Eprints.whiterose.ac.uk
EFFECT OF VITAMIN K ON BONE MINERAL DENSITY AND FRACTURES IN ADULTS: AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED CONTROLLED TRIALSAndrew Mott1*, Thomas Bradley2, Kath Wright3, Elizabeth Sarah Cockayne1, Martin J Shearer4, Joy Adamson5, Susan Alexandra Lanham-New6, David J Torgerson1York Trials Unit, Department of Health Sciences, University of York, York, YO10 5DDChesterfield Hospital, Chesterfield Road, Calow, United Kingdom, S44 5BLCentre for Reviews & Dissemination, University of York, York, YO10 5DDCentre for Haemostasis and Thrombosis, Guy’s and St Thomas’ NHS Trust, London SE1 7EHInstitute of Health & Society, Newcastle University, Baddiley-Clark Building, Richardson Road, Newcastle upon Tyne, NE2 4AXNutritional Sciences Department, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH*Correspondence to: Andrew Mott E: andrew.mott@york.ac.uk T: 0044 (0)1904 321 727Address: York Trials Unit, Department of Health Sciences, ARRC Building, University of York, York, United Kingdom, YO10 5DDKeywords: Vitamin K, Fracture, Systematic Review, Bone Health, Bone Mineral Density, OsteoporosisDisclosures: Andrew Mott, Thomas Bradley, Kath Wright, Elizabeth Sarah Cockayne, Martin J Shearer, Joy Adamson, Susan Alexandra Lanham-New, and David Torgerson declare that they have no conflict of interest.MINI ABSTRACTVitamin K supplementation may reduce fractures and increase bone health. Previous research aimed at assessing these effects has been undermined by fabricated data and is now outdated. We conducted a systematic review of randomised controlled trials to assess whether vitamin K affects these outcomes. We found that vitamin K does not affect bone mineral density but may reduce fracture risk.ABSTRACTPurpose: Vitamin K may affect bone mineral density and fracture incidence. Since publication of a previous systematic review the integrity of some of the previous evidence has been questioned and further trials have been published. Our objective was to assess the effectiveness of oral vitamin K supplementation for increasing bone mineral density and reducing fractures in adults.Methods: MEDLINE, EMBASE, CENTRAL, CINAHL, , WHO-ICTRP were searched for eligible trials. Randomised controlled trials assessing oral vitamin K supplementation that assessed bone mineral density or fractures in adult populations were included. A total of 36 studies were identified. Two independent reviewers extracted data using a piloted extraction form. Results: For post-menopausal or osteoporotic patients meta-analysis showed that the odds of any clinical fracture were lower for vitamin K compared to controls (OR:0.72, 95%CI: 0.55 to 0.95). Restricting the analysis to low risk of bias trials reduced the OR to 0.76 (95%CI: 0.58 to 1.01). There was no difference in vertebral fractures between the groups (OR:0.96, 95%CI: 0.83 to 1.11). In the bone mineral density meta-analysis, percentage change from baseline at the lumbar spine was higher at 1 year (MD:0.93, 95% CI: -0.02 to 1.89) and 2 years (MD:1.63%, 95%CI: 0.10 to 3.16) for vitamin K compared to controls; however, removing trials at high risk of bias tended to result in smaller differences that were not statistically significant. At 6 months it was higher in the hip (MD:0.42%, 95%CI: 0.01 to 0.83) and femur (MD:0.29%, 95%CI: 0.17 to 0.42). There was no significant difference at other anatomical sites.Conclusions: For post-menopausal or osteoporotic patients there is no evidence that vitamin K affects bone mineral density or vertebral fractures, it may reduce clinical fractures however the evidence is insufficient to confirm this. There are too few trials to draw conclusions for other patient groups.INTRODUCTIONRationaleThe present study is an update of a previous systematic review of vitamin K supplementation and the prevention of fractures published in 2006 ADDIN EN.CITE <EndNote><Cite><Author>Cockayne</Author><Year>2006</Year><RecNum>349</RecNum><DisplayText>[1]</DisplayText><record><rec-number>349</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1515506246">349</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cockayne, S.</author><author>Adamson, J.</author><author>Lanham-New, S.</author><author>Shearer, M. J.</author><author>Gilbody, S.</author><author>Torgerson, D. J.</author></authors></contributors><auth-address>York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, England. djt6@york.ac.uk</auth-address><titles><title>Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials</title><secondary-title>Arch Intern Med</secondary-title></titles><periodical><full-title>Arch Intern Med</full-title></periodical><pages>1256-61</pages><volume>166</volume><number>12</number><keywords><keyword>Bone Density/drug effects</keyword><keyword>Fractures, Bone/*prevention & control</keyword><keyword>Humans</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Treatment Outcome</keyword><keyword>Vitamin K 1/*administration & dosage</keyword><keyword>Vitamin K 2/*administration & dosage</keyword><keyword>Vitamins/*administration & dosage</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun 26</date></pub-dates></dates><isbn>0003-9926 (Print)
0003-9926 (Linking)</isbn><accession-num>16801507</accession-num><urls><related-urls><url>;[1]. The original analysis, identified 13 trials with data on bone loss and 7 with data on fractures. Eleven of these trials had used nutritional supplements of menaquinone-4 (MK-4), a member of the vitamin K2 family, while 2 trials had used phylloquinone (vitamin K1). At that time, all the trials with fracture outcomes had been undertaken in Japan with MK-4 supplementation in patients with pre-existing osteoporosis or in patients with diseases or treatments known to predispose to osteoporosis. An important incentive for us to update our systematic review was that in 2016 Bolland and colleagues conducted a review and statistical analysis of 33 RCTs (identified as originating from a group led by Yoshihiro Sato) which raised serious concerns regarding their integrity and validity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub3JnZXJzb248L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA [2,3]. A number of the trials from the 2006 systematic review were identified as being problematic in this review, a correction was issued for the systematic review. ADDIN EN.CITE <EndNote><Cite><Author>Torgerson</Author><Year>2018</Year><RecNum>353</RecNum><DisplayText>[2]</DisplayText><record><rec-number>353</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529588838">353</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Torgerson, D. J.</author></authors></contributors><auth-address>York Trials Unit, Department of Health Sciences, University of York, York, England.</auth-address><titles><title>Caution to Readers About Systematic Review on Vitamin K and Prevention of Fractures That Included Problematic Trials</title><secondary-title>JAMA Intern Med</secondary-title></titles><periodical><full-title>JAMA Intern Med</full-title></periodical><pages>863-864</pages><volume>178</volume><number>6</number><dates><year>2018</year><pub-dates><date>Jun 1</date></pub-dates></dates><isbn>2168-6114 (Electronic)
2168-6106 (Linking)</isbn><accession-num>29582044</accession-num><urls><related-urls><url>;[2] A retraction notice confirmed that Sato had fabricated trial data. ADDIN EN.CITE <EndNote><Cite><Author>Sato</Author><Year>2018</Year><RecNum>438</RecNum><DisplayText>[4]</DisplayText><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1550575500">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sato, Y.</author><author>Honda, Y.</author><author>Iwamoto, J.</author></authors></contributors><auth-address>Department of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan; Department of Sport Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan.
