The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and ß-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.

Calcium Oxalate Induces Renal Injury through Calcium-Sensing Receptor.

Objective. To investigate whether calcium-sensing receptor (CaSR) plays a role in calcium-oxalate-induced renal injury. Materials and Methods. HK-2 cells and rats were treated with calcium oxalate (CaOx) crystals with or without pretreatment with the CaSR-specific agonist gadolinium chloride (GdCl3) or the CaSR-specific antagonist NPS2390. Changes in oxidative stress (OS) in HK-2 cells and rat kidneys were assessed. In addition, CaSR, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 expression was determined. Further, crystal adhesion assay was performed in vitro, and the serum urea and creatinine levels and crystal deposition in the kidneys were also examined. Results. CaOx increased CaSR, ERK, JNK, and p38 protein expression and OS in vitro and in vivo. These deleterious changes were further enhanced upon pretreatment with the CaSR agonist GdCl3 but were attenuated by the specific CaSR inhibitor NPS2390 compared with CaOx treatment alone. Pretreatment with GdCl3 further increased in vitro and in vivo crystal adhesion and renal hypofunction. In contrast, pretreatment with NPS2390 decreased in vitro and in vivo crystal adhesion and renal hypofunction. Conclusions. CaOx-induced renal injury is related to CaSR-mediated OS and increased mitogen-activated protein kinase (MAPK) signaling, which subsequently leads to CaOx crystal adhesion.

Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens.

The calcium-sensing receptor is a G protein-coupled receptor that exerts cell-type specific functions in numerous tissues and some cancers. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. We have now assessed cinacalcet, an allosteric activator of the CaSR approved for clinical use, as targeted therapy for this developmental tumor using neuroblastoma cell lines and patient-derived xenografts (PDX) with different MYCN and TP53 status. In vitro, acute exposure to cinacalcet induced endoplasmic reticulum stress coupled to apoptosis via ATF4-CHOP-TRB3 in CaSR-positive, MYCN-amplified cells. Both phenotypes were partially abrogated by phospholipase C inhibitor U73122. Prolonged in vitro treatment also promoted dose- and time-dependent apoptosis in CaSR-positive, MYCN-amplified cells and, irrespective of MYCN status, differentiation in surviving cells. Cinacalcet significantly inhibited tumor growth in MYCN-amplified xenografts and reduced that of MYCN-non amplified PDX. Morphology assessment showed fibrosis in MYCN-amplified xenografts exposed to the drug. Microarrays analyses revealed up-regulation of cancer-testis antigens (CTAs) in cinacalcet-treated MYCN-amplified tumors. These were predominantly CTAs encoded by genes mapping on chromosome X, which are the most immunogenic. Other modulated genes upon prolonged exposure to cinacalcet were involved in differentiation, cell cycle exit, microenvironment remodeling and calcium signaling pathways. CTAs were up-regulated in PDX and in vitro models as well. Moreover, progressive increase of CaSR expression upon cinacalcet treatment was seen both in vitro and in vivo. In summary, cinacalcet reduces neuroblastoma tumor growth and up-regulates CTAs. This effect represents a therapeutic opportunity and provides surrogate circulating markers of neuroblastoma response to this treatment.

Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor.

The calcium-sensing receptor (CaSR) is a G-coupled protein expressed in renal juxtaglomerular (JG) cells. Its activation stimulates calcium-mediated decreases in cAMP content and inhibits renin release. The postreceptor pathway for the CaSR in JG cells is unknown. In parathyroids, CaSR acts through G(q) and/or G(i). Activation of G(q) stimulates phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP(3)), releasing calcium from intracellular stores. G(i) stimulation inhibits cAMP formation. In afferent arterioles, the ryanodine receptor (RyR) enhances release of stored calcium. We hypothesized JG cell CaSR activation inhibits renin via the PLC/IP(3) and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release. Renin release from primary cultures of isolated mouse JG cells (n = 10) was measured. The CaSR agonist cinacalcet decreased renin release 56 ± 7% of control (P < 0.001), while the PLC inhibitor U73122 reversed cinacalcet inhibition of renin (104 ± 11% of control). The IP(3) inhibitor 2-APB also reversed inhibition of renin from 56 ± 6 to 104 ± 11% of control (P < 0.001). JG cells were positively labeled for RyR, and blocking RyR reversed CaSR-mediated inhibition of renin from 61 ± 8 to 118 ± 22% of control (P < 0.01). Combining inhibition of IP(3) and RyR was not additive. G(i) inhibition with pertussis toxin plus cinacalcet did not reverse renin inhibition (65 ± 12 to 41 ± 8% of control, P < 0.001). We conclude stimulating JG cell CaSR activates G(q), initiating the PLC/IP(3) pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition.

