{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T05:03:35Z","timestamp":1764997415543,"version":"3.46.0"},"reference-count":31,"publisher":"BMJ","issue":"8","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2019,7,22]]},"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Clinical trials and systematic reviews of trials involving vitamin D supplementation have mainly focused on defining the optimal amount of vitamin D dosage. However, the comparative effectiveness of different dosing schedules (ie, daily vs bolus dosing schedule) has been largely unexplored; and currently, there is no consensus regarding the optimal vitamin D dosing schedule. Our objective is to conduct a systematic review and network meta-analysis (NMA) to evaluate the comparative effectiveness and safety of steady (eg, daily, weekly) and intermittent high-dose (eg, monthly, yearly) vitamin D dosing schedules; and to determine the effectiveness of the various dosing schedules and combinations of treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>We will conduct a systematic search and review of literature from major medical databases (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) involving studies that compare vitamin D supplementation alone or in combination with calcium. Only randomised controlled trials (RCTs) will be considered. We will, however, consider various settings (eg, community, institutional care) and study designs (eg, cluster RCTs, cross-over trials). Our primary outcomes include falls and fractures including hip-fracture and non-vertebral fractures. Secondary outcomes will include muscle strength, physical performance, gait and mobility limitation. A Bayesian NMA will be conducted, and the results will be presented in the form of treatment effect estimates and ranking probabilities, with corresponding CIs. Pairwise meta-analysis will also be conducted for studies reporting head-to-head comparisons. Subgroup analysis will be performed with respect to pre-determined subgroups; including vitamin D status as measured by serum 25-hydroxyvitamin D levels, age and follow-up time. Sensitivity analysis will also be performed with respect to risk of bias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>This study is a systematic review and meta-analysis of published RCTs; therefore, no ethical approval is required. Results will be disseminated through open access peer-reviewed publications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>PROSPERO CRD42018112662.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2018-027349","type":"journal-article","created":{"date-parts":[[2019,8,21]],"date-time":"2019-08-21T06:13:08Z","timestamp":1566367988000},"page":"e027349","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Effectiveness and safety of steady versus intermittent high dose vitamin D supplementation for the prevention of falls and fractures among adults: a protocol for systematic review and network meta-analysis"],"prefix":"10.1136","volume":"9","author":[{"given":"Banaz","family":"Al-khalidi","sequence":"first","affiliation":[{"name":"School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joycelyne Efua","family":"Ewusie","sequence":"additional","affiliation":[{"name":"Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jemila","family":"Hamid","sequence":"additional","affiliation":[{"name":"Clinical Research Unit, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Kimball","sequence":"additional","affiliation":[{"name":"Research Department, Pure North S'Energy Foundation, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2019,8,20]]},"reference":[{"key":"2025120520555588000_9.8.e027349.1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2704"},{"key":"2025120520555588000_9.8.e027349.2","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1001\/jama.2018.4023","article-title":"Preventing fractures and falls: a limited role for calcium and vitamin D supplements?","volume":"319","author":"Bischoff-Ferrari","year":"2018","journal-title":"JAMA"},{"key":"2025120520555588000_9.8.e027349.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109617"},{"key":"2025120520555588000_9.8.e027349.4","doi-asserted-by":"crossref","unstructured":"Zhao J-G , Zeng X-T , Wang J , et al . Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults. JAMA 2017;318.doi:10.1001\/jama.2017.19344","DOI":"10.1001\/jama.2017.19344"},{"key":"2025120520555588000_9.8.e027349.5","doi-asserted-by":"crossref","unstructured":"Avenell A , Mak JCS , O'Connell D . Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev 2014;(4):CD000227.doi:10.1002\/14651858.CD000227.pub4","DOI":"10.1002\/14651858.CD000227.pub4"},{"key":"2025120520555588000_9.8.e027349.6","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S2213-8587(14)70068-3","article-title":"Vitamin D supplementation and falls: a trial sequential meta-analysis","volume":"2","author":"Bolland","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025120520555588000_9.8.e027349.7","doi-asserted-by":"publisher","DOI":"10.1111\/nure.12090"},{"key":"2025120520555588000_9.8.e027349.8","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1195"},{"key":"2025120520555588000_9.8.e027349.9","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12020-017-1245-1","article-title":"Optimal vitamin D supplementation strategies","volume":"56","author":"Bouillon","year":"2017","journal-title":"Endocrine"},{"key":"2025120520555588000_9.8.e027349.10","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0115850","article-title":"A meta-analysis of high dose, intermittent vitamin D supplementation among older adults","volume":"10","author":"Zheng","year":"2015","journal-title":"PLoS One"},{"key":"2025120520555588000_9.8.e027349.11","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.117.006802","article-title":"Effect of monthly, high-dose, long-term vitamin D supplementation on central blood pressure parameters: a randomized controlled trial substudy","volume":"6","author":"Sluyter","year":"2017","journal-title":"J Am Heart Assoc"},{"key":"2025120520555588000_9.8.e027349.12","doi-asserted-by":"crossref","unstructured":"Scragg R , Stewart AW , Waayer D , et al . Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study. JAMA Cardiol 2017;2.doi:10.1001\/jamacardio.2017.0175","DOI":"10.1001\/jamacardio.2017.0175"},{"key":"2025120520555588000_9.8.e027349.13","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/S2213-8587(18)30265-1","article-title":"Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis","volume":"6","author":"Bolland","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025120520555588000_9.8.e027349.14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2653"},{"key":"2025120520555588000_9.8.e027349.15","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.mehy.2017.12.017","article-title":"Serum cholecalciferol may be a better marker of vitamin D status than 25-hydroxyvitamin D","volume":"111","author":"Jorde","year":"2018","journal-title":"Med Hypotheses"},{"key":"2025120520555588000_9.8.e027349.16","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.g7647","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation","volume":"350","author":"Shamseer","year":"2015","journal-title":"BMJ"},{"key":"2025120520555588000_9.8.e027349.17","unstructured":"Cochrane Handbook . Cross-over trials, (n.d.). Available: https:\/\/handbook-5-1.cochrane.org\/chapter_16\/16_4_cross_over_trials.htm [Accessed 1 Apr 2019]."},{"key":"2025120520555588000_9.8.e027349.18","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane collaboration's tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"2025120520555588000_9.8.e027349.19","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19961230)15:24<2733::AID-SIM562>3.0.CO;2-0"},{"key":"2025120520555588000_9.8.e027349.20","doi-asserted-by":"crossref","unstructured":"Whitehead A . Meta-Analysis of controlled clinical trials. John Wiley & Sons, 2002.","DOI":"10.1002\/0470854200"},{"key":"2025120520555588000_9.8.e027349.21","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1875"},{"key":"2025120520555588000_9.8.e027349.22","doi-asserted-by":"publisher","DOI":"10.2165\/00019053-200624010-00001"},{"key":"2025120520555588000_9.8.e027349.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2010.03.016"},{"key":"2025120520555588000_9.8.e027349.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2016.02.016"},{"key":"2025120520555588000_9.8.e027349.25","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dys222"},{"key":"2025120520555588000_9.8.e027349.26","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3767"},{"key":"2025120520555588000_9.8.e027349.27","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1186"},{"key":"2025120520555588000_9.8.e027349.28","doi-asserted-by":"crossref","unstructured":"Veroniki AA , Huedo-Medina TB , Fountoulakis KN . Appraising Between-Study homogeneity, Small-Study effects, Moderators, and confounders, in: umbrella Rev. Cham: Springer International Publishing, 2016: 161\u201388.","DOI":"10.1007\/978-3-319-25655-9_12"},{"key":"2025120520555588000_9.8.e027349.29","unstructured":"W. The BUGS project . WinBUGS - MRC Biostatistics Unit, (n.d.). Available: https:\/\/www.mrc-bsu.cam.ac.uk\/software\/bugs\/the-bugs-project-winbugs\/ [Accessed 12 Oct 2018]."},{"key":"2025120520555588000_9.8.e027349.30","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1214\/ss\/1177011136","article-title":"Inference from iterative simulation using multiple sequences","volume":"7","author":"Gelman","year":"1992","journal-title":"Statist. Sci."},{"key":"2025120520555588000_9.8.e027349.31","unstructured":"R project for statistical computing, 2018. Available: https:\/\/www.r-project.org\/ [Accessed 12 Oct 2018]."}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2018-027349","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T04:56:07Z","timestamp":1764996967000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2018-027349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,8,20]]},"published-print":{"date-parts":[[2019,8]]}},"alternative-id":["10.1136\/bmjopen-2018-027349"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2018-027349","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2019,8]]}}}