Chapter

Calcimimetics and calcilytics in the treatment of chronic kidney disease-mineral and bone disorder

Edward F. Nemeth

in The Spectrum of Mineral and Bone Disorders in Chronic Kidney Disease

Second edition

Published on behalf of Oxford University Press

Published in print June 2010 | ISBN: 9780199559176
Published online November 2012 | e-ISBN: 9780191753350 | DOI: http://dx.doi.org/10.1093/med/9780199559176.003.026

Series: Oxford Clinical Nephrology Series

Calcimimetics and calcilytics in the treatment of chronic kidney disease-mineral and bone disorder

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The introduction of calcimimetics into clinical practice has improved the management of 2HPT in patients receiving dialysis. The results obtained so far show that treatment with cinacalcet in combination with phosphate binders and low doses of vitamin D sterols can achieve KDOQI guidelines to an extent not possible with traditional therapy alone and in patients where these therapies fail to lower PTH levels. The unique feature of cinacalcet in comparison to traditional therapies is the inhibition of hormone secretion that results in a rapid lowering of plasma PTH levels. These rapid decreases in PTH levels occur independently of those of phosphate and 1,25-(OH)2vitamin D3 and reflect the dominant role of the calcium receptor in parathyroid physiology. Targeting this key receptor enables calcimimetics to inhibit several distinct functions including the synthesis and secretion of PTH and parathyroid cell proliferation. It has been suggested that in patients on dialysis, calcimimetics should be a first line therapy; levels of phosphate and calcium can then be managed with phosphate binders and active vitamin D sterols.

Although optimal treatment with cinacalcet and traditional therapies clearly improves the biochemical abnormalities of 2HPT in dialysis patients, it is still uncertain if such effects will translate into clinically meaningful outcomes. The clinical usefulness of cinacalcet in managing 2HPT in patients not on dialysis is likewise uncertain. In these patients the question is not efficacy: cinacalcet is quite effective in lowering plasma levels of PTH in predialysis patients, and it appears to be generally effective in lowering PTH and calcium in renal transplant patients with persistent HPT. Rather, the concern is safety, specifically the mild, but sustained increases in levels of serum phosphate and urinary calcium. As mentioned earlier, these are the expected outcomes of lowering plasma levels of PTH in patients with some degree of kidney function. Additionally, actions of cinacalcet on renal calcium receptors might augment the effect of lowered plasma PTH levels. Fortunately, the pharmacology of the calcium receptor and G protein-coupled receptors in general, allows signaling-specific, activating ligands. It is quite possible to imagine calcimimetic chemotypes that inhibit parathyroid cell proliferation yet have minimal effects on synthesis and/or secretion of PTH and totally lack actions at renal calcium receptors. Therefore, there is reason to suppose that calcimimetics might achieve therapeutic benefits in patients with preserved kidney function. Continued research with cinacalcet in the clinic and with novel calcimimetic chemotypes in animal models of 2HPT is warranted.

Considerably more problematic is the use of calcilytics in low turnover forms of renal osteodystrophy. While the success of exogenously administered PTH peptides in treating osteoporosis provides a solid justification for studying calcilytics in the same indication, such vanguard data are not yet available for CKD patients with low turnover renal osteodystrophy. There are also a number of safety issues inherent in the use of a calcilytic compound that would not apply to exogenously administered PTH peptides. These include the possibility of triggering parathyroid cell proliferation and actions on calcium receptors in other tissues, particularly the skeleton and vascular smooth muscle. Nonetheless, both long and short-acting calcilytics are very effective in stimulating bone turnover and they could prove useful in treating ABD in patients with relative hypoparathyroidism.

Chapter.  8947 words. 

Subjects: Rheumatology ; Nephrology

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