Vitamin D analogs as therapeutic agents: a clinical study update.
Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver and 25-hydroxyvitamin D3-1 alpha-hydroxylase in the kidney to form the active metabolite 1 alpha,25-dihydroxyvitamin D3. The binding of 1 alpha,25-dihydroxyvitamin D3 to the vitamin D receptor (VDR), a nuclear receptor, activates VDR to interact with retinoid X receptor (RXR) and form the VDR/RXR/co-factor complex, which binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription. 1 alpha,25-dihydroxyvitamin D3 regulates the homeostasis of calcium and phosphorus, and also controls the expression of parathyroid hormone. Chronic renal disease is characterized by reduced synthesis of 1 alpha,25-dihydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, over-stimulation of the parathyroid gland, and increased parathyroid hormone synthesis. This secondary hyperparathyroidism (HPT) can cause renal osteodystrophy unless treated. Several vitamin D analogs are currently available or under investigation for the treatment of secondary HPT, psoriasis and osteoporosis. Additional clinical studies are being conducted for a variety of indications, including bone diseases, cell proliferation disorders and autoimmune diseases. Different vitamin D analogs seem to exhibit differential effects as exemplified by the survival benefit provided by paricalcitol over 1 alpha,25-dihydroxyvitamin D3 for end-stage renal disease patients on hemodialysis. Elucidation of the mechanism of action for the different vitamin D analogs will enhance our understanding of the vitamin D pathway and improve therapeutic uses of these analogs. This review discusses recent progress on the use of vitamin D and its analogs in the management of HPT secondary to chronic renal disease.
Wu-Wong
J Ruth
JR
Abbott Laboratories, R4CM Building AP52, 200 Abbott Park Rd, Abbott Park, IL 60064, USA. ruth.r.wuwong@abbott.com
Tian
Jin
J
Goltzman
David
D
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004872:Ergocalciferols / Q000627:therapeutic use; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy / Q000209:etiology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000627:therapeutic use
D004872:Ergocalciferols; D007166:Immunosuppressive Agents; D014807:Vitamin D; C084656:paricalcitol; D002117:Calcitriol; C078903:seocalcitol