Calcimimetics and calcilytics—fooling the calcium receptor

doi:10.1016/S0140-6736(05)66782-7

The Lancet

Volume 365, Issue 9478, 25 June–1 July 2005, Pages 2237-2239

https://doi.org/10.1016/S0140-6736(05)66782-7 Get rights and content

Summary

Context

Just a decade after the the calcium-sensing receptor (CaR) was identified, pharmacological manipulation of the CaR is about to enter routine practice. For hyperparathyroid states, calcimimetics, which increase activation of the CaR, have been licensed in Europe and the USA. Calcilytics, which decrease CaR function and increase secretion of parathyroid hormone (PTH), might allow the anabolic effects of PTH on bone to be harnessed for the prevention and treatment of osteoporosis.

Starting point

In a multicentre randomised double-blind placebo-controlled study, Munro Peacock and colleagues recently confirmed the efficacy of the oral calcimimetic cinacalcet for achieving long-term reductions in serum calcium and PTH concentrations in primary hyperparathyroidism (J Clin Endocrinol Metab 2005; 90: 135–41). The arrival of a non-surgical option for this common disorder is important.

What next?

Study in primary and uraemic secondary hyperparathyroidism will indicate whether the efficacy of calcimimetic agents extends into the longer term. The extracellular relation between the CaR and its ligands and the intracellular signalling cascades that modify PTH gene transcription and secretion need further study. Drugs acting on the CaR might treat other disorders of bone remodelling, including osteoporosis. CaR expression in tissues beyond those involved in mineral ion homoeostasis should remain an important focus of research.

Section snippets

Calcimimetic agents

Calcium is not a unique ligand for the CaR, although it is the only one with a convincing physiological role. Type I calcimimetics directly activate the CaR, and include calcium and other divalent and trivalent cations, spermine, aminogylcoside antibiotics, and some polyvalent aminoacids and peptides. Type II agents are not strictly agonists but positive allosteric modulators, increasing the receptor's sensitivity to ambient Ca²⁺ (or other type I agents) through binding within the transmembrane

Secondary hyperparathyroidism

In chronic kidney disease, reductions in serum Ca²⁺ and calcitriol, with accompanying increases in phosphorus, stimulate the synthesis and release of PTH. Early in the natural history, directly and through an increase in extracellular Ca²⁺, treatment with vitamin D sterols inhibits PTH synthesis and proliferation of parathyroid cells, although these suppressive effects can be undermined by concomitant hypocalcaemia and/or hyperphosphataemia. Later, the prolonged stimulation of parathyroid

Primary hyperparathyroidism

These days, primary hyperparathyroidism is more often associated with unexpected elevations of serum calcium than with the more overt manifestations of renal calculi, osteopenia, or disturbed neuromuscular function. The patient is often asymptomatic and parathyroidectomy might not be the appropriate recourse. Unfortunately, the alternative—prospective biochemical and radiological surveillance—is often accompanied by clinical unease about the pathological cost of leaving PTH hypersecretion

Calcilytics

Calcilytics decrease the sensitivity of the CaR to calcium, thereby increasing PTH secretion,²³ and will probably prove to be more than just pharmacological tools. PTH has powerful effects on bone remodelling. Sustained elevations of PTH, as in hyperparathyroid states, have a net catabolic effect on bone, favouring resorption. Short bursts are anabolic, favouring formation. This discrepancy has been exploited therapeutically, with intermittent bolus doses of synthetic PTH increasing bone mass

Conclusions

Manipulation of the CaR opens up a new therapeutic dimension in the metabolic bone diseases. Though much work remains outstanding, it is likely that the calcimimetics will provide the means to control serum PTH in hyperparathyroid states much more effectively than has previously been possible. The future use of calcilytics in disorders beyond primary and secondary hyperparathyroidism, including osteoporosis, is an enticing prospect.