Kokumi substances, enhancers of basic tastes, induce responses in calcium-sensing receptor expressing taste cells.

Recently, we reported that calcium-sensing receptor (CaSR) is a receptor for kokumi substances, which enhance the intensities of salty, sweet and umami tastes. Furthermore, we found that several γ-glutamyl peptides, which are CaSR agonists, are kokumi substances. In this study, we elucidated the receptor cells for kokumi substances, and their physiological properties. For this purpose, we used Calcium Green-1 loaded mouse taste cells in lingual tissue slices and confocal microscopy. Kokumi substances, applied focally around taste pores, induced an increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in a subset of taste cells. These responses were inhibited by pretreatment with the CaSR inhibitor, NPS2143. However, the kokumi substance-induced responses did not require extracellular Ca(2+). CaSR-expressing taste cells are a different subset of cells from the T1R3-expressing umami or sweet taste receptor cells. These observations indicate that CaSR-expressing taste cells are the primary detectors of kokumi substances, and that they are an independent population from the influenced basic taste receptor cells, at least in the case of sweet and umami.

Extracellular calcium-sensing receptor mediates human bronchial epithelial wound repair.

The airway epithelium routinely undergoes damage that requires repair to restore epithelial barrier integrity. Cell migration followed by proliferation are necessary steps to achieve epithelial repair. Calcium-sensing receptor (CaSR) is implicated in cell migration and proliferation processes. Thus we hypothesized that CaSR mediates lung epithelial wound repair. We detected CaSR expression in human lung and in well-differentiated human bronchial epithelial cells (HBEC). To test the CaSR functionality, HBEC loaded with fura-2 were stimulated with extracellular Ca(2+) ([Ca(2+)](out)) which resulted in a concentration-dependent intracellular Ca(2+) ([Ca(2+)](i)) increase (potency approximately 5.6mM [Ca(2+)](out)). Furthermore, increasing [Ca(2+)](out) induced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) which was blocked by siRNA-CaSR and the specific inhibitor of CaSR, NPS2390. Epithelial repair after mechanical injury of differentiated HBEC was a process dependent of [Ca(2+)](out) since it accelerated wound repair and HBEC proliferation being highest at 5mM [Ca(2+)](out). Furthermore, U73122 (an inhibitor of phospholipase C (PLC)) and PD 98059 (an inhibitor of ERK1/2) as well as siRNA-CaSR and NPS2390 partially inhibited wound repair and HBEC proliferation. On the other hand, mechanical injury produced an [Ca(2+)](i) wave propagation that was partially inhibited by siRNA-CaSR, NPS2390 and the extracellular Ca(2+) chelator EGTA, which suggest a link of CaSR between cell-cell communication and wound repair in differentiated HBEC. Our data, for the first time, shows that CaSR plays an important role in airway epithelial repair, which may help to develop novel regenerative therapeutics allowing the rapid repair of lung damaged epithelium.

Effects of potential calcium sensing receptor inducers on promoting chemosensitivity of human colon carcinoma cells.

