Nature
The health effects of vitamin D supplementation: evidence from human studies
Vitamin D supplementation has been the subject of numerous human studies to determine its health effects. Some studies suggest that higher vitamin D intake is necessary to achieve optimal levels and prevent diseases associated with low vitamin D status. However, Mendelian randomization studies and randomized controlled trials (RCTs) have not confirmed these claims in vitamin D-replete adults. Vitamin D supplementation does not appear to prevent negative health outcomes such as cancer, cardiovascular disease, type 2 diabetes, or bone loss in individuals with sufficient vitamin D levels. While some studies suggest potential benefits in specific subgroups, the overall evidence does not support widespread use of vitamin D supplementation. The link between vitamin D status and COVID-19 outcomes is still uncertain, and ongoing trials may provide more clarity.
ocrinology volume 18, pages 96–110 (2022)Cite this article • 99k Accesses • 152 Citations • 193 Altmetric • Metrics details Abstract Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. 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. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. 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. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected. Key points • Vita...
...min 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. • 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. • 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. • A meta-analysis suggested that vitamin D supplementation results in a modest decrease in cancer mortality. • 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. • In conclusion, supplementation of vitamin D-replete individuals does not generate overall health benefits; however, correction of severe vitamin D deficiency remains essential. Similar content being viewed by others
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...enzyme primarily responsible for producing the active form of vitamin D, 1,25-dihydroxyvitamin D or 1,25(OH)2D3) are widely expressed, including in tissues that are not involved in calcium or phosphate transport (Fig. 1). In addition, ~3% of the human and mouse genomes are under the direct or indirect control of 1,25(OH)2D3 (refs8,9). Finally, many diseases and illnesses in humans are associated with a poor vitamin D status, as measured by low serum levels of 25OHD. 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. Furthermore, if the link is causal, the threshold serum level of 25OHD below which the risk of these diseases is increased must be identified8. Fig. 1: The many plausible target tissues and effects of the vitamin D endocrine system. [
](https://www.nature.com/articles/s41574-021-00593-z/figures/1) The potential skeletal and extra-skeletal target tissues and effects of the vitamin D endocrine system (vitamin D and vitamin D receptor) as based on preclinical and observational studies, Mendelian randomization studies and randomized controlled trials (RCTs). In vitro studies have identified many molecular and genetic targets of vitamin D action. Animal models have confirmed a variety of skeletal and extra-skeletal actions. Human observational data are largely in line with preclinical data. However, Mendelian randomization studies and RCTs have not confirmed such a widespread action profile in vitamin D-replete adults. Therefore, the health consequences of poor vitamin D stat (View Highlight)