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Pan-cancer analysis reveals the prognostic gene CASR suppresses tumor progression and epithelial–mesenchymal transition in renal clear cell carcinoma
2023, Cell Calcium
Calcium-sensing receptor (CASR), primarily found in the parathyroid gland and other tissues, plays a crucial role in sensing and regulating extracellular calcium, which was also aberrantly expressed in human tumors. Nevertheless, a comprehensive analysis of CASR in pan-cancer has yet to be conducted. To gain a better understanding of CASR in pan-cancer, data profiles on CASR cancers were collected from TCGA database. The expression level, clinical significance, prognostic value, and potential mechanisms of CASR in pan-cancer were analyzed via multiple public databases. The functional assays were conducted using human kidney renal clear cell carcinoma (KIRC) cell lines, clinical samples, and nude mice. Our research revealed that the abnormal expression of CASR was found in a variety of tumors. The expression and mutation of CASR were significantly associated with tumor prognosis and stage. Pathway analyses suggested that CASR was involved in the epithelial–mesenchymal transition (EMT) progress. Besides, CASR expression was correlated with immune inhibitory genes and immunotherapy in cancers. Particularly in KIRC, we established that CASR mRNA and protein levels were downregulated in clinical samples and cell lines. Moreover, a Cox regression analysis revealed that CASR was an independent prognostic factor in both TCGA-KIRC samples and clinical samples from our center. In vitro and in vivo experiments revealed that blocking CASR with lentivirus could suppress tumor growth and invasion, and EMT progress in KIRC cells. In summary, our study provides a comprehensive bioinformatic analysis of CASR in pan-cancer, offering deeper insights into its function and the EMT mechanism in KIRC, warranting further investigation.
Disorders of Mineral Metabolism: Normal Homeostasis
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and Print
Calcium and phosphate homeostasis is maintained by the interaction of parathyroid hormone (PTH), calcitriol—the primary bioactive metabolite of vitamin D, the phosphatonin—fibroblast growth factor-23 (FGF23), and the thyroid gland product—calcitonin—acting in a coordinated manner upon the intestinal absorption of these ions, the proximal renal tubular reabsorption of filtered calcium and its excretion of phosphate, the deposition of these analytes into bone by the osteoblast, and their reabsorption from this site by the osteoclast. Calcium is essential for intracellular signal transduction, nerve conduction, blood clotting, and the strength and structural integrity of bone hydroxyapatite. Phosphate, second to calcium in abundance, is present in DNA and RNA nucleotides, requisite for energy generation, and a component of cell membranes, signal transduction pathways, and the bone mineral—hydroxyapatite. Phosphate is absorbed by the intestinal duodenum and jejunum, filtered through the renal glomerulus, reabsorbed by the proximal renal tubule or excreted in urine, and deposited into bone linked to calcium as hydroxyapatite from which site it may be reabsorbed by PTH and calcitriol. Under usual circumstances, the serum concentrations of calcium and phosphate are reciprocally related. Intact PTH is an 84-amino-acids (AA) peptide that is released from the parathyroid glands in response to declining serum concentrations of Ca^2 + detected by the calcium sensing receptor expressed on the plasma membrane of the parathyroid gland chief cell whose message is transmitted through the seven transmembrane-heterotrimeric guanine nucleotide-binding PTH receptor that inhibits renal tubular reabsorption of filtered phosphate; increases synthesis of calcitriol, which enhances intestinal absorption of calcium; and activates osteoclastogenesis, thereby mobilizing calcium from bone . FGF23 inhibits renal tubular reabsorption of phosphate and decreases renal synthesis of calcitriol, thereby depressing intestinal absorption of calcium and phosphate; FGF23 increases the synthesis of water-soluble 1,24,25-trihydroxyvitamin D and thus its urinary excretion. Calcitonin, a 32 AA product of the parafollicular “C” cells of the thyroid gland, depresses serum calcium concentrations by inhibiting osteoclast function, thereby impairing its release from bone, and increasing its urinary excretion.