We have previously reported that by inducing calcium sensing receptor (CaSR), calcitriol, the active form of vitamin D, promoted the sensitivity of the human colon carcinoma cells to anticancer drugs. In the current study we tested several other potential CaSR modulators, calcipotriol and the effective components of Chinese herbal medicine lentinan, for their functions in inducing CaSR expression in human colon carcinoma cell line CBS, Moser, Fet, and SW480 cells and subsequently promoting sensitivity of the cells to anticancer drugs. Calcipotriol and lentinan suppressed invasion of the colon carcinoma cells and enhanced the cytotoxicity of anticancer regimen FOLFIRI to cells in culture or in anchorage-independent growth. In the mechanism study we found that calcipotriol and lentinan suppressed protein expression and gene transcriptional activities of survivin and thymidylate synthase, increased E-cadherin cell membrane localization and complex formation of E-cadherin and beta-catenin, and repressed TCF4 transcriptional activation. These effects were attenuated, however, in CaSR knocked-down cells, indicating that CaSR was required in the pathway. We concluded that calcipotriol and lentinan are efficient in promoting chemosensitivity in colon carcinoma cells. Since both compounds have much less side effects than calcitriol in clinic, they have greater potential to be applied as supplements of colon cancer therapy.

Agonists and allosteric modulators of the calcium-sensing receptor and their therapeutic applications.

The calcium-sensing receptor (CaR) belongs to the G protein-coupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain. The primary physiological function of the CaR is the maintenance of constant blood Ca2+ levels, as a result of its ability to sense very small changes in extracellular Ca2+ (Ca2+(o)). Nevertheless, in addition to being expressed in tissues involved in Ca2+(o) homeostasis, the CaR is also expressed in tissues not involved in mineral homeostasis, suggestive of additional physiological functions. Numerous agonists and modulators of the CaR are now known in addition to Ca2+(o), including various divalent and trivalent cations, aromatic l-amino acids, polyamines, and aminoglycoside antibiotics. The signaling of the CaR is also regulated by extracellular pH and ionic strength. The activated CaR couples mainly to the phospholipase Cbeta and extracellular signal-regulated kinase 1/2 signaling pathways, and it decreases intracellular cAMP levels, leading to various physiological effects. The recent identification of synthetic allosteric modulators of the CaR has opened up a new field of research possibilities. Calcimimetics and calcilytics, which increase and decrease agonist signaling via the CaR, respectively, may facilitate the manipulation of the CaR and thus aid in further investigations of its precise signaling. These allosteric modulators, as well as strontium, have been demonstrated to have therapeutic potential for the treatment of disorders involving the CaR. This review discusses the various agonists and modulators of the CaR, differences in their binding and signaling, and their roles as therapeutics in various diseases.

Calcimimetic inhibits late-stage cyst growth in ADPKD.

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.

The role of the calcium-sensing receptor in bone biology and pathophysiology.

Bone cells, particularly osteoblasts and osteoclasts, exhibit functional responses to calcium (Ca(2+)). The identification of the calcium-sensing receptor (CaR) in parathyroid glands as the master regulator of parathyroid hormone (PTH) secretion proved that cells could specifically respond to changes in divalent cation concentration. Yet, after many years of study, it remains unclear whether this receptor, which has also been identified in bone, has functional import there. Various knockout and transgenic mouse models have been developed, but conclusions about skeletal phenotypes remain elusive. Complex endocrine feedback loops involving calcium, phosphorus, vitamin D, and PTH confound efforts to isolate the effects of a single mineral, hormone, or receptor and most models fail to account for other local factors such as parathyroid hormone related protein (PTHrP). We review the relevant mouse models and discuss the importance of CaR in chondrogenesis and osteogenesis. We present the evidence for a non-redundant role for CaR in skeletal mineralization, including our experience in patients with activating CaR mutations. Additionally, we review emerging research on the importance of the CaR to the regulation of serum calcium homeostasis independent of PTH, the role of the CaR in the hematopoietic stem cell niche with implications for bone marrow transplant, and early evidence that implies a role for the CaR as a factor in skeletal metastasis from breast and prostate cancer. We conclude with a discussion of drugs that target the CaR directly either as agonists (calcimimetics) or antagonists (calcilytics), and the consequences for bone physiology and pathology.