Department of Sport Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.</auth-address><titles><title>RETRACTED: Etidronate for fracture prevention in amyotrophic lateral sclerosis: A randomized controlled trial</title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>214</pages><volume>106</volume><dates><year>2018</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1873-2763 (Electronic)
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ADDIN EN.CITE.DATA [5,6] The major bone Gla protein is osteocalcin (OC) which is synthesised by bone-forming osteoblasts with serum concentrations of OC correlating with the rate of bone formation. ADDIN EN.CITE <EndNote><Cite><Author>Gundberg</Author><Year>2012</Year><RecNum>371</RecNum><DisplayText>[7]</DisplayText><record><rec-number>371</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1532953767">371</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gundberg, C. M.</author><author>Lian, J. B.</author><author>Booth, S. L.</author></authors></contributors><auth-address>Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT, USA. caren.gundberg@yale.edu</auth-address><titles><title>Vitamin K-dependent carboxylation of osteocalcin: friend or foe?</title><secondary-title>Adv Nutr</secondary-title></titles><periodical><full-title>Adv Nutr</full-title></periodical><pages>149-57</pages><volume>3</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Biomarkers/metabolism</keyword><keyword>Bone Remodeling/drug effects</keyword><keyword>Glutamic Acid/physiology</keyword><keyword>Humans</keyword><keyword>Osteocalcin/*drug effects/metabolism</keyword><keyword>Vitamin K/*physiology</keyword><keyword>Vitamin K Deficiency/metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>2156-5376 (Electronic)
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ADDIN EN.CITE.DATA [8-12]. It was therefore anticipated that reducing the fraction of ucOC by vitamin K supplementation might slow the rate of age-related bone loss and because a low BMD is associated with increased fracture risk, ADDIN EN.CITE <EndNote><Cite><Author>Marshall</Author><Year>1996</Year><RecNum>365</RecNum><DisplayText>[13]</DisplayText><record><rec-number>365</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1530095526">365</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marshall, D.</author><author>Johnell, O.</author><author>Wedel, H.</author></authors></contributors><titles><title>Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures</title><secondary-title>Bmj</secondary-title></titles><periodical><full-title>Bmj</full-title></periodical><pages>1254-1259</pages><volume>312</volume><number>7041</number><dates><year>1996</year></dates><isbn>0959-8138
1468-5833</isbn><urls></urls><electronic-resource-num>10.1136/bmj.312.7041.1254</electronic-resource-num></record></Cite></EndNote>[13] might offer a treatment option for osteoporosis prevention. A recent systematic review of observational studies found that increased dietary intake of vitamin K may reduce the risk of fractures. ADDIN EN.CITE <EndNote><Cite><Author>Hao</Author><Year>2017</Year><RecNum>363</RecNum><DisplayText>[14]</DisplayText><record><rec-number>363</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1530094641">363</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hao, G.</author><author>Zhang, B.</author><author>Gu, M.</author><author>Chen, C.</author><author>Zhang, Q.</author><author>Zhang, G.</author><author>Cao, X.</author></authors></contributors><auth-address>aDepartment of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command bDepartment of Gynaecology and Obstetrics, First People's Hospital of Jinan, Jinan, China.</auth-address><titles><title>Vitamin K intake and the risk of fractures: A meta-analysis</title><secondary-title>Medicine (Baltimore)</secondary-title></titles><periodical><full-title>Medicine (Baltimore)</full-title></periodical><pages>e6725</pages><volume>96</volume><number>17</number><keywords><keyword>*Diet</keyword><keyword>Fractures, Bone/*epidemiology</keyword><keyword>Humans</keyword><keyword>Observational Studies as Topic</keyword><keyword>Risk</keyword><keyword>*Vitamin K</keyword></keywords><dates><year>2017</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1536-5964 (Electronic)
0025-7974 (Linking)</isbn><accession-num>28445289</accession-num><urls><related-urls><url>;[14] Vitamin K comprises a family of different molecular forms, a single form synthesized by plants (vitamin K1), and multiple forms mainly synthesised by bacteria (vitamins K2). The forms of vitamin K used in all RCTs to date are either vitamin K1 (the major dietary source) or two members of the vitamin K2 series, menaquinone-4 (MK-4) and menaquinone-7 (MK-7). MK-4 is unique in not being of bacterial origin but is able to be synthesised from dietary vitamin K1 within the body. In the light of evidence presented above that the data from some trials used for the previous systematic review are unreliable ADDIN EN.CITE <EndNote><Cite><Author>Bolland</Author><Year>2016</Year><RecNum>114</RecNum><DisplayText>[3]</DisplayText><record><rec-number>114</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1505720109">114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bolland, M. J.</author><author>Avenell, A.</author><author>Gamble, G. D.</author><author>Grey, A.</author></authors></contributors><auth-address>From the Department of Medicine (M.J.B., G.D.G., A.G.), University of Auckland, New Zealand; and Health Services Research Unit (A.A.), University of Aberdeen, Foresterhill, Scotland. m.bolland@auckland.ac.nz.
