The Nonskeletal Effects of Vitamin D: An Endocrine Society Scientific Statement

Abstract

Significant controversy has emerged over the last decade concerning the effects of vitamin D on skeletal and nonskeletal tissues. The demonstration that the vitamin D receptor is expressed in virtually all cells of the body and the growing body of observational data supporting a relationship of serum 25-hydroxyvitamin D to chronic metabolic, cardiovascular, and neoplastic diseases have led to widespread utilization of vitamin D supplementation for the prevention and treatment of numerous disorders. In this paper, we review both the basic and clinical aspects of vitamin D in relation to nonskeletal organ systems. We begin by focusing on the molecular aspects of vitamin D, primarily by examining the structure and function of the vitamin D receptor. This is followed by a systematic review according to tissue type of the inherent biological plausibility, the strength of the observational data, and the levels of evidence that support or refute an association between vitamin D levels or supplementation and maternal/child health as well as various disease states. Although observational studies support a strong case for an association between vitamin D and musculoskeletal, cardiovascular, neoplastic, and metabolic disorders, there remains a paucity of large-scale and long-term randomized clinical trials. Thus, at this time, more studies are needed to definitively conclude that vitamin D can offer preventive and therapeutic benefits across a wide range of physiological states and chronic nonskeletal disorders.

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

“…We have now produced Cyp2r1 −/− mice. These mice had greater than 50% reduction in serum 25-hydroxyvitamin D 3 . Curiously, the 1α,25-dihydroxyvitamin D 3 level in the serum remained unchanged.…”

“…Bioactivation of vitamin D consists of two sequential hydroxylation steps to produce 1α,25-dihydroxyvitamin D 3 . It is clear that the second or 1α-hydroxylation step is carried out by a single enzyme, 25-hydroxyvitamin D 1α-hydroxylase CYP27B1.…”

Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status?

“…A large number of people around the world have low serum 25(OH)D concentrations which may increase their risk for skeletal and possibly also for extra-skeletal diseases and risks (18,19 Although several groups confirmed low DBP levels in African Americans (21-24) using the monoclonal R&D assay, questions were rapidly raised as to whether the monoclonal R&D assay used in these studies could be relied upon to measure polymorphic DBP as present in the serum of subjects of different races or DBP/GC genotypes (25). …”

Maternal vitamin D status in Type 1 diabetic pregnancy: Impact on neonatal vitamin D status and association with maternal glycaemic control

“…Increased synthesis of the active vitamin D form is due to the enhanced production of 1a-hydroxylase in the decidua and placenta, as well as an oestrogen-dependent increase in vitamin D binding protein [7]. This apparent rise in 1,25(OH) 2 D has led to the suggestion that pregnant women may require higher cellular exposure to active vitamin D during the second and third trimesters, and has been interpreted by some as providing evidence for its potential role in obstetric well-being [8].…”