A New Paradigm for the Treatment of Secondary Hyperparathyroidism

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Abstract

The global rise in chronic kidney disease makes secondary hyperparathyroidism (SHPT) a growing medical concern. Conventional therapies for treating SHPT are limited and include calcium-based and calcium-free phosphate binders for reducing serum phosphorus and vitamin D or its analogues for simultaneous stimulation of calcium absorption and suppression of parathyroid hormone (PTH) gene expression. Control of SHPT using these therapies has typically been poor. Recent studies have demonstrated that use of calcimimetics that reduce PTH secretion by increasing the sensitivity of the parathyroid gland calcium-sensing receptor to circulating calcium allow improved control of serum PTH, calcium, phosphorus and calcium–phosphorus product. This review describes experimental data and the clinical rationale supporting novel strategies for the integration of calcimimetics with conventional therapies to improve control of SHPT.

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Most cited references 47

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Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

E M Brown, G Gamba, D. Riccardi … (1993)

Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.

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Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

Geoffrey A Block, Kevin J Martin, Angel de Francisco … (2004)

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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Arterial stiffening and vascular calcifications in end-stage renal disease.

A P Guerin, G. M. London, S. Marchais … (2000)

Epidemiological studies have identified aortic stiffness as an independent predictor of cardiovascular mortality in end-stage renal disease (ESRD) patients. In these patients, aortic pulse wave velocity (PWV) was associated with mediacalcosis, but the influence of arterial calcifications on the viscoelastic properties of large arteries was not well characterized. The purpose of the present study was to analyse the influence of arterial calcifications on arterial stiffness in stable haemodialysed patients. We studied 120 stable ESRD patients on haemodialysis. All patients underwent B-mode ultrasonography of common carotid artery (CCA), aorta, and femoral arteries to determine CCA distensibility, the elastic incremental modulus (Einc), and the presence of vascular calcifications. All patients underwent measurement of aortic PWV and echocardiogram. The presence of calcifications was analysed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. Our observations indicate that arterial and aortic stiffness is significantly influenced by the presence and extent of arterial calcifications. The extent of arterial calcifications is in part responsible for increased left ventricular afterload, and is inversely correlated with stroke volume. The influence of calcifications is independent of the role of ageing and blood pressure. Arterial calcifications density increases with age, duration of haemodialysis, the fibrinogen level, and the prescribed dose of calcium-based phosphate binders. The results of this study showed that the presence of vascular calcifications in ESRD patients was associated with increased stiffness of large capacity, elastic-type arteries, like the aorta and CCA. The extent of arterial calcifications increased with the use of calcium-based phosphate-binders.

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Author and article information

Journal

Journal ID (nlm-ta): NDT Plus

Journal ID (iso-abbrev): NDT Plus

Journal ID (hwp): ndtplus

Journal ID (publisher-id): ckj

Title: NDT Plus

Publisher: Oxford University Press

ISSN (Print): 1753-0784

ISSN (Electronic): 1753-0792

Publication date (Print): January 2008

Publication date PMC-release: January 2008

Volume: 1

Issue: Suppl 1

Pages: i24-i28

Affiliations

[1 ]Servicio de Nefrología, Hospital Universitario Valdecilla , Santander, Spain

[2 ]Eurodial, Euromedic, Dialysis Unit, Leiria, Portugal

Author notes

Angel L. M. de Francisco, Servicio de Nefrología, Hospital Universitario Valdecilla, Avda Valdecilla s/n, E-39008 Santander, Spain. E-mail: martinal@ 123456medi.unican.es

Article

Publisher ID: sfm041

DOI: 10.1093/ndtplus/sfm041

PMC ID: 4421151

PubMed ID: 25983953

SO-VID: 98fb31a5-6375-43d1-8e44-90abb795d90d

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The online version of this article has been published under an open access model http://creativecommons.org/licenses/by-nc/2.0/uk/. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

A New Paradigm for the Treatment of Secondary Hyperparathyroidism

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Karger: Nephrology

Most cited references 47

Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

Arterial stiffening and vascular calcifications in end-stage renal disease.

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