The new role of calcimimetics as vasculotropic agents.

The discovery of the calcium-sensing receptor (CaSR) and the development of calcimimetics have provided new insights into calcium homeostasis and new therapeutic opportunities for parathyroid-related disorders. However, the CaSR is also implicated in various other cellular processes, and the translational applications of calcimimetics may not be exclusively calcium-centric. Koleganova et al. describe a novel role for calcimimetics as vasculotropes, which provides the impetus for further studies to characterize their effects on vascular biology.

Potential new drug targets for osteoporosis.

Osteoporosis is a worldwide health problem with a high prevalence. Agents for the treatment of osteoporosis are classified as either antiresorptive or anabolic. Antiresorptive agents work by inhibiting the activity of osteoclasts and, therefore, reducing bone resorption. Currently available antiresorptive agents include bisphosphonates, selective estrogen-receptor modulators, calcitonin and estrogen. Various novel antiresorptive agents are in development. Receptor activator of nuclear factor kappa B ligand is an important cytokine involved in osteoclast activation; denosumab, a fully human monoclonal antibody to this molecule, has finished a major fracture trial. Assessment is underway of odanacatib--an inhibitor of cathepsin K, which is an osteoclast enzyme required for resorption of bone matrix. Glucagon-like peptide 2 is being evaluated for the prevention of the nocturnal rise in bone resorption without affecting bone formation. Anabolic agents act by stimulating formation of new bone. The only anabolic agent currently available in the US is teriparatide--recombinant human parathyroid hormone (PTH)(1-34)--and recombinant human PTH(1-84) is available in Europe. PTH stimulates osteoblast function and bone formation. Novel anabolic agents in development include: antibodies such as sclerostin and dickkopf-1 that target molecules involved in Wnt signaling, a pathway that regulates gene transcription of proteins that are important for osteoblast function; an antagonist to the calcium-sensing receptor; and an activin receptor fusion protein, which functions as an activin antagonist and has shown promise as an anabolic agent in early human trials.

Nicotine-induced Ca2+-myristoyl switch of neuronal Ca2+ sensor VILIP-1 in hippocampal neurons: a possible crosstalk mechanism for nicotinic receptors.

Visinin-like protein (VILIP-1) belongs to the neuronal Ca2+ sensor family of EF-hand Ca2+-binding proteins that regulate a variety of Ca2+-dependent signal transduction processes in neurons. It is an interaction partner of alpha4beta2 nicotinic acetylcholine receptor (nAChR) and increases surface expression level and agonist sensitivity of the receptor in oocytes. Nicotine stimulation of nicotinic receptors has been reported to lead to an increase in intracellular Ca2+ concentration by Ca2+-permeable nAChRs, which in turn might lead to activation of VILIP-1, by a mechanism described as the Ca2+-myristoyl switch. It has been postulated that this will lead to co-localization of the proteins at cell membranes, where VILIP-1 can influence functional activity of alpha4-containing nAChRs. In order to test this hypothesis we have investigated whether a nicotine-induced and reversible Ca2+-myristoyl switch of VILIP-1 exists in primary hippocampal neurons and whether pharmacological agents, such as antagonist specific for distinct nAChRs, can interfere with the Ca2+-dependent membrane localization of VILIP-1. Here we report, that only alpha7- but not alpha4-containing nAChRs are able to elicit a Ca2+-dependent and reversible membrane-translocation of VILIP-1 in interneurons as revealed by employing the specific receptor antagonists dihydro-beta-erythroidine and methylallylaconitine. The nAChRs are associated with processes of synaptic plasticity in hippocampal neurons and they have been implicated in the pathology of CNS disorders, including Alzheimer's disease and schizophrenia. VILIP-1 might provide a novel functional crosstalk between alpha4- and alpha7-containing nAChRs.

[Cinacalcet - an allosteric enhancer at the Ca2+-receptor]. / Cinacalcet - ein allosterischer Verstärker am Ca2+-Rezeptor.

