Rapid Decrease of Intact Parathyroid Hormone Could Be a Predictor of Better Response to Cinacalcet in Hemodialysis Patients

Cinacalcet is effective for treating refractory secondary hyperparathyroidism (SHPT), but little is known about the response rates and clinical factors influencing the response.  A prospective, single-arm, multi-center study was performed for 24 weeks. Cinacalcet was administered to patients with intact parathyroid hormone (iPTH) level greater than 300 pg/mL. Cinacalcet was started at a dose of 25 mg daily and titrated until 100 mg to achieve a serum iPTH level <300 pg/mL (primary end point). Early response to cinacalcet was defined as a decrease of iPTH more than 50% within one month.  Fifty-seven patients were examined. Based on the magnitude of iPTH decrease, patients were divided into responder (n=47, 82.5%) and non-responder (n=10, 17.5%) groups. Among the responders, 38 achieved the primary end point, whereas 9 patients showed a reduction in serum iPTH of 30% or more, but did not reach the primary end point. Compared to non-responders, responders were significantly older (p=0.026), female (p=0.041), and diabetics (p<0.001). Additionally, early response was observed more frequently in the responders (30/47, 63.8%), of whom the majority (27/30, 90.0%) achieved the primary end point. Multivariate analysis showed that lower baseline iPTH levels [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-0.99], the presence of diabetes (OR 46.45, CI 1.92-1125.6) and early response (OR 21.54, CI 2.94-157.7) were significant clinical factors affecting achievement of iPTH target.  Cinacalcet was effective in most hemodialysis patients with refractory SHPT. The presence of an early response was closely associated with the achievement of target levels of iPTH.

Related papers:

title: Improved parathyroid hormone control by cinacalcet is associated with reduction in darbepoetin requirement in patients with end-stage renal disease.
abstract: Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to erythropoietin (EPO) resistance. Medical treatment with cinacalcet is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on darbepoetin dosing is unknown.



We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 ± 14; mean ± SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in darbepoetin responsiveness before and after 12 months of cinacalcet therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement.



Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 ± 6 to 63 ± 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 ± 13 to 116 ± 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) μg/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004).



Reduction of PTH by cinacalcet is associated with a decrease in darbepoetin requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation.

title: A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.
abstract: The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied.



Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 (N = 16) or placebo (N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15.



Pretreatment PTH levels were 599 +/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 +/- 5%, 78 +/- 3%, and 70 +/- 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 +/- 70 and 443 +/- 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced.



The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

title: Early initiation of cinacalcet for the treatment of secondary hyperparathyroidism in hemodialysis patients: a three-year clinical experience.
abstract: Despite the availability of standard therapy (vitamin D sterols and phosphate binders) for the treatment of secondary hyperparathyroidism (SHPT) in hemodialyzed (HD) patients, a significant percentage of patients still fail to achieve targets recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation for parathyroid hormone (PTH), calcium, and phosphorus. The calcimimetic cinacalcet (CN) has been shown to be an effective treatment for SHPT, significantly reducing serum PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product levels, thus increasing the proportion of patients achieving the K/DOQI targets for bone mineral parameters. The aim of this study was to evaluate if early treatment with CN had beneficial effects in HD patients with mild-to-moderate SHPT in whom conventional treatments had failed to achieve NKF-K/DOQI targets for PTH, serum-corrected calcium, and phosphorus while minimizing the risk of paradoxical hypercalcemia and/or hyperphosphatemia. Clinical practice data were collected monthly, starting from 6 months prior to, and up to 36 months after, the start of CN therapy. CN was started at a dose of 30 mg daily or every other day, and titrated thereafter to achieve intact PTH (iPTH) <300 pg/mL. The dose of concomitant vitamin D and phosphate binders were also adjusted in order to achieve K/DOQI targets. Data from 32 patients were collected, 28 of whom had been treated with CN for at least 36 months at the time of data analysis. At baseline, patients had serum iPTH >300 pg/mL (570 ± 295 pg/mL) and/or serum-corrected calcium >9.5 mg/dL. CN induced significant decreases in iPTH, calcium, and calcium-phosphorus product with respect to baseline levels. The percentage of patients within K/DOQI target levels at baseline, 12, 24, and 36 months was 0, 81.2, 83.3, and 86.2% for iPTH; 34.4, 65.6, 86.6, and 89.6% for serum-corrected calcium; 40.6, 56.2, 69.6, and 72.4% for phosphorus; and 37.5, 62.5, 80, and 82.7% for calcium-phosphorus product. The mean dose of CN at the end of the observation period was 38 mg/day. The mean dose of concomitant medication (calcitriol, Al-containing phosphate binders, and sevelamer) decreased from baseline to 36 months. Early treatment with CN in HD patients with SHPT increases the proportion of patients achieving and maintaining K/DOQI targets with a low dose of CN (38 mg/day). These results suggest that the metabolic control obtained with low-dose CN administered early in the course of SHPT can be maintained or increased over time.

