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.     

Similar predictive value of bone turnover using first- and second-generation immunometric PTH assays in pediatric patients treated with peritoneal dialysis

BACKGROUND: Accurate measurements of the concentration of parathyroid hormone (PTH) in serum or plasma are essential for the proper assessment of renal osteodystrophy. The first-generation immunometric PTH assay (1st PTH-IMA) not only detects the intact hormone, but also additional PTH fragments truncated at the amino N-terminally truncated PTH-derived fragments [ntPTH(1-84)]. A second-generation immunometric PTH assay (2nd PTH-IMA) recognizes only PTH(1-84) and possibly PTH fragments that are truncated at the carboxyl-terminus but not PTH(7-84). Whether estimates of the ratio between PTH(1-84) and ntPTH(1-84) fragments are a better predictor of bone turnover remains controversial. METHODS: Thirty-three patients aged 12.8 +/- 4.4 years treated with continuous cycling peritoneal dialysis (CCPD) for 13 +/- 9 months underwent iliac crest bone biopsy. PTH levels were measured by two newly developed first-generation and second-generation PTH-IMA. The ntPTH(1-84) fragments were calculated by subtracting PTH values determined using the 2nd PTH-IMA from values obtained using 1st PTH-IMA that detects both PTH(1-84) and relatively large ntPTH(1-84). RESULTS: Determinations of PTH levels by both assays were highly correlated (r = 0.89, P < 0.001). The relationships between first-generation and second-generation PTH-IMA and bone formation were similar (r = 0.67, P < 0.0001 and r = 0.64, P < 0.0001, respectively). When patients were grouped according to the presence or absence of secondary hyperparathyroidism, the ratio PTH(1-84) to ntPTH(1-84) did not differ between groups. CONCLUSION: PTH concentrations determined by either the first- or the second-generation PTH-IMA were found to be better predictors of bone formation than the PTH(1-84) to ntPTH(1-84) fragments ratio.     

Reduction of whole PTH/intact PTH ratio as a predictor of bone metabolism in cinacalcet treatment of hemodialysis patients with secondary hyperparathyroidism

Summary  

In cinacalcet treatment of hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), not only intact parathyroid hormone (I-PTH), whole PTH (W-PTH), and bone markers, but also W-PTH/I-PTH ratio as proportion of active PTH(1–84) molecules were decreased. Changes in W-PTH/I-PTH ratio significantly correlated and predicted changes in bone marker.     

An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism

AIMS: Cinacalcet lowers plasma parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism (sHPT), but the bone histologic response has not been described. This prospective, double-blind, placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT. METHODS: Patients with intact PTH (iPTH) > or = 300 pg/ml were randomly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and/or phosphate binder therapy. Cinacalcet (30 - 180 mg/day) was used to achieve iPTH levels < or = 200 pg/ml. Bone biopsies were performed before and after one year of treatment. RESULTS: Baseline and end-of-study data were available from 32 patients (19 cinacalcet, 13 placebo). Baseline bone turnover was elevated in 27, reduced in 3 and normal in 2 patients. Serum bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTx) were elevated. Cinacalcet treatment decreased PTH and diminished activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (< 100 pg/ml). The histomorphometric parameter changes in bone corresponded to PTH, BSAP and NTx reductions. Bone mineralization parameters remained normal. CONCLUSIONS: Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT.     

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 相似文献   

Successful use of cinacalcet HCl in a patient with end-stage renal failure and refractory secondary hyperparathyroidism due to parathyromatosis

We present the case of a 65-year-old male on long-term dialysis for end-stage renal failure, who developed persistent secondary hyperparathyroidism after subtotal parathyroidectomy, which proved refractory to treatment. Parathyromatosis, a rare cause of recurrent hyperparathyroidism, which may develop when tissue seeded into the neck during subtotal or total parathyroidectomy becomes hyperfunctioning [Maxwell and Winearls 1997], was diagnosed. The patient had excessively high levels of circulating parathyroid hormone (PTH), elevated serum calcium and deteriorating cardiovascular status. Repeated surgery and treatment with high-dose vitamin D failed to provide a sustained decrease in serum PTH levels. Administration of cinacalcet HCl, a second generation calcimimetic, at doses of 30 - 180 mg/day provided a gradual and sustained suppression of PTH (> 1,700 - 344 ng/l) without increasing the calcium-phosphate product.     

Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism.

BACKGROUND: Cinacalcet lowers plasma parathyroid hormone (PTH) levels in primary and secondary hyperparathyroidism. The efficacy and safety of cinacalcet have not been examined in renal transplant patients with persistent hyperparathyroidism. The aim of this study was to evaluate the effect of cinacalcet as a novel therapy for the management of such patients. METHODS: Eleven renal allograft recipients with persistent hyperparathyroidism were treated with cinacalcet. The total study time was 10 weeks. Individual cinacalcet doses were adjusted to obtain a serum calcium in the predefined normal target range of 2.10-2.60 mmol/l. RESULTS: Serum calcium decreased significantly from 2.73+/-0.05 mmol/l to 2.44+/-0.05 and 2.42+/- 0.04 mmol/l after 2 and 10 weeks of treatment, respectively. All patients reached the target range rapidly and remained normocalcaemic throughout the study. Serum PTH significantly decreased 16.1 and 21.8% at study weeks 2 and 10, respectively, compared with week 0. Serum phosphate increased. Renal function remained stable and no allograft rejection was observed. From weeks 2 to 10, daily cinacalcet doses administered were 30 mg (n = 8), 15 mg (n = 1) and 60 mg (n = 1), respectively. CONCLUSION: Cinacalcet was effective in correcting the hypercalcaemia associated with persistent hyperparathyroidism after renal transplantation. It appears to be safe. Thus, cinacalcet represents a promising alternative for parathyroidectomy in these patients.     

Treatment of hyperparathyroidism with cinacalcet in kidney transplant recipients

Background

After successful kidney transplantation, hyperparathyroidism can persist in 10%–50% of patients and can harmfully affect bone metabolism. Calcimimetic cinacalcet is a new treatment option in the management of persistent hyperparathyroidism in these patients.

Methods

This prospective, clinical study of 11 patients included those who had a serum intact parathyroid hormone (iPTH) concentration >65 ng/L, a serum creatinine concentration was <200 μmol/L, stable kidney graft function, and were >1 year since transplantation. Patients were not treated with drugs other than calcitriol that could influence bone metabolism. During the 6-month observation period, in which the stability of measured parameters was determined, and in the 12-month treatment period (cinacalcet 30 mg/d), we followed serum concentrations of calcium, phosphate, iPTH, creatinine, vitamin 25OH D₃, bone-specific alkaline phosphatase (ALP), osteocalcin, collagen degradation fragments (CTX), urinary calcium excretion, and bone mineral density (BMD).

Results

During the treatment period, the serum calcium concentration decreased significantly (from 2.50 ± 0.12 to 2.32 ± 0.12 mmol/L; P < .01). Serum iPTH concentration decreased significantly (from 247 [range, 199–362] at time 0 to 198 [range, 165–233] ng/L after 1 month of treatment; P < .05), but increased slightly thereafter. After 6 months of treatment, the serum concentration of ALP and CTX increased significantly, but decreased thereafter. There were no significant changes in the other parameters assessed. Renal function remained stable during the treatment period. The BMD of the lumbar spine, hip, and forearm did not change during the 12 months of treatment.

Conclusion

Cinacalcet was effective in treating posttransplant hyperparathyroidism, resulting in decreased calcemia and transient decreased iPTH. ALP and CTX transiently increased during therapy, but other markers of bone metabolism remained unchanged. Twelve months of cinacalcet treatment did not result in a change in BMD. Cinacalcet seems to be a safe drug with no negative effect on renal function.     

