title: 1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism.
abstract: 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) {(alphaR)-(-)-alpha-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 D(3) (0.1 microg, 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., One Amgen Center Drive, MS 15-2-A, Thousand Oaks, CA 91320, USA. chenley@amgen.com
authors.forename: Charles
authors.initials: C
authors.lastname: Henley
authors.forename: Matt
authors.initials: M
authors.lastname: Colloton
authors.forename: Russell C
authors.initials: RC
authors.lastname: Cattley
authors.forename: Edward
authors.initials: E
authors.lastname: Shatzen
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Towler
authors.forename: David
authors.initials: D
authors.lastname: Lacey
authors.forename: David
authors.initials: D
authors.lastname: Martin
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D002114:Calcinosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D002117:Calcitriol / Q000009:adverse effects / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D002120:Calcium Channel Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D000069449:Cinacalcet; D004195:Disease Models, Animal; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000150:complications*; D007674:Kidney Diseases / Q000097:blood / Q000150:complications; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002120:Calcium Channel Agonists; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010758:Phosphorus; D002117:Calcitriol; D002118:Calcium; D000069449:Cinacalcet