Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism

Denver Nephrologists, Denver, CO 80230, USA.
Nephrology Dialysis Transplantation (Impact Factor: 3.58). 07/2008; 23(7):2311-8. DOI: 10.1093/ndt/gfn026
Source: PubMed


Adequate control of all four KDOQI biochemical targets for chronic kidney disease, bone and mineral disorder (CKD-MBD), which include parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and Ca x P, remains difficult and is accomplished in <6% of patients receiving haemodialysis. The objective of the current study was to determine whether treatment with cinacalcet combined with low doses of vitamin D sterols improves control of both PTH and Ca x P among haemodialysis patients with secondary hyperparathyroidism (sHPT).
This multicentre, open-label study enrolled haemodialysis subjects (N = 444) with moderate to severe sHPT (mean serum biPTH > 160-430 pg/mL) (approximately iPTH 300-800 pg/mL or ng/L). Cinacalcet was titrated sequentially (30-180 mg/day) during an 8-week dose-titration phase to achieve biPTH <or=160 pg/mL (approximately iPTH 300 pg/mL or ng/L) and efficacy was assessed over 8 weeks. At week 2 of the study, subjects receiving vitamin D sterols had doses reduced to the equivalent of 2 mcg of paricalcitol three times a week or 6 mcg/week. Among the efficacy endpoints were the proportion of subjects with mean biPTH <or=160 pg/mL (approximately iPTH 300 pg/mL or ng/L), with mean Ca x P <or=55 mg(2)/dL(2) (4.4 mmol(2)/L(2)) and with both simultaneously during the assessment phase.
The majority of subjects (n = 375) reached the assessment phase of the study and were included in efficacy analyses; 39 subjects withdrew due to adverse events. Sixty-two percent of subjects achieved the biPTH target, 83% achieved the Ca x P target and 54% reached both targets. Treatment reduced biPTH by 35% (P < 0.0001), calcium by 11% (P < 0.0001), phosphorus by 7% (P < 0.0001) and Ca x P by 17% (P < 0.0001). The proportion of subjects with values for biPTH, for Ca x P and for both biPTH and Ca x P within the target range during the assessment phase did not differ between subjects who received cinacalcet together with vitamin D sterols, and those who received cinacalcet alone.
Among subjects with moderate to severe sHPT undergoing haemodialysis, combined therapy with cinacalcet and low doses of vitamin D sterols improved achievement of the biochemical targets for CKD-MBD recommended by the KDOQI guidelines.