From the Department of Medicine (M.J.B., G.D.G., A.G.), University of Auckland, New Zealand; and Health Services Research Unit (A.A.), University of Aberdeen, Foresterhill, Scotland.</auth-address><titles><title>Systematic review and statistical analysis of the integrity of 33 randomized controlled trials</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>2391-2402</pages><volume>87</volume><number>23</number><keywords><keyword>Data Accuracy</keyword><keyword>*Data Interpretation, Statistical</keyword><keyword>Humans</keyword><keyword>Meta-Analysis as Topic</keyword><keyword>Randomized Controlled Trials as Topic/*standards/statistics & numerical data</keyword></keywords><dates><year>2016</year><pub-dates><date>Dec 06</date></pub-dates></dates><isbn>1526-632X (Electronic)
0028-3878 (Linking)</isbn><accession-num>27920281</accession-num><urls><related-urls><url>;[3] and new vitamin K trials have been published in the interim, we considered that an updated systematic review is required.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJuZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [15] We have also expanded this systematic review to include bone mineral density (BMD) as an outcome measure in the meta-analysis. ObjectivesTo assess the effectiveness of oral vitamin K supplementation in increasing BMD and reducing fractures in adults.METHODSProtocolA protocol for this systematic review was prospectively registered on PROSPERO (CRD42018087492).Eligibility criteriaStudies were eligible for inclusion if they fulfilled the below criteria:Population: Adults (defined as over 18 years of age)Intervention: Oral vitamin K supplement of any form or dosage administered for at least 6 months (min 25 weeks)Control: no treatment, treatment as usual, placebo, calcium, vitamin D, Hormone Replacement Therapies, bisphosphonatesOutcomes: Any fracture outcome and/or BMD after 6 monthsStudy design: Randomised controlled trialExclusion criteriaRemoval of studies that have been questioned with respect to their scientific integrity. The exclusion was applied to any articles published by Yoshihiro Sato or any of his known collaborators, irrespective of retraction status. This was done as serious concerns about the integrity and validity of the results have been raised.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xsYW5kPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA [3,16,17] Literature SearchThe following electronic databases were searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, , WHO ICTRP up till the 22nd January 2018. Searches relevant to fractures, BMD, vitamin K, and randomised controlled trials were made. Hand searching of references within records was undertaken to identify further eligible trials. The search strategy can be found in Supplement 1.Study SelectionRecords identified from searches were de-duplicated and the titles and abstracts were independently screened for inclusion by two authors, a decision on inclusion was reached through discussion. Full-text records were collated for the remaining articles and screened by the two authors, with any disagreements resolved by discussion.Data CollectionData extraction was undertaken on the included studies independently by two authors. A piloted data extraction form, developed from the Cochrane Data Extraction and Assessment Template, was used to collect the information. Data reported only in graphical form were extracted using the Digitize package in R. ADDIN EN.CITE <EndNote><Cite><Author>Poisot</Author><Year>2011</Year><RecNum>354</RecNum><DisplayText>[18]</DisplayText><record><rec-number>354</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529588999">354</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Timothée Poisot</author></authors></contributors><titles><title>The digitize Package: Extracting Numerical Data from Scatterplots</title><secondary-title>The R Journal</secondary-title></titles><periodical><full-title>The R Journal</full-title></periodical><pages>25-26</pages><volume>3</volume><number>1</number><dates><year>2011</year><pub-dates><date>June 2011</date></pub-dates></dates><isbn>ISSN 2073-4859</isbn><urls></urls></record></Cite></EndNote>[18]For each trial the following data were collected: i) Participant characteristics (age, presence or severity of disease); ii) intervention information (vitamin K form, frequency, dose); iii) study design and conduct information (funding, ethical approval, protocols and registry entries, eligibility criteria); and iv) fracture and BMD outcomes.Percentage change in BMD at 6 months, 1 year, and 2 years at the lumbar spine, femur, radius, and hip; total clinical fractures; total vertebral fractures; and total hip fractures were the outcomes of interest.The Cochrane risk of bias tool was used to assess studies as having a high or low risk of bias. ADDIN EN.CITE <EndNote><Cite><Author>Higgins</Author><Year>2011</Year><RecNum>70</RecNum><DisplayText>[19]</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1505720101">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Higgins, J. P.</author><author>Altman, D. G.</author><author>Gotzsche, P. C.</author><author>Juni, P.</author><author>Moher, D.</author><author>Oxman, A. D.</author><author>Savovic, J.</author><author>Schulz, K. F.</author><author>Weeks, L.</author><author>Sterne, J. A.</author><author>Cochrane Bias Methods, Group</author><author>Cochrane Statistical Methods, Group</author></authors></contributors><auth-address>MRC Biostatistics Unit, Institute of Public Health, Cambridge CB2 0SR, UK. julian.higgins@mrc-bsu.cam.ac.uk</auth-address><titles><title>The Cochrane Collaboration's tool for assessing risk of bias in randomised trials</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>Bmj</full-title></periodical><pages>d5928</pages><volume>343</volume><keywords><keyword>Bias</keyword><keyword>Humans</keyword><keyword>Randomized Controlled Trials as Topic/*standards</keyword><keyword>Research Design</keyword><keyword>Risk Assessment</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct 18</date></pub-dates></dates><isbn>1756-1833 (Electronic)
0959-8138 (Linking)</isbn><accession-num>22008217</accession-num><urls><related-urls><url>;[19] Two authors independently assessed each study and agreed a final classification through discussion. Studies that presented an unclear risk of bias were classified as having a high risk of bias if randomisation procedures were not clearly described.Statistics To assess the overall quality of the randomisation in the trials included in the meta-analysis heterogeneity of age was assessed using the method specified by Hicks et al ADDIN EN.CITE <EndNote><Cite><Author>Hicks</Author><Year>2018</Year><RecNum>356</RecNum><DisplayText>[20]</DisplayText><record><rec-number>356</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529589299">356</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hicks, A.</author><author>Fairhurst, C.</author><author>Torgerson, D. J.</author></authors></contributors><auth-address>York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, UK. Electronic address: amy.hicks@.
York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, UK.</auth-address><titles><title>A simple technique investigating baseline heterogeneity helped to eliminate potential bias in meta-analyses</title><secondary-title>J Clin Epidemiol</secondary-title></titles><periodical><full-title>J Clin Epidemiol</full-title></periodical><pages>55-62</pages><volume>95</volume><keywords><keyword>Baseline variables</keyword><keyword>Bias</keyword><keyword>Heterogeneity</keyword><keyword>Meta-analysis</keyword></keywords><dates><year>2018</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1878-5921 (Electronic)
