The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats.
Calcimimetics and vitamin D sterols reduce serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism receiving dialysis, a disease state associated with parathyroid hyperplasia, vascular calcification, bone disease, and increased mortality. The aim of this study was to determine the effects of the research calcimimetic AMG 641 (Amgen, Inc., Thousand Oaks, CA) or calcitriol (Sigma Aldrich Corporation, St. Louis, MO) on vascular calcification in a rodent model of progressive uremia with accompanying secondary hyperparathyroidism induced by dietary adenine. Treatment effects on parathyroid gland hyperplasia and bone loss were also investigated. Rats were treated daily with vehicle, calcitriol (10 ng), AMG 641 (3 mg/kg), or no treatment during the 4 week period the animals were fed adenine. The uremia-induced increases in serum PTH levels were significantly attenuated by both AMG 641 (>90%) and calcitriol (approximately 50%). AMG 641 significantly reduced calcium-phosphorus product (CaxP) and significantly attenuated the development of both parathyroid hyperplasia and vascular calcification. In addition, AMG 641 prevented the defects in trabecular bone volume, trabecular number, and bone mineralization, as well as increases in trabecular spacing in this rodent model of secondary hyperparathyroidism. Calcitriol (10 ng/rat) decreased osteoid surface/bone surface, but had no effects on other bone parameters, or parathyroid hyperplasia (likely due to the lower PTH suppressive effect of calcitriol at the dose used in this study). However, this dose of calcitriol significantly exacerbated vascular calcification. These results suggest that calcimimetics can reduce the development of vascular calcification, parathyroid hyperplasia and bone abnormalities associated with secondary hyperparathyroidism.
Henley
Charles
C
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320, USA. chenley@amgen.com
Davis
James
J
Miller
Gerald
G
Shatzen
Edward
E
Cattley
Russ
R
Li
Xiaodong
X
Martin
David
D
Yao
Wei
W
Lane
Nancy
N
Shalhoub
Victoria
V
D000225:Adenine / Q000494:pharmacology; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002114:Calcinosis / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D000069449:Cinacalcet; D004305:Dose-Response Relationship, Drug; D006965:Hyperplasia / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008297:Male; D008970:Molecular Weight; D009281:Naphthalenes / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010280:Parathyroid Glands / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000139:chemically induced / Q000150:complications*
D001713:Biphenyl Compounds; C544316:N-((6-(methyloxy)-4'-(trifluoromethyl)-3-biphenylyl)methyl)-1-phenylethanamine; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010627:Phenethylamines; D000225:Adenine; D002118:Calcium; D000069449:Cinacalcet