Activation of the Calcium Receptor by Calcimimetic Agents Is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia.

BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

Etelcalcetide, A Novel Calcimimetic, Prevents Vascular Calcification in A Rat Model of Renal Insufficiency with Secondary Hyperparathyroidism.

Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with chronic kidney disease (CKD) and is a consequence of impaired mineral homeostasis and secondary hyperparathyroidism (SHPT). Etelcalcetide substantially lowers parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) levels in SHPT patients on hemodialysis. This study compared the effects of etelcalcetide and paricalcitol on vascular calcification in rats with adenine-induced CKD and SHPT. Uremia and SHPT were induced in male Wistar rats fed a diet supplemented with 0.75% adenine for 4 weeks. Rats were injected with vehicle, etelcalcetide, or paricalcitol for 4 weeks from the beginning of adenine diet. Rats fed an adenine-free diet were included as nonuremic controls. Similar reductions in plasma PTH and parathyroid chief cell proliferation were observed in both etelcalcetide- and paricalcitol-treated rats. Serum calcium and phosphorus were significantly lower in etelcalcetide-treated uremic rats and was unchanged in paricalcitol-treated rats. Both serum FGF23 and aortic calcium content were significantly lower in etelcalcetide-treated uremic rats compared with either vehicle- or paricalcitol-treated uremic rats. The degree of aortic calcium content for etelcalcetide-treated rats was similar to that in nonuremic controls and corroborated findings of lack of histologic aortic mineralization in those groups. In conclusion, etelcalcetide and paricalcitol similarly attenuated progression of SHPT in an adenine rat model of CKD. However, etelcalcetide differentially prevented vascular calcification, at least in part, due to reductions in serum FGF23, calcium, and phosphorus levels.

Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis.

BACKGROUND: Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies. METHODS: We updated a prior systematic review through 2010. Studies included adults receiving dialysis and reported categorical data for calcium, phosphorus, and/or parathyroid hormone (PTH) together with all-cause mortality. We performed 2 separate meta-analyses to compare higher-than-referent levels vs referent and lower-than-referent levels vs referent levels. RESULTS: A literature review showed that when a linear relationship between the minerals and mortality was assumed, the estimated associations were more likely to be smaller or non-significant compared to non-linear models. In the meta-analyses, higher-than-referent levels of phosphorus (4 studies, RR = 1.20, 95% CI = 1.15-1.25), calcium (3 studies, RR = 1.10, 95% CI = 1.05-1.14), and PTH (5 studies, RR = 1.11, 95% CI = 1.07-1.16) were significantly associated with increased mortality. Although no significant associations between relatively low phosphorus or PTH and mortality were observed, a protective effect was observed for lower-than-referent calcium (RR = 0.86, 95% CI = 0.83-0.89). CONCLUSIONS: Higher-than-referent levels of PTH, calcium, and phosphorus in dialysis patients were associated with increased mortality risk in a selection of observational studies suitable for meta-analysis of non-linear relationships. Findings were less consistent for lower-than-referent values. Future analyses should incorporate the non-linear relationships between the minerals and mortality to obtain accurate effect estimates.

Cinacalcet HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results.

BACKGROUND AND OBJECTIVES: Patients with chronic kidney disease (CKD) receiving dialysis often develop secondary hyperparathyroidism with disturbed calcium and phosphorus metabolism. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) was established to guide treatment practices for these disorders. The ACHIEVE study was designed to test two treatment strategies for achieving KDOQI goals. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: Individuals on hemodialysis treated with vitamin D sterols were enrolled in this 33-week study. Subjects were randomly assigned to treatment with either cinacalcet and low-dose vitamin D (Cinacalcet-D) or flexible vitamin D alone (Flex-D) to achieve KDOQI-recommended bone mineral targets. ACHIEVE included a 6-week screening phase, including vitamin D washout, a 16-week dose-titration phase, and an 11-week assessment phase. RESULTS: Of 173 subjects enrolled, 83% of Cinacalcet-D and 67% of Flex-D subjects completed the study. A greater proportion of Cinacalcet-D versus Flex-D subjects had a >30% reduction in parathyroid hormone (PTH) (68% versus 36%, P < 0.001) as well as PTH <300 pg/ml (44% versus 23%, P = 0.006). The proportion of subjects simultaneously achieving targets for intact PTH (150-300 pg/ml) and calcium-phosphorus product (Ca x P) (<55 mg2/dl2) was also greater (21% versus 14%), but this was not statistically significant. This was attributable to 19% of Cinacalcet-D subjects with a PTH value below the KDOQI target range. CONCLUSIONS: Achievement of KDOQI targets was difficult, especially with Flex-D. Maintaining calcium and phosphorus target values precluded the use of vitamin D doses necessary to lower PTH to within the narrow target range and highlighted limitations inherent to the KDOQI treatment algorithm.

First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl.

BACKGROUND: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis. METHODS: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays. RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH). CONCLUSION: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.

Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.

BACKGROUND: Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients. METHODS: Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted. RESULTS: The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day. CONCLUSIONS: In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.

Calcium and phosphorus metabolism in patients who have chronic kidney disease.

