Vitamin D analogues for the management of secondary hyperparathyroidism

Abstract

Secondary hyperparathyroidism complicating chronic kidney disease requires therapy to minimize the effects of parathyroid hormone (PTH) on bone and other tissues. Low levels of calcitriol in blood play a major role in the initiation and maintenance of hyperparathyroidism. Accordingly, administration of calcitriol has been demonstrated to be an effective form of therapy. While this therapy is effective in controlling hyperparathyroidism, side effects of calcitriol, including increased intestinal absorption of calcium and phosphate, often complicate therapy by giving rise to hypercalcemia and hyperphosphatemia, which may be important risk factors for extraskeletal calcifications. Over the last several years, interest has turned toward vitamin D analogs, which may be able to affect parathyroid function with lesser effects on calcium and phosphorus in serum, and thereby, minimizing the undesirable toxicities of vitamin D therapy. Two vitamin D analogs are available in this country for the control of hyperparathyroidism in the setting of advanced kidney disease, and include 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), and more recently, 1-alpha-hydroxyvitamin D(2) (doxercalciferol). 19-nor-1,25-dihydroxyvitamin D(2) is widely used and was evaluated extensively in animals, revealing that this vitamin D sterol had a selective effect on increasing PTH suppression, with lesser effects on calcium and phosphorus metabolism. These studies lead to clinical trials which showed the efficacy of this therapy in that PTH could be lowered satisfactorily in patients with calcium and phosphorus values within the normal range. The selectivity of 19-nor-1,25-dihydroxyvitamin D(2) seen in animals has also been found in humans, such that therapy with this sterol can achieve control of hyperparathyroidism with a wider therapeutic window than the predecessor, calcitriol. 1-alpha-hydroxyvitamin D(2) has recently been introduced, but in contrast to paracalcitol, there is little reason to believe that there is any selectivity in its actions in terms of suppressing PTH, compared with its ability to raise serum calcium or phosphorus in serum. However, this vitamin D sterol can effectively decrease PTH levels in patients with advanced renal failure. Comparative studies of paricalcitol and doxercalciferol have not been undertaken at the present time. Further studies on the mechanism of actions might explain the differences between these sterols and their effects on the intestinal absorption of calcium and phosphate. At the present, the use of vitamin D analogs can achieve control of hyperparathyroidism with a wider therapeutic window than the native sterol, calcitriol.