 12 months120Zoledronic acid + ADT vs placebo + ADT12 monthsIncrease in LS and hip BMD in zoledronic acid group compared with placebo (p<0.0001 for both)2007ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1464-410X.2007.06853.x","ISBN":"1464-4096 (Print)\\r1464-4096 (Linking)","ISSN":"14644096","PMID":"17552955","abstract":"To report a randomized, placebo-controlled study of treatment with zoledronic acid every 3 months in patients with hormone-sensitive prostate cancer, both with and without bone metastases, to assess the effect on bone mineral density (BMD) and markers of bone turnover.","author":[{"dropping-particle":"","family":"Ryan","given":"Christopher W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huo","given":"Dezheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bylow","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Demers","given":"Laurence M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stadler","given":"Walter M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henderson","given":"Tara O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vogelzang","given":"Nicholas J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJU International","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2007"]]},"page":"70-75","title":"Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid","type":"article-journal","volume":"100"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁰","plainTextFormattedCitation":"70","previouslyFormattedCitation":"⁷⁰"},"properties":{"noteIndex":0},"schema":""}70Localised and metastatic PC receiving ADT <12 months42Zoledronic acid + ADT vs placebo + ADT12 monthsIncrease in LS (+4.9% vs -2.2% p<0.0001) and femoral neck (0.9% vs -3.2% p<0.0001) BMD in zoledronic acid group compared with placebo 2007 /8 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"1539-3704","PMID":"17371886","abstract":"BACKGROUND Androgen deprivation therapy (ADT) in men with prostate cancer is associated with bone loss and fractures. OBJECTIVE To determine whether once-weekly oral bisphosphonate can prevent bone loss and reduce bone turnover in men receiving ADT. DESIGN Randomized, double-blind, placebo-controlled, partial crossover trial. First-year, preplanned analysis of a 2-group, parallel-design phase. SETTING University medical center. PATIENTS 112 men with nonmetastatic prostate cancer receiving ADT. INTERVENTION Alendronate, 70 mg once weekly, or placebo. All patients received calcium and vitamin D supplementation. MEASUREMENTS Bone mineral density of the spine and hip and markers of bone resorption and formation. RESULTS At baseline, 39% of men had osteoporosis and 52% had low bone mass. In men treated with alendronate, bone mineral density increased over 1 year by 3.7% (95% CI, 2.8% to 4.6%; P < 0.001) at the spine and 1.6% (CI, 0.4% to 2.8%; P = 0.008) at the femoral neck. Men in the placebo group had losses of 1.4% (CI, -2.7% to - 0.03%; P = 0.045) at the spine and 0.7% (CI, -1.5% to 0.01%; P = 0.081) at the femoral neck. At 12 months, the difference between the 2 groups was 5.1 percentage points (CI, 3.5 to 6.7 percentage points; P < 0.001) at the spine and was 2.3 percentage points (CI, 1.0 to 3.7 percentage points; P < 0.001) at the femoral neck. Bone turnover statistically significantly decreased with active therapy compared with placebo. The groups did not differ in adverse events. LIMITATIONS The study was short (1 year) and was not powered to detect differences in the frequency of fractures. CONCLUSIONS Bone loss that occurred with ADT was prevented and improved with once-weekly oral alendronate. Because most men have low bone mass or osteoporosis, physicians should assess their patients' bone density and provide preventive and therapeutic measures as appropriate. registration number: NCT00048841.","author":[{"dropping-particle":"","family":"Greenspan","given":"Susan L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Joel B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trump","given":"Donald L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resnick","given":"Neil M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of internal medicine","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2007","3","20"]]},"page":"416-24","title":"Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial.","type":"article-journal","volume":"146"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1200/JCO.2007.15.1233","ISBN":"1527-7755 (Electronic)","ISSN":"0732183X","PMID":"18802155","abstract":"PurposeAndrogen-deprivation therapy (ADT) for prostate cancer is associated with bone loss and osteoporotic fractures. Our objective was to examine changes in bone density and turnover with sustained, discontinued, or delayed oral bisphosphonate therapy in men receiving ADT. Patients and MethodsA total of 112 men with nonmetastatic prostate cancer receiving ADT were randomly assigned to alendronate 70 mg once weekly or placebo in a double-blind, partial-crossover trial with a second random assignment at year 2 for those who initially received active therapy. Outcomes included bone mineral density and bone turnover markers. ResultsMen initially randomly assigned to alendronate and randomly reassigned at year 2 to continue had additional bone density gains at the spine (mean, 2.3% {+/-} 0.7) and hip (mean, 1.3% {+/-} 0.5%; both P < .01); those randomly assigned to placebo in year 2 maintained density at the spine and hip but lost (mean, -1.9% {+/-} 0.6%; P < .01) at the forearm. Patients randomly assigned to begin alendronate in year 2 experienced improvements in bone mass at the spine and hip, but experienced less of an increase compared with those who initiated alendronate at baseline. Men receiving alendronate for 2 years experienced a mean 6.7% ({+/-} 1.2%) increase at the spine and a 3.2% ({+/-} 1.5%) at the hip (both P < .05). Bone turnover remained suppressed. ConclusionAmong men with nonmetastatic prostate cancer receiving ADT, once-weekly alendronate improves bone density and decreases turnover. A second year of alendronate provides additional skeletal benefit, whereas discontinuation results in bone loss and increased bone turnover. Delay in bisphosphonate therapy appears detrimental to bone health.","author":[{"dropping-particle":"","family":"Greenspan","given":"Susan L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Joel B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trump","given":"Donald L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wagner","given":"Julie M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Megan E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perera","given":"Subashan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resnick","given":"Neil M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-2","issue":"27","issued":{"date-parts":[["2008"]]},"page":"4426-4434","title":"Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"^73,74","plainTextFormattedCitation":"73,74","previouslyFormattedCitation":"^73,74"},"properties":{"noteIndex":0},"schema":""}73,74Non-metastatic PC112Alendronic acid + ADT vsplacebo + ADT(crossover at 12 months)24 monthsBMD increased at LS and hip with alendronic acid, and decreased with placebo (p<0.001) at 1 yearAt crossover, significant LS and hip BMD gains continued during second year of alendronic acid. BMD maintained at hip and spine in those who switched to placebo, but BMD loss at radius.2007ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2006.07.3361","ISBN":"1527-7755 (Electronic)","ISSN":"0732183X","PMID":"17369566","abstract":"PURPOSE: Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.\\n\\nPATIENTS AND METHODS: In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than -2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.\\n\\nRESULTS: Mean (+/- SE) BMD of the posteroanterior lumbar spine decreased by 3.1% +/- 1.0% in men assigned to placebo and increased by 4.0% +/- 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% +/- 0.7% in men assigned to placebo and increased by 0.7% +/- 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.