0895-4356 (Linking)</isbn><accession-num>29032245</accession-num><urls><related-urls><url>;[20]. For multi-arm trials, where appropriate the separate treatment arms were pooled for all analyses, each arm was used only once.For fracture outcomes a meta-analysis of odds ratios (ORs) was used. As fracture rates were expected to be low, a fixed-effects meta-analysis using the Peto odds ratio method was used with no correction for zero event counts. ADDIN EN.CITE <EndNote><Cite><Author>Higgins</Author><Year>2011</Year><RecNum>357</RecNum><DisplayText>[21]</DisplayText><record><rec-number>357</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529589453">357</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Higgins, Julian P. T.</author><author>Green, Sally</author></authors></contributors><titles><title>Cochrane Handbook for Systematic Reviews of Interventions</title></titles><volume>5.1.0</volume><dates><year>2011</year></dates><urls><related-urls><url>;[21] For BMD outcomes a random-effects meta-analysis of weighted mean-difference in percentage change from baseline was used at the four anatomical sites at 6 months, 1 year, and 2 years. The heterogeneity of each meta-analysis was assessed using Cochran’s Q and the I2 statistic, using the interpretation thresholds suggested by the Cochrane handbook. ADDIN EN.CITE <EndNote><Cite><Author>Higgins</Author><Year>2011</Year><RecNum>357</RecNum><DisplayText>[21]</DisplayText><record><rec-number>357</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529589453">357</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Higgins, Julian P. T.</author><author>Green, Sally</author></authors></contributors><titles><title>Cochrane Handbook for Systematic Reviews of Interventions</title></titles><volume>5.1.0</volume><dates><year>2011</year></dates><urls><related-urls><url>;[21] For each meta-analysis a funnel plot was used to assess potential publication bias, for any meta-analysis where 10 or more studies were available, an Egger weighted-regression test was undertaken. ADDIN EN.CITE <EndNote><Cite><Author>Sterne</Author><Year>2011</Year><RecNum>360</RecNum><DisplayText>[22]</DisplayText><record><rec-number>360</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1530010835">360</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sterne, J. A.</author><author>Sutton, A. J.</author><author>Ioannidis, J. P.</author><author>Terrin, N.</author><author>Jones, D. R.</author><author>Lau, J.</author><author>Carpenter, J.</author><author>Rucker, G.</author><author>Harbord, R. M.</author><author>Schmid, C. H.</author><author>Tetzlaff, J.</author><author>Deeks, J. J.</author><author>Peters, J.</author><author>Macaskill, P.</author><author>Schwarzer, G.</author><author>Duval, S.</author><author>Altman, D. G.</author><author>Moher, D.</author><author>Higgins, J. P.</author></authors></contributors><auth-address>School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK. jonathan.sterne@bristol.ac.uk</auth-address><titles><title>Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>Bmj</full-title></periodical><pages>d4002</pages><volume>343</volume><keywords><keyword>*Meta-Analysis as Topic</keyword><keyword>*Randomized Controlled Trials as Topic</keyword><keyword>Selection Bias</keyword><keyword>Statistics as Topic/*methods</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 22</date></pub-dates></dates><isbn>1756-1833 (Electronic)
0959-8138 (Linking)</isbn><accession-num>21784880</accession-num><urls><related-urls><url>;[22] Sensitivity analyses were undertaken accounting for the effect of risk of bias in individual studies when a suitable number of studies were available for an outcome. All analyses were undertaken in R and the metafor package was used for all meta-analyses. ADDIN EN.CITE <EndNote><Cite><Author>Viechtbauer</Author><Year>2010</Year><RecNum>355</RecNum><DisplayText>[23,24]</DisplayText><record><rec-number>355</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529589170">355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Viechtbauer, Wolfgang</author></authors></contributors><titles><title>Conducting Meta-Analyses inRwith themetaforPackage</title><secondary-title>Journal of Statistical Software</secondary-title></titles><periodical><full-title>Journal of Statistical Software</full-title></periodical><volume>36</volume><number>3</number><dates><year>2010</year></dates><isbn>1548-7660</isbn><urls></urls><electronic-resource-num>10.18637/jss.v036.i03</electronic-resource-num></record></Cite><Cite><Author>R Development Core Team</Author><Year>2017</Year><RecNum>359</RecNum><record><rec-number>359</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1529663067">359</key></foreign-keys><ref-type name="Computer Program">9</ref-type><contributors><authors><author>R Development Core Team,</author></authors></contributors><titles><title>R: A Language and Environment for Statistical Computing</title></titles><edition>3.4.0</edition><dates><year>2017</year></dates><pub-location>Vienna, Austria</pub-location><publisher>R Foundation for Statistical Computing</publisher><isbn>3-900051-07-0</isbn><urls><related-urls><url>;[23,24] RESULTSStudy SelectionOur search identified 470 records, and after de-duplication 275 were available for screening. Of the 275 screened, 47 were included for full-text review along with the 8 records from the original review. Two further records were identified through hand searching of references and the full-texts of these articles were reviewed. Following full-text review 44 records were eligible for inclusion describing 38 studies. a2V5d29yZD5Cb25lIERlbnNpdHkvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5Cb25l
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ADDIN EN.CITE.DATA [53] The decision for each full-text record that was screened can be found in Supplement 2.A flow diagram of the number of records at each stage can be seen in Figure 1. Study CharacteristicsThe 36 included studies had a total of 11,112 participants with follow-up ranging from 6 to 48 months. Twenty-four of the trials included postmenopausal women with or without osteoporosis, three included patients with cirrhosis, two included patients with chronic glomerular nephritis, and of the remaining trials two were in healthy populations and five were in patient populations. Thirteen of the trials were placebo-controlled. Sixteen of the trials were conducted in Japan. Table 1 shows a summary of the study characteristics for the included trials. Details of outcome reporting can be seen in Supplement 3 and 4. We classified 19 trials as being at high risk of bias and 17 trials as being at low risk of bias. The decisions and classifications for each trial can be seen in Supplement 5. Meta-analysesA test for baseline heterogeneity of age revealed no concerning heterogeneity (Supplement 6).FracturesFracture data were available for 12 trials, 9 reported total clinical fractures, 8 reported vertebral fractures, and hip fractures were reported by only one trial (Supplement 3). Cheung et al reported hip fractures, there were none reported in the vitamin K group and one reported in the placebo group, this trial was classified as low risk of bias, the trial assessed 5 mg vitamin K1 against placebo with both groups also receiving calcium and vitamin D.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGV1bmc8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [30] Of the trials that reported other clinical fracture outcomes, 11 studies were conducted solely in post-menopausal or osteoporotic women and one was in chronic glomerulonephritis patients (Sasaki et al), these two groups were deemed too clinically heterogeneous to be combined in meta-analyses.Sasaki et al recruited 20 patients with chronic glomerulonephritis and randomised these patients (1:1) to either glucocorticoids alone or glucocorticoids and 45 mg/day vitamin K (MK-4).