Elsevier

Biochemical Pharmacology

Volume 80, Issue 3, 1 August 2010, Pages 297-307
Biochemical Pharmacology

Commentary
Clinical utility of calcimimetics targeting the extracellular calcium-sensing receptor (CaSR)

https://doi.org/10.1016/j.bcp.2010.04.002Get rights and content

Abstract

Calcimimetics, which activate the extracellular calcium (Cao2+)-sensing receptor in the parathyroid and other tissues participating in Cao2+ homeostasis, were the first described allosteric activators of a G-protein-coupled receptor. Cinacalcet, the only calcimimetic currently approved for human use, is used clinically for treating secondary hyperparathyroidism (e.g., overactivity of parathyroid glands) in patients being dialyzed for chronic kidney disease. By sensitizing the parathyroids to Cao2+, cinacalcet lowers the circulating parathyroid hormone (PTH) level. It also reduces serum calcium and phosphate, changes increasing the percentage of patients achieving the guidelines recommended by the National Kidney Foundation (NKF) for these minerals. Studies are underway addressing whether better adherence to these guidelines in patients receiving cinacalcet reduces cardiovascular disease and related mortality, which are both common is the dialysis population. The second approved use of cinacalcet is for treating hypercalcemia in patients with inoperable parathyroid carcinoma. In this setting, it provides the first medical therapy chronically lowering serum calcium concentration in this condition, albeit not to normal in most patients. Its effect on the long-term prognosis of these patients, if any, is presently unclear. “Off-label” administration of cinacalcet [i.e., not yet approved by the US Food and Drug Administration (FDA)] effectively lowers serum calcium and/or PTH in various other forms of hyperparathyroidism and increases serum phosphate in renal phosphate-wasting syndromes by reducing PTH-induced phosphaturia. In the future, the drug could conceivably be utilized to modulate the activity of the CaSR in other tissues (i.e., kidney, colon) in therapeutically desirable ways.

Introduction

Calcimimetics are allosteric activators of the extracellular calcium (Cao2+)-sensing receptor (CaSR). Their development has provided an important advance in the treatment of disorders of mineral metabolism by sensitizing the receptor to its physiological agonist, the extracellular calcium ion (Cao2+) [1]. This mode of action makes it possible to suppress the secretion of parathyroid hormone (PTH) from the parathyroid glands in patients with overactivity of these glands. The calcimimetic, cinacalcet® (or sensipar®), initially received approval from the US Food and Drug Administration (FDA) solely for treating two conditions: severe hyperparathyroidism in patients being dialyzed for chronic kidney disease (so-called stage 5 CKD) and hypercalcemia in patients with parathyroid cancer. It is the only calcimimetic currently approved for use in humans. Subsequently, cinacalcet has been utilized in a variety of clinical settings with a primary goal of reducing PTH secretion in order to decrease the serum calcium concentration and/or elevate the serum phosphate concentration. This review will cover this rapidly developing field, with the following aims: (1) to describe the properties and functions of the CaSR and its roles in maintaining Cao2+ homeostasis; (2) to briefly outline the pharmacology of the calcimimetics; (3) to describe both the approved and the “off-label” (i.e., not yet approved by the FDA for human use) applications of the drug to date, and finally (4) to comment on future prospects for this class of drugs. I will cite representative and important articles but not attempt to be exhaustive. As there are numerous reviews of the use of cinacalcet in patients with stage 5 CKD, this review will summarize this area succinctly. The primary focus will be on other potential applications of cinacalcet in order to highlight the therapeutic versatility inherent in being able to pharmacologically manipulate PTH secretion and, potentially, the functions of other tissues expressing the CaSR.

Section snippets

What is the CaSR?

To maintain near constancy of the blood Ca2+ level, a mechanism must exist that senses small changes in Cao2+ and responds appropriately so as to normalize Cao2+[2]. The CaSR serves this function. It is a G-protein-coupled receptor (GPCR) that has Cao2+ as its principal physiological ligand. The cloning of the CaSR from bovine parathyroid was reported in 1993 [3]. Shortly thereafter, the receptor was cloned from human parathyroid [4] and, subsequently, from parathyroid and/or other tissues in a

Role of CaSR in Cao2+ homeostasis

The Cao2+ homeostatic system has three key components: (1) the cells, tissues and organs transporting Ca2+ out of or into the ECF [kidney, bone and intestine (and, in some stages of the life cycle, placenta and breast)]; (2) hormones regulating these fluxes [parathyroid hormone (PTH), calcitonin (CT), and 1,25(OH)2D3]; and (3) Cao2+-sensors (principally the CaSR) controlling the secretion/production of those hormones or the Ca2+ fluxes themselves [2], [12]. Of these three Cao2+-regulating

Development of calcimimetics

The discovery of calcimimetics occurred as a result of screening organic compounds for their ability to mobilize intracellular calcium stores in bovine parathyroid cells by potentiating the action of Cao2+ on the CaSR [1]. Mobilization of intracellular calcium owing to activation of phospholipase C is a characteristic “signature” of activation of the CaSR. Inorganic polyvalent cations that are agonists of the CaSR, such as Ca2+, Mg2+, La3+ or Gd3+, activate the receptor without the need for any

Studies in experimental animals

It remains to be proven that the actions of calcimimetics on rats with experimentally induced uremia are generally applicable to humans. Nevertheless, these animal studies have provided proof-of-principle that calcimimetics, as expected, sensitize the CaSR in the parathyroid to Cao2+ in vivo, thereby producing the expected changes in parathyroid function. In addition, the available data provide benchmarks for the subsequent investigation of potentially beneficial effects that the drug might

Future prospects

In addition to the conditions for which cinacalcet is approved in the U.S. and Europe, the results reviewed here indicate that there are additional disorders for which the drug could be useful therapeutically. They have in common overactivity of the parathyroid glands or the desirability of lowering PTH in order to mitigate hypophosphatemia, i.e., in XLH and TIO. The next frontier of calcimimetic therapy will likely be their application to CaSR-expressing tissues other than the parathyroid

Disclosure

Edward M. Brown has a financial interest in the calcimimetic, cinacalcet® (sensipar®).

Acknowledgment

Edward M. Brown, M.D. receives grant support from the US National Institutes of Health (DK078331).

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