\\n\\nCONCLUSION: In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.","author":[{"dropping-particle":"","family":"Michaelson","given":"M. Dror","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"Donald S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Hang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGovern","given":"Francis J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kantoff","given":"Philip W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fallon","given":"Mary Anne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finkelstein","given":"Joel S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2007"]]},"page":"1038-1042","title":"Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁵","plainTextFormattedCitation":"65","previouslyFormattedCitation":"⁶⁵"},"properties":{"noteIndex":0},"schema":""}65Non-metastatic PC receiving ADT44Zoledronic acid + ADT vs placebo + ADT12 monthsIncrease in hip (+4.0% vs -3.1% p<0.001) and LS (+0.7% vs -1.9% p=0.004) BMD with zoledronic acid compared with placebo 2009ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.juro.2009.07.046","ISBN":"0022-5347","ISSN":"00225347","PMID":"19758618","abstract":"Purpose: Androgen deprivation therapy for prostate cancer is associated with osteoporosis and increased fracture risk. Previous studies of zoledronic acid demonstrated bone loss prevention in patients initiating androgen deprivation therapy. There are limited data on patients on prolonged androgen deprivation therapy or in Veterans Affairs patients with multiple risk factors for osteoporosis. Methods: We randomized 93 patients with M0 prostate cancer in this placebo controlled trial in the Veterans Affairs health care system. Preplanned strata included 50 patients on androgen deprivation therapy for less than 1 year (stratum 1) and 43 on androgen deprivation therapy for greater than 1 year (stratum 2). In each stratum patients were randomized to 4 mg zoledronic acid intravenously every 3 months for 4 treatments or intravenous placebo. The primary end point was the percent change in bone mineral density at the lumbar spine at 12 months. Results: Age, race, body mass index and osteoporosis risk factors were similar for the 2 treatments. Most patients were former smokers, had moderate alcohol intake, were not on calcium/vitamin D supplements and were relatively sedentary at baseline. In stratum 1 spine bone mineral density increased 5.95% in the zoledronic acid arm and decreased 3.23% in the placebo arm (p = 0.0044). In stratum 2 spine bone mineral density increased 6.08% in the zoledronic acid arm and only increased 1.57% in the placebo arm (p = 0.0005). Treatment was well tolerated with minimal impact on renal function. Conclusions: Zoledronic acid improved bone mineral density in patients with M0 prostate cancer on androgen deprivation therapy for 1 year or less, or greater than 1 year. This finding indicates that bisphosphonate therapy remains effective when initiated later in the course of androgen deprivation therapy and is efficacious in Veterans Affairs patients with multiple risk factors for osteoporosis. ? 2009 American Urological Association.","author":[{"dropping-particle":"","family":"Bhoopalam","given":"Nirmala","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Campbell","given":"Steven C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moritz","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Broderick","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iyer","given":"Padmini","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arcenas","given":"Anthony G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Veldhuizen","given":"Peter J.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedman","given":"Nicholas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reda","given":"Domenic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Stuart","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Garewal","given":"Harinder","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Urology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2009"]]},"page":"2257-2264","publisher":"Elsevier Inc.","title":"Intravenous Zoledronic Acid to Prevent Osteoporosis in a Veteran Population With Multiple Risk Factors for Bone Loss on Androgen Deprivation Therapy","type":"article-journal","volume":"182"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁶","plainTextFormattedCitation":"66","previouslyFormattedCitation":"⁶⁶"},"properties":{"noteIndex":0},"schema":""}66Non metastatic PC initiating or already receiving ADT93Zoledronic acid + ADT vs placebo + ADT12 monthsIncreased LS BMD with zoledronic acid in those receiving ADT for <1year (+5.12% vs -3.13% with placebo, p=0.0029) and in those receiving ADT for more than 2 years (+4.82% vs +0.99% with placebo, p=0.0013)2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Choo R, Lukka H, Cheung P","given":"et al.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Radiation Oncology, Biology, Physics","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"page":"1239-1245","title":"Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy.","type":"article-journal","volume":"85"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷²","plainTextFormattedCitation":"72","previouslyFormattedCitation":"⁷²"},"properties":{"noteIndex":0},"schema":""}72ADT for 2-3 years and OP 104Risedronate + ADT vsplacebo + ADT2 yearsDecreased LS BMD in both groups, no significant difference between groups2013 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.eururo.2012.09.007","ISBN":"1873-7560 (Electronic)\\r0302-2838 (Linking)","ISSN":"03022838","PMID":"23040208","abstract":"Background: Androgen-deprivation therapy (ADT) induces loss of bone mineral density (BMD) and increases the risk of fractures in patients with prostate cancer (PCa). We sought to determine whether a weekly dose of alendronate, an oral bisphosphonate, could reduce this unwanted side-effect. Objective: To assess whether once-weekly oral alendronate therapy would maintain or improve BMD in men initiating ADT for localised PCa. Design, setting, and participants: A multicentre, double-blind, randomised, placebo-controlled study, we included hormonally na?ve PCa patients initiating ADT with leuprolide acetate 30 mg intramuscularly every 4 mo. Intervention: Patients were randomised to receive either oral alendronate 70 mg once weekly or placebo for 1 yr. Both groups received daily calcium 1 g and vitamin D 400 international units. Outcome measurements and statistical analysis: Changes in BMD (at the lumbar spine [LS] and total hip [TH]) and bone markers. Results and limitations: One hundred ninety-one subjects were enrolled, and 186 were randomised between alendronate (n = 84) and placebo (n = 102). The alendronate group demonstrated a mean spine BMD increase of 1.7% compared with -1.9% in the placebo group (p < 0.0001). Alendronate also increased the BMD at the hip (percent change: 0.7%) compared to placebo (-1.6%). Median urinary N-terminal crosslinking telopeptide of type I collagen (Ntx) values decreased by 3.5% in the alendronate group and increased by 16.5% in the placebo arm, even after adjusting for centre (p = 0.510) and baseline urinary Ntx (p < 0.0001). Bone-specific alkaline phosphatase (BSAP) decreased a median of 2.25% in the alendronate group and increased a median of 3.12% in the placebo arm, regardless of centre or baseline BSAP or other covariates (p < 0.0001). The safety and tolerability profile was similar for the two treatment groups. Conclusions: Although the study was closed early because of slow accrual, it showed that weekly oral alendronate prevented bone loss and increased bone mass in addition to decreasing bone turnover in patients initiating ADT for localised PCa, with few related side-effects. ? 