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXNha2k8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [66,67] Methods for the diagnosis of clinical fracture differed between the studies with Cheung, Inoue, Tanaka, and Shiraki all confirming fractures using radiography at the time of fracture; Emaus collected self-reported fractures at each follow-up from the participants; all the other trials did not report their method for the diagnosis or reporting of fractures. Of the trials reporting clinical fractures, six used vitamin K2 (five with 45 mg MK-4, one with 360 ?g MK-7) and three used vitamin K1 (ranging from 200 ?g to 10 mg). Of the trials reporting vertebral fractures six used vitamin K2 (five with 45 mg MK-4, one with 360 ?g MK-7) and one used vitamin K1 (5 mg).Meta-analyses were undertaken for both total clinical fractures and vertebral fractures for all trials including osteoporotic or post-menopausal women. For total clinical fractures a statistically significant Odds Ratio (OR) of 0.72 (95% CI: 0.55 to 0.95) was observed, representing a lower odds of fractures for those taking vitamin K (2.24% vs 3.06%) (Figure 2). The vertebral fractures meta-analysis showed a non-statistically significant OR of 0.96 (95% CI: 0.83 to 1.11) with those taking vitamin K having fewer fractures (10.55% vs 10.82%) (Figure 3). Sensitivity analysis showed that in low risk of bias trials there was no statistically significant effect between control and vitamin K seen in either total clinical (2.34% vs 3.01%; OR: 0.76, 95% CI: 0.58 to 1.02) or vertebral fractures (10.87% vs 10.24%; OR: 1.06, 95% CI: 0.91 to 1.24). Substantial heterogeneity was observed in the vertebral fractures meta-analysis, however no heterogeneity was present in the sensitivity analysis. The funnel plot for total clinical fractures showed no concerning asymmetry (Supplement 7). However, the funnel plot for vertebral fractures showed some asymmetry, this appears to be due to the studies with high and low risk of bias presenting differing results (Supplement 8)Bone Mineral DensityThirty-six trials reported collecting BMD data (Supplement 4). Twenty-two of these trials included post-menopausal or osteoporotic women and provided data that could be combined in meta-analyses for our pre-specified time-points. Both the K1 and K2 forms of vitamin K were used in the included trials with the K1 doses ranging from 100 ?g to 5 mg and the K2 doses ranging from 180 ?g to 45 mg.At 6 months, the percentage change in BMD was statistically significantly higher for those receiving vitamin K supplementation at the hip (Mean Difference [MD]: 0.42%, 95% Confidence Interval [CI]: 0.01 to 0.83) and the femur 0.29% (95% CI: 0.17 to 0.42) but was not statistically significantly different at the lumbar spine or the radius (Supplement 9). At 1 year BMD was not statistically significantly different between the vitamin K and control groups. (Figure 4). At 2 years the change in BMD was statistically significantly higher in the vitamin K group at the lumbar spine (MD: 1.63%, 95% CI: 0.10 to 3.16) and the femur (MD: 0.45, 95% CI: 0.05 to 0.85), but no statistically significant change was seen at other sites (Figure 5). Considerable heterogeneity was observed for the lumbar spine at the 6 month and 1 year time-points and for the radius at 1 and 2 years. Only one trial reported hip BMD at 24 months which indicated no difference between the groups (MD: 0.19%, 95% CI:-0.38 to 0.77).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGV1bmc8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [30]Sensitivity analyses accounting for the individual risk of bias in the studies showed that for studies with a low risk of bias the percentage change in lumbar spine at 6 months was higher for the controls than vitamin K (MD: -0.21, 95% CI:-0.38 to -0.03), and that there was no statistically significant difference at 1 year (MD: 0.41, 95% CI: -0.32 to 1.14), or 2 years (MD: -0.04, 95% CI: -0.53 to 0.46). The sensitivity analyses also confirmed that there was no statistically significant difference in BMD at the femur at 1 year (MD: 0.19, 95% CI: -0.17 to 0.55). Heterogeneity remained high at the lumbar spine at 1 year in the sensitivity analysis, although this appears to be caused by the inclusion of one study. ADDIN EN.CITE <EndNote><Cite><Author>Purwosunu</Author><Year>2006</Year><RecNum>368</RecNum><DisplayText>[54]</DisplayText><record><rec-number>368</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1530191456">368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Purwosunu, Y.</author><author>Muharram,</author><author>Rachman, I. A.</author><author>Reksoprodjo, S.</author><author>Sekizawa, A.</author></authors></contributors><auth-address>Department of Obstetrics and Gynecology, University of Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia. yudi@med.showa-u.ac.jp</auth-address><titles><title>Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia</title><secondary-title>J Obstet Gynaecol Res</secondary-title></titles><periodical><full-title>J Obstet Gynaecol Res</full-title></periodical><pages>230-4</pages><volume>32</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Bone Density</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Indonesia</keyword><keyword>Middle Aged</keyword><keyword>Osteocalcin/blood</keyword><keyword>Osteoporosis, Postmenopausal/*drug therapy</keyword><keyword>Placebos</keyword><keyword>Vitamin K 2/*therapeutic use</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1341-8076 (Print)
1341-8076 (Linking)</isbn><accession-num>16594930</accession-num><urls><related-urls><url>;[54]The funnel plots for BMD outcomes did not show any concerning asymmetry, Egger weighted regression for the lumbar spine at 1 year meta-analyses confirmed a lack of significant asymmetry (Supplement 10, 11, 12).A summary of studies in other patient groups is provided in supplement 13 as these were not suitable for meta-analysis.DISCUSSIONSummary of Evidence The majority of trials identified in this systematic review were conducted in postmenopausal or osteoporotic patients. For other groups of patients there is limited evidence on the effect of vitamin K supplementation on fractures or BMD, therefore no conclusions can be drawn on its clinical benefit for these groups. For postmenopausal and osteoporotic patients, clinical fractures were lower in the vitamin K group (2.24% vs 3.06%) with an OR of 0.72; when restricted to low risk of bias studies the effect was smaller (2.34% vs 3.01%) with an OR of 0.76. The trials in this review that were powered to detect a reduction in the risk of fractures defined the minimum clinically important reduction as being between 20% and 35%. We observed a reduction of 28% in all trials and 24% in trials with a low risk of bias. Whilst a fracture reduction of this magnitude would be considered clinically relevant, the translation of this data to clinical practice is hampered by the high variability in study designs, especially concerning treatment regimens (e.g. form of vitamin K, dosage, co-supplementation with drugs, vitamin D, and minerals, length of treatment, etc.) The odds of vertebral fractures were lower in the vitamin K group compared to the control group (10.55% vs 10.82%; OR: 0.96), however the odds of fracture were higher in the vitamin K group when the analysis was restricted to low risk of bias trials (10.87% vs 10.24%; OR:1.06). This suggests that vitamin K is unlikely to have an effect on vertebral fracture and that if it does this effect is unlikely to be clinically significant. There is insufficient data to suggest an effect of vitamin K on hip fractures in post-menopausal or osteoporotic patients. A previous systematic review assessing the effect of calcium supplementation on BMD defined an increase of 1 to 2% per year as unlikely to result in a clinically meaningful reduction in fracture risk. ADDIN EN.CITE <EndNote><Cite><Author>Tai</Author><Year>2015</Year><RecNum>366</RecNum><DisplayText>[68]</DisplayText><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1530104220">366</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tai, V.</author><author>Leung, W.</author><author>Grey, A.</author><author>Reid, I. R.</author><author>Bolland, M. J.</author></authors></contributors><auth-address>Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Department of Public Health, University of Otago, PO Box 7343, Wellington 6242, New Zealand.
Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand m.bolland@auckland.ac.nz.</auth-address><titles><title>Calcium intake and bone mineral density: systematic review and meta-analysis</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>Bmj</full-title></periodical><pages>h4183</pages><volume>351</volume><keywords><keyword>Aged</keyword><keyword>*Bone Density</keyword><keyword>*Calcium, Dietary</keyword><keyword>*Dietary Supplements</keyword><keyword>Fractures, Bone/*prevention & control</keyword><keyword>Humans</keyword><keyword>Middle Aged</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2015</year><pub-dates><date>Sep 29</date></pub-dates></dates><isbn>1756-1833 (Electronic)
0959-8138 (Linking)</isbn><accession-num>26420598</accession-num><urls><related-urls><url>;[68] The change in BMD seen in the full analysis was less than 1% at 1 year and less than 2% at 2 years at all sites, with smaller effects in sensitivity analyses of trials with a low risk of bias. Therefore, if vitamin K does exert an effect on BMD it is unlikely to yield a beneficial clinical effect.Another recent systematic review found that the clinical use of oral vitamin K antagonists (VKA) for anticoagulant therapy was not associated with an increased fracture risk, neither did they reduce BMD beyond the effects seen in medical illness.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJvbmVzZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA [69] and knowledge that exposure to even low doses of VKA raises the fraction of ucOC/OC to extremely high levels ADDIN EN.CITE <EndNote><Cite><Author>Bach</Author><Year>1996</Year><RecNum>379</RecNum><DisplayText>[70]</DisplayText><record><rec-number>379</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1534240743">379</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bach, A. U.</author><author>Anderson, S. A.</author><author>Foley, A. L.</author><author>Williams, E. C.</author><author>Suttie, J. W.</author></authors></contributors><auth-address>Department of Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706, USA.</auth-address><titles><title>Assessment of vitamin K status in human subjects administered "minidose" warfarin</title><secondary-title>Am J Clin Nutr</secondary-title></titles><periodical><full-title>Am J Clin Nutr</full-title></periodical><pages>894-902</pages><volume>64</volume><number>6</number><keywords><keyword>1-Carboxyglutamic Acid/urine</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Anticoagulants/*pharmacology</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteocalcin/blood</keyword><keyword>Prothrombin/analysis</keyword><keyword>Thrombosis/epidemiology/prevention & control</keyword><keyword>Vitamin K/*blood</keyword><keyword>Vitamin K 1/analogs & derivatives/blood</keyword><keyword>Warfarin/*pharmacology</keyword></keywords><dates><year>1996</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0002-9165 (Print)
0002-9165 (Linking)</isbn><accession-num>8942414</accession-num><urls><related-urls><url>;[70]. This supports our results that vitamin k is unlikely to have a clinically meaningful effect on BMD.The results of this review differ from those of the original review ADDIN EN.CITE <EndNote><Cite><Author>Cockayne</Author><Year>2006</Year><RecNum>349</RecNum><DisplayText>[1]</DisplayText><record><rec-number>349</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1515506246">349</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cockayne, S.</author><author>Adamson, J.</author><author>Lanham-New, S.</author><author>Shearer, M. J.</author><author>Gilbody, S.</author><author>Torgerson, D. J.</author></authors></contributors><auth-address>York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, England. djt6@york.ac.uk</auth-address><titles><title>Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials</title><secondary-title>Arch Intern Med</secondary-title></titles><periodical><full-title>Arch Intern Med</full-title></periodical><pages>1256-61</pages><volume>166</volume><number>12</number><keywords><keyword>Bone Density/drug effects</keyword><keyword>Fractures, Bone/*prevention & control</keyword><keyword>Humans</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Treatment Outcome</keyword><keyword>Vitamin K 1/*administration & dosage</keyword><keyword>Vitamin K 2/*administration & dosage</keyword><keyword>Vitamins/*administration & dosage</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun 26</date></pub-dates></dates><isbn>0003-9926 (Print)
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ADDIN EN.CITE.DATA [71,14,72] on the use of vitamin K, which have demonstrated a larger effect on fractures and BMD. This difference is likely a result of the inclusion of more recent large trials reporting fracture outcomes, the removal of potentially fraudulent studies in this systematic review, inclusion of all forms of vitamin k, and accounting for the methodological quality of the included trials in our analyses. Other biological mechanisms may explain the results seen in this review. For example, there is substantial evidence that the molecule MK-4 is able to modulate cellular functions such as gene expression and signal transduction that control bone processes such as the generation of bone osteoclasts. ADDIN EN.CITE <EndNote><Cite><Author>Newman</Author><Year>2008</Year><RecNum>437</RecNum><DisplayText>[73]</DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1550574336">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Newman, Paul</author><author>Shearer, Martin J.</author></authors></contributors><titles><title>Metabolism and cell biology of vitamin K</title><secondary-title>Thrombosis and Haemostasis</secondary-title></titles><periodical><full-title>Thrombosis and Haemostasis</full-title></periodical><pages>530-547</pages><volume>100</volume><number>10</number><dates><year>2008</year></dates><isbn>0340-6245
2567-689X</isbn><urls><related-urls><url>;[73] Note, that such a mechanism does not rule out that vitamin K1 acts in the same way because vitamin K1 is a precursor of MK-4 in the human body. ADDIN EN.CITE <EndNote><Cite><Author>Newman</Author><Year>2008</Year><RecNum>437</RecNum><DisplayText>[73]</DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1550574336">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Newman, Paul</author><author>Shearer, Martin J.</author></authors></contributors><titles><title>Metabolism and cell biology of vitamin K</title><secondary-title>Thrombosis and Haemostasis</secondary-title></titles><periodical><full-title>Thrombosis and Haemostasis</full-title></periodical><pages>530-547</pages><volume>100</volume><number>10</number><dates><year>2008</year></dates><isbn>0340-6245