Cinacalcet (trade name: Mimpara) enhances allosterically the action of Ca (2+)-ions at the parathyroid gland Ca (2+)-receptor which belongs to the superfamily of G protein-coupled receptors. As a consequence blood levels of Ca (2+) and parathyroid hormone decline. Cinacalcet is orally administered and approved for a) the treatment of secondary hyperparathyroidism in patients with end stage renal disease receiving hemodialysis and b) to lower hypercalcemia in patients with parathyroid carcinoma. Therapeutic monitoring includes measurement of blood levels of Ca (2+) and parathyroid hormone. The stable suppression of parathyroid hormone levels under chronic treatment was shown in clinical trials. Clinically relevant outcome parameters, such as bone mass and fracture risk, remain to be evaluated.

Enterotoxin preconditioning restores calcium-sensing receptor-mediated cytostasis in colon cancer cells.

Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs), inhibits colorectal cancer cell proliferation by co-opting Ca(2+) as the intracellular messenger. Similarly, extracellular Ca(2+) (Ca(2+)(o)) opposes proliferation and induces terminal differentiation in intestinal epithelial cells. In that context, human colon cancer cells develop a phenotype characterized by insensitivity to cytostasis imposed by Ca(2+)(o). Here, preconditioning with ST, mediated by GCC signaling through cyclic nucleotide-gated channels, restored Ca(2+)(o)-dependent cytostasis, reflecting posttranscriptional regulation of calcium-sensing receptors (CaRs). ST-induced GCC signaling deployed CaRs to the surface of human colon cancer cells, whereas elimination of GCC signaling in mice nearly abolished CaR expression in enterocytes. Moreover, ST-induced Ca(2+)(o)-dependent cytostasis was abrogated by CaR-specific antisense oligonucleotides. Importantly, following ST preconditioning, newly expressed CaRs at the cell surface represented tumor cell receptor targets for antiproliferative signaling by CaR agonists. Since expression of the endogenous paracrine hormones for GCC is uniformly lost early in carcinogenesis, these observations offer a mechanistic explanation for the Ca(2+)(o)-resistant phenotype of colon cancer cells. Restoration of antitumorigenic CaR signaling by GCC ligand replacement therapy represents a previously unrecognized paradigm for the prevention and treatment of human colorectal cancer employing dietary Ca(2+) supplementation.

[Hyperparathyroidism--new aspects]. / Neue Aspekte bei Hyperparathyreoidismus.

Hyperparathyroidism is generally classified into a primary and secondary form. The primary form is caused by an autonomous adenomatous hypertrophy and/or hyperplasia of parythyroideal glands without known cause in most of the patients. Resulting elevated levels of parathyroid hormone cause elevation of serum calcium, subsequently followed by cerebral symptoms, fatigue and calcinosis of vessels and kidneys. The mainstay of secondary HPT is the initial vitamin D deficiency such as associated with kidney failure. Via an increased PTH secretion, calcium homeostasis will be maintained together with ongoing hyperplasia of the parathyroidea. Therapeutic approaches are related to pathophysiological mechanisms. While surgical removal of adenomatous glands is the mainstay of therapy in primary and late secondary forms, during the still regulated initial period of secondary HPT supplementation of vitamin D and/or sensitation of parathyroideal Calcium-sensing-receptors are therapy of choice.

Ion channels in analgesia research.

The distribution of ion channels in neurons associated with pain pathways is becoming better understood. In particular, we now have insights into the molecular nature of the channels that are activated by tissue-damaging stimuli, as well as the mechanisms by which voltage-gated channels alter the sensitivity of peripheral neurons to change pain thresholds. This chapter details the evidence that individual channels may be associated with particular pain states, and describes genetic approaches to test the possible utility of targeting individual channels to treat pain.

Calcification inhibitors and Wnt signaling proteins are implicated in bovine artery smooth muscle cell calcification in the presence of phosphate and vitamin D sterols.