2012 Published by Elsevier B.V. on behalf of European Association of Urology.","author":[{"dropping-particle":"","family":"Klotz","given":"Laurence H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McNeill","given":"Irene Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kebabdjian","given":"Marlene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Liying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chin","given":"Joseph L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2013"]]},"page":"927-935","title":"A phase 3, double-blind, randomised, parallel-group, placebo-controlled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: The cancer and osteoporosis research with alendronate and leupr","type":"article-journal","volume":"63"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷¹","plainTextFormattedCitation":"71","previouslyFormattedCitation":"⁷¹"},"properties":{"noteIndex":0},"schema":""}71Localised PC186Alendronic acid + ADT vs placebo + ADT12 monthsSignificant increase in LS BMD with alendronic acid (+1.7% and -1.9% with placebo, p<0.0001)1.6 Fracture risk assessment toolsRisk assessment tools are available to determine the risk of fragility fracture on an individual basis. Additional clinical risk factors contribute to the risk of fracture at least partially independently of BMD (most fractures occur in individuals subsequently found to have non-osteoporotic BMD). The two most frequently used tools are the Fracture Risk Assessment Tool (FRAX? available at ) and QFracture (); however, neither has been specifically developed for use in men with PC. QFracture does not incorporate BMD assessment, whereas FRAX? may be used with or without it. NICE have recommended FRAX? should primarily be used where DXA is available, in order to provide a BMD value to integrate into the risk calculation (described later). Fracture risk assessment tools estimate the 1 to 10-year probability of both hip fracture and major osteoporotic fracture (hip, spine, wrist or humerus). Short-term risk is preferable to calculating lifetime risk due to several factors; assumptions regarding future mortality become increasingly uncertain after 10 years; interventions are not usually given for life but for a period of a few years; and the long-term prognostic value of risk factors may decrease over time.QFractureQFracture is based on a prospective open cohort study of routinely collected data from general practice and considers several fracture risk factors. The tool is available online, and can be used to estimate the 1-10-year cumulative incidence of hip or other major osteoporotic fractures. There are no published intervention thresholds using the QFracture tool.FRAX?FRAX?, developed by the then WHO Collaborating Centre for Metabolic Bone Diseases at the University of Sheffield was launched in 2008 and is based upon primary data from 12 prospectively studied population based international cohorts. Follow-up was extensive, and included more than 60,000 patients and 5,000 fractures, with subsequent external validation in a further 11 cohorts comprising 230,486 individuals. Given the historical focus of osteoporosis on women rather than men, it is unsurprising that men comprise only a minority of the original FRAX? cohorts (25%). There has been much debate as to whether the gradient of risk (change in risk of fracture per SD change in BMD) or the absolute risk (risk of fracture at a given T-score) differs between men and women. Current evidence suggests that the risk appears to be the same in both sexes, and the tool has been shown to be of predictive value in both male and mixed gender cohorts ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-017-4134-9","ISSN":"1433-2965","PMID":"28668994","abstract":"Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD) for hip fracture prediction was validated in a Norwegian population 50-90?years. Fracture risk increased with higher FRAX score, and the observed number of hip fractures agreed well with the predicted number, except for the youngest and oldest men. Self-reported fall was an independent risk factor for fracture in women. INTRODUCTION The primary aim was to validate FRAX without BMD for hip fracture prediction in a Norwegian population of men and women 50-90?years. Secondary, to study whether information of falls could improve prediction of fractures in the subgroup aged 70-90?years. METHODS Data were obtained from the third survey of the Nord-Tr?ndelag Health Study (HUNT3), the fracture registry in Nord-Tr?ndelag, and the Norwegian Prescription Database (NorPD), including 15,432 women and 13,585 men. FRAX hip without BMD was calculated, and hip fractures were registered for a median follow-up of 5.2?years. The number of estimated and observed fractures was assessed, ROC curves with area under the curve (AUC), and Cox regression analyses. For the group aged 70-90?years, self-reported falls the last year before HUNT3 were included in the Cox regression model. RESULTS The risk of fracture increased with higher FRAX score. When FRAX groups were categorized in a 10-year percentage risk for hip fracture as follows, <4, 4-7.9, 8-11.9, and ≥12%, the hazard ratio (HR) for hip fracture between the lowest and the highest group was 17.80 (95% CI: 12.86-24.65) among women and 23.40 (13.93-39.30) in men. Observed number of hip fractures agreed quite well with the predicted number, except for the youngest and oldest men. AUC was 0.81 (0.78-0.83) for women and 0.79 (0.76-0.83) for men. Self-reported fall was an independent risk factor for fracture in women (HR 1.64, 1.20-2.24), and among men, this was not significant (1.09, 0.65-1.83). CONCLUSIONS FRAX without BMD predicted hip fracture reasonably well. In the age group 70-90?years, falls seemed to imply an additional risk among women.","author":[{"dropping-particle":"","family":"Hoff","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meyer","given":"H E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Skurtveit","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Langhammer","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"S?gaard","given":"A J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Syversen","given":"U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dhainaut","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Skovlund","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abrahamsen","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schei","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2017","10","1"]]},"page":"2935-2944","title":"Validation of FRAX and the impact of self-reported falls among elderly in a general population: the HUNT study, Norway.","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁴","plainTextFormattedCitation":"84","previouslyFormattedCitation":"⁸⁴"},"properties":{"noteIndex":0},"schema":""}84. FRAX? is currently the most widely used fracture risk assessment tool in clinical practice, and has been incorporated into an increasing number of guidelines worldwide ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"National institute of health and care excellence (NICE)","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2012"]]},"number-of-pages":"1-23","title":"National institute of health and care excellence. Osteoporosis: assessing the risk of fragility fracture","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁵","plainTextFormattedCitation":"85","previouslyFormattedCitation":"⁸⁵"},"properties":{"noteIndex":0},"schema":""}85,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-012-2074-y","ISBN":"0937-941X\\n1433-2965","ISSN":"0937941X","PMID":"23079689","abstract":"UNLABELLED Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk of fractures due to osteoporosis. INTRODUCTION The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2008. This manuscript updates these in a European setting. METHODS Systematic literature reviews. RESULTS The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk, general and pharmacological management of osteoporosis, monitoring of treatment, assessment of fracture risk, case finding strategies, investigation of patients and health economics of treatment. CONCLUSIONS A platform is provided on which specific guidelines can be developed for national use.","author":[{"dropping-particle":"","family":"Kanis","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rizzoli","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reginster","given":"J. Y.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"23-57","title":"European guidance for the diagnosis and management of osteoporosis in postmenopausal women","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁶","plainTextFormattedCitation":"86","previouslyFormattedCitation":"⁸⁶"},"properties":{"noteIndex":0},"schema":""}86,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-014-2794-2","ISBN":"978-0-9798989-9-0","ISSN":"14332965","PMID":"25182228","abstract":"The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication. ","author":[{"dropping-particle":"","family":"Cosman","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beur","given":"S. J.","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"LeBoff","given":"M. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewiecki","given":"E. