The health effects of vitamin D supplementation: evidence from human studies

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.

Fig. 1. The many plausible target tissues and effects of the vitamin D endocrine system.

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 status remain controversial. The strength of the relationship between the vitamin D endocrine system and health effects are indicated by the arrow thickness. FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.