Comparison of active vitamin D compounds and a calcimimetic in mineral homeostasis.
The differential effects between cinacalcet and active vitamin D compounds on parathyroid function, mineral metabolism, and skeletal function are incompletely understood. Here, we studied cinacalcet and active vitamin D compounds in mice expressing the null mutation for Cyp27b1, which encodes 25-hydroxyvitamin D-1α-hydroxylase, thereby lacking endogenous 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Vehicle-treated mice given high dietary calcium had hypocalcemia, hypophosphatemia, and marked secondary hyperparathyroidism. Doxercalciferol and 1,25(OH)(2)D(3) each normalized these parameters and corrected both the abnormal growth plate architecture and the diminished longitudinal bone growth observed in these mice. In contrast, cinacalcet suppressed serum parathyroid hormone (PTH) cyclically and did not correct the skeletal abnormalities and hypocalcemia persisted. Vehicle-treated mice given a "rescue diet" (high calcium and phosphorus, 20% lactose) had normal serum calcium and PTH levels; cinacalcet induced transient hypocalcemia and mild hypercalciuria. The active vitamin D compounds and cinacalcet normalized the increased osteoblast activity observed in mice with secondary hyperparathyroidism; cinacalcet, however, increased the number and activity of osteoclasts. In conclusion, cinacalcet reduces PTH in a cyclical manner, does not eliminate hypocalcemia, and does not correct abnormalities of the growth plate. Doxercalciferol and 1,25(OH)(2)D(3) reduce PTH in a sustained manner, normalize serum calcium, and improve skeletal abnormalities.
Nguyen-Yamamoto
Loan
L
Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada.
Bolivar
Isabel
I
Strugnell
Stephen A
SA
Goltzman
David
D
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001842:Bone and Bones / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects*; D000069449:Cinacalcet; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010280:Parathyroid Glands / Q000187:drug effects* / Q000473:pathology; D014807:Vitamin D / Q000494:pharmacology* / Q000627:therapeutic use; D014808:Vitamin D Deficiency / Q000097:blood / Q000188:drug therapy / Q000473:pathology
D050071:Bone Density Conservation Agents; D009281:Naphthalenes; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D000069449:Cinacalcet