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tanner","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Randall","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lindsay","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2014"]]},"page":"2359-2381","title":"Clinician’s Guide to Prevention and Treatment of Osteoporosis","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁷","plainTextFormattedCitation":"87","previouslyFormattedCitation":"⁸⁷"},"properties":{"noteIndex":0},"schema":""}87,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"al","family":"Papaioannou A","given":"et","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2010"]]},"number-of-pages":"1-89","title":"Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada: Background and Technical Report","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁸","plainTextFormattedCitation":"88","previouslyFormattedCitation":"⁸⁸"},"properties":{"noteIndex":0},"schema":""}88. A range of clinical risk factors along with age and sex are included in the algorithm, which can be accessed online (Figure 1) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2016","11","28"]]},"author":[{"dropping-particle":"","family":"WHO","given":"Universty of Sheffield","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"FRAX online calculator","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁹","plainTextFormattedCitation":"89","previouslyFormattedCitation":"⁸⁹"},"properties":{"noteIndex":0},"schema":""}89. Anticancer treatments are not currently included as a specific risk factor.As fracture probability differs markedly in different regions of the world, FRAX? models are available to calibrate the tool for use in various countries where the epidemiology of fracture and death are known. Unlike other algorithms, FRAX? computes fracture probability taking both the risk of fracture and risk of death into account. This is important because some of the risk factors affect the risk of death as well as the fracture risk. Examples include increasing age, low body mass index (BMI), low BMD, glucocorticoids and smoking. In addition to providing an estimate of risk, the FRAX? website in some country models has a link to national guidance for the management of osteoporosis, such as the UK National Osteoporosis Guideline Group (NOGG) in the UK. FRAX has recently been shown to be predictive of falls in elderly men ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-015-3295-7","ISSN":"14332965","PMID":"26391036","abstract":"UNLABELLED: Falls and fractures share several common risk factors. Although past falls is not included as an input variable in the FRAX calculator, we demonstrate that FRAX probability predicts risk of incident falls in the MrOs Sweden cohort.\\n\\nINTRODUCTION: Although not included in the FRAX? algorithm, it is possible that increased falls risk is partly dependent on other risk factors that are incorporated into FRAX. The aim of the present study was to determine whether fracture probability generated by FRAX might also predict risk of incident falls and the extent that a falls history would add value to FRAX.\\n\\nMETHODS: We studied the relationship between FRAX probabilities and risk of falls in 1836 elderly men recruited to the MrOS study, a population-based prospective cohort of men from Sweden. Baseline data included falls history, clinical risk factors, bone mineral density (BMD) at femoral neck, and calculated FRAX probabilities. Incident falls were captured during an average of 1.8 years of follow-up. An extension of Poisson regression was used to investigate the relationship between FRAX, other risk variables, and the time-to-event hazard function of falls. All associations were adjusted for age and time since baseline.\\n\\nRESULTS: At enrolment, 15.5 % of the men had fallen during the preceding 12 months (past falls) and 39 % experienced one or more falls during follow-up (incident falls). The risk of incident falls increased with increasing FRAX probabilities at baseline (hazard ratio (HR) per standard deviation (SD), 1.16; 95 % confidence interval (95%CI), 1.06 to 1.26). The association between incident falls and FRAX probability remained after adjustment for past falls (HR per SD, 1.12; 95%CI, 1.03 to 1.22). High compared with low baseline FRAX score (>15 vs <15 % probability of major osteoporotic fracture) was strongly predictive of increased falls risk (HR, 1.64; 95%CI, 1.36 to 1.97) and remained stable with time. Whereas past falls were a significant predictor of incident falls (HR, 2.75; 95%CI, 2.32 to 3.25), even after adjustment for FRAX, the hazard ratio decreased markedly with increasing follow-up time.\\n\\nCONCLUSIONS: Although falls are not included as an input variable, FRAX captures a component of risk for future falls and outperforms falls history with an extended follow-up time.","author":[{"dropping-particle":"","family":"Harvey","given":"N. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Odén","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karlsson","given":"M. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosengren","given":"B. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ljunggren","given":"","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCloskey","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanis","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohlsson","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mellstr?m","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"267-274","title":"FRAX predicts incident falls in elderly men: findings from MrOs Sweden","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁰","plainTextFormattedCitation":"90","previouslyFormattedCitation":"⁹⁰"},"properties":{"noteIndex":0},"schema":""}90. This is of particular significance in older men receiving ADT for prostate cancer, as ADT alters body composition. As well as increasing the risk of falls, sarcopenia also decreases rehabilitation potential in the post-fall setting ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-017-3929-z","abstract":"This study evaluates the prevalence of sarcopenia among older people admitted to a rehabilitation unit after hip fracture and the association between sarcopenia and functional outcomes. The results show that sarcopenia had a negative impact on functional recovery. The assessment of sarcopenia among older adults receiving rehabilitation programs is crucial. Introduction Sarcopenia is a highly prevalent geriatric syndrome associated with adverse outcomes, including falls, disability, institutionalization, and mortality. Few studies assessed sarcopenia among older adults receiving rehabilitation programs. Methods Patients aged 70 years or more consecutively admitted to in-hospital rehabilitation programs that had suffered from hip fracture entered the study. Sarcopenia was defined according to the Foundation for National Institutes of Health (FNIH) criteria. Multivariable linear regression models were used to analyze the association between the sarcopenia and functional recovery. Results The recruited population was composed of 127 patients, with a mean age of 81.3 ± 4.8 years, predominantly females (64.6%). Using the criteria proposed by the FNIH, patients with a diagnosis of sarcopenia were 43 (33.9%). After adjustment for potential confounders, participants with sarcopenia had a significant increased risk of incomplete functional recovery compared with non-sarcopenic patients (OR 3.07, 95% CI 1.07-8.75). Compared with participants without sarcopenia, those with sarcopenia showed lower Barthel index scores at the time of discharge from the rehabilitation unit (69.2 versus 58.9, respectively; p < 0.001) and after 3 months of follow-up (90.9 versus 80.5, respectively; p = 0.02). Conclusions These findings support the systematic assessment of sarcopenia among older adults receiving rehabilitation programs to assist in the development of personalized treatment plans aimed at improving functional outcomes.","author":[{"dropping-particle":"","family":"Landi","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calvani","given":"& R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ortolani","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salini","given":"& S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martone","given":"& A