Therapeutic uses of vitamin D analogues

The vitamin D endocrine system has been implicated in numerous biological a ctivities throughout the body. The breadth and magnitude of vitamin D activ ity suggest potential therapeutic applications for the treatment of several diseases and disorders, including hyperproliferative diseases, immune dysf unction, endocrine disorders, and metabolic bone diseases. However, therapy using natural vitamin D hormone, 1,25-dihydroxyvitamin D-3 (1,25[OH](2)D-3 ) has been precluded in most cases because of the potent calcemic activity shown by this hormone. Newly developed vitamin D analogues with lower calce mic activity have been shown to retain many therapeutic properties of 1,25( OH)(2)D-3. Molecular studies discussed in this article provide insights int o the unique target cell specificity afforded by these analogues. In partic ular, the importance of the nuclear vitamin D receptor (VDR), serum vitamin D-binding protein, 24-hydroxylase, and membrane receptor is noted because analogue selectivity, specificity, and potency are afforded through their m olecular interactions. The nuclear VDR has been isolated from a variety of target cells and tissues, suggesting that vitamin D compounds may have ther apeutic potential throughout several body systems. Five vitamin D analogues have been approved for use in patients: calcipotriol (Dovonex; Leo Pharmac euticals, Copenhagen, Denmark) for the treatment of psoriasis, 19-nor-1,25( OH)(2)D-2 (Zemplar; Abbott Laboratories, Abbott Park, IL) for secondary hyp erparathyroidism, doxercalciferol (Hectorol; Bone Care Int, Madison, WI) fo r reduction of elevated parathyroid hormone levels, 22-oxacalcitriol (Maxac alcitol; Chugai Pharmaceuticals, Tokyo, Japan), and alfacalcidol. Several o ther analogues are currently being tested in preclinical and clinical trial s for the treatment of various types of cancer and osteoporosis, as well as immunosuppression. Understanding how analogues exert their selective actio ns may allow for the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders. (C) 2001 by the N ational Kidney Foundation, Inc.