The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats

Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320, USA.
European journal of pharmacology (Impact Factor: 2.53). 05/2009; 616(1-3):306-13. DOI: 10.1016/j.ejphar.2009.05.013
Source: PubMed


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.

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    • "Serum calcium as sensed by the CaSR, a G protein-coupled receptor located on the parathyroid gland, is a critical negative regulator of PTH secretion and resultant serum levels [17] and the CaSR is thought to play a key role in parathyroid cell proliferation and hyperplasia [18]. Calcimimetics including R-568, AMG 641 [19] and cinacalcet (Sensipar®/Mimpara®) act as allosteric modulators of the CaSR to increase sensitivity to endogenous calcium [19–21], thereby shifting leftward the set point for calcium-regulated PTH secretion [20, 22]. In dialysis patients with sHPT, cinacalcet simultaneously lowers plasma PTH, serum calcium and serum phosphorus [22]. "
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    ABSTRACT: Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT. We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT. Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium. The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.
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    ABSTRACT: The calcium-sensing receptor (CaSR), which is involved in systemic calcium homeostasis, has also been found to be functionally expressed on cells of the vascular wall. Its activation on perivascular nerves and endothelial cells has been shown to regulate arterial tone, peripheral vascular resistance and possibly local tissue perfusion. The expression of the CaSR on immune cells involved in vascular inflammation, such as macrophages, and its increased expression in inflammation indicates the central role extracellular calcium plays in vascular inflammation and repair. Further detailed analysis will clarify the role the vascular CaSR plays as a therapeutic target for complex disease conditions such as hypertension, tissue hypoperfusion, atherosclerosis and vascular calcification.
    Current pharmaceutical biotechnology 05/2009; 10(3):282-8. DOI:10.2174/138920109787847466 · 2.51 Impact Factor
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