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    • "Nevertheless, nodular hyperplasia, typically associated with more advanced 2HPT, is less responsive to conservative treatment, presumably because of the reduced expression of calcium-sensing receptors (CaSR) and vitamin D receptors (VDR). Although cinacalcet hydrochloride effectively reduces intact parathyroid hormone (iPTH) levels, and is also effective in patients refractory to vitamin D therapy, the effect of cinacalcet hydrochloride in marked glandular hyperplasia is still the subject of active research [3]. We report the case of a patient with 2HPT, documenting that cinacalcet hydrochloride is able to reduce gland size, but is not able in all cases to reduce PTH secretion. "
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    ABSTRACT: Introduction In the treatment of secondary hyperparathyroidism of chronic kidney disease, calcimimetics - allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia and significantly reduce circulating parathyroid hormone levels. They have a major impact on the management of secondary hyperparathyroidism. Case presentation We present the clinical case of a 41-year-old Caucasian man undergoing chronic hemodialysis, who had a parathyroidectomy to treat severe secondary hyperparathyroidism resistant to cinacalcet treatment. Preoperatively, 24 months after high-dose cinacalcet hydrochloride, we observed a persistently elevated intact parathyroid hormone serum level, and detected clear parathyroid gland hyperplasia regression on ultrasound. We performed a three-gland parathyroidectomy, which was assumed to be total, associated with a hemithyroidectomy. Our patient then entered a hypoparathyroid state. A histopathological examination showed that the removed parathyroid glands were of small size, with a total weight of 1g, associated with a multifocal small papillary thyroid cancer. Conclusion In the management of secondary hyperparathyroidism, cinacalcet hydrochloride effectively reduces total parathyroid gland hyperplasia. However, a persisting elevated intact parathyroid hormone serum level may be observed, demonstrating that reduced parathyroid hyperplastic tissue may still be associated with severe secondary hyperparathyroidism. Even if calcimimetics are very effective in secondary hyperparathyroidism treatment, further studies are necessary for a better understanding of their actions.
    Journal of Medical Case Reports 12/2012; 6(1):417. DOI:10.1186/1752-1947-6-417
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    • "These findings are consistent with published data, which demonstrate a reduction in plasma iPTH levels as well as serum Ca and phosphorus levels for adult patients on hemodialysis following the administration of cinacalcet [5, 8, 19, 20]. Furthermore, results from small observational studies suggest that the administration of cinacalcet when PTH levels are between 300–500 pg/mL or 501–800 pg/mL decreases PTH to <300 pg/mL within 16–28 weeks of therapy [11] (Amgen; data on file). Achieving therapeutic target ranges is important in decreasing the risk of other bone and mineral comorbidities associated with sHPT that when left untreated can lead to increased rates of hospitalization. "
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    ABSTRACT: There is limited knowledge of the effectiveness and safety profile of cinacalcet in pediatric patients with secondary hyperparathyroidism (sHPT) treated with dialysis. This was an open-label, single-dose study conducted on 12 pediatric subjects with chronic kidney disease treated with dialysis. Subjects were stratified by four age cohorts and given a single 15-mg oral dose of cinacalcet. Multiple blood samples were collected up to 72 h post-dose for the assessment of serum calcium (Ca), serum intact parathyroid hormone (iPTH), and plasma cinacalcet concentrations. Overall, cinacalcet was well tolerated with no serious adverse events. Mean (standard deviation) percentage change in serum Ca over the first 12 h post-dose was -2.93 % (5.70 %) with a nadir of -4.34 % (6.04 %) at 8 h; Ca values returned to baseline by 48 h post-dose. Mean percentage change in iPTH over the first 12 h post-dose was 57.94 % (71.82 %) with a nadir of -35.65 % (55.82 %) at 2 h. There was an inverse relationship between peak serum Ca concentration and body surface area (BSA) (r (2) = 0.41), although no relationship was found between area under the curve and age or BSA. These data support future analysis to determine the therapeutic starting dose of cinacalcet for pediatric patients with sHPT on dialysis.
    Pediatric Nephrology 05/2012; 27(10):1953-9. DOI:10.1007/s00467-012-2186-9 · 2.86 Impact Factor
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    • "Results of a large observational study of haemodialysis subjects who responded to cinacalcet treatment showed that treatment with cinacalcet was associated with significant reductions in all-cause and cardiovascular mortality rates [23]. The results of two recent clinical studies further suggest that combination therapy with cinacalcet and low-dose vitamin D may provide effective control of iPTH levels in patients with SHPT on dialysis while minimizing the risk of hypercalcaemia [24, 25]. "
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    ABSTRACT: Optimal treatment for secondary hyperparathyroidism (SHPT) has not been defined. The IMPACT SHPT ( identifier: NCT00977080) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone (iPTH) levels in patients with SHPT on haemodialysis. In this 28-week, multicentre, open-label Phase 4 study, participants were randomly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. Randomization and analyses were stratified by mode of paricalcitol administration [intravenous (IV) or oral]. The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150-300 pg/mL during Weeks 21-28. Of 272 subjects randomized, 268 received one or more dose of study drug; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21-28 were included in the primary analysis. In the IV stratum, 57.7% of subjects in the paricalcitol versus 32.7% in the cinacalcet group (P = 0.016) achieved the primary end point. In the oral stratum, the corresponding proportions of subjects were 54.4% for paricalcitol and 43.4% for cinacalcet (P = 0.260). Cochran-Mantel-Haenszel analysis, controlling for stratum, revealed overall superiority of paricalcitol (56.0%) over cinacalcet (38.2%; P = 0.010) in achieving iPTH 150-300 pg/mL during Weeks 21-28. Hypercalcaemia occurred in 4 (7.7%) and 0 (0%) of paricalcitol-treated subjects in the IV and oral strata, respectively. Hypocalcaemia occurred in 46.9% and 54.7% of cinacalcet-treated subjects in the IV and oral strata, respectively. Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH, with low incidence of hypercalcaemia.
    Nephrology Dialysis Transplantation 03/2012; 27(8):3270-8. DOI:10.1093/ndt/gfs018 · 3.58 Impact Factor
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