M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santoro","given":"& L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santoliquido","given":"& A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sisto","given":"& A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Picca","given":"& A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marzetti","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"The association between sarcopenia and functional outcomes among older patients with hip fracture undergoing in-hospital rehabilitation","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹¹","plainTextFormattedCitation":"91","previouslyFormattedCitation":"⁹¹"},"properties":{"noteIndex":0},"schema":""}91.FRAX? and ADTADT is not included as a specific risk variable within FRAX. There is insufficient evidence that ADT is independently associated with fracture risk as calculated using FRAX? (particularly when BMD is included). Multivariate analysis of the placebo arm of a prospective study of toremifene, (with ADT duration included as one of the variables) reported that older age and lower BMD were the only statistically significant independent predictors of fracture risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Lin D, Smith MR, Morton RA","given":"Steiner MS","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"15S","issued":{"date-parts":[["2009"]]},"page":"9517-9517","title":"Use of age and BMD to predict fracture risk in men on androgen deprivation therapy","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹²","plainTextFormattedCitation":"92","previouslyFormattedCitation":"⁹²"},"properties":{"noteIndex":0},"schema":""}92. A population-based prospective study in men (including 43 men with PC), found that older age, lower BMD and increased rate of bone loss were the only significant predictors of fracture risk ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.bone.2008.05.003","ISSN":"87563282","PMID":"18585119","abstract":"BACKGROUND Men with prostate cancer on androgen deprivation therapy (ADT) are at increased risk of bone loss. The present study sought to determine the incidence of low trauma fracture in men with prostate cancer (PC), and to characterize the association between potential risk factors and fracture risk in these men. METHODS In the prospective, population-based Dubbo Osteoporosis Epidemiology Study, 43 men aged 60+ years reported a history of prostate cancer; among whom, 22 men received ADT, and 21 men did not. Low-trauma fractures were ascertained between 1989 and 2004. Bone mineral density at the femoral neck (FNBMD), postural instability and lifestyle factors were obtained at baseline. RESULTS Men with prostate cancer had significantly higher lumbar spine BMD than those without cancer (p=0.013). During the follow-up period, 15 men with prostate cancer had sustained a fracture, yielding the age-adjusted incidence of fracture among this group was 31.6 per 1000 person-years, which was greater than those without cancer (22.1 per 1000 person-years). The age-adjusted incidence of fracture was more pronounced among those with prostate cancer on ADT (40.2 per 1000 person-years). After adjusting for age, the increase in fracture risk among prostate cancer patients was associated with lower femoral neck BMD (hazard ratio [HR] per SD=1.8, 95% CI: 1.0-3.4) and increased rate of bone loss (HR 2.3, 1.2-4.6). CONCLUSIONS Men with prostate cancer, particularly those treated with ADT, had an increased fracture risk. Although the average BMD in men with prostate cancer was higher than men without cancer, a low BMD prior to treatment or increased rate of bone loss after initiating ADT treatment was each a significant predictor of fracture in these.","author":[{"dropping-particle":"","family":"Ahlborg","given":"Henrik G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nguyen","given":"Nguyen D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Center","given":"Jacqueline R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eisman","given":"John A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Nguyen","given":"Tuan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bone","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2008","9"]]},"page":"556-560","title":"Incidence and risk factors for low trauma fractures in men with prostate cancer","type":"article-journal","volume":"43"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹³","plainTextFormattedCitation":"93","previouslyFormattedCitation":"⁹³"},"properties":{"noteIndex":0},"schema":""}93. An on-going collaboration between some authors of this guidance aims to determine the fracture risk in a large (over 7,000 men) cohort of patients who are currently participating in the STAMPEDE trial ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2016","10","1"]]},"author":[{"dropping-particle":"","family":"MRC","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Systemic therapy in advancing or metastatic prostate cancer: evaluation of drug efficacy (STAMPEDE)","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁴","plainTextFormattedCitation":"94","previouslyFormattedCitation":"⁹⁴"},"properties":{"noteIndex":0},"schema":""}94. It is hoped that this analysis will identify the extent of the risk in this population and better inform future guideline development and service delivery plans.A conservative assumption would be that the modification of fracture risk by ADT is captured almost completely by its impact on BMD. The secondary osteoporosis variable in FRAX? already serves this function. This variable contains a number of risk factors that have been shown to be associated with fracture risk (RR 1.3-1.7) but with little or no evidence that this risk is truly independent of BMD. Thus, once BMD is entered to the calculation, no further weight is accorded to the presence of this risk factor. Secondary causes are distinct from rheumatoid arthritis, where there is good evidence the disease itself conveys an increase in fracture risk that is not completely captured by BMD, BMI or glucocorticoid use. As for any clinical prediction tool, interpretation should be tempered by additional information of clinical significance; such as a high falls risk, multiple prior fractures, immobility and severe rheumatoid arthritis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-011-1713-z","ISSN":"0937-941X","PMID":"21779818","abstract":"UNLABELLED The introduction of the WHO FRAX? algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. Its use in fracture risk prediction has strengths, but also limitations of which the clinician should be aware and are the focus of this review INTRODUCTION The International Osteoporosis Foundation (IOF) and the International Society for Clinical Densitometry (ISCD) appointed a joint Task Force to develop resource documents in order to make recommendations on how to improve FRAX and better inform clinicians who use FRAX. The Task Force met in November 2010 for 3?days to discuss these topics which form the focus of this review. METHODS This study reviews the resource documents and joint position statements of ISCD and IOF. RESULTS Details on the clinical risk factors currently used in FRAX are provided, and the reasons for the exclusion of others are provided. Recommendations are made for the development of surrogate models where country-specific FRAX models are not available. CONCLUSIONS The wish list of clinicians for the modulation of FRAX is large, but in many instances, these wishes cannot presently be fulfilled; however, an explanation and understanding of the reasons may be helpful in translating the information provided by FRAX into clinical practice.","author":[{"dropping-particle":"","family":"Kanis","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hans","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baim","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bilezikian","given":"J. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Binkley","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cauley","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Compston","given":"J. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dawson-Hughes","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"El-Hajj Fuleihan","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leslie","given":"W. D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewiecki","given":"E. