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KSR Number: KSRA80685

Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

Evidence indicates that vitamin D supplementation may not prevent fractures or falls, or have clinically meaningful effects on bone mineral density. In addition, there were no differences between the effects of higher and lower doses of vitamin D. There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health. Restriction to one index term for vitamin D in the searches means some relevant studies may have been missed. There was some evidence of publication bias.

Risk of Bias Assessment

Overall summary High risk of bias in the review


The search strategies were not very sensitive, relevant studies may have been missed.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably no
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review High

Details of Review

Number of studies 81
Number of participants 53537
Last search date Feb 26, 2018
Review type Intervention
Objective To assess the effect of vitamin D supplementation on fractures, falls, and bone density.
Population Adults (>18 years).

Studies with pregnant women and non-adults were excluded.
Interventions Vitamin D supplements (800 IU/day or more [high dose]).

Studies with multiple interventions (e.g., coadministered calcium and vitamin D) were included.
Comparator Placebo, or lower-dose vitamin D supplements, untreated controls.
Outcome Co-primary outcomes: Participants with at least one fracture, at least one hip fracture, or at least one fall.

Secondary outcomes: Percentage change in bone mineral density from baseline at the lumbar spine, total hip, femoral neck, total body, and forearm.
Study design Randomised controlled trials, quasi-randomised and open-label trials.


The pooled analyses reported no significant difference in the total fracture (Relative risk [RR] 1·00, 95% Confidence interval [CI] 0.93 to 1.07, 36 trials, n= 44790 participants), hip fracture (RR 1.11, 0.97 to 1.26, 20 trials, n= 36655 participants), or falls (RR 0.97, 0.93 to 1.02, 37 trials, n= 34144 participants) between the vitamin D supplementation and control groups.

Trial sequential analyses reported that vitamin D supplementation does not reduce fractures and falls, the effect estimate lay within the futility boundary for relative risks of 15%, 10%, 7.5%, and 5%. Similarly, vitamin D supplementation does not reduce hip fractures the effect estimate lay between the futility boundary and the inferior boundary at a 15% RR.

The subgroup analysis based on the doses of vitamin D supplementation reported no significant difference in the total fracture (RR 0.65, 95% CI 0.39 to 1.07, 7 trials), hip fracture (RR 0.42, 95% CI 0.12 to 1.47, 2 trials) and falls (RR 0.90, 95% CI 0.69 to 1.18, 7 trials) between the high and low dose vitamin D supplementation.

Full Risk of Bias Assessment

The research objective was clearly stated. Eligibility criteria were well described and appeared appropriate to address the present review question. No restrictions were reported based on study characteristics. No restrictions were reported based on sources of information.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Yes
Concerns regarding specification of study eligibility criteria Low

PubMed, Embase, and Cochrane Central were searched for relevant studies. and the WHO clinical trials portal were searched for completed and ongoing trials. The search strategy was reported and appeared inappropriate, as no free text words for vitamin D were used, only the single index term. Searches were restricted to studies published between 2015 and 2018, and to studies included in earlier systematic reviews. One author screened titles and abstracts and two authors independently reviewed the full text of potentially relevant studies.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? No
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Probably no
Concerns regarding methods used to identify and/or select studies High

One author extracted the data from the included studies and these were checked by a second author. Sufficient study characteristics appear to have been extracted to allow interpretation of results. Relevant study results appear to have been extracted. Methodological quality of the included studies was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Two reviewers were independently assessed the quality of the included studies and any disagreements were resolved by discussion.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Yes
3.3 Were all relevant study results collected for use in the synthesis? Yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Yes
3.5 Were efforts made to minimise error in risk of bias assessment? Probably yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis appeared to include all eligible studies. The method of analysis was explained and appeared appropriate. Evidence of significant publication bias was found using Egger's test and funnel plot. The quality of individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low