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



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.



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.



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.

title: Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism.
abstract: Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and secondary HPT.



We undertook a combined analysis of safety data (parathyroidectomy, fracture, hospitalizations, and mortality) from 4 similarly designed randomized, double-blind, placebo-controlled clinical trials enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled secondary HPT (intact PTH > or =300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for hyperphosphatemia and secondary HPT (phosphate binders and vitamin D). Relative risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. Health-related quality-of-life (HRQOL) data were obtained from the Medical Outcomes Study Short Form-36 (SF-36), and the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF).



Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI 0.01-0.55), fracture (RR 0.46, 95% CI 0.22-0.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.43-0.86) compared with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component Summary score and the specific domains of Bodily Pain and General Health Perception.



Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on important clinical outcomes.

title: Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients.
abstract: Secondary hyperparathyroidism (SHPT) affects a significant number of hemodialysis patients, and metabolic disturbances associated with it may contribute to their high mortality rate. As patients with lower serum calcium, phosphorus, and parathyroid hormone are reported to have improved survival, we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival. We prospectively collected data on hemodialysis patients from a large provider beginning in 2004, a time coincident with the commercial availability of cinacalcet hydrochloride. This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality. Patients included in the study received intravenous (i.v.) vitamin D therapy (a surrogate for the diagnosis of SHPT). Of 19,186 patients, 5976 received cinacalcet and all were followed from November 2004 for up to 26 months. Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic. Hence, this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v. vitamin D. Definitive proof, however, of a survival advantage awaits the performance of randomized clinical trials.

title: Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.
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.

title: New insights into the role of calcium-sensing receptor activation.
abstract: The discovery of the calcium-sensing receptor (CaSR) prompted the identification of substances that affect its function. Cinacalcet, for example, is a drug that allosterically modifies the receptor so as to increase its sensitivity to circulating calcium (thus the name "calcimimetic") and in this way decreases parathyroid hormone secretion. Clinical use of cinacalcet is already approved for the treatment of primary and secondary hyperparathyroidism, but research is ongoing to identify further potential actions of this drug. The effects and functions of the CaSR have been evaluated in different systems and tissues, beyond parathyroid glands, such arterial walls. A complete understanding of the properties of calcimimetics are of obvious clinical interest, since therapeutic indications may be affected accordingly.

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



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.



Cinacalcet-treated subjects were more likely to achieve a mean iPTH </=300 pg/mL (31.8 pmol/L) than were control subjects on traditional therapy (56% vs. 10%, P < 0.001). Cinacalcet-treated subjects were more likely to achieve concentrations of serum calcium within 8.4 to 9.5 mg/dL (2.10-2.37 mmol/L) and serum phosphorus within 3.5 to 5.5 mg/dL (1.13-1.78 mmol/L) than were control subjects (49% vs. 24% and 46% vs. 33%, P < 0.001 for each). Cinacalcet also improved achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and concurrent achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and iPTH </=300 pg/mL (31.8 pmol/L) (65% vs. 36% and 41% vs. 6%, P < 0.001 for each).



In subjects on dialysis with secondary HPT, cinacalcet facilitates achievement of the K/DOQI-recommended targets for PTH, calcium, phosphorus, and Ca x P.

title: Treatment of secondary hyperparathyroidism in CKD patients with cinacalcet and/or vitamin D derivatives.
abstract: The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics.

title: Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals.
abstract: Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called 'kidney bone disease', also known as 'mineral and bone disorders', is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-kappaB ligand modulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD patients.

title: Cinacalcet reduces plasma intact parathyroid hormone, serum phosphate and calcium levels in patients with secondary hyperparathyroidism irrespective of its severity.
abstract: To evaluate the relationship between the severity of secondary hyperparathyroidism (SHPT) - defined in terms of baseline plasma intact parathyroid hormone (iPTH) level - and the magnitude of response to cinacalcet.



