The paper by Kramer et al. reported statistically significant increased risk of death only for those with serum 25-hydroxyvitamin D [25(OH)D] concentrations below 12 ng/ml [1]. This finding differs somewhat from a meta-analysis of 11 studies, which found statistically significant reductions in mortality rate for those with 25(OH)D concentrations above 16 ng/ml [2]. It could be that the number of cases used in Ref. 1 precluded a significant finding for those with serum 25(OH)D concentration between 12 and 16 ng/ml.

However, there are two more methodological problems with the study reported in Ref. 1. One was that serum 25(OH)D concentrations in the south were measured in the winter while those in the north were measured in the summer. There are strong seasonal variations in serum 25(OH)D concentration [3]. In addition, there are seasonal variations in mortality rate: “In summer 1987 the average increase in cardiovascular deaths due to a 10 degrees F increase in temperature was 4.7%. By summer 2000, the risk with higher temperature had disappeared (-0.4%).” [4]. Cardiovascular death rates are higher in winter than in summer [5]. Serum 25(OH)D concentrations are inversely correlated with cardiovascular disease risk [6,7].

A second, more important methodological problem is the 18-year follow-up period after serum draw. Using a single value from time of enrollment in a study assumes that this yields a value of 25(OH)D concentration representative of the time when vitamin D would affect mortality rate. There is little to suggest that a serum 25(OH)D concentration at one time accounts for all subsequent health outcomes, and serum 25(OH)D concentrations change with time due to changes in lifestyle, publicity about vitamin D, etc. In a recent paper, it was shown that the regression fit to hazard ratio for mortality went from 0.82 for six years of follow up to 0.96 for 14-years of follow up [8]. The zero year follow-up hazard ratio was 0.72. Similar results were also found for breast and colorectal cancer [9]. Thus, the findings in Ref. 1 greatly underestimate the beneficial effects of vitamin D in reducing all-cause mortality rates. An estimate of the beneficial effects on all-cause mortality rate possible by increasing population mean serum 25(OH)D concentrations from 22 to 44 ng/ml was given in Ref. 10, indicating a 8-18% reduction in mortality rates and an increased life expectancy of two years throughout the world.

Given the lackluster findings in Ref. 1, it is not surprising that the authors sought support for their findings in other journal papers. However, such support does not hold up under close scrutiny. First, randomized controlled trials (RCTs) are required under the tenants of “evidence based medicine” for pharmaceutical drugs. Even so, they fail to account for adverse effects often found years after the drugs have been on the market. Unfortunately, many consider RCTs required for proof of causality of vitamin D in reducing risk of disease and premature death. However, an alternate approach much more suited to vitamin D, an natural compound with which man has always existed, is use of Hill’s criteria for causality. The primary criteria for cancer include strength of association, consistent findings in different populations, biological gradient, plausibility (mechanisms), and experiment (e.g., RCT) [11]. Hill’s criteria have been found generally satisfied for cancer in general [12] and breast cancer in particular [13]. RCTs with vitamin D are particularly difficult to do correctly as the study design should know the expected dose-response relation for the health outcome considered, enroll people near the lower end of 25(OH)D concentration, give people sufficient vitamin D to raise concentrations to the concentration for significant reduction, account for other sources of vitamin D, and measure serum 25(OH)D concentration after supplementing [14]. There have been two RCTs reporting reduced risk of cancer using a combination of calcium plus vitamin D [15,16].

As to the studies on prostate and pancreatic cancer (Refs. 34 and 35 in [1]), these should not be considered as representative. The prostate cancer study had a 15-17 year follow up and could have been affected by vitamin A in cod liver oil. A meta-analysis of prostate cancer shows no correlation with respect to serum 25(OH)D concentration [17]. A recent study conducted in the U.S. shows a significant inverse correlation between serum 25(OH)D concentration and incidence of pancreatic cancer [18]. Vitamin D is not a risk factor for kidney stones [19]. Ref. 36 in [1] was based on a study using 1500 mg/d calcium and 400 IU/d vitamin D3. The calcium intake was too high since participants had additional calcium intake, and the vitamin D3 intake was so low that very few beneficial effects were found.

As to guidelines for serum 25(OH)D concentration and vitamin D intake, the Endocrine Society guidelines, >30 ng/ml and 1500-2000 IU/d are appropriate [20,21].

References
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2. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, et al. Vitamin D deficiency and mortality risk in the general population: A meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95(1):91-100.
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