Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States
BMJ 2014; 348 ; (Published 17 June 2014)
Cite this as: BMJ 2014;348:g3656

Abstract
Objective
To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences.

Design Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US.

Setting General population.
Participants 26 018 men and women aged 50-79 years

Main outcome measures: All-cause, cardiovascular, and cancer mortality.

Results 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed.

During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality.

Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline.

With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)).
Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships.
No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses.

Conclusions
Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent.

Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

It is not clear whether supplementation therefore should or should not be recommended—results from a long term randomised controlled trial addressing longevity are expected between 2017 and 2020.

SUMMARY-G MOHAN

What is already known on this subject

Mean serum 25-hydroxyvitamin D (25(OH)D) concentrations vary by country, sex, age, and season of blood draw
Vitamin D deficiency has been linked to all-cause and cardiovascular mortality, whereas results on cancer mortality have been inconsistent

What this study adds
In this large consortium of eight cohort studies from Europe and the United States, the bottom 25(OH)D quintile was associated with increased all-cause and cardiovascular mortality and with cancer mortality in subjects with a history of cancer but not in subjects without a history of cancer.
These relationships were compellingly consistent across countries, sexes, age groups, and seasons of blood draw, although cut-off values for the 25(OH)D quintiles varied among the analyses

In clinical practice, cut-off values for vitamin D deficiency might need to be made region-, sex-, and season-specific to identify those in the population with the relatively lowest 25(OH)D concentrations
Vitamin D may play an important role in cancer prognosis.