Administration of active vitamin D sterols to treat secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis has been associated with elevated serum calcium and phosphorus levels, which may lead to increased risk of vascular calcification. However, calcimimetics, by binding to the parathyroid gland calcium-sensing receptors, reduce serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Using cultured bovine aorta vascular smooth muscle cells (BASMCs), an in vitro model of vascular calcification, we compared calcification levels and gene expression profiles after exposure to the phosphate source ss-glycerolphosphate (BGP), the active vitamin D sterols calcitriol and paricalcitol, the calcimimetic R-568, or BGP with the active vitamin D sterols or R-568. Cells exposed to BGP (10 mM) alone or with calcitriol or paricalcitol showed dose-dependent BASMC calcification. No change in calcification was observed in cultures exposed to BGP with R-568, consistent with the observed lack of calcium-sensing receptor expression. Microarray analysis using total cellular RNA from cultures exposed to vehicle or BGP in the absence and presence of 10(-8) M calcitriol or paricalcitol for 7 days showed that cells exposed to BGP with calcitriol or BGP with paricalcitol had virtually identical gene expression profiles, which differed from those of cells treated with BGP or vehicle alone. Several osteoblast- and chondrocyte-associated genes were modulated by BGP and vitamin D exposure. In this study, exposure of BASMCs to phosphate and active vitamin D sterols induced calcification and changes in expression of genes associated with mineralized tissue.

[Cinacalcet--a new drug for the treatment of secondary hyperparathyroidism in patients with uraemia, parathyroid cancer or primary hyperparathyroidism]. / Cinacalcet--et nyt medicinsk behandlingsprincip til sekundaer hyperparatyroidisme ved uraemi, parathyroideacancer og primaer hyperparatyroidisme.

Cinacalcet is a new drug with antiparathyroid effects that belongs to the class of calcimimetics. It increases the sensitivity of the calcium-sensing receptor (CaSR) to calcium, thus inducing a decrease in plasma parathyroid (PTH) levels. In patients with uncontrolled secondary hyperparathyroidism due to uremia, cinacalcet has been shown to decrease the levels of PTH even in those optimally treated with calcium and 1-ahydroxylated vitamin D. Cinacalcet decreases plasma calcium and plasma PTH levels in patients with primary hyperparathyroidism or parathyroid cancer.

Looking at calcimimetics impact on hypercalcemia of immobilization: hypotheses and a case study.

For the treatment of secondary hyperparathyroidism (HPTH-II) in dialysis patients and hypercalcemia in patients with parathyroid carcinoma. Calcimimetics are a new class of drugs approved in the European Community and the United States by the Food and Drug Administration that were designed to suppress parathyroid hormone (PTH) levels with a simultaneous reduction in serum calcium and phosphorus levels, and calcium phosphorus product (Ca x P). Hypocalcemia is a frequent finding during the correction phase of the HPTH-II with calcimimetics. By contrast, the appearance of a hypercalcemia has yet to be described. In this paper, we report a case of severe hypercalcemia of immobilization in a 40-year-old hemodialyzed woman treated by cinacalcet HCl for a severe HPTH-II (PTH>1,000 pg/mL). A kidney transplantation recipient 1983 to 1995, she was diagnosed with Charcot-Marie Tooth disease in 1991. She had multiple orthopedic interventions for kidney-related osteoarticular problems probably favored by the kidney graft and the immunosuppressive treatment. While she was receiving the maximum dose of 180 mg/day of cinacalcet HCl and PTH at 443 pg/mL, she needed to be hospitalized for a right hip prothesis. Two weeks after the intervention she developed a symptomatic hypercalcemia of 3.57 mmol/L which was resistant to several measures including lowering the calcium concentration in the dialysate, withdrawing all vitamin D and calcium supplementation and the administration of calcitonin. Her serum calcium level was finally stabilized in the 2.37-2.95 mmol/L by administration of a single intravenous dose of pamidronate. This observation illustrates that the pharmacological activation of the parathyroid CaR and other putative CaR on bone cells by calcimimetics did not protect against the occurrence of hypercalcemia of immobilization favored by a severe HPTH-II in a hemodialysis patient.