By Jessica Orner, MD

Family Medicine Physician, Lebanon, PA

Dr. Orner reports no financial relationships relevant to this field of study.

EXECUTIVE SUMMARY

When evaluating specific forms of vitamin D, sub-analyses found that all-cause mortality was lower in trials with vitamin D3 than with vitamin D2.


SYNOPSIS: In this systematic review and meta-analysis of randomized controlled trials, researchers determined that when compared with placebo or no treatment, vitamin D supplementation alone was not associated with an increase in overall all-cause mortality, though there were some nuances based on vitamin D form and type of mortality.

SOURCE: Zhang Y, Fang F, Tang J, et al. Association between vitamin D supplementation and mortality: Systematic review and meta-analysis. BMJ 2019;366:l4673. doi:10.1136/bmj.l4673.

Researchers from observation studies have shown an association between low serum vitamin D levels and higher mortality. In this systematic review and meta-analysis of randomized controlled trials, researchers investigated whether vitamin D supplementation was associated with lower mortality in adults. The researchers conducted an analysis of 52 randomized controlled trials involving a total of 75,454 participants gleaned from Medline, Embase, and Cochrane Central Register databases from inception through Dec. 26, 2018.

Trials excluded from analysis were those including pregnant or lactating women, the critically ill, vitamin D analogs, or in which all participants received vitamin D. For example, if both arms of a study included vitamin D supplementation, that trial was excluded. The analysis focused on vitamin D supplementation vs. placebo or no treatment. If other agents, such as calcium, were given in a trial, it had to be the same dosage in all groups. All-cause mortality was the primary outcome, with cerebrovascular disease mortality, ischemic heart disease mortality, cancer mortality, cardiovascular mortality, and non-cancer or non-cardiovascular mortality, being secondary.

Researchers determined that when compared with placebo or no treatment, vitamin D supplementation alone was not associated with either a positive or negative effect on overall all-cause mortality (risk ratio [RR], 0.98; 95% confidence interval [CI]; 0.95-1.02; I2 = 0%). However, when evaluating specific types of vitamin D, sub-analyses found that all-cause mortality was lower in trials with vitamin D3 (cholecalciferol) than with vitamin D2 (ergocalciferol) (P for interaction = 0.04). Vitamin D supplementation was associated with a reduction in cancer mortality (RR, 0.84; 95% CI; 0.74-0.95; I2 = 0%), but only in those receiving vitamin D3 supplementation. There was no significant reduced risk of cardiovascular mortality, death from cerebrovascular disease, or ischemic heart disease.

Regarding mortality benefits, there is not strong enough evidence to recommend vitamin D supplementation for the general adult population. Vitamins D2 and D3 come from different sources, with D2 mainly coming from plants and some culinary mushrooms, whereas animal sources contain D3. It appears that if vitamin D has a mortality benefit, it is more likely to be the D3 form; however, more studies researching that form are needed before changing clinical practice. In this study, researchers did not provide commentary on the role of serum vitamin D levels or whether study participants had known deficiencies, which arguably may be even more important than the form of vitamin D ingested.