ReviewEffect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials
Introduction
Findings from numerous epidemiological studies have shown that in people of all ages, and irrespective of sex and ethnic origin, the lower a person's vitamin D status, the greater the likelihood of poor health, disease occurrence, and reduced life expectancy. Therefore, improving the vitamin D status of individuals was expected to help to prevent and treat various acute and chronic diseases. However, because findings from non-experimental studies can result from bias and of confounding variables, this theory needed to be verified by randomised trials.1 The most reliable indication for the possibility of a cause–effect relation are meta-analyses of randomised trials on vitamin D supplementation that include large numbers of participants (for outcomes measured on a continuous scale) or of events (for binary outcomes) with low heterogeneity of results across trials. Trials done in people with low serum concentrations of 25-hydroxyvitamin D (25[OH]D) should provide the strongest evidence on the presence or absence of a causal relation between supplementation and health outcomes.2, 3
Substantial discrepancies have emerged between results of observational studies and of randomised trials with respect to vitamin D and health. Large reviews published in 2013–14 documented that, although many observational studies suggested strong associations between low 25(OH)D and ill health, most randomised trials that investigated community-dwelling or home-dwelling people did not provide evidence that supplementation affects the burden of non-skeletal health conditions.4, 5, 6 In observational studies, increased disease risk and shorter life expectancy was mainly seen in people with low (<50 nmol/L) or very low (<30 nmol/L) 25(OH)D concentrations. However, analyses of randomised trial data in people with 25(OH)D concentrations below 50 nmol/L did not show that vitamin D supplementation offered health benefits.
This discrepancy lends support to the hypothesis that a low vitamin D status is a consequence, rather than a cause, of ill health (ie, reverse causality).4 The only data to suggest that vitamin D supplementation is possibly beneficial to health were the slightly decreased mortality seen in elderly people given ordinary doses (ie, 10–20 μg/day) of vitamin D3.4
In our previous Review on the health effects of vitamin D,4 we evaluated the scientific literature published to Dec 31, 2012, and included seven meta-analyses and 88 trials not included in meta-analyses. For this new Review, we did a systematic review of meta-analyses of vitamin D supplementation and non-skeletal conditions published between Jan 1, 2013, and May 31, 2017, which included people of all ages, including pregnant women. We also searched for randomised trials not included in meta-analyses. The main goal was to determine whether an examination of the more recently published meta-analyses and trials would change previous conclusions about the effects of vitamin D supplementation on various health outcomes.
Section snippets
Search strategy
We have regularly updated the list of English-language scientific literature gathered for our previous Review4 using the same literature search methods,4 except that we have focused on randomised trials and extended the searches to include trials in children and pregnant women. Details of the literature search strategy are outlined in the appendix (pp 41–42). Because no adequate meta-analyses have been reported on the effects of vitamin D supplementation on biomarkers of systemic chronic
Study inclusion
We identified 80 systematic reviews with meta-analyses published between Jan 1, 2013, and May 31, 2017, that reported the effects of vitamin D supplementation on non-skeletal outcomes in children and adults. We selected 28 adequate or acceptable meta-analyses, which mainly covered adult conditions (table 1). 52 systematic reviews were not selected (appendix pp 2–8) because they did not include a meta-analysis (five articles), had major flaws (39 articles), were dominated (five articles),
Discussion
Table 8 is an overview of results shown in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7. The meta-analyses included in this Review that had different article selection and subgroup analyses continue to support the finding of a longer life expectancy after ordinary doses of vitamin D (20–30 μg/day) are given to middle-aged and older people, mainly when they are in hospital or living in an institution. The 6% (95% CI 2–9) reduction in all-cause mortality found with vitamin D3
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