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Osteoporosis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Mazen Nasrallah, Marcy B. Bolster
Calcium-sensing receptor antagonism. Calcium-sensing receptors (CaSR) play a key role in regulating calcium homeostasis and indirectly modulating skeletal homeostasis through regulation of PTH secretion. Inhibitors of CaSR, termed calcilytics, transiently increase PTH secretion and have an anabolic effect on bone. Several CaSR inhibitors have been investigated in clinical trials and failed to demonstrate superior efficacy compared to current therapeutics. Future developments in this field may yield more promising results.51
Endocrine diseases and pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Hypercalcemic disorders other than PHP are very rarely encountered in pregnancy. Familial hypocalciuric hypercalcemia, also known as familial benign hypercalcemia, was first characterized in the early 1970s as an autosomal dominant genetic disorder notable for mild to moderate hypercalcemia accompanied by extremely low fractional excretion of calcium (ratio of calcium to creatinine clearance <0.01). It is now known to result from a mutation of the calcium-sensing receptor in both parathyroid and renal tubular tissues. There are no maternal consequences of this disorder, but neonatal hypocalcemic tetany can occur, with management similar as in maternal hyperparathyroidism (85). It is important to recognize the disorder for what it is so that maternal parathyroidectomy