2567-689X</isbn><urls><related-urls><url>;[73]Alternatively, there is currently an ongoing trial (ISRCTN18436190) investigating whether vitamin K has an effect on balance, falls, and postural blood pressure, which if demonstrated, could explain why the data from this systematic review suggests that vitamin K reduces clinical fractures but not vertebral fractures or bone mineral density.Strengths and LimitationsThe main strength of our study was the exclusion of trials that have been reported as questionable and the inclusion of more recent trials that were larger and analysed both BMD and fracture outcomes. The analysis of a larger number of trials with a higher methodological quality allowed planned sensitivity analyses to be undertaken, which allow more robust conclusions regarding the efficacy of vitamin K. More trials have also been published that are powered to detect an effect on fractures. All the trials used a validated method for the diagnosis of vertebral fractures and only one low risk of bias trial relied on self-reporting of incident clinical fractures. The number of vertebral fractures aligns with those reported in comparable studies. However, the prevalence of vertebral fractures has been reported to be more variable in studies in Asia, which may affect the generalisability of our results.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxsYW5lPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA [74] Our analyses still indicate uncertainty regarding the effect of vitamin K supplementation on the rates of total clinical fractures, which may reflect the differing methods for reporting and diagnosis of fractures.Our study also has limitations. Some trials did not provide suitable data to be combined in meta-analysis. Many of the trials included were conducted in Japanese populations and post-menopausal women, thus further research is required to draw conclusions for the efficacy of vitamin K in other populations. Some BMD outcomes had considerable heterogeneity which may be a result of trial methodology, measurement methods, vitamin K form and dosage used, or baseline population characteristics, which could not be explored further. It is also possible that differences in concurrent treatments, such as vitamin D, calcium or bisphosphonates could influence our results, especially as no trials stratified by baseline vitamin D status in their randomization protocol. This would allow the trials to mitigate the differing effects of some concurrent treatments on individuals with different baseline values. Many of the trials provided baseline BMD, which varied between the trials. As there is likely to be little effect in participants with a low fracture risk, the inclusion of participants with normal BMD at baseline may reduce the size of any effect seen on fractures that may be present in those with a low BMD at baseline. There is also little reporting on baseline vitamin K, as benefit is only likely to be gained in patients who are deficient in vitamin K. However, the question of whether vitamin K supplementation would have had a greater effect in patients with vitamin K deficiency cannot be answered from the available data within these trials for several reasons. Apart from the absence of appropriate baseline data for many trials, there is no common agreement on either the definition of vitamin K deficiency, the assay methodology used to assess it, or how to create and interpret cross assay reference ranges of the various available biomarkers. ADDIN EN.CITE <EndNote><Cite><Author>Shea</Author><Year>2016</Year><RecNum>436</RecNum><DisplayText>[75]</DisplayText><record><rec-number>436</rec-number><foreign-keys><key app="EN" db-id="0sdsxx5sqzfs5aetf21pspw325xp9sx0tz2z" timestamp="1550574138">436</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shea, M. K.</author><author>Booth, S. L.</author></authors></contributors><auth-address>USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. sarah.booth@tufts.edu.</auth-address><titles><title>Concepts and Controversies in Evaluating Vitamin K Status in Population-Based Studies</title><secondary-title>Nutrients</secondary-title></titles><periodical><full-title>Nutrients</full-title></periodical><volume>8</volume><number>1</number><keywords><keyword>Biomarkers/blood</keyword><keyword>Humans</keyword><keyword>*Nutrition Assessment</keyword><keyword>*Nutritional Status</keyword><keyword>Proteins/*metabolism</keyword><keyword>Vitamin K/administration & dosage/*blood</keyword><keyword>biomarkers</keyword><keyword>epidemiology</keyword><keyword>review</keyword><keyword>vitamin K</keyword><keyword>vitamin K intake</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan 2</date></pub-dates></dates><isbn>2072-6643 (Electronic)
2072-6643 (Linking)</isbn><accession-num>26729160</accession-num><urls><related-urls><url>;[75] Standardisation of this should be a priority for any future trials.The majority of the trials included in our analyses used the MK-4 form of vitamin K2 with a dosage of 45 mg, however, many trials also used vitamin K1 and some MK-7 at various dosages. The fracture meta-analyses showed little statistical heterogeneity between these different forms and doses, however our results cannot be confirmatory with regards to the relative effectiveness of different vitamin K regimens.ConclusionsVitamin K supplementation appears to have little effect on BMD for post-menopausal or osteoporotic patients. Whilst no effect was seen on vertebral fracture outcomes for these patients, a potentially clinically relevant effect was seen on clinical fractures, although further high quality research is required to confirm this. Further research might focus on the use of vitamin K supplementation in individuals with a high baseline fracture risk or with clear biochemically defined vitamin K insufficiency, and outcomes that can explore alternative mechanisms of action. The possible value of vitamin K supplementation could also be expanded to other patient groups where evidence is presently lacking.ACKNOWLEDGEMENTSFUNDINGThere was no funding for this systematic review. CONTRIBUTOR INFORMATIONAll authors designed and planned the study; KW developed and completed the searches using terms suggested by the other authors; AM, TB, and DT screened and extracted data from the studies; AM completed the analysis; all authors contributed to the interpretation of the results and the writing of the final manuscript. Andrew Mott, Thomas Bradley, Kath Wright, Elizabeth Sarah Cockayne, Martin J Shearer, Joy Adamson, Susan Alexandra Lanham-New, and David Torgerson declare that they have no conflict of interest.DATA Data and R code are available at and .References ADDIN EN.REFLIST 1. Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ (2006) Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 166 (12):1256-1261. doi:10.1001/archinte.166.12.12562. Torgerson DJ (2018) Caution to Readers About Systematic Review on Vitamin K and Prevention of Fractures That Included Problematic Trials. JAMA Intern Med 178 (6):863-864. doi:10.1001/jamainternmed.2018.11273. Bolland MJ, Avenell A, Gamble GD, Grey A (2016) Systematic review and statistical analysis of the integrity of 33 randomized controlled trials. Neurology 87 (23):2391-2402. doi:10.1212/WNL.00000000000033874. Sato Y, Honda Y, Iwamoto J (2018) RETRACTED: Etidronate for fracture prevention in amyotrophic lateral sclerosis: A randomized controlled trial. Bone 106:214. doi:10.1016/j.bone.2017.10.0085. Booth SL (2009) Roles for vitamin K beyond coagulation. Annu Rev Nutr 29:89-110. doi:10.1146/annurev-nutr-080508-1412176. Bügel S (2008) Vitamin K and Bone Health in Adult Humans. 