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

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Date

2018-12-06

Authors

Diaz-Tocados, Juan M
Rodriguez-Ortiz, Maria E
Almaden, Yolanda
Pineda, Carmen
Martinez-Moreno, Julio M
Herencia, Carmen
Vergara, Noemi
Pendon-Ruiz de Mier, M Victoria
Santamaría, Rafael
Rodelo-Haad, Cristian

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Elsevier
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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.

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MeSH Terms

Animals
Biphenyl compounds
Bone remodeling
Calcimimetic agents
Disease models, animal
Humans
Hyperparathyroidism, secondary
Kidney failure, chronic
Male
Osteoblasts
Parathyroid hormone
Phenethylamines
Rats
Rats, Wistar
Receptors, calcium-sensing

DeCS Terms

Calcimiméticos
Compuestos de Bifenilo
Fallo renal crónico
Hiperparatiroidismo secundario
Hormona paratiroidea
Osteoblastos
Receptores sensibles al calcio
Remodelación ósea

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Keywords

CaSR, Bone, Calcimimetic, Chronic kidney disease, Mineral metabolism, Parathyroid hormone

Citation

Díaz-Tocados JM, Rodríguez-Ortiz ME, Almadén Y, Pineda C, Martínez-Moreno JM, Herencia C, et al. Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration. Kidney Int. 2019 May;95(5):1064-1078