CommentaryClinical utility of calcimimetics targeting the extracellular calcium-sensing receptor (CaSR)
Graphical abstract
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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2020, Life SciencesCitation Excerpt :Among the many drugs been exploited for kidney injury treatment, calcimimetics have been studied for decades and proven to be efficient in some clinical investigations [15,16]. Calcimimetics [15,16] are allosteric activators of the calcium-sensing receptor (CaSR). The CaSR regulates the aforementioned processes affected by toxicants and is significantly involved in a variety of physiological cellular processes [17–19].
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2018, Best Practice and Research: Clinical Endocrinology and MetabolismCitation Excerpt :Furthermore, the role of CaSR in the skeleton is likewise still under investigation, as targeting the CaSR in that tissue and in specific bone cell populations may have therapeutic potential [65]. Finally, in addition to the utility of using CaSR-directed therapies in the treatment of PHPT [66–70], uremic secondary HPT [71–73] and parathyroid carcinoma [74], treatment with calcimimetics has been reported to be effective in patients with FHH [59–64] and NSHPT [75] with varying degrees of success. Future controlled trials of these medications in the context of specific genetic mutations would be difficult to conduct due to the rarity of FHH and NSHPT, but small case series and reports on long-term outcomes would be beneficial to those with clinically significant symptomatic FHH.
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