The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

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Using the technique of centrifugal ultrafiltration isodialysis to measure the free concentration of 1,25-dihydroxyvitamin D [1,25-(OH)2D], we determined the affinity of serum proteins for 1,25-(OH)2D both by Scatchard analysis (increasing ligand concentration at fixed binding site concentrations) and by a novel analysis in which the binding site concentrations were varied (serial dilution) at fixed ligand concentrations. The high affinity binding constant in serum for 1,25-(OH)2D was 3.7 X 10(7) M-1 by Scatchard analysis and 4.2 X 10(7) M-1 by serial dilution analysis. Human serum albumin had a much lower affinity for 1,25-(OH)2D (5.4 X 10(4) M-1). When vitamin D-binding protein (DBP) was selectively removed from serum by an actin affinity column, the affinity of the remaining serum proteins for 1,25-(OH)2D was that of albumin. Postulating a two-site model (DBP and albumin) for transport of 1,25-(OH)2D in serum and incorporating the estimated affinity constants of DBP and albumin for this metabolite, we calculated that 85% of total circulating 1,25-(OH)2D is transported in blood bound to DBP in normal individuals (0.4% is free and 14.6% is bound to albumin). In patients with liver disease, 73% is bound to DBP (1.1% is free and 25.9% is bound to albumin). Using this same two site model, we found a reasonable correlation (r = 0.612; P less than 0.001) between the measured free 1,25-(OH)2D level and the calculated free 1,25-(OH)2D level in serum based on albumin and DBP concentrations in 16 normal subjects and 16 patients with liver disease. These results confirm the concept that although DBP is the principal protein carrier of 1,25-(OH)2D in serum, albumin is a major secondary carrier, especially in patients with low DBP levels.

The interest in vitamin D continues unabated with thousands of publications contributing to a vast and growing literature each year. It is widely recognized that the vitamin D receptor (VDR) and the enzymes that metabolize vitamin D are found in many cells, not just those involved with calcium and phosphate homeostasis. In this mini review I have focused primarily on recent studies that provide new insights into vitamin D metabolism, mechanisms of action, and clinical applications. In particular, I examine how mutations in vitamin D metabolizing enzymes—and new information on their regulation—links vitamin D metabolism into areas such as metabolism and diseases outside that of the musculoskeletal system. New information regarding the mechanisms governing the function of the VDR elucidates how this molecule can be so multifunctional in a cell-specific fashion. Clinically, the difficulty in determining vitamin D sufficiency for all groups is addressed, including a discussion of whether the standard measure of vitamin D sufficiency, total 25OHD (25 hydroxyvitamin) levels, may not be the best measure—at least by itself. Finally, several recent large clinical trials exploring the role of vitamin D supplementation in nonskeletal diseases are briefly reviewed, with an eye toward what questions they answered and what new questions they raised.

We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and basal cell carcinoma (BCC) risk in a nested case-control study at Kaiser Permanente Northern California (KPNC). 220 case patients with BCC diagnosed after serum collection were matched to 220 control subjects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. Fully adjusted models included body mass index (BMI), smoking, education, sun-exposure variables, x-ray exposure, and personal history of cancer. For each measure of serum 25(OH)D (continuous, clinically relevant tertiles, quintiles), we found an increased risk of BCC in unadjusted models (OR=1.03, 95% CI 1.00–1.05, p<0.05; OR= 3.98, 95% CI: 1.31–12.31, deficient vs. sufficient, test for trend p value <0.01; OR=2.32, 95% CI: 1.20–4.50, 1st vs. 5th quintile, test for trend p value 0.03). In fully adjusted models, the values attenuated slightly (OR=1.02, 95% CI 1.00–1.05, p<0.05; OR= 3.61, 95% CI: 1.00–13.10, deficient vs. sufficient, t-trend p=0.03; OR=2.09 1st vs. 5th quintile, 95% CI: 0.95–4.58, t-trend p=0.11). Our findings suggest that higher pre-diagnostic serum 25(OH)D levels may be associated with increased risk of subsequent BCC. Further studies to evaluate the effect of sun exposure on BCC and serum 25(OH)D levels may be warranted.

Although the kidney was initially thought to be the sole organ responsible for the production of 1,25(OH)2D via the enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is wide spread. However, the kidney is the major source for circulating 1,25(OH)2D. Only in certain granulomatous diseases such as sarcoidosis does the extra renal tissue produce sufficient 1,25(OH)2D to contribute to the circulating levels, generally associated with hypercalcemia, as illustrated by the case report preceding the review. Therefore the expression of CYP27b1 outside the kidney under normal circumstances begs the question why, and in particular whether the extra renal production of 1,25(OH)2D has physiologic importance. In this chapter this question will be discussed. First we discuss the sites for extra renal 1,25(OH)2D production. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH)2D3 production is examined, with special focus on the role of CYP27b1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. At this point the data do not clearly demonstrate an essential role for CYP27b1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided. With the availability of the mouse enabling tissue specific deletion of CYP27b1, the role of extra renal CYP27b1 expression in normal and pathologic states can now be addressed definitively.

Wound healing is essential for survival. This is a multistep process involving a number of different cell types. In the skin wounding triggers an acute inflammatory response, with the innate immune system contributing both to protection against invasive organisms and to triggering the invasion of inflammatory cells into the wounded area. These cells release a variety of cytokines and growth factors that stimulate the proliferation and migration of dermal and epidermal cells to close the wound. In particular, wounding activates stem cells in the interfollicular epidermis (IFE) and hair follicles (HF) to proliferate and send their progeny to re-epithelialize the wound. β-catenin and calcium signaling are important for this activation process. Mice lacking the VDR when placed on a low calcium diet have delayed wound healing. This is associated with reduced β-catenin transcriptional activity and proliferation in the cells at the leading edge of wound closure. These data suggest that vitamin D and calcium signaling are necessary components of the epidermal response to wounding, likely by regulating stem cell activation through increased β-catenin transcriptional activity.

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