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luckey","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oden","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Papapoulos","given":"S. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Poiana","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rizzoli","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"D. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Task Force of the FRAX Initiative","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2011","9","21"]]},"page":"2395-2411","title":"Interpretation and use of FRAX in clinical practice","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁵","plainTextFormattedCitation":"95","previouslyFormattedCitation":"⁹⁵"},"properties":{"noteIndex":0},"schema":""}95. Intervention thresholdsApproaches used to set intervention thresholds depend on local factors such as reimbursement policies, health economic assessment, willingness to pay for health care in osteoporosis and access to DXA ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Kanis JA, McCloskey EV, Johansson H","given":"the National Osteoporosis Guideline Group","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis International","id":"ITEM-1","issued":{"date-parts":[["2009"]]},"page":"1395-1408: Erratum published 2009 Osteoporos Int 2","title":"Case finding for the management of osteoporosis with FRAX?—assessment and intervention thresholds for the UK.","type":"article-journal","volume":"19"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.maturitas.2008.11.022","ISSN":"03785122","PMID":"19135323","abstract":"In 1999 and 2000 the Royal College of Physicians published guidelines for the prevention and treatment of osteoporosis [Royal College of Physicians. Osteoporosis: clinical guidelines for the prevention and treatment. London: Royal College of Physicians; 1999; Royal College of Physicians and Bone and Tooth Society of Great Britain. Update on pharmacological interventions and an algorithm for management. London, UK: Royal College of Physicians; 2000.; Royal College of Physicians. Glucocorticoid-induced osteoporosis. Guidelines on prevention and treatment; Bone and Tooth Society of Great Britain, National Osteoporosis Society and Royal College of Physicians. London, UK: Royal College of Physicians; 2002]. Since then, there have been significant advances in the field of osteoporosis including the development of new techniques for measuring bone mineral density, improved methods of assessing fracture risk and new treatments that have been shown to significantly reduce the risk of fractures. Against this background, the National Osteoporosis Guideline Group (NOGG), in collaboration with many Societies in the UK, have updated the original guidelines [Royal College of Physicians, National Osteoporosis Guideline Group on behalf of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, Society for Endocrinology. Osteoporosis. Clinical guideline for prevention and treatment, Executive Summary. University of Sheffield Press; 2008], a practical summary of which is detailed below. The management algorithms are underpinned by a health economic analysis applied to the epidemiology of fracture in the UK.","author":[{"dropping-particle":"","family":"Compston","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Francis","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanis","given":"J.A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marsh","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCloskey","given":"E.V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reid","given":"D.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Selby","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilkins","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"National Osteoporosis Guideline Group (NOGG)","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Maturitas","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2009","2","20"]]},"page":"105-108","title":"Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK","type":"article-journal","volume":"62"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2008-0926","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Dawson-Hughes","given":"Bess","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-3","issue":"7","issued":{"date-parts":[["2008","7"]]},"page":"2463-2465","publisher":"Oxford University Press","title":"A Revised Clinician’s Guide to the Prevention and Treatment of Osteoporosis","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"^96–98","plainTextFormattedCitation":"96–98","previouslyFormattedCitation":"^96–98"},"properties":{"noteIndex":0},"schema":""}96–98. Most recommendations for intervention thresholds in osteoporosis are based on postmenopausal osteoporosis where there is an established evidence base. In the UK, NOGG has included the management of male osteoporosis in their most recent guidance ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"National Osteoporosis Guideline Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2017"]]},"number-of-pages":"1-36","publisher-place":"Sheffield","title":"NOGG 2017: Clinical guideline for the prevention and treatment of osteoporosis shef.ac.uk/NOGG 1 NOGG 2017: Clinical guideline for the prevention and treatment of osteoporosis","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁹","plainTextFormattedCitation":"59","previouslyFormattedCitation":"⁵⁹"},"properties":{"noteIndex":0},"schema":""}59.NOGG takes the approach that most guidelines recommend that postmenopausal women with a prior fragility fracture may be considered for intervention without the absolute need for a BMD test (a BMD test may be independently requested to monitor treatment)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-008-0560-z","ISSN":"0937-941X","PMID":"18266020","abstract":"UNLABELLED Guidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis. INTRODUCTION The European Foundation for Osteoporosis and Bone disease (subsequently the International Osteoporosis Foundation) published guidelines for the diagnosis and management of osteoporosis in 1997. This manuscript updates these in a European setting. METHODS The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk; general and pharmacological management of osteoporosis; monitoring of treatment; assessment of fracture risk; case finding strategies; investigation of patients; health economics of treatment. RESULTS AND CONCLUSIONS A platform is provided on which specific guidelines can be developed for national use.","author":[{"dropping-particle":"","family":"Kanis","given":"J A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burlet","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Delmas","given":"P D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reginster","given":"J-Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borgstrom","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rizzoli","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)","given":"on behalf of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2008","4"]]},"page":"399-428","publisher":"Springer","title":"European guidance for the diagnosis and management of osteoporosis in postmenopausal women.","type":"article-journal","volume":"19"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1503/cmaj.100771","ISSN":"0820-3946","PMID":"20940232","author":[{"dropping-particle":"","family":"Papaioannou","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morin","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheung","given":"A. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Atkinson","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"J. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanley","given":"D. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hodsman","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jamal","given":"S. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaiser","given":"S. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kvern","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siminoski","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leslie","given":"W. 