78:393-416. doi:10.1016/s0083-6729(07)00016-77. Gundberg CM, Lian JB, Booth SL (2012) Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr 3 (2):149-157. doi:10.3945/an.112.0018348. Liu G, Peacock M (1998) Age-Related Changes in Serum Undercarboxylated Osteocalcin and its Relationships with Bone Density, Bone Quality, and Hip Fracture. Calcified Tissue International 62 (4):286-289. doi:10.1007/s0022399004329. Szulc P, Chapuy MC, Meunier PJ, Delmas PD (1993) Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. 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Su S, He N, Men P, Song C, Zhai S (2019) The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. doi:10.1007/s00198-019-04853-773. Newman P, Shearer MJ (2008) Metabolism and cell biology of vitamin K. Thrombosis and Haemostasis 100 (10):530-547. doi:10.1160/th08-03-014774. Ballane G, Cauley JA, Luckey MM, El-Hajj Fuleihan G (2017) Worldwide prevalence and incidence of osteoporotic vertebral fractures. Osteoporos Int 28 (5):1531-1542. doi:10.1007/s00198-017-3909-375. Shea MK, Booth SL (2016) Concepts and Controversies in Evaluating Vitamin K Status in Population-Based Studies. Nutrients 8 (1). doi:10.3390/nu8010008Table 1: Study Characteristics of Included StudiesAuthor, YearPopulationCountryRandomized (n)Intervention(type, dose)ControlFollow up (months)AgeControlVitamin KControlVitamin KBinkley, 2009Postmenopausal, FemaleAmerica129126/126Ca – 315 mgVD – 200 IUK1 – 1 mg/MK-4 - 45mgMatched placeboCa – 315 mgVD – 200 IUMatched placebos1 yearNRNRBolton-Smith, 2007Healthy, female, >60 yearsUnited Kingdom123(61 + 62)121(60+61)K1 - 200 μgPlacebo2 years68.6 (67.7)67.8 (5.15)K1 - 200 μgVD – 10 μgCa – 1000 mgVD – 10 μgCa – 1000 mgBooth et al, 2008Healthy, postmenopausal Females and males between 60-80 years America236238VD – 10 ?gCa – 600 mgK1 - 500 ?gVD – 10 ?gCa – 600 mg3 years68.4 (6)68.4 (6)Braam, 2003 (a)Healthy, postmenopausal, FemaleThe Netherlands122(61+61)66Ca – 500 mg Zn – 10 mgMag – 150 mgVD - 8 μgK1 – 1 mgCa – 500 mg Zn – 10 mgMag – 150 mgVD - 8 μg3 years55.1 (2.9)55.3 (2.8)PlaceboBraam, 2003 (b)Female Endurance athletesNorth Europe5659K1 – 10 mgPlacebo2 yearsNRNRCheung et al, 2008Postmenopausal, osteopenic, FemaleCanada223217VD – 800 IUCa – 1,500 mgK1 – 5 mgVD – 800 IUCa – 1,500 mgPlacebo2 years (ext to 4)59.258.9Emaus et al, 2010Healthy, postmenopausal, FemaleNorway167167MK-7 capsule – 360 ?gPlacebo capsule1 year54.2 (2.5)54.7 (2.5)Forli et al, 2010Transplant PatientsNorway4846VD – 10 - 20 ?gCa –1000 mgMK-7 – 180 ?gVD – 10 - 20 ?gCa –1000 mg1 yearNRNRGleeson, 2004(abstract only)Primary Biliary CirrhosisUnited Kingdom2522K2 (NR) – 2 mgCa – 1000 mgVD - 20 μgCa – 1000 mgVD - 20 μgPlacebo1 year63 (11)Hampson(Ongoing)Hirao et al, 2008Healthy Postmenopausal femaleJapan2622Alendronate – 5 mgMK-4 – 45 mgAlendronate – 5 mg1 year69.8 (8.7)67.0 (6.6)Holden et al (Ongoing)Hozuki et al, 2010Patients with neuromuscular disordersJapan88Risedronate - 2.5 mgcorticosteroids MK-4 – 45 mgRisedronate - 2.5 mgcorticosteroids 1 year54.7 (5.4)53.6 (5.6)Inoue et al, 2009Postmenopausal, Female, osteoporosisJapan21932185Ca – 1.2 g/3 gMK-4 – 45 mgCa – 1.2g/3g4 years69.6 (8.25)69.6 (8.32)Inoue et al, 2014Patients with IgA NephropathyJapan64MK-4 – 45 mgCalcitriol – 0.5 μgCalcitriol - 0.5 μg6 months25.4 (5.9)29.3 (4.2)Ishida & Kawai, 2004Postmenopausal, Female, osteoporosisJapan6666MK-4 – 45 mgNothing2 years68 (8)68 (11)Iwamoto et al, 1999Postmenopausal, FemaleJapan1917MK-4 – 45 mgNothing1 year53.6 (3.7)52.6 (6.4)Je et al, 2011Postmenopausal, FemaleKorea4038VD – 400 IUCa – 630 mgMK-4 - 45 mgVD – 400 IUCa – 630 mg6 months67.6 (6.2)68.1 (6.3)Jiang et al, 2014Postmenopausal, FemaleChina105108Alfacalcidol – 0.5 ?gCa – 500 mgMK-4 – 45 mgAlfacalcidol – 0.5 ?gCa – 500 mg1 year64.2 (6.3)64.6 (6.1)Jokar et al, 2016Postmenopausal, Female, osteoporosisIran2324Alendronate – 70 mgCa – 500 mgVD – 200 IUK1 – 10 mgAlendronate – 70 mgCa – 500 mgVD – 200 IU1 year59.0 (6.3)59.0 (6.3)Kanellakis/Moschonis et al, 2011/12Healthy, Postmenopausal, FemaleGreece6550K1 - 100 ?gCa - 800 mgVD –10 ?gCa - 800 mgVD -10 ?g1 year62.44 (5.93)61.43 (5.88)Ca - 800 mgVD –10 ?gMK-7 -100 ?gKasukawa et al, 2014Postmenopausal, Female, osteoporosisJapan5051Risedronate – 17.5 mg (wk)MK-4 – 45 mgRisedronate – 17.5 mg (wk)1 year74.0 (6.9)75.4 (5.7)Knapen et al, 2013Healthy, postmenopausal, FemaleThe Netherlands124120MK-7 – 180 μgPlacebo3 years59 (3)60(4)Knapen et al, 2007Healthy, postmenopausal, FemaleThe Netherlands164161MK-4 – 45 mgPlacebo3 years66.0 (6.4)65.9 (5.1)Koitaya et al, 2014Postmenopausal women, FemaleJapan2424MK-4 – 1.5 mgPlacebo1 year58.5 (3.7)58.3 (4.0)Nishiguchi, 2001Female, Primary Billiary CirrhosisJapan1515MK-4 – 45 mgNothing2 years55 (7)56 (8)O’Connor et al, 2014Pts with Crohn’s in remissionIreland4343VD – 10 μgCa – 500 mgK1 – 1 mgVD – 10 μgCa – 500 mgplacebo1 year40.7 (10.5)42.0 (10.0)Purswosunu et al , 2006Postmenopausal, Female, osteoporosisIndonesia3033Ca – 1.5 gMK-4 – 45 mgCa - 1.5 gplacebo1 year60.6 (5.7)60.9 (4.9)Ronn et al, 2016(3 year follow-up to publish)Healthy, postmenopausal, Female, osteopeniaDenmark7171Ca – 800 mgVD – 38 μgMK-7 – 375 μgCa – 800 mgVD – 38 μgplacebo1 year 67.0 (4.5)67.9 (4.6)Sasaki, 2005Chronic glomerulonephritis patientsJapan1010GlucocorticoidsMK-4 – 45 mgGlucocorticoids1 year38.5 (6.4)41.6 (7.2)Shiomi, 2005Cirrhosis + viral hepatitis, FemaleJapan2223MK-4 – 45 mgNone2 years59 (9)61(8)Shiraki, 2000Osteoporosis, FemaleJapan121120Ca – 150 mgMK-4 – 45 mgCa – 150 mg2 years68.0 (0.8)66.4 (0.8)Shiraki & Itabashi, 2009Postmenopausal, Female, osteoporosisJapan6062Ca – 1.2 gMK-4 – 45 mgCa – 1.2 g6 months69.3 (7.4)67.8 (7.9)Somekawa, 1999Female, uterine leiomyomas/endometriosisJapan5252Leuprolide acetate – 1.88 mg/month.MK-4 – 45 mgLeuprolide acetate - 1.88 mg/month.6 months46 (1)46 (1)Leuprolide acetate – 1.88 mg/month.MK-4 – 45 mgVD – 0.5 μgLeuprolide acetate – 1.88 mg/month.VD – 0.5 μgTanaka et al, 2017Female, osteoporosis, >65 yearsJapan991992Risedronate – 2.5 mgMK-4 – 45 mgRisedronate – 2.5 mg2 years75.3 (5.9)75.3 (5.8)Ushiroyama, 2001Postmenopausal, FemaleJapan6561MK-4 – 45 mgNone2 years53.2 (5.8)53.7 (6.1)MK-4 – 45 mgVD - 1 μgVD - 1 μgVolpe et al, 2008Pre & peri menopausal women America1011K1 – 600 μgPlacebo6 months37.05 (9.55)35.36 (8.02)Yuko, 2014Chronic glomerulonephritisJapan1923Risedronate 17.5 mg (wk)MK-4 – 45 mgRisedronate 17.5 mg (wk)6 months39.4 (17.0)Ca = Calcium, Zn = Zinc, VD = vitamin D, Mag = magnesium, K1 = vitamin K1, MK-4 = menaquinone-4, MK-7 = menaquinone-7; NR: Not Reported.Figure TitlesFigure 1: A PRISMA flow diagram of study selectionFigure 2: Meta-analysis of Peto odds ratio of any clinical fracture outcomes for trials including Osteoporotic or Postmenopausal participants Figure 3: Meta-analysis of Peto odds ratio of any vertebral fracture outcomes for trials including Osteoporotic or Postmenopausal participantsFigure 4: Meta-analyses of mean difference in percentage change from baseline in Bone Mineral Density at 12 months for trials including Osteoporotic or Postmenopausal participantsFigure 5: Meta-analyses of mean difference in percentage change from baseline in Bone Mineral Density at 24 months for trials including Osteoporotic or Postmenopausal participants ADDIN ................
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