Vitamin D Supplementation in the Age of Lost Innocence

Recently, we have witnessed an explosion of scientific and media attention to the health effects of vitamin D status and vitamin D supplementation (1). Vitamin D 3 (cholecalciferol), the most powerful form of vitamin D, is synthesized in the skin from 7-dehydrocholesterol by action of sunlight (ultraviolet B radiation) (2). Vitamin D is biologically inert and must be converted to the active hormone 1,25-dihydroxy vitamin D [1,25(OH)2D] (calcitriol). Vitamin D's pivotal role in regulating calcium homeostasis and bone metabolism has been long recognized (2–4); however, mounting evidence suggests that vitamin D may also influence various nonskeletal medical conditions, including cardiovascular disease, hypertension, diabetes, cancer, autoimmune disorders, and overall mortality (5–8). Indeed, claims that large segments of the population have inadequate vitamin D concentrations have prompted calls to increase vitamin D intake through supplementation or fortification (9, 10). The claims of wide-ranging health benefits from increased vitamin D intake follow decades of research that led to the collapse of similar claims regarding antioxidant vitamins and folic acid supplementation (11–13). In addition, randomized, controlled clinical trials showed increased all-cause mortality with high-dose β-carotene and vitamin E supplements, 2 antioxidant vitamins that were widely believed to be safe (11, 14). Will history repeat itself, or will widespread vitamin D supplementation overcome a real nutritional deficiency? Two systematic reviews in this issue (15, 16) summarize the role of vitamin D in cardiovascular disease and provide insight into the type of evidence that is necessary to fully understand the effects of vitamin D. Pittas and colleagues (15) reviewed the prospective observational studies on the association between vitamin D status, assessed by 25-hydroxyvitamin D [25(OH)D] concentration in blood or reported vitamin D intake, and incident cardiometabolic outcomes. For clinical cardiovascular outcomes, 4 of 7 analyses (originating from …