Vitamin D and Cancer Mortality

In Response: Freedman et al. (1) found no significant association between 25-hydroxyvitamin D [25(OH)D] levels and total cancer mortality in the Third National Health and Nutrition Examination Survey (NHANES III). In their present letter, they report on the results of a reanalysis of NHANES III with a careful consideration of seasonal variations of 25(OH)D and of persons with marked vitamin D deficiency (2). Restricting their analyses to non-Hispanic whites and using 25(OH)D quantiles based on monthly blood draws, Freedman et al. observed a 22% lower risk of cancer mortality when comparing the highest quartile with the lowest 5%. Given the small number of cases with such low 25(OH)D values in NHANES III, this risk difference was not significant. Consistent with the results of the LUdwighsafen RIsk and Cardiovascular Health (LURIC) study (3), the risk of cancer mortality in NHANES III remained relatively unchanged over a broad range of 25(OH)D levels except for the stepwise increase in the lowest 5%.

What are the possible explanations to reconcile the present findings of NHANES III with the LURIC study, which showed a significant association of vitamin D deficiency and cancer mortality? Concluding their letter, Freedman at al. point toward possible differences between the two study populations. These differences are indeed significant. First, LURIC participants were largely patients with coronary heart disease and on average ∼20 years older. Thus, subjects in the LURIC study might have been at a differential risk for cancer sites specifically associated with low 25(OH)D, e.g., colon cancer, for which NHANES III reported a significant association. Considering the requirement of UVB radiation for dermal vitamin D synthesis, the geographic difference between the average latitude in NHANES III and the LURIC site made it less likely for the Americans to be vitamin D deficient. Accordingly, only 5% of the NHANES III population provided similar low levels as the lowest 25% in LURIC, limiting the ability to detect a possible nonlinear association of vitamin D deficiency and cancer mortality below certain thresholds. In view of the increasing molecular and clinical evidence in favor of an anticarcinogenic effect of vitamin D (4, 5), we suggest further studies among populations at high risk of vitamin D deficiency. These studies should be designed to further address the issue of a cancer-specific association of 25(OH)D as well as the possibility of a nonlinear relationship between 25(OH)D and cancer mortality.