Vitamin D and its analogs

The association of vitamin D deficiency with a broad spectrum of common diseases, including breast, colorectal, and prostate cancers; cardiovascular disease; autoimmune conditions; and infections, has led to a renewed interest in using vitamin D metabolites and analogs to treat a host of clinical conditions. Since vitamin D regulates gene expression in functions as varied as calcium and phosphate homeostasis, cell growth regulation, and cell differentiation of a variety of cell types such as enterocytes, keratinocytes, and epithelial cells of the vasculature and gastrointestinal tract, it constitutes a valuable agent to modulate disease states. The discovery of the metabolites 25-hydroxyvitamin D3 (25(OH)D3; calcidiol) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3; calcitriol) in the early 1970s led to their chemical synthesis and, since the 1980s, the development of several generations of calcitriol analogs. The pharmaceutical industry has attempted to separate the calcemic properties of 1α,25(OH)2D3 from its cell-differentiating properties so as to develop vitamin D analogs with specialized “calcemic” or “noncalcemic” (cell-differentiating) uses. Several agents in the form of calcipotriol, 22-oxacalcitriol, 19-nor-1α,25-(OH)2D2, and 1α(OH)D2, with “reduced calcemic activity” have resulted, finding widespread use in the treatment of psoriasis and secondary hyperparathyroidism. Other vitamin D analogs, e.g., ED-71 and 2-MD, primarily targeted to bone, have been touted as drugs for treatment of osteoporosis. Research has also focused on the synthesis of vitamin D compounds with multiple transcriptional targets in addition to the vitamin D receptor (VDR), VDR antagonists, and cytochrome P450 family 24 inhibitors, which block VDR-mediated action or the catabolism of 25(OH)D and 1α,25(OH)2D, to provide agents with possible utility in metabolic bone diseases, osteoporosis, and cancer. Our perception of the importance of vitamin D/25(OH)D repletion has been modified by the concept that some 1α,25(OH)2D3 is produced locally by target cells, making this molecule an endocrine and a paracrine factor. This review will discuss the full spectrum of vitamin D compounds currently available and some of their possible uses and potential mechanisms of action.