In this post hoc analysis, data were pooled from three randomized, placebo-controlled trials in which dialysis patients with iPTH ≥ 300 pg/ml were dose-titrated with cinacalcet or placebo in addition to conventional treatment to achieve iPTH ≤ 250 pg/ml. In 953 patients analyzed (cinacalcet, 545; placebo, 408), baseline iPTH levels were categorized in 100 pg/ml intervals (300 - ≥ 1,000 pg/ml), and the impact of baseline iPTH on changes in iPTH, phosphate (P), calcium (Ca) and calcium- phosphate product (Ca × P) was evaluated.



Cinacalcet reduced iPTH (47% reduction), P (9%), Ca (7%), and Ca × P (15%) across all subgroups. For patients receiving cinacalcet, the mean percentage reduction from baseline in iPTH varied from 35 to 55%, being consistently decreased across the severity subgroups. The mean absolute change in iPTH was more pronounced in patients with higher baseline iPTH levels, particularly in the ≥ 1,000 pg/ml subgroup vs. the other subgroups. However, as baseline iPTH levels increased, iPTH ≤ 250 pg/ml was achieved in fewer patients. A trend towards greater absolute change from baseline was observed for P in patients with more severe disease (iPTH ≥ 800 pg/ml) treated with cinacalcet compared with patients with less severe disease (iPTH 300 - < 800 pg/ml).



Cinacalcet lowers plasma iPTH and serum P, Ca and Ca × P levels in dialysis patients with SHPT, regardless of disease severity. Patients with more severe disease experienced greater reductions in PTH and P, but fewer achieved iPTH ≤ 250 pg/ml by the efficacy assessment phase. Use of cinacalcet when baseline PTH is lower may result in more stable control of SHPT and help to control bone and mineral alterations.

title: Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).
abstract: Mineral metabolism has emerged as an important predictor of morbidity and mortality in dialysis patients, independent of bone and muscle concerns. Several expert panels have issued management guidelines for mineral metabolism.



The state of mineral metabolism (serum parathyroid hormone [PTH], phosphorus, calcium, and calcium-phosphorus product) was described for representative samples of patients and facilities from 7 countries (France, Germany, Italy, Japan, Spain, United Kingdom, and United States) participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS I, 1996-2001; DOPPS II, 2002-2004).



A relatively modest percentage of patients fell within the guideline range for PTH (21.4% in DOPPS I, 26.2% in DOPPS II), serum phosphorus (40.8%, 44.4%), albumin-corrected serum calcium (40.5%, 42.5%), and calcium-phosphorus product (56.6%, 61.4%). Results were not dramatically different across countries. The majority of patients not within guideline ranges had high serum levels of phosphorus (51.6% in DOPPS I, 46.7% in DOPPS II), calcium (50.1%, 48.6%), and calcium-phosphorus product (43.4%, 38.6%) and low (<150 pg/mL) concentrations of PTH (52.9%, 47.5%). It was rare for patients to fall within recommended ranges for all indicators of mineral metabolism; 23% to 28% fell within guideline for at least 3 measures and only 4.6% to 5.5% of patients were within range for all 4. The risks of all-cause and cardiovascular mortality were directly and independently associated with each of the 4 indicators.



The DOPPS provides a useful comparison benchmark for the state of mineral metabolism management of patients with kidney disease; it also affirms the association between mineral metabolism and important patient outcomes.

title: Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS).
abstract: Abnormalities in serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations are common in patients with chronic kidney disease and have been associated with increased morbidity and mortality. No clinical trials have been conducted to clearly identify categories of calcium, phosphorus, and PTH levels associated with the lowest mortality risk. Current clinical practice guidelines are based largely on expert opinions, and clinically relevant differences exist among guidelines across countries. We sought to describe international trends in calcium, phosphorus, and PTH levels during 10 years and identify mortality risk categories in the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international study of hemodialysis practices and associated outcomes.



Prospective cohort study.



25,588 patients with end-stage renal disease on hemodialysis therapy for longer than 180 days at 925 facilities in DOPPS I (1996-2001), DOPPS II (2002-2004), or DOPPS III (2005-2007).



Serum calcium, albumin-corrected calcium (Ca(Alb)), phosphorus, and PTH levels.



Adjusted hazard ratios for all-cause and cardiovascular mortality calculated using Cox models.



