Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies

The BMJ

Apr 2014

DOI: 10.1136/bmj.g1903

Citations:587

Influential Citations:16

Systematic Reviews / Meta-Analyses

COI

Enhanced Details

Methods

Systematic review and meta-analysis of adults; included 73 observational cohorts (849,412 participants) and 22 randomized controlled trials (30,716 participants); primary and secondary prevention settings; exposure: circulating 25-hydroxyvitamin D or vitamin D alone; outcomes: all-cause and cause-specific mortality; data sources: Medline, Embase, Cochrane Library; last search August 2013; data extraction by two independent investigators with a third for consensus; risk of bias assessed with Newcastle-Ottawa Scale for cohorts and Cochrane tool for RCTs.

Intervention

Vitamin D3 (cholecalciferol): 10–6000 IU/day, oral tablets; duration 0.38–6.8 years. Vitamin D2 (ergocalciferol): 208–4500 IU/day, oral tablets; duration varied, with several trials <1.5 years and others longer.

Results

Observational cohorts show an inverse association between circulating 25-hydroxyvitamin D and mortality risk from cardiovascular disease, cancer, and other causes. Bottom vs top thirds: CVD death RR 1.35 (1.13–1.61); cancer death RR 1.14 (1.01–1.29); non-vascular, non-cancer death RR 1.30 (1.07–1.59); all-cause mortality RR 1.35 (1.22–1.49). In RCTs of vitamin D given alone, vitamin D3 reduced all-cause mortality (RR 0.89; 0.80–0.99); vitamin D2 showed no overall reduction (RR 1.04; 0.97–1.11). Effects of D3 were consistent across subgroups; D2 showed higher mortality with lower doses and shorter durations and higher bias risk. Observational data suggest inverse associations; vitamin D3 supplementation may reduce mortality in older adults, but optimal dose and differential effects of D3 vs D2 require further study. Public health strategies to improve vitamin D status could impact premature mortality, pending more robust trials.

Limitations

Observational data cannot establish causality; potential residual confounding (lifestyle, socioeconomic status); heterogeneity across studies; limited data for some cause-specific mortalities; lack of serial 25-hydroxyvitamin D measurements; majority of cohorts involved older populations; relatively few randomized trials per vitamin D subtype; insufficient power to define optimal dose/duration or long-term safety; potential biases in some trials and limited data on calcium co-supplementation.

Abstract

Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. Design Systematic review and meta-analysis of observational studies and randomised controlled trials. Data sources Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. Study selection Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. Data extraction Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849 412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30 716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. Results In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk. show less