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Royal College of Physicians, London, UK","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"^99–101","plainTextFormattedCitation":"99–101","previouslyFormattedCitation":"^99–101"},"properties":{"noteIndex":0},"schema":""}99–101. In the UK, the age-specific FRAX? intervention threshold is set to that of women with a prior fracture; the corollary is that women without fracture but with a similar or greater age-specific fracture probability would merit consideration for treatment. The threshold rises with age until the age of 70 years, and at 70 years and above fixed thresholds are applied (Figure 2) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s11657-016-0278-z","ISSN":"1862-3522","PMID":"27465509","abstract":"UNLABELLED This systematic review identified assessment guidelines for osteoporosis that incorporate FRAX.?The rationale for intervention thresholds is given in a minority of papers. Intervention thresholds (fixed or age-dependent) need to be country-specific. INTRODUCTION In most assessment guidelines, treatment for osteoporosis is recommended in individuals with prior fragility fractures, especially fractures at spine and hip. However, for those without prior fractures, the intervention thresholds can be derived using different methods. The aim of this report was to undertake a systematic review of the available information on the use of FRAX? in assessment guidelines, in particular the setting of thresholds and their validation. METHODS We identified 120 guidelines or academic papers that incorporated FRAX of which 38 provided no clear statement on how the fracture probabilities derived are to be used in decision-making in clinical practice. The remainder recommended a fixed intervention threshold (n?=?58), most commonly as a component of more complex guidance (e.g. bone mineral density (BMD) thresholds) or an age-dependent threshold (n?=?22). Two guidelines have adopted both age-dependent and fixed thresholds. RESULTS Fixed probability thresholds have ranged from 4 to 20?% for a major fracture and 1.3-5?% for hip fracture. More than one half (39) of the 58 publications identified utilised a threshold probability of 20?% for a major osteoporotic fracture, many of which also mention a hip fracture probability of 3?% as an alternative intervention threshold. In nearly all instances, no rationale is provided other than that this was the threshold used by the National Osteoporosis Foundation of the USA. Where undertaken, fixed probability thresholds have been determined from tests of discrimination (Hong Kong), health economic assessment (USA, Switzerland), to match the prevalence of osteoporosis (China) or to align with pre-existing guidelines or reimbursement criteria (Japan, Poland). Age-dependent intervention thresholds, first developed by the National Osteoporosis Guideline Group (NOGG), are based on the rationale that if a woman with a prior fragility fracture is eligible for treatment, then, at any given age, a man or woman with the same fracture probability but in the absence of a previous fracture (i.e. at the 'fracture threshold') should also be eligible. Under current NOGG guidelines, based on age-dependent probability thresholds, inequalities…","author":[{"dropping-particle":"","family":"Kanis","given":"John A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harvey","given":"Nicholas C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Cyrus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Helena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Odén","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Advisory Board of the National Osteoporosis Guideline Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Osteoporosis","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016","12","27"]]},"page":"25","title":"A systematic review of intervention thresholds based on FRAX","type":"article-journal","volume":"11"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰²","plainTextFormattedCitation":"102","previouslyFormattedCitation":"¹⁰²"},"properties":{"noteIndex":0},"schema":""}102. In light of the fact that it would be difficult to justify a different (i.e. lower) intervention threshold in men, it is logical to apply the same thresholds in both men and women. Some countries have decided to apply a fixed, age-independent threshold for intervention, largely driven by a health economics analysis from within the US which might not be appropriate within other healthcare settings ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00198-008-0560-z","ISSN":"0937-941X","PMID":"18266020","abstract":"UNLABELLED Guidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis. INTRODUCTION The European Foundation for Osteoporosis and Bone disease (subsequently the International Osteoporosis Foundation) published guidelines for the diagnosis and management of osteoporosis in 1997. This manuscript updates these in a European setting. METHODS The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk; general and pharmacological management of osteoporosis; monitoring of treatment; assessment of fracture risk; case finding strategies; investigation of patients; health economics of treatment. RESULTS AND CONCLUSIONS A platform is provided on which specific guidelines can be developed for national use.","author":[{"dropping-particle":"","family":"Kanis","given":"J A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burlet","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Delmas","given":"P D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reginster","given":"J-Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borgstrom","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rizzoli","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)","given":"on behalf of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2008","4"]]},"page":"399-428","publisher":"Springer","title":"European guidance for the diagnosis and management of osteoporosis in postmenopausal women.","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁹","plainTextFormattedCitation":"99","previouslyFormattedCitation":"⁹⁹"},"properties":{"noteIndex":0},"schema":""}99. Assessment of fracture riskTo minimise the risk of fracture in men receiving treatment for PC, all men (irrespective of whether they have metastatic bone disease) should have their BMD measured at the time of ADT initiation. Men with a previous fracture and/or who are found to be osteoporotic should have further investigations to exclude causes of secondary osteoporosis as treatment of underlying causes (for example malabsorption or liver disease) form part of the overall management. This may best be achieved by referral to appropriate services (metabolic bone/ endocrinology). The femoral neck BMD result is used in FRAX to calculate the 10 year probability of major osteoporotic fracture ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.maturitas.2008.11.022","ISSN":"03785122","PMID":"19135323","abstract":"In 1999 and 2000 the Royal College of Physicians published guidelines for the prevention and treatment of osteoporosis [Royal College of Physicians. Osteoporosis: clinical guidelines for the prevention and treatment. London: Royal College of Physicians; 1999; Royal College of Physicians and Bone and Tooth Society of Great Britain. Update on pharmacological interventions and an algorithm for management. London, UK: Royal College of Physicians; 2000.; Royal College of Physicians. Glucocorticoid-induced osteoporosis. Guidelines on prevention and treatment; Bone and Tooth Society of Great Britain, National Osteoporosis Society and Royal College of Physicians. London, UK: Royal College of Physicians; 2002]. Since then, there have been significant advances in the field of osteoporosis including the development of new techniques for measuring bone mineral density, improved methods of assessing fracture risk and new treatments that have been shown to significantly reduce the risk of fractures. Against this background, the National Osteoporosis Guideline Group (NOGG), in collaboration with many Societies in the UK, have updated the original guidelines [Royal College of Physicians, National Osteoporosis Guideline Group on behalf of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, Society for Endocrinology. Osteoporosis. Clinical guideline for prevention and treatment, Executive Summary. University of Sheffield Press; 2008], a practical summary of which is detailed below. The management algorithms are underpinned by a health economic analysis applied to the epidemiology of fracture in the UK.","author":[{"dropping-particle":"","family":"Compston","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Francis","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanis","given":"J.A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marsh","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCloskey","given":"E.V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reid","given":"D.