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      Relationship between Reductions in Parathyroid Hormone and Serum Phosphorus during the Management of Secondary Hyperparathyroidism with Calcimimetics in Hemodialysis Patients

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          Abstract

          Background/Aim: The relationship between changes in plasma parathyroid hormone (PTH) and serum phosphorus levels during treatment with cinacalcet was evaluated in hemodialysis patients with secondary hyperparathyroidism (SHPT) receiving stable doses of vitamin D. Methods: Post hoc analysis of the relationship between PTH and phosphorus levels before and during treatment with cinacalcet in adult subjects on hemodialysis with inadequately controlled SHPT (PTH ≥300 pg/ml) included: (1) correlation of absolute changes from baseline in mean PTH and phosphorus at week 2 and during weeks 13–26; (2) phosphorus levels at baseline and absolute and percent change of phosphorus after cinacalcet administration stratified by baseline PTH level; (3) two regression analyses models were fitted that (a) adjusted for baseline lab values to quantify the relationship between changes in PTH and changes in phosphorus and (b) a multivariate regression analysis that adjusted for clinically relevant subject characteristics. Results: Serum phosphorus concentrations at baseline were incrementally greater by PTH stratum from lowest to highest. Reductions in PTH from baseline after 13–26 weeks of treatment with cinacalcet were associated with corresponding reductions in serum phosphorus. Two weeks after starting treatment with cinacalcet when doses of vitamin D analogues, phosphate binders, and cinacalcet remained unchanged, there was a statistically significant association (p < 0.0001) between the decreases from baseline in PTH and phosphorus. Conclusions: Reductions in PTH during cinacalcet therapy are associated with decreases in serum phosphorus that cannot be explained by changes in vitamin D or phosphate binder therapy, and may reflect diminished phosphorus release from bone.

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          Most cited references18

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          Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

          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. Copyright 2004 Massachusetts Medical Society
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            Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

            Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. Methods. The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. Results. Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62–2.73; 2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19–2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04–1.37) and high calcium (HR = 1.74, 95% CI 1.30–2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern ( 1.78 mmol/L, HR = 1.32, 95% CI 1.13–1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. Conclusion . Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.
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              Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism.

              Management of secondary hyperparathyroidism has included the use of active vitamin D or vitamin D analogs for the suppression of parathyroid hormone (PTH) secretion. Although, these agents are effective, therapy is frequently limited by hypercalcemia, hyperphosphatemia, and/or elevations in the calcium-phosphorus (Ca x P) product. In clinical studies, paricalcitol was shown to be effective at reducing PTH concentrations without causing significant hypercalcemia or hyperphosphatemia as compared to placebo. A comparative study was undertaken in order to determine whether paricalcitol provides a therapeutic advantage to calcitriol. A double-blind, randomized, multicenter study comparing the safety and effectiveness of intravenous paricalcitol and calcitriol in suppressing PTH concentrations in hemodialysis patients was performed. A total of 263 randomized patients were enrolled at domestic and international sites. Following the baseline period, patients with serum Ca x P or =300 pg/mL were randomly assigned to receive either paricalcitol or calcitriol in a dose-escalating fashion for up to 32 weeks. Dose adjustments were based on laboratory results for PTH, calcium, and Ca x P. The primary end point was the greater than 50% reduction in baseline PTH. Secondary end points were the occurrence of hypercalcemia and elevated Ca x P product. Paricalcitol-treated patients achieved a > or =50% reduction from baseline PTH significantly faster than did the calcitriol-treated patients (P = 0.025) and achieved a mean reduction of PTH into a desired therapeutic range (100 to 300 pg/mL) at approximately week 18, whereas the calcitriol-treated patients, as a group, were unable to achieve this range. Moreover, paricalcitol-treated patients had significantly fewer sustained episodes of hypercalcemia and/or increased Ca x P product than calcitriol patients (P = 0.008). Paricalcitol treatment reduced PTH concentrations more rapidly with fewer sustained episodes of hypercalcemia and increased Ca x P product than calcitriol therapy.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2012
                February 2013
                29 November 2012
                : 121
                : 3-4
                : c124-c130
                Affiliations
                aAmgen Inc., Thousand Oaks, Calif., and bThe University of Tennessee Health Sciences Center, Memphis, Tenn., USA
                Author notes
                *Kerry Cooper, MD, Amgen Inc., One Amgen Center Dr., M/S 38-3-C, Thousand Oaks, CA 91320-1799 (USA), E-Mail kcooper@amgen.com
                Article
                345164 Nephron Clin Pract 2012;121:c124–c130
                10.1159/000345164
                23208191
                4c141efe-3c38-43d7-837e-4a46ca861082
                © 2012 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 11 July 2012
                : 15 October 2012
                Page count
                Figures: 4, Pages: 7
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Parathyroid hormone,Cinacalcet,Hyperphosphatemia,Secondary hyperparathyroidism

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