Up to about a decade ago, there was tremendous uncertainty about vitamin D supplementation for the maintenance of adequate health levels. Furthermore, if the link is causal, the threshold serum level of 25OHD below which the risk of these diseases is increased must be identified 8. Therefore, one of the major clinical questions in the field is whether poor vitamin D status plays a causal role in the diseases and conditions associated with low 25OHD levels, such as cancer, impaired muscle strength and falls, and immune, metabolic or cardiovascular diseases. Finally, many diseases and illnesses in humans are associated with a poor vitamin D status, as measured by low serum levels of 25OHD. In addition, ~3% of the human and mouse genomes are under the direct or indirect control of 1,25(OH) 2D 3 (refs 8, 9). For example, the vitamin D receptor (VDR) and CYP27B1 (the enzyme primarily responsible for producing the active form of vitamin D, 1,25-dihydroxyvitamin D or 1,25(OH) 2D 3) are widely expressed, including in tissues that are not involved in calcium or phosphate transport (Fig. The potential extra-skeletal effects of the vitamin D endocrine system (which refers to vitamin D in its active form, its precursors and metabolites, and vitamin D receptor) are based on several arguments. By contrast, others have suggested that the vitamin D intake requirement is much higher than currently achieved by the general population and that people should aim to achieve 25-hydroxyvitamin D (25OHD, the major marker of vitamin D status) concentrations similar to those found in certain tribes in equatorial Africa with a sun exposure lifestyle that might be similar to that of early humans 3, 4, 5, 6, 7. Some people consider that vitamin D supplementation is futile 2. However, the skeletal effects of vitamin D deficiency in adults and older adults (aged >65 years), and the potential extra-skeletal effects of vitamin D are more controversial. There is consensus that daily intake of 400 IU of vitamin D can prevent nutritional rickets in infants and children 1. In conclusion, supplementation of vitamin D-replete individuals does not generate overall health benefits however, correction of severe vitamin D deficiency remains essential. Over 60 Mendelian randomization studies have examined causal links between genetically lower vitamin D levels and health outcomes most studies generated null effects except four studies that demonstrated an increased risk of multiple sclerosis. Post-hoc analysis of large supplementation trials has suggested that supplementation of individuals with vitamin D deficiency modestly delays age-related bone loss and progression to T2DM, and improves lung function.Ī meta-analysis suggested that vitamin D supplementation results in a modest decrease in cancer mortality. Large supplementation trials recruiting vitamin D-replete adults (serum 25OHD concentration >50 nmol/l) have demonstrated no effects on the incidence of cancer, cardiovascular events or type 2 diabetes mellitus (T2DM) and no benefits in terms of bone density and the risk of falls. Vitamin D and calcium supplementation can cure nutritional rickets and can modestly decrease the risk of major fractures in older adults with poor vitamin D status or calcium intake. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration 50 nmol/l for optimal bone health in older adults. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. Vitamin D supplementation can prevent and cure nutritional rickets in infants and children.
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