Distributions of mineral metabolism markers differed across DOPPS countries and phases, with lower calcium and phosphorus levels observed in the most recent phase of DOPPS. Survival models identified categories with the lowest mortality risk for calcium (8.6 to 10.0 mg/dL), Ca(Alb) (7.6 to 9.5 mg/dL), phosphorus (3.6 to 5.0 mg/dL), and PTH (101 to 300 pg/mL). The greatest risk of mortality was found for calcium or Ca(Alb) levels greater than 10.0 mg/dL, phosphorus levels greater than 7.0 mg/dL, and PTH levels greater than 600 pg/mL and in patients with combinations of high-risk categories of calcium, phosphorus, and PTH.



Because of the observational nature of DOPPS, this study can only indicate an association between mineral metabolism categories and mortality.



Our results provide important information about mineral metabolism trends in hemodialysis patients in 12 countries during a decade. The risk categories identified in the DOPPS cohort may be relevant to efforts at international harmonization of existing clinical guidelines for mineral metabolism.

title: Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study.
abstract: Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH > or =300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of < or =250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels < or =300 pg/ml (46 versus 9%), proportion of patients with > or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with > or =20, > or =40, or > or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

title: Decreases in PTH in Japanese hemodialysis patients with secondary hyperparathyroidism: associations with changing practice patterns.
abstract: Control of serum concentrations of calcium (Ca), phosphorus (P), and parathyroid hormone (PTH) is essential for management of secondary hyperparathyroidism (SHPT).



This is a planned interim analysis of a longitudinal cohort study. The settings are dialysis facilities in Japan. Eligible patients comprise all those who were receiving hemodialysis at one of 86 participating facilities and who have SHPT. Using data from a random sample (n = 3276) of the participants from January 2008 through June 2009, we measured changes in the percentages of patients who were within the national guideline-specified target ranges of Ca (8.4 to 10 mg/dl), P (3.5 to 6.0 mg/dl), and intact PTH (iPTH) (60 to 180 pg/ml), and changes in prescriptions of drugs targeting SHPT. We used regression models to identify factors affecting the achievement of the guideline-specified targets.



There were no notable changes in the percentage of patients who were within the guideline for Ca, P, or both. The percentage who were within the iPTH guideline increased from 14.5% to 43.3% (P < 0.001). There were no remarkable changes in the percentage of patients receiving vitamin D or phosphate binders. The percentage who received cinacalcet increased from 0% to 29%. Prescription of cinacalcet was associated with improvement or target-achievement for iPTH and for Ca by 16.8 percentage points (95% CI: 8.1 to 17.0) and by 12.6 percentage points (13.7 to 19.9), respectively.



In the routine care of hemodialysis patients, increasing use of cinacalcet was associated with better control of SHPT.

title: Does cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism, improve arterial stiffness in patients on continuous ambulatory peritoneal dialysis?
abstract: Vascular calcification (VC) and arterial stiffness (AS) are major contributors to cardiovascular disease, and in chronic kidney disease, VC and AS are correlated. Disorders of calcium and phosphate metabolism contribute to the progression of VC and to increases in AS. The efficacy of cinacalcet (CIN) in reducing AS in patients on continuous ambulatory peritoneal dialysis (CAPD) has not been determined. The present study enrolled 19 CAPD patients (12 women, 7 men; mean age: 62.2 +/- 3.6 years) with serum intact parathyroid hormone (iPTH) greater than 500 ng/dL (mean value: 675 +/- 106 ng/dL) in whom daily oral treatment with CIN 25 mg was started. If administration of CIN for 3 months failed to reduce the level of iPTH to less than 300 ng/dL, the dose of CIN was increased to 50 mg daily. Before the start of CIN and at 3 years after the start of CIN, pulse wave velocity (PWV) was determined. In 11 patients, levels of iPTH were reduced to less than 300 ng/dL; levels in the rest of the patients remained high. We observed no significant differences in PWV before CIN and at 3 years after CIN start (1856 +/- 198 cm/s vs. 1726 +/- 187 cm/s). Multivariate regression analysis of PWV demonstrated that both systolic blood pressure and changes in serum levels of phosphate contributed to decreases in PWV In patients receiving CAPD, VC and AS might be the result of higher systolic blood pressure and increased serum levels of phosphate.

title: Impact of the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in a large dialysis network.
abstract: The impact of the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease has not been assessed.



