Vitamin D and Mortality

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Vitamin D and Specific Causes of Death

While we mainly report on vitamin D and all-cause mortality in this review, it is also important to briefly summarize the literature on specific causes of death, in order to gain more knowledge on the potential pathways and mechanisms that may link vitamin D and fatal events.

In observational studies, low 25(OH)D levels have been associated with increased risk of mortality due to cardiovascular diseases, cancer, respiratory disease, and non-vascular, non-cancer causes (33, 35, 36, 43, 44, 49, 73-76).

In the Mendelian randomization study by Afzal et al. it was reported that the odds ratio (95% CI) for cardiovascular mortality for each decrease of 20 nmol/l in plasma 25(OH)D was 1.13 (1.03 to 1.24), and the respective odds ratio (95% CI) for the genetically determined 25(OH)D levels was 0.77 (0.55 to 1.08) (68). This may suggest that the association between low 25(OH)D and cardiovascular deaths may not be causal. For cancer mortality, the respective odds ratios (95% CI) for each decrease of 20 nmol/l 25(OH)D was 1.10 (1.02 to 1.19) for plasma 25(OH)D and 1.43 (1.02 to 1.99) for genetically determined 25(OH)D. These data argue for causality with regard to the association of vitamin D deficiency and increased cancer mortality.

Meta-analyses of RCTs further support a causal effect of vitamin D on cancer mortality. In the Cochrane meta-analysis by Bjelakovic et al. involving 44,492 study participants from four trials, it was documented that vitamin D₃ supplementation statistically significantly reduced cancer mortality, with a risk ratio of 0.88 (95% CI=0.78-0.98). In line with this, Keum et al. also reported in their meta-analysis involving 44,260 participants that the RR for cancer mortality in the vitamin D-treated versus the placebo-treated group was 0.88 (95% CI=0.78-0.98) (77). These findings along with various molecular anticancer effects of vitamin D suggest that vitamin D supplementation may be useful for the prevention of cancer deaths. By contrast, there was no effect in meta-analyses on cancer incidence, suggesting that vitamin D might rather be relevant for the progression than for the initiation of cancer (77-79).

With regard to cardiovascular mortality, there was no significant effect of vitamin D as reported by Bjelakovic et al. (69). Although observational studies highlight vitamin D deficiency as a risk factor for cardiovascular events and strokes, most RCTs did not show any effect of vitamin D on these outcomes (69, 71, 80-83). It must, however, be acknowledged that no published RCT on vitamin D has been designed and statistically powered to assess cardiovascular events. Existing knowledge on the potential role of vitamin D for various other health outcomes have been extensively reviewed elsewhere (1-6, 84, 85).

 ....Regarding vitamin D research, there are some large ongoing RCTs on vitamin D in the general population that will significantly increase our knowledge on whether general vitamin D supplementation in the older population has an effect on clinical endpoints, including mortality (92, 93). It is, however, of concern that all large RCTs on vitamin D recruited participants regardless of their 25(OH)D levels, thereby increasing the probability of missing beneficial effects of vitamin D supplementation in individuals with low 25(OH)D concentrations. Null effects of such RCTs would definitely argue against major effect sizes but definite answers on whether vitamin D supplementation has relevant effects on mortality outcomes and other clinical endpoints should be derived from RCTs in severely vitamin D-deficient individuals, as this is the target population for vitamin D interventions (92-95).