Vitamin D, bone, and HIV infection.

Vitamin D is synthesized in the form of cholecalciferol (vitamin D3) in the epidermis upon exposure to ultraviolet light. Cholecalciferol is also available through diet via animal sources; plant sources provide ergocalciferol (vitamin D2). These forms of vitamin D, which are inert and have a short half-life, are converted in the liver via 25 hydroxylase to 25(OH)D3, or calcidiol. This inert form is converted by 1-α hydroxylase, which is predominantly found in the kidney, to 1,25(OH)2D3, or calcitriol, which is the active form of vitamin D. Calcitriol synthesized in the kidney resides in the circulation for a brief period and is active in endocrine signaling. 1-α hydroxylase is also found in macrophages and monocytes, with vitamin D synthesized in these cells participating in autocrine and paracrine signaling. Vitamin D regulates calcium and phosphate homeostasis, interacting with parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) in increasing intestinal absorption of calcium and exerting direct effects on bone cells. Vitamin D also has immunomodulatory effects. In innate immunity, it increases cathelicidin gene expression in macrophages, which is associated with bactericidal activity, including antimycobacterial effects. In adaptive immunity, it predominantly targets T cells, acting to downregulate activation and recruitment of helper T cell (TH) subtypes 1 (TH1) and 17 (TH17) and polarize phentoypes towards TH2 and regulatory T cells (Treg). Numerous effects of vitamin D and vitamin D deficiency have been reported for specific disease states (Table 1). Vitamin D deficiency has been associated with increased risk for fractures and falls in the elderly, metabolic disorders (obesity, diabetes, metabolic syndrome) and cardiovascular disease, some cancers, tuberculosis (TB), and reduced likelihood of sustained virologic response (SVR) in patients receiving treatment for hepatitis C virus (HCV) infection. The potential effects by which vitamin D may act to reduce risk of such diseases include improvement of bone strength and muscle function; reduced lipogenesis and increased lipolysis; antiinflammatory, antiangiogenic, and proapoptotic effects; improvement of vascular compliance; increased cathelicidin gene expression; and a synergistic interaction with interferon alfa in reducing HCV replication. Results of randomized controlled trials of vitamin D supplementation in most of these settings with the exception of reduction of fall and fracture risk in the elderly,1,2 have yielded negative or inconsistent results to date. Table 1 Immune Effects of Vitamin D and Effects of Vitamin D on Disease Vitamin D deficiency currently is defined as a 25-hydroxyvitamin D (25[OH]D) level below 20 ng/mL, with levels below 10 ng/mL, levels between 20 ng/mL and 30 ng/mL, and levels above 30 ng/mL constituting severe deficiency, insufficiency, and normal levels, respectively. Most of the data supporting this classification come from 2 studies. One was an observational study in approximately 1300 post-menopausal women, predominantly white, in the Northeast United States who had a median age of 70 years.3 When PTH level was plotted against serum vitamin D levels, the inflection point at which increasing concentrations of vitamin D did not produce lower PTH levels was around 30 ng/mL, suggesting absence of physiologic response of PTH to vitamin D beyond this concentration. The second study was a meta-analysis examining relative risks according to vitamin D level using clinical trial data for falls and fractures and observational data for other disease endpoints, including cardiovascular mortality, colorectal cancer, hypertension, and all-cause mortality. Relative risks decreased to about 1 as vitamin D level increased to the range of 30 ng/mL to 44 ng/mL, suggesting that benefit in preventing such outcomes becomes apparent when the vitamin D level is above 30 ng/mL.4