Vitamin D analogs: perspectives for treatment

Vitamin D therapy is widely used for the treatment of secondary hyperparathyroidism associated with chronic renal failure. However, administration of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] or its precursor 1alpha(OH)D(3), especially in combination with calcium-based phosphate binders, often produces hypercalcemia. Several vitamin D analogs have been developed that retain the direct suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands but have less calcemic activity. These analogs offer a safer and more effective means of controlling secondary hyperparathyroidism. 22-Oxa-1,25(OH)(2)D(3) (22-oxacalcitriol or OCT), 19-nor-1, 25(OH)(2)D(2) (19-norD(2)) and 1alpha(OH)D(2) have been tested in animal models of uremia and in clinical trials. Intravenous 19-norD(2) and oral 1alpha(OH)D(2) have been approved for use in the United States; OCT is currently under review. The mechanisms by which these analogs exert their selective actions on the parathyroid glands are under investigation. The low calcemic activity of OCT has been attributed to its rapid clearance which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression. The selectivity of 19-norD(2) and 1alpha(OH)D(2) is achieved by a distinct mechanism(s). Knowledge of how these compounds exert their selective actions on the parathyroid glands may allow the design of more effective analogs in the future.