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Concept: Cinacalcet

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Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.

Concepts: Renal failure, Chronic kidney disease, Nephrology, Erythropoietin, Disease, Cardiovascular disease, Hyperparathyroidism, Cinacalcet

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Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

Concepts: Scientific method, Epidemiology, Bone fracture, Fracture, Medical terms, Placebo, Hyperparathyroidism, Cinacalcet

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The IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism] study compared the effectiveness of paricalcitol and cinacalcet in the management of secondary hyperparathyroidism in haemodialysis patients but did not report the costs or cost effectiveness of these treatments.

Concepts: Costs, Hemodialysis, Parathyroid hormone, Parathyroid gland, Hypoparathyroidism, Hyperparathyroidism, Cinacalcet, Calcium-sensing receptor

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To observe the clinical outcome and the effect of the combination of cinacalcet hydrochloride with low-dose calcitriol on bone metabolism in maintenance hemodialysis (MHD) patients with severe secondary hyperparathyroidism (SHPT).
 Methods: Thirty SHPT patients were enrolled to receive treatment of cinacalcet combined with low-dose calcitriol, with inclusion criteria as follows: maintenance on MHD>6 months; serum intact parathyroid hormone (iPTH)>600 pg/mL; parathyroid glands with more than 1 nodules by ultrasonography; traditional therapy with no effects. All patients were given cinacalcet 25-75 mg and 0.5 μg calcitriol daily. Serum Ca, P, iPTH, bone metabolic markers and bone density were measured before and after treatment. The clinical symptoms and their changes were recorded.
 Results: The baseline levels of iPTH, Ca and P were (1787.3±1 321.0) pg/mL, (2.54±0.19) mmol/L, and (2.06±0.15) mmol/L, respectively. After 2 weeks of treatment, serum phosphorus decreased by 20%; after 1 and 3 months of treatment, iPTH decreased by 35% and 70%. Ca and P fell to (2.39±0.17) and (1.56±0.50) mmol/L (P<0.05), respectively. The symptoms of the patients relieved. The above indicators remained stable after 12 months. Moreover, after 6 months of treatment, the alkaline phosphatase, osteocalcin and β-cross levels were decreased by 50%, 37% and 49%, respectively. The decline in patients' bone density was inhibited. No severe adverse events were observed.
 Conclusion: Cinacalcet hydrochloride combined with low dose calcitriol can improve high calcium, high phosphorus and high iPTH in MHD patients with severe SHPT, relieve symptoms, and improve bone metabolism. It can be used as a favorable choice for the treatment of SHPT.

Concepts: Osteoporosis, Bone, Parathyroid hormone, Parathyroid gland, Hypoparathyroidism, Hyperparathyroidism, Cinacalcet, Calcium-sensing receptor

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Persistent secondary hyperparathyroidism is common after successful kidney transplant, with concomitant hypercalcemia and hypophosphatemia potentially leading to reduced graft survival and increased cardiovascular risk. Cinacalcet, a calcimimetic agent that activates the calcium-sensing receptors in parathyroid glands, is a therapeutic option. In this study, we assessed the long-term treatment effects of cinacalcet for a period of up to 5 years in a cohort of kidney transplant recipients.

Concepts: Parathyroid hormone, Parathyroid gland, Hyperparathyroidism, Cinacalcet, Parathyroid disorders

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Cinacalcet is an effective and safe alternative to parathyroidectomy in end stage renal disease (ESRD) patients with secondary hyperparathyroidism. Hypocalcemia is a known complication of treatment that is usually readily reversible upon discontinuation of the drug. It rarely manifests severely and symptomatically requiring hospital admission. We present the case of a 55 year old man with severe, symptomatic and prolonged hypocalcemia that occurred 2 weeks after starting cinacalcet. Cinacalcet induced a state of pharmacological parathyroidectomy with subsequent hungry bone syndrome. Serum calcium returned to normal range after 4 weeks of stopping the drug while receiving high doses of elemental calcium and vitamin D receptor activation therapy (VDRA).

Concepts: Osteoporosis, Kidney, Bone, Vitamin D, Parathyroid hormone, Calcium, Hyperparathyroidism, Cinacalcet

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This study explored the use of a value-based pricing approach for the new calcimimetic etelcalcetide indicated for the treatment of secondary hyperparathyroidism (SHPT) in patients receiving hemodialysis. It used the US payer perspective and applied the cost-effectiveness framework. Because etelcalcetide is an intravenous therapy that can be titrated for individual patients, and because its utilization is yet to be assessed in real world settings, a range of plausible doses were estimated for etelcalcetide to define a range of prices. These were either in relation to the existing oral calcimimetic cinacalcet or compared to no calcimimetic treatment.

Concepts: Intravenous therapy, Price, Hyperparathyroidism, Cinacalcet, Explorer, Pricing, Secondary hyperparathyroidism, Value-based pricing

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The parathyroid oxyphil cell content increases in patients with chronic kidney disease (CKD), and even more in patients treated with the calcimimetic cinacalcet and/or calcitriol for hyperparathyroidism. Oxyphil cells have significantly more calcium-sensing receptors than chief cells, suggesting that the calcium-sensing receptor and calcimimetics are involved in the transdifferentiation of a chief cell to an oxyphil cell type. Here, we compared the effect of the vitamin D analog paricalcitol (a less calcemic analog of calcitriol) and/or cinacalcet on the oxyphil cell content in patients with CKD to further investigate the genesis of these cells. Parathyroid tissue from four normal individuals and 27 patients with CKD who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Prior to parathyroidectomy, patients had received the following treatment: seven with no treatment, seven with cinacalcet only, eight with paricalcitol only, or cinacalcet plus paricalcitol in five. Oxyphilic areas of parathyroid tissue, reported as the mean percent of total tissue area per patient, were normal, 1.03; no treatment, 5.3; cinacalcet, 26.7 (significant vs. no treatment); paricalcitol, 6.9 (significant vs. cinacalcet; not significant vs. no treatment); and cinacalcet plus paricalcitol, 12.7. Cinacalcet treatment leads to a significant increase in parathyroid oxyphil cell content but paricalcitol does not, reinforcing a role for the calcium-sensing receptor activation in the transdifferentiation of chief-to-oxyphil cell type. Thus, two conventional treatments for hyperparathyroidism have disparate effects on parathyroid composition, and perhaps function. This finding is provocative and may be useful when evaluating future drugs for hyperparathyroidism.

Concepts: Protein, Chronic kidney disease, Vitamin D, Parathyroid hormone, Hyperparathyroidism, Cinacalcet

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To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients.

Concepts: Receptor antagonist, Serotonin, Agonist, Inverse agonist, Cinacalcet

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We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet.

Concepts: DNA, SNP array, Single-nucleotide polymorphism, Cinacalcet, Calcium-sensing receptor