Impact of frequent apheresis blood donation on bone density: A prospective, longitudinal, randomized, controlled trial
2019, Bone Reports
Citation Excerpt :
There remains the possibility that high frequency apheresis affects women differently than men, particularly during the peri-menopausal period when changes in serum estrogen have been correlated with large declines in BMD, with supplemental estrogen improving bone-related health outcomes (Kiel et al., 1987; Weiss et al., 1980). The scarcity of higher frequency female apheresis donors at the blood center studied indicates that any exploration of the impact of high frequency apheresis on BMD among women would require a multi-center design Furthermore, the high prevalence of low BMD among women, especially that increases over the life course (Looker et al., 1995), indicates this would be an ideal group to evaluate the possible benefit of repeated alterations to PTH through apheresis (Bialkowski et al., 2016; Steddon and Cunningham, 2005) that resemble those of synthetic PTH treatments for osteopenia/osteoporosis with demonstrable improvement in BMD (Jehle et al., 2013). Any change in BMD that exceeds the LSC is a clinically meaningful finding.
Blood for transfusion is lifesaving and essential to many elements of modern medical practice. The global blood supply relies on volunteer blood donors. Apheresis is increasingly used to collect blood and requires anticoagulant to prevent extracorporeal coagulation. Citrate, the standard apheresis anticoagulant, chelates ionized calcium with consequent perturbations of serum calcium, parathyroid hormone, vitamin D, and markers of bone remodeling in donors. Cross-sectional studies of bone mineral density (BMD) among apheresis donors exhibit conflicting results.
The longitudinal, randomized, controlled ALTRUYST trial (NCT02655055) was undertaken to determine whether BMD declined following high frequency apheresis blood donation over 1 year. The study was powered at 80% to detect the primary outcome of a 3% decline in BMD. Subjects new to apheresis agreed to make ≥20 apheresis donations in a one-year period and were randomized to treatment (high frequency apheresis) or control (no apheresis). Dual-energy x-ray absorptiometry was performed before and after participation. Two-sided t-test and multivariable logistic regression were used to assess outcomes.
Mean lumbar spine BMD did not change during the study among control donors (−0.002 g/cm², 95%CI [−0.020, 0.016], p = 0.78), or among donors in the apheresis arm (mean change = 0.007 g/cm², 95%CI [−0.005, 0.018], p = 0.24). Mean total hip BMD did not change for control donors (mean change = 0.002 g/cm², 95%CI [−0.006, 0.009], p = 0.63) or apheresis donors (−0.004 g/cm², 95%CI [−0.10, 0.002], p = 0.16). Tests for differences in proportions of donors with change in BMD exceeding the least significant change at the lumbar spine in either a positive [8 apheresis (31%), 4 control (27%), p = 0.78] or negative direction [4 apheresis (15%), 5 control (33%)] were statistically non-significant (p = 0.18). Proportional increases [0 apheresis (0%), 1 control (7%), p = 0.18] and decreases [3 apheresis (12%), 1 control (14%)] were also not significantly different at the total hip (p = 0.61).
ALTRUYST is the first longitudinal trial to demonstrate that apheresis blood collection guidelines in the United States adequately protect the skeletal health of male volunteer blood donors.
Marquette University and the BloodCenter Research Foundation.
The calcilytics Calhex-231 and NPS 2143 and the calcimimetic Calindol reduce vascular reactivity via inhibition of voltage-gated Ca<sup>2+</sup>channels
2016, European Journal of Pharmacology
Citation Excerpt :
As such, Cinacalcet (Mimpara®), the only allosteric modulator of Gprotein coupled receptors currently approved for clinical use, is used to treat uraemic secondary hypercalcaemia, and hyperparathyroidism, associated with parathyroid malignancy (Hebert, 2006; Jensen and Bräuner-Osborne, 2007; Steddon and Cunningham, 2005). Conversely, negative CaSR modulators such as NPS 2143 and Calhex-231, termed calcilytics, decrease stimulation of CaSRs to increase PTH release (Mancilla and De Luca, 1998; Nemeth et al., 2001; Petrel et al., 2003; Steddon and Cunningham, 2005). Calcilytics have been proposed to treat patients with gain-of-function CaSR-mutations, and osteoporosis as increases in plasma PTH levels may have anabolic effects on trabecular and compact bone (Fitzpatrick et al., 2011; Han and Wan, 2012).
