Vitamin D Supplementation and Total MortalityA Meta-analysis of Randomized Controlled Trials

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Abstract
Ecological studies in North America have suggested that mortality from several potentially life-threatening chronic health conditions such as cancer, cardiovascular diseases, and diabetes mellitus would increase with increasing latitude, that is, with residence increasingly distant from the equator.1,2 Other studies have shown that the survival of patients with cardiovascular disease or with some cancer (eg, lung, colorectal, and breast cancer) was greater if the diagnosis was made during summer as compared with the winter.3,4 Increasing distance from the equator and winter period were equated to decreasing exposure to sunlight, especially to UV-B radiation (280-315 nm) because with increasing latitude, amounts of UV-B radiation reaching the earth surface decrease faster than amounts of UV-A radiation (315-400 nm).5 Also, seasonal variations are more pronounced for UV-B radiation than for the UV-A radiation.5 Because UV-B radiation is necessary for the synthesis of vitamin D in the skin, it has been hypothesized that associations found between latitude or seasonality and mortality from several chronic conditions could be owing to variations in vitamin D status.6-10Some food products may also represent a source of vitamin D, although of highly variable content (eg, fortified foods, oily fish, eggs, and butter). Hence, low vitamin D status could proceed from the conjunction of insufficient intakes (exogenous source) and of insufficient skin synthesis (endogenous source) of vitamin D. Biological findings have reinforced the likelihood of the vitamin D hypothesis. First, vitamin D receptors have been found in various organs, and activation of these receptors by 1α,25 dihydroxyvitamin D3 (calcitriol), the physiologically active form of vitamin D, induces cell differentiation and inhibits proliferation, invasiveness, angiogenesis, and metastatic potential.11,12 These biological phenomena are typical of cancer genesis and some of them (eg, differentiation and proliferation) are also involved in cardiovascular ischemic diseases. Second, many tissues express the 1α-hydroxylase enzyme.11 So, after 25-hydroxylation of vitamin D in the liver, many cell types are able to convert the circulating 25-hydroxyvitamin D into 1α,25-dihydroxyvitamin D, and autocrine or paracrine production of 1α,25-dihydroxyvitamin D would depend on serum concentration of 25-hydroxyvitamin D.