Results
Overall, 1256 articles searched yielded 107 systematic reviews without meta-analyses (presented in 24 papers) 74 meta-analyses (47 papers) of observational studies that investigated associations with circulating vitamin D concentrations. In addition, we identified and included 87 meta-analyses (32 papers) of randomised controlled trials of vitamin D supplementation (Fig 1; Supplementary Tables C-E). Across all three study types, results on 137 unique outcomes were reported (Fig 2; Supplementary Table B).
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Figure 1.
Flow chart of eligible studies
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Figure 2.
Map of 137 vitamin D related outcomes: percentage of outcomes per outcome category for all study designs
Vitamin D Concentrations and Health Outcomes: Systematic Reviews of Observational Studies
The median number of observational studies included in the systematic reviews was four (range 1-28) (Supplementary Table C). Among the 107 identified systematic reviews, 76 unique ones were presented in 21 papers (Supplementary Table B), whereas more than one systematic review existed for 24 outcomes (in 15 of which the authors reached the same qualitative conclusion; Supplementary Table C).
For only six (8%) of the 76 unique outcomes, the systematic reviews concluded that a definite association existed (Supplementary Tables B and F). These were rheumatoid arthritis activity, colorectal cancer, hypertension in children, bacterial vaginosis in pregnant women, falls in older people, and rickets in children; for all these outcomes, higher concentrations of vitamin D were associated with lower risk. Conversely, for 10 (13%) outcomes, the authors concluded that no association existed between the examined outcome and vitamin D status. For 60 of the 76 unique outcomes, the systematic reviews did not reach a firm, unequivocal conclusion: for 43 (57%) authors reported that the reviewed data were inconclusive or insufficient to draw any firm conclusions, and 17 (22%) found that an inverse association was possible or suggestive. No systematic reviews concluded that a definite or suggestive association existed for increased risk with higher concentrations of vitamin D.
Vitamin D Concentrations and Health Outcomes: Meta-analyses of Observational Studies
We identified 74 meta-analyses of observational studies (Supplementary Table D). Among these, 48 unique meta-analyses were presented in 28 papers (Fig 1; Supplementary Table G). Forty three meta-analyses examined the link between vitamin D and outcome by using 25-hydroxyvitamin D and five by using 1,25-dihydroxyvitamin D. All meta-analyses reported estimates adjusted for a wide variety of other covariates. Meta-analyses examined a very wide range of outcomes including cancers (n=20), cardiovascular diseases (n=8), cognitive disorders (n=4), metabolic disorders (n=4), neonatal/infant/child related outcomes (n=4), skeletal diseases (n=3), pregnancy related outcomes (n=2), infectious disease (n=1), or other outcomes (n=2) (Supplementary Table G). The median number of studies included was seven (range 2-37), the median number of participants was 5905 (39-82 982), and the median number of events was 1289 (18-15 447). Overall, 30 (63%) of the 48 meta-analyses of observational studies reported a nominally statistically significant summary result ( Table 1 and Table 2 ). Figure 3 shows a forest plot with the summary effects of all the non-overlapping meta-analyses of observational studies (for binary outcomes).
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Figure 3.
Forest plot of all meta-analyses of observational studies stratified by measured biomarker with relative risk as type of metric
We found more than one published meta-analysis for 11 outcomes: Alzheimer's disease (n=2 meta-analyses), breast cancer (n=6), colorectal adenoma (n=3), colorectal cancer (n=7), cardiovascular diseases (n=3), gestational diabetes (n=2), hypertension (n=3), prostate cancer (n=4), stroke (n=2), type 2 diabetes (n=3), and prevalence of type 2 diabetes (n=2). For all the outcomes, agreement existed between the meta-analyses on the direction, magnitude, and statistical significance of the association (Supplementary Table H).
Summary Effects, Heterogeneity, and Bias Tests For Meta-analyses of Observational Associations
Of the 48 non-overlapping meta-analyses of observational studies, the largest study had statistically significant results in 21 (44%) meta-analyses (Supplementary Figure A). The largest study's result was more conservative than the summary result in 20 (42%) meta-analyses. Fifteen (31%) meta-analyses had large heterogeneity (I>50%), and seven (15%) had very large heterogeneity (I>75%). Evidence for significant small study effects was noted in three meta-analyses (breast cancer, all cause mortality, and cardiovascular disease mortality) ( Table 1 and Table 2 ). Evidence for statistically significant excess significance bias was seen for three outcomes (sporadic colorectal adenoma recurrence, Alzheimer’s disease, and fractures; Supplementary Table I).