We compared albumin-adjusted serum calcium, phosphate, calcium x phosphate (Ca x P) product, and parathyroid hormone (PTH) values among active hemodialysis patients who received care at Dialysis Clinic Inc facilities during 8-month periods before (n = 9,516) and after (n = 9,543) the October 2003 release of the KDOQI guidelines. We examined the impact of missed sessions, abbreviated sessions, and patient-dietitian ratio on achievement of consistent control (defined as >or= 75% values within guideline targets) for each parameter. We also evaluated whether achievement of consistent control of a given parameter precluded control of another.



There was a modest decrease in mean per-patient concentration for all mineral metabolic indicators after release of the guidelines. Similarly, the proportion of values within the recommended ranges for serum calcium, phosphate, and Ca x P product increased, but remained unchanged for PTH. The likelihood of achieving consistent control for each indicator increased when other parameters were concomitantly in range. Missed dialysis sessions were associated with a lower likelihood of achieving consistent control of calcium, phosphate, and Ca x P product levels, whereas abbreviated sessions were associated inversely with consistent achievement of phosphate and Ca x P product target levels. Variations in patient-dietitian ratio had no discernible association with mineral metabolic control.



The KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease had a small, but noticeable, effect in the year after their release. Additional studies should evaluate whether achievement of the prescribed target levels confers an advantage with respect to relevant clinical outcomes.

title: Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism.
abstract: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume.



This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls.



Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm(3) (group S) and 25 had at least one enlarged gland larger than 500 mm(3) (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone.



Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

title: Renal osteodystrophy in diabetic patients.
abstract: To assess the effects of diabetes mellitus on renal osteodystrophy, we examined the database of 256 patients (45% on hemodialysis and 55% on peritoneal dialysis) who were prospectively studied in three Toronto dialysis centers between October of 1987 and 1989. All patients had serial documentation of their clinical, laboratory and risk parameters of bone disease, and completed a series of investigations that included the deferoxamine test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Twenty-five percent of these patients were diabetic. When compared to non-diabetic patients, they were on dialysis for a shorter duration (2.4 +/- 0.3 vs. 4.7 +/- 0.3 years; P < 0.0002), used calcium carbonate as the only phosphate binder more frequently (40 vs. 25%; P < 0.007), and had lower parathyroid hormone levels (12 +/- 1.4 vs. 24 +/- 2.3 pmol/liter; P < 0.002). High-turnover bone disorders (that is, osteitis fibrosa and mixed disorder) were distinctly uncommon (8 vs. 33%; P < 0.01 by Fisher's exact test), while the mild (19 vs. 9%; P = NS) and the aplastic disorders (with mean stainable bone surface aluminum of 6.5 +/- 0.7%) (46 vs. 31%; P = NS) tended to be more common in diabetic patients. The prevalence of aluminum bone disease was the same in both groups (27%). Diabetic patients ingested a smaller cumulative dose of aluminum gels (3.7 +/- 0.6 vs. 9.3 +/- 1.1 kg; P < 0.005), yet had a higher rate of aluminium accumulation on bone surfaces than non-diabetic patients (1.5 +/- 0.19 vs. 0.96 +/- 0.10% per month on dialysis; P < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

title: Decreased secondary hyperparathyroidism in diabetic patients receiving hemodialysis.
abstract: Biochemical and bone scintigraphic studies were performed in nondiabetic and diabetic patients receiving hemodialysis at the time of kidney transplantation to assess the degree of secondary hyperparathyroidism. Despite lower serum calcium concentrations, diabetic patients had significantly lower parathyroid hormone (PTH) levels than nondiabetic patients. In addition, diabetic patients had lower graded total-skeletal scintigraphic scores than nondiabetic patients. The PTH levels showed positive correlations with bone scan scores and with alkaline phosphatase in nondiabetic patients but not in diabetic patients. Avascular necrosis occurred in 17% of nondiabetic patients and in only 2% of diabetic patients. Patients with avascular necrosis had significantly higher PTH levels than patients without avascular necrosis. Diabetes mellitus seems to confer a protective effect from the skeletal manifestations of secondary hyperparathyroidism, including avascular necrosis.

title: The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
abstract: Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4-10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10-65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2-4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.