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Selby","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilkins","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"National Osteoporosis Guideline Group (NOGG)","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Maturitas","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2009","2","20"]]},"page":"105-108","title":"Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK","type":"article-journal","volume":"62"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s11657-016-0278-z","ISSN":"1862-3522","PMID":"27465509","abstract":"UNLABELLED This systematic review identified assessment guidelines for osteoporosis that incorporate FRAX.?The rationale for intervention thresholds is given in a minority of papers. Intervention thresholds (fixed or age-dependent) need to be country-specific. INTRODUCTION In most assessment guidelines, treatment for osteoporosis is recommended in individuals with prior fragility fractures, especially fractures at spine and hip. However, for those without prior fractures, the intervention thresholds can be derived using different methods. The aim of this report was to undertake a systematic review of the available information on the use of FRAX? in assessment guidelines, in particular the setting of thresholds and their validation. METHODS We identified 120 guidelines or academic papers that incorporated FRAX of which 38 provided no clear statement on how the fracture probabilities derived are to be used in decision-making in clinical practice. The remainder recommended a fixed intervention threshold (n?=?58), most commonly as a component of more complex guidance (e.g. bone mineral density (BMD) thresholds) or an age-dependent threshold (n?=?22). Two guidelines have adopted both age-dependent and fixed thresholds. RESULTS Fixed probability thresholds have ranged from 4 to 20?% for a major fracture and 1.3-5?% for hip fracture. More than one half (39) of the 58 publications identified utilised a threshold probability of 20?% for a major osteoporotic fracture, many of which also mention a hip fracture probability of 3?% as an alternative intervention threshold. In nearly all instances, no rationale is provided other than that this was the threshold used by the National Osteoporosis Foundation of the USA. Where undertaken, fixed probability thresholds have been determined from tests of discrimination (Hong Kong), health economic assessment (USA, Switzerland), to match the prevalence of osteoporosis (China) or to align with pre-existing guidelines or reimbursement criteria (Japan, Poland). Age-dependent intervention thresholds, first developed by the National Osteoporosis Guideline Group (NOGG), are based on the rationale that if a woman with a prior fragility fracture is eligible for treatment, then, at any given age, a man or woman with the same fracture probability but in the absence of a previous fracture (i.e. at the 'fracture threshold') should also be eligible. Under current NOGG guidelines, based on age-dependent probability thresholds, inequalities…","author":[{"dropping-particle":"","family":"Kanis","given":"John A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harvey","given":"Nicholas C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Cyrus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Helena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Odén","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"McCloskey","given":"Eugene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Advisory Board of the National Osteoporosis Guideline Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of Osteoporosis","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2016","12","27"]]},"page":"25","title":"A systematic review of intervention thresholds based on FRAX","type":"article-journal","volume":"11"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/yd.20075","ISSN":"1537-5781","PMID":"24474255","author":[{"dropping-particle":"","family":"National Osteoporosis Guideline Group","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-3","issue":"January","issued":{"date-parts":[["2016"]]},"number-of-pages":"1-8","title":"Osteoporosis Clinical guideline for prevention and treatment: Executive Summary","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"^34,97,102","plainTextFormattedCitation":"34,97,102","previouslyFormattedCitation":"^34,97,102"},"properties":{"noteIndex":0},"schema":""}34,97,102. Using the NOGG threshold (Figure 2), men with probabilities above the upper threshold should be offered treatment. Dosing regimensNOGG recommends oral bisphosphonates such as alendronic acid (10mg daily) or risedronate sodium (5mg daily) for osteoporosis in men. If compliance with daily therapy is poor, weekly oral bisphosphonate therapy is an alternative. When oral therapy is not feasible or tolerated, intravenous zoledronic acid may be used (5mg once yearly), or denosumab may be given subcutaneously at a dose of 60 mg once every 6 months.Reassessment of fracture riskIn men found to lie below (but close to) the intervention threshold, a reassessment including a repeat BMD should be undertaken after 12-18 months of ADT. Figure 1: Screenshot of the UK FRAX? tool showing a calculation of major fracture and hip fracture probability in a man aged 70 years with secondary osteoporosis (e.g. prostate cancer on ADT) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2016","11","28"]]},"author":[{"dropping-particle":"","family":"WHO","given":"Universty of Sheffield","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"FRAX online calculator","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁹","plainTextFormattedCitation":"89","previouslyFormattedCitation":"⁸⁹"},"properties":{"noteIndex":0},"schema":""}89.Figure 2: NOGG intervention thresholds. The thresholds depicted by the lines between the green and red areas above are the 10-year probabilities of a major osteoporotic fracture (left graph) or hip fracture (right graph) in women with a previous fracture. Treatment should strongly be considered in those with fracture probabilities at or above the threshold.1.7 RecommendationsAll men starting long-term ADT for PC (with or without metastatic bone involvement) should:Be provided with individualised and patient-centred information, including appropriate lifestyle advice regarding optimisation of bone healthBe referred to a supervised resistance and aerobic exercise programme of at least 12 weeks duration (in accordance with NICE guidelines)Have daily calcium intake calculated to identify need for supplementation (using a tool such as the Edinburgh calculator) or maintain adequate daily calcium (700- 1200mg) and vitamin D (800 IU) intake through dietary intake, sunlight exposure, and supplementationUndergo DXA to assess BMD when ADT is commencedHave their fracture risk assessed using FRAX? with BMD to determine 10-year probability of major osteoporotic and hip fracture ; Those found to have a high probability of fracture as defined by NOGG treatment threshold should be offered appropriate pharmacological treatment. Choice of therapy should follow current NOGG guidance : oral alendronate and risedronate, denosumab (subcutaneous) or zoledronic acid (intravenous) Those below the intervention threshold should have their BMD reassessed after 12-18 months of ADTBe investigated for other causes of secondary osteoporosis if BMD is within the osteoporosis range; this can best be achieved by referral to specialist centres for on-going managementAlgorithm ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Mistry M, Parkin DM, Ahmad a S, Sasieni P. Cancer incidence in the United Kingdom: projections to the year 2030. Br J Cancer [Internet] 2011 [cited 2014 Apr 11];105(11):1795–803. Available from: . CRUK. Cancer statistics [Internet]. 2013 [cited 2016 Apr 15];Available from: . CRUK. Cancer research UK mortality statistics [Internet]. [cited 2016 May 5];Available from: . Thorstenson A, Bratt O, Akre O, et al. 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