NDT Advance Access originally published online on April 26, 2005
Nephrology Dialysis Transplantation 2005 20(7):1370-1377; doi:10.1093/ndt/gfh834
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1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar®/Mimpara®) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism
1 Department of Metabolic Disorders and 2 Department of Pathology, Amgen Inc, Thousand Oaks, CA 91320, USA and 3 Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
Correspondence and offprint requests to: Dr Charles Henley, Department of Metabolic Disorders, Amgen, Inc., One Amgen Center Drive, MS 15-2-A, Thousand Oaks, CA 91320, USA. Email: chenley{at}amgen.com
Background. Calcitriol treatment of secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) patients can lead to increased serum calcium and phosphorus, which have been associated as risk factors for vascular calcification. Cinacalcet HCl (Sensipar®/Mimpara®) {(
R)-(–)--methyl-N-[3-[3-(trifluoromethylphenyl)propyl]-1-napthalenemethanamine hydrochloride} lowers serum parathyroid hormone (PTH), calcium, phosphorus and calcium–phosphorous (CaxP) product in stage 5 CKD dialysis patients; however, its effects on vascular calcification are unknown.
Methods. Cinacalcet HCl (10 or 1 mg/kg, p.o. gavage), 1,25-dihydroxyvitamin D3 (0.1 µg, s.c, calcitriol) or the combination was administered daily for 26 days in a rat model of secondary HPT [5/6 nephrectomy]. After dosing, aortic calcification was determined using the von Kossa staining method. Serum PTH and blood chemistries were determined on days 0, 26 and 0, 14, 26, respectively, prior to and after dosing.
Results. Calcitriol-treated rats had moderate to marked aortic calcification, whereas no significant calcification was observed in vehicle- or cinacalcet HCl-only treated groups. Co-administration of cinacalcet HCl with calcitriol did not attenuate the calcitriol-mediated increase in CaxP product or calcitriol-mediated aortic calcification. Both calcitriol and cinacalcet HCl therapy significantly reduced serum PTH levels. Calcitriol significantly elevated serum calcium, serum phosphorous and CaxP product above pretreatment levels, or those seen with vehicle or cinacalcet HCl. Cinacalcet HCl (10 or 1 mg/kg) decreased serum ionized calcium and decreased calcitriol-induced hypercalcaemia.
Conclusion. Cinacalcet HCl and calcitriol both effectively reduce PTH, albeit via different mechanisms, but unlike calcitriol, cinacalcet HCl did not produce hypercalcaemia, an increased CaxP product or vascular calcification.
Keywords: calcimimetics; calcitriol; cinacalcet HCl; hypercalcaemia; secondary hyperparathyroidism; vascular calcification
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