Disturbances in calcium and phosphorus metabolism are almost invariable consequences of chronic kidney disease (CKD). Because the capacity to regulate calcium and phosphorus metabolism becomes compromised progressively as kidney function declines, calcium and phosphorus homeostasis is disrupted and serum calcium or phosphorus levels are perturbed in many patients with CKD. The level of interest in, and concerns about, abnormalities in calcium and phosphorus metabolism among patients with CKD has increased substantially in recent years. Strategies for clinical management are being revised, and recent recommendations differ substantially from those used previously with a renewed emphasis on safety.

Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT. METHODS: Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels. RESULTS: Cinacalcet-treated subjects were more likely to achieve a mean iPTH

The consequences of uncontrolled secondary hyperparathyroidism and its treatment in chronic kidney disease.

Secondary hyperparathyroidism (HPT) is a common complication of chronic kidney disease (CKD) and a frequent cause of clinically significant bone disease. Soft-tissue and vascular calcification, cardiovascular disease, and calcific uremic arteriolopathy (CUA) are additional serious consequences of the disorder that may contribute directly to cardiovascular morbidity and mortality in patients with CKD. Less widely appreciated manifestations include neurological disturbances, hematological abnormalities, and endocrine dysfunction. Secondary HPT arises from alterations in calcium, phosphorus, and vitamin D metabolism that develop early in the course of CKD and become more pronounced as kidney function declines. Treatment is often delayed, however, until the disease is well established. Current therapeutic strategies rely largely on the use of vitamin D sterols to diminish excess parathyroid hormone (PTH) synthesis and to lower serum or plasma PTH levels, but their use is often confounded by increases in serum calcium and phosphorus concentrations, changes that can aggravate soft-tissue and vascular calcification. As such, there is a need for new therapeutic interventions that can effectively lower serum or plasma PTH levels without producing untoward side effects. The current review summarizes the diverse manifestations of secondary HPT in patients with CKD. The consequences of inadequately controlled secondary HPT and the adverse effects of selected therapeutic interventions for the disorder on vascular calcification and cardiovascular disease in those with CKD are discussed.

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

Medical management of secondary hyperparathyroidism in chronic renal failure.

Abnormalities in calcium and phosphorus metabolism are common, and metabolic bone disease develops often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions appear to increase the risk of soft tissue and vascular calcification in patients with end-stage renal disease (ESRD), changes that may contribute to the development of cardiovascular disease. Current therapeutic approaches are thus being re-evaluated in an effort to limit these risks. Despite the importance of controlling phosphorus retention and preventing hyperphosphataemia in patients with CRF, current management strategies often are inadequate, particularly in those ingesting diets containing adequate amounts of protein. Results from clinical trials using daily haemodialysis strongly suggest that thrice-weekly haemodialysis regimens are only marginally adequate for achieving weekly phosphorus balance in many patients with ESRD. The safety of large oral doses of calcium as a phosphate-binding agent in patients with ESRD has also been questioned because excess amounts of calcium that are absorbed from the gastrointestinal tract may lead to ongoing calcium retention in those with little or no residual renal function. Arterial calcification and cardiac valve calcification are two serious complications that adversely affect cardiovascular haemodynamics. The use of large, often supraphysiological, doses of calcitriol or other vitamin D sterols to treat secondary hyperparathyroidism may aggravate hypercalcaemia and hyperphosphataemia, further increasing the risk of soft tissue and vascular calcification. Phosphate-binding agents that do not contain calcium, new vitamin D analogues and calcimimetic compounds offer new therapeutic alternatives for managing renal osteodystrophy. The integration of these novel agents into existing treatment regimens may provide safer and more effective methods for controlling secondary hyperparathyroidism and renal bone disease, while limiting the risks of soft tissue and vascular calcification in patients with CRF.

The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism.

BACKGROUND: A need exists for a therapy that lowers parathyroid hormone (PTH) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary hyperparathyroidism. METHODS: Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week, double-blind, randomized, placebo-controlled, dose titration study. Daily oral AMG 073 doses were administered to determine the effect on PTH, serum calcium, phosphorus, and calcium x phosphorus. RESULTS: The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% in the placebo group (P < 0.001). A greater proportion in the AMG 073 group (38%) had a decrease in PTH >or=30%, compared with the placebo group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar between treatment groups. Administration of AMG 073 was safe and well tolerated in this 18-week study. CONCLUSIONS: The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism.

Cardiovascular calcification in end-stage renal disease.

Cardiovascular diseases are common in patients with end-stage renal disease (ESRD) and cardiovascular morbidity and mortality among dialysis patients are substantially higher than in the general population. The reasons for this high incidence are multiple. They include traditional factors such as hypertension, diabetes, dyslipidaemia, sodium overload, and elevated homocysteine levels as well as disturbances of mineral metabolism, specifically abnormalities in phosphorus and calcium homeostasis. This review will describe the specific cardiovascular complications related to calcifications in ESRD, the implications of the abnormalities of mineral metabolism in its pathogenesis and the current imaging techniques available for the detection of cardiovascular calcifications. Excess of calcium load contributes to the development of cardiac calcifications; therefore, alternative strategies to diminish exogenous calcium load should be considered in patients with ESRD.