Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration

Juan M Díaz-Tocados, María E Rodríguez-Ortiz, Yolanda Almadén, Carmen Pineda, Julio M Martínez-Moreno, Carmen Herencia, Noemi Vergara, M Victoria Pendón-Ruiz de Mier, Rafael Santamaría, Cristian Rodelo-Haad, Antonio Casado-Díaz, Víctor Lorenzo, Catarina Carvalho, João M Frazão, Arnold J Felsenfeld, William G Richards, Escolástico Aguilera-Tejero, Mariano Rodríguez, Ignacio López, Juan R Muñoz-Castañeda, Juan M Díaz-Tocados, María E Rodríguez-Ortiz, Yolanda Almadén, Carmen Pineda, Julio M Martínez-Moreno, Carmen Herencia, Noemi Vergara, M Victoria Pendón-Ruiz de Mier, Rafael Santamaría, Cristian Rodelo-Haad, Antonio Casado-Díaz, Víctor Lorenzo, Catarina Carvalho, João M Frazão, Arnold J Felsenfeld, William G Richards, Escolástico Aguilera-Tejero, Mariano Rodríguez, Ignacio López, Juan R Muñoz-Castañeda

Abstract

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

Keywords: CaSR; bone; calcimimetic; chronic kidney disease; mineral metabolism; parathyroid hormone.

Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Source: PubMed