帕立骨化醇联合西那卡塞治疗血液透析伴继发性甲状旁腺功能亢进的效果研究

目的:研究帕立骨化醇联合西那卡塞治疗维持性血液透析(MHD)继发性甲状旁腺功能亢进(SHPT)患者的疗效和安全性。方法:选取2019年8月至2020年8月本院血液净化中心收治的22例MHD伴SHPT患者为研究对象,所有患者根据全段甲状旁腺激素(iPTH)水平予以帕立骨化醇联合西那卡塞治疗。分别于治疗前及治疗后2、4、8...     

Long-term outcomes of cinacalcet and paricalcitol titration protocol for treatment of secondary hyperparathyroidism

Long-term outcomes of combined cinacalcet and paricalcitol therapy for secondary hyperparathyroidism (SHPT) in patients failing traditional therapies with phosphate binders and active vitamin D compound analogs are not well described. We implemented a titration protocol for cinacalcet and paricalcitol and assessed its long-term effects on bone metabolism and disease in hemodialysis (HD) patients. Thirty-five patients were started on 30 mg of cinacalcet daily. After 12 months, median cinacalcet dose was 60 mg. There was a 33% increase in number of patients receiving paricalcitol. Average corrected serum calcium (Ca) decreased from 9.5 to 8.8 mg/dl (p = 0.003, 95% CI 0.34-1.04); phosphorus (P) from 6.2 to 5.5 mg/dl (p = 0.047, 95% CI 0.01-1.34); Ca x P product from 58 to 48 (p = 0.001, 95% CI 4.2-15.7); and intact PTH (iPTH) from 426 +/- 274 to 300 +/- 228 pg/ml (p = 0.03, 95% CI 19.3-401.7). Number of patients achieving three or more K/DOQI criteria increased by 29% (p = 0.009).     

Intraoperative monitoring of intact PTH during surgery for primary hyperparathyroidism

The intraoperative differential diagnosis between adenoma and hyperplasia during surgery for primary hyperparathyroidism (pHPT) is sometimes difficult. Several methods have been proposed to aid the surgeon in deciding on the amount of parathyroid tissue to be resected. We examined the use of intraoperative monitoring of intact PTH in 47 patients operated upon for pHPT. The highly sensitive assay for intact PTH was modified to permit a total turn-around time from gland excision to obtained result of about 60 min. The correlation (r) between the results of the modified and the conventional method; which requires 24 h of incubation, was 0.98. At 15 min after removal of the parathyroid adenoma the levels of intact PTH had decreased by [mean (SD)] 85 (11)%. A decrease of 63% in intact PTH in patients with parathyroid adenoma predicted with 95% confidence the 4 patients with primary hyperplasia as not having parathyroid adenoma. We conclude that intraoperative measurement of intact PTH could be a valuable adjunct to surgical skill, especially for reoperative parathyroid surgery.

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Intraoperatives monitoring der intakten PTH-sekretion bei eingriffen wegen primärem Hyperparathyreoidismus

Zusammenfassung Die intraoperative Differentialdiagnose zwischen Adenom und Hyperplasie bereitet bei Eingriffen wegen primarem Hyperparathyreoidismus (pHPT) gelegentlich Schwierigkeiten. Es wurden verschiedene Methoden vorgeschlagen, nach denen der Chirurg entscheiden kann, wieviel parathyreoides Gewebe zu resezieren ist. Wir untersuchten bei 47 Patienten, die wegen pHPT operiert wurden, die Anwendung des intraoperativen Monitoring der intakten PTH-Sekretion. Der entsprechende hochsensitive PTH-Assay wurde modifiziert, damit ein komplettes Resultat von der Exzision an über 60 min zu erzielen war. Die Korrelation r zwischen den Ergebnissen nach modifizierter und konventioneller Methode (die eine 24-h-Inkubation erfordert) betrug 0,98. Die intakte PTH-Sekretion verringerte sich 15 min nach Entfernung des parathyreoiden Adenoms um 85 (11)% [Mittelwert (SD)]. Die Patienten mit parathyreoidem Adenom wiesen eine PTH-Verringerung von 63% auf; dies ließ bei den 4 Patienten mit primärer Hyperplasie zu 95% zuverlässig erkennen, daß sie kein parathyreoides Adenom hatten. Wir folgern daraus, daß die intraoperative Messung der PTH-Sekretion ein wichtiges chirurgisches Hilfsmittel (insbesondere bei Reoperationen) sein kann.