The present study investigates the effect of commonly used negative and positive allosteric modulators of the calcium-sensing receptor (CaSR) on vascular reactivity. In wire myography studies, increasing [Ca²⁺]_o from 1 mM to 6 mM induced concentration-dependent relaxations of methoxamine-induced pre-contracted rabbit mesenteric arteries, with 6 mM [Ca²⁺]_o producing almost complete relaxation. [Ca²⁺]_o-induced relaxations were attenuated in the presence of the calcilytics Calhex-231 and NPS 2143, and abolished by the removal of the endothelium. In addition to their calcilytic effects, Calhex-231 and NPS 2143 also produced concentration-dependent inhibitions of methoxamine- or KCl-induced precontracted tone, which were unaffected by removal of the endothelium and unopposed in the presence of the calcimimetic Calindol. In vessels with depleted Ca²⁺ stores, contractions mediated by Ca²⁺ influx via voltage-gated Ca²⁺ channels (VGCCs) were inhibited by Calhex231. In freshly isolated single rabbit mesenteric artery smooth muscle cells, Calhex-231 and NPS 2143 inhibited whole-cell VGCC currents. Application of Calindol also inhibited methoxamine- and KCl-induced pre-contracted tone, and inhibited whole-cell VGCC currents. In conclusion, in addition to their CaSR-mediated actions in the vasculature, Calhex-231, NPS 2143 and Calindol reduce vascular contractility via direct inhibition of VGCCs.
Fragility fractures and osteoporosis in CKD: Pathophysiology and diagnostic methods
2014, American Journal of Kidney Diseases
Both chronic kidney disease (CKD) and osteoporosis are major public health problems associated with an aging population. Osteoporosis is characterized by reduced bone mineral density, while CKD results in qualitative changes in bone structure; both conditions increase the predisposition to fragility fractures. There is a significant coprevalence of osteoporotic fractures and CKD, particularly in the elderly population. Not only is the risk of fracture higher in the CKD population, but clinical outcomes are significantly worse, with substantial health care costs. Management of osteoporosis in the CKD population is particularly complex given the impact of renal osteodystrophy on bone quality and the limited safety and hard outcome data for current therapy in patients with severe CKD or on dialysis therapy. In this review, we discuss the pathophysiology of osteoporosis, the impact of CKD on bone strength, and the role of novel imaging techniques and biomarkers in predicting underlying renal osteodystrophy on bone histomorphometry in the context of CKD.
Disorders of calcium and phosphorus homeostasis in the newborn and infant
2014, Pediatric Endocrinology: Fourth Edition

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Rapid ReviewCalcimimetics and calcilytics—fooling the calcium receptor

Summary

Context

Starting point

What next?

Section snippets

Calcimimetic agents

Secondary hyperparathyroidism

Primary hyperparathyroidism

Calcilytics

Conclusions

Am J Kidney Dis

Am J Kidney Dis

Extracellular calcium sensing and signalling

Nat Rev Mol Cell Biol

Extracellular calcium sensing and extracellular calcium signaling

Physiol Rev

Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism

Cell

Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations of the Ca(2+)-sensing receptor

J Clin Endocrinol Metab

Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism

J Clin Invest

Evidence for distinct cation and calcimimetic compound (NPS 568) recognition domains in the transmembrane regions of the human Ca2+ receptor

J Biol Chem

Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl

J Pharmacol Exp Ther

Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients

J Am Soc Nephrol

Cardiac valve calcification in haemodialysis patients: role of calcium-phosphate metabolism

Nephrol Dial Transplant

Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis

N Engl J Med

Rapid Review
Calcimimetics and calcilytics—fooling the calcium receptor