Vitamin D analogs for secondary hyperparathyroidism: what does the future hold?
Secondary hyperparathyroidism (2 degrees HPT) commonly develops in patients with chronic kidney disease (CKD) in response to high phosphate, low calcium and low 1,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. High PTH levels increase the rate of bone turnover, with a net efflux of calcium and phosphate leading to vascular calcification and coronary artery disease. Treatment of 2 degrees HPT with 1alpha,25(OH)(2)D(3) and calcium-based phosphate binders often produces hypercalcemia and over-suppression of PTH, resulting in adynamic bone that cannot buffer excess calcium and phosphate, which increases the risk of vascular calcification. It is essential, then, to reduce PTH levels to a range that supports normal bone turnover and minimizes ectopic calcification. Vitamin D analogs that inhibit PTH gene transcription and parathyroid hyperplasia, and that have less calcemic activity than 1alpha,25(OH)(2)D(3,) have provided a greater safety margin for the treatment of 2 degrees HPT, as well as enhancing the survival of CKD patients. Although several analogs with less calcemic activity are now used in patients (paricalcitol and doxercalciferol in the USA, and OCT and falecalcitriol in Japan), efforts to develop even more selective analogs continue. Parathyroid glands express both 25-hydroxylase and 1alpha-hydroxylase and may be capable of activating prohormones or prodrugs to suppress PTH and parathyroid growth by an autocrine mechanism. Moreover, the introduction of non-calcium-based phosphate binders (sevelamer and lanthanum carbonate) and cinacalcet (an allosteric activator of the calcium receptor that reduces PTH and the serum calciumxphosphate product) may reduce the risk of hypercalcemia with vitamin D therapy. Combining these agents with higher doses of vitamin D compounds may achieve greater suppression of PTH and possibly enhance survival in patients with chronic kidney disease.
Brown
Alex J
AJ
Renal Division, Washington University School of Medicine, Box 8126, 660 S. Euclid, St. Louis, MO 63110, USA. abrown@im.wustl.edu
D000818:Animals; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D014807:Vitamin D