This study was supported by grants from the Medical Faculty, Lund University, Lund, Sweden     

Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.     

Bone metabolism after cinacalcet administration in patients with secondary hyperparathyroidism

Cinacalcet, an allosteric modulator of a calcium (Ca)-sensing receptor, significantly suppresses parathyroid hormone (PTH) secretion and bone turnover rate in chronic hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). In this study, bone metabolism after cinacalcet treatment was examined, because hungry bone syndrome is sometimes experienced after parathyroidectomy in severe SHPT. We conducted a prospective observational study in 17 HD patients with SHPT. Cinacalcet was started at 25 mg/day, and the dose was increased step by step based on serum calcium level. A significant decrease in serum Ca and intact PTH concentration was found within 2 weeks. Tartrate-resistant acid phosphatase 5b, a good bone resorption marker, was significantly decreased at week 2 of the study. Serum bone alkaline phosphatase, a marker of bone formation, was increased at week 2 compared with the basal level. It became, however, gradually decreased until week 14. Only one patient whose bone turnover was considerably high had a mild numbness feeling. These results suggest that cinacalcet treatment might transiently accelerate bone formation with rapid suppression of bone resorption. This uncoupling could be involved in a mechanism by which cinacalcet decreases serum Ca level.     

1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism.

BACKGROUND: Calcitriol treatment of secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) patients can lead to increased serum calcium and phosphorus, which have been associated as risk factors for vascular calcification. Cinacalcet HCl (Sensipar/Mimpara) {(alphaR)-(-)-alpha-methyl-N-[3-[3-(trifluoromethylphenyl)propyl]-1-napthalenemethanamine hydrochloride} lowers serum parathyroid hormone (PTH), calcium, phosphorus and calcium-phosphorous (CaxP) product in stage 5 CKD dialysis patients; however, its effects on vascular calcification are unknown. METHODS: Cinacalcet HCl (10 or 1 mg/kg, p.o. gavage), 1,25-dihydroxyvitamin D(3) (0.1 microg, s.c, calcitriol) or the combination was administered daily for 26 days in a rat model of secondary HPT [5/6 nephrectomy]. After dosing, aortic calcification was determined using the von Kossa staining method. Serum PTH and blood chemistries were determined on days 0, 26 and 0, 14, 26, respectively, prior to and after dosing. RESULTS: Calcitriol-treated rats had moderate to marked aortic calcification, whereas no significant calcification was observed in vehicle- or cinacalcet HCl-only treated groups. Co-administration of cinacalcet HCl with calcitriol did not attenuate the calcitriol-mediated increase in CaxP product or calcitriol-mediated aortic calcification. Both calcitriol and cinacalcet HCl therapy significantly reduced serum PTH levels. Calcitriol significantly elevated serum calcium, serum phosphorous and CaxP product above pretreatment levels, or those seen with vehicle or cinacalcet HCl. Cinacalcet HCl (10 or 1 mg/kg) decreased serum ionized calcium and decreased calcitriol-induced hypercalcaemia. CONCLUSION: Cinacalcet HCl and calcitriol both effectively reduce PTH, albeit via different mechanisms, but unlike calcitriol, cinacalcet HCl did not produce hypercalcaemia, an increased CaxP product or vascular calcification.