Significant Observational Associations Without Hints of Bias
Of the 48 meta-analyses, 18 (38%) had nominally statistically significant summary associations according to random effects calculations and had no evidence of small study effects (P≥0.10), not very large heterogeneity (I≤75%), and no evidence for excess significance ( Table 1 and Table 2 ). Overall, 12 of these 18 associations were based on cumulative evidence of more than 500 disease events (or more than 5000 total participants if the type of metric was continuous) and also had P≤0.001 for the association. These included vitamin D associations with one cancer (colorectal cancer), five cardiovascular (cardiovascular disease, prevalence of cardiovascular disease, hypertension, ischaemic stroke, and stroke), two cognitive (cognition and depression (cohort studies)), two metabolic (prevalence of metabolic syndrome and type 2 diabetes), one neonatal/infant/child related (small for gestational age), and one pregnancy related outcome (gestational diabetes). Across these 12 associations, the relative risk of the highest versus the lowest category had a median of 0.63 (interquartile range 0.52-0.67).
Meta-analyses of Randomised Controlled Trials of Vitamin D Supplementation
We identified 87 meta-analyses of randomised controlled trials of vitamin D supplementation (Supplementary Table E). Among these, 57 non-overlapping meta-analyses were presented in 19 papers, including 21 (37%) in skeletal diseases, seven (12%) in metabolic disorders, four (7%) in neonatal/infant/child related outcomes, three (5%) in cardiovascular diseases, three (5%) in pregnancy related outcomes, and 18 (32%) in other outcomes. The median number of studies included was four (range 2-38), and the median number of participants was 446 (38-25 016) ( Table 3 and Table 4 ). Overall, 13 (23%) of the 57 meta-analyses of randomised controlled trials reported a nominally statistically significant summary result, and these were related to the following outcomes: total cholesterol concentrations, birth weight, head circumference at birth, maternal vitamin D concentrations at term, balance sway, femoral neck bone mineral density, muscle strength, non-vertebral fractures, rate of falls, dental caries in children, parathyroid hormone concentrations in patients with chronic kidney disease (requiring or not requiring dialysis), and risk of hypercalcaemia in patients with chronic kidney disease not requiring dialysis ( Table 3 and Table 4 ). Figure 4 shows a forest plot with the summary effects of all the non-overlapping meta-analyses of randomised controlled trials (for binary outcomes).
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Figure 4.
Forest plot of all meta-analyses of randomised controlled trials with relative risk as type of metric by compound administered. CKD=chronic kidney disease patients; NRD=not requiring dialysis; RD=requiring dialysis; UV=ultraviolet
We found more than one meta-analysis of randomised controlled trials for 10 outcomes: cardiovascular disease (n=2 meta-analyses), diastolic blood pressure (n=3), systolic blood pressure (n=3), birth weight (n=3), falls (n=11), fractures (n=5), hip fractures (n=4), non-vertebral fractures (n=2), rate of falls (n=3), and mortality (n=5). For half of the outcomes, agreement existed between the meta-analyses on the direction, magnitude, and statistical significance of the effect. Only one of the overlapping meta-analyses reported a statistically significant effect for diastolic blood pressure, birth weight, and non-vertebral fractures. Eleven meta-analyses examined risk of falling, and differences existed in both the magnitude and the statistical significance of the effect but not in the direction of the effect. Finally, three meta-analyses examined rate of falls, and differences existed in the direction, magnitude, and statistical significance of the effect (Supplementary Table J).
Comparison of Findings From Observational Studies and Clinical Trials
One hundred and twenty three (90%) outcomes were examined only by syntheses of observational evidence (n=84) or only by meta-analyses of randomised evidence (n=39), so we could not compare observational and randomised evidence.
Ten (7%) outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials: cardiovascular disease, hypertension, birth weight, birth length, head circumference at birth, small for gestational age birth, mortality in patients with chronic kidney disease, all cause mortality, fractures, and hip fractures ( Table 5 ). The direction of the association/effect and level of statistical significance was concordant only for birth weight, but this outcome could not be tested for hints of bias in the meta-analysis of observational studies (owing to lack of the individual data). The direction of the association/effect but not the level of statistical significance was concordant in six outcomes (cardiovascular disease, hypertension, birth length, head circumference small for gestational age births, and all cause mortality), but only two of them (cardiovascular disease and hypertension) could be tested and were found to be free from hint of bias and of low heterogeneity in the meta-analyses of observational studies. For mortality in chronic kidney disease patients, fractures in older populations, and hip fractures, both the direction and the level of significance of the association/effect were not concordant.
Finally, four (3%) outcomes were examined by meta-analyses of randomised controlled trials and systematic reviews of observational studies without a formal meta-analysis (Supplementary Table B). These included falls, for which systematic reviews concluded that a definite association existed whereas meta-analyses of randomised controlled trials reported a non-statistically significant effect, and length of gestation and bone mineral density in adults and in children, for which the systematic reviews concluded that a suggestive association existed whereas meta-analyses of randomised controlled trials reported a non-statistically significant effect.