The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats.
ABSTRACT 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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ABSTRACT: Calcitriol putatively suppresses bone activity by decreasing parathyroid hormone (PTH) levels. Results of studies in a 52-year-old female maintenance hemodialysis patient suggest that calcitriol may also have a direct suppressive effect on bone. The PTH-calcium relationship was evaluated through the use of low (1 mEq/l) and high (4 mEq/l) calcium hemodialyses that were performed before the initiation of calcitriol treatment, at the end of 6 weeks of thrice-weekly intravenous calcitriol administration, and 6 weeks after the discontinuation of calcitriol. During the low-calcium dialysis, serum calcium decreased more rapidly and to a greater magnitude after calcitriol treatment despite no appreciable difference in basal and maximally stimulated PTH levels; during the high-calcium dialysis, calcitriol treatment resulted in a more rapid increase in serum calcium despite no appreciable difference in basal and maximally suppressed PTH levels. Discontinuation of calcitriol resulted in responses to the low and high calcium dialyses that were similar to those observed before calcitriol treatment. In conclusion, the results suggest that calcitriol may have a direct suppressive effect on bone that is independent of PTH.Nephron 02/1995; 71(2):218-23. · 13.26 Impact Factor
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ABSTRACT: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.New England Journal of Medicine 04/2004; 350(15):1516-25. · 51.66 Impact Factor
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ABSTRACT: Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX + R-568, SNX + calcitriol, SNX + vehicle, sham-op + R-568, sham-op + calcitriol, and sham-op + vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum- and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 +/- 1.46 vs. 2.70 +/- 0.91 mm(3)), podocyte volume (831 +/- 127 vs. 397 +/- 67 microm(3)), the degree of foot process fusion (mean width of foot processes = 958 +/- 364 vs. 272 +/- 35 nm), and glomerular basement membrane thickness (244 +/- 6 vs. 267 +/- 23 nm), as well as desmin staining, were significantly higher in vehicle-treated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage.American journal of physiology. Renal physiology 05/2008; 294(4):F748-57. · 3.61 Impact Factor