title: Parathyroid and bone response of the diabetic patient to uremia.
abstract: Biochemical and radiologic indices of bone disease were assessed in 26 insulin-dependent diabetic patients and 28 nondiabetic patients with endstage kidney disease. The two groups were comparable in age, sex, duration of renal failure, and length of time on dialysis. Diabetic patients showed significantly lower serum calcium and immunoreactive parathyroid hormone (iPTH) levels than nondiabetic patients. iPTH was not related to total serum calcium, but was positively correlated with serum phosphorous (r = 0.37, P less than 0.05 and r = 0.54, P less than 0.005, in nondiabetic and diabetic patients, respectively). iPTH correlated with alkaline phosphatase (r = 0.59, P less than 0.0009) and calcitonin (r = 0.51, P less than 0.05) only in nondiabetic patients. Osteitis fibrosa was noted radiologically in 30% of nondiabetic patients and in none of the diabetic patients (P less than 0.03). Bone morphology in eight diabetic patients who underwent iliac bone biopsy was characterized by reduced trabecular and osteoid bone volume, no woven bone, and marked reduction in indices of bone formation and resorption. The small amount of bone and lack of osteomalacia are a unique feature of the diabetic patient with chronic renal disease. The long-term sequelae of low bone turnover and reduced circulating iPTH may present a special problem to the long term diabetic survivor on the current therapies of uremia.

title: Ca2+ as an extracellular signal in bone.
abstract: Bone is the major sink and store for calcium and it fulfils essential roles in the maintenance of extracellular free ionised calcium concentration ([Ca2+]e) within its homeostatic range (1.1-1.3 mM). In response to acute hypercalcaemia or hypocalcaemia, Ca2+ is rapidly transported into or out of bone. Bone turnover (and therefore bone Ca2+ turnover) achieves the long-term correction of the [Ca2+]e by the metabolic actions of osteoblasts and osteoclasts, as they respectively incorporate or release Ca2+ from bone. These processes are regulated by the actions of hormones, such as parathyroid hormone (PTH), the release of which is a function of the [Ca2+]e, and is regulated by the action of the Ca2+-sensing receptor (CaR) in the parathyroid gland. Tissue culture studies indicate that bone cells also directly respond to increasing and decreasing [Ca2+]e in their vicinity, independently of the systemic factors. Nevertheless, further studies are necessary to identify how the acute and long-term local changes in [Ca2+]e affect bone cells and the physiological processes they are involved in. Also, the molecular mechanisms which enable the bone cells to sense and respond to [Ca2+]e are not clear. Like the parathyroid cells, bone cells also express the CaR, and accumulating evidence indicates the involvement of this receptor in their responses to the changing extracellular ionic environment.

title: The Extracellular Calcium-Sensing Receptor (CaSR) Is a Critical Modulator of Skeletal Development
abstract: The extracellular calcium-sensing receptor (CaSR) is essential for embryonic and postnatal skeletal development. Bone Censor The extracellular calcium-sensing receptor (CaSR) is a guanine nucleotide-binding protein (G protein)–coupled receptor (GPCR) that responds to changes in the concentration of extracellular calcium ([Ca2+]e) and modulates various functions of parathyroid cells (PTCs), chondrocytes (the cells that produce cartilage), osteoblasts, and renal tubular cells. Previous attempts to characterize the CaSR in Casr−/− mice have been hampered by the expression of an alternatively spliced form of the receptor that provides at least partial compensation for loss of the full-length receptor (see the Perspective by Brown and Lian). Chang et al. have now developed mice with cell type–specific knockout of Casr that do not express the alternative receptor. Mice with PTC- or osteoblast-specific deletion of Casr were viable but had postnatal skeletal defects. Unexpectedly, knockout of Casr in chondrocytes was lethal. Mice in which chondrocyte-specific knockout of Casr was induced late in embryonic life were viable but had delayed growth plate development. Together, these findings reveal a previously unappreciated role for the CaSR in embryonic and postnatal skeletal development. The extracellular Ca2+-sensing receptor (CaSR) plays a nonredundant role in the functions of the parathyroid gland (PTG) and the kidney. Severe hyperparathyroidism, premature death, and incomplete gene excision in Casr−/− mice have precluded the assessment of CaSR function in other tissues. We generated mice with tissue-specific deletion of Casr in the PTG, bone, or cartilage. Deletion of Casr in the PTG or bone resulted in profound bone defects, whereas deletion of Casr in chondrocytes (cartilage-producing cells) resulted in death before embryonic day 13 (E13). Mice in which chondrocyte-specific deletion of Casr was induced between E16 and E18 were viable but showed delayed growth plate development. Our data show a critical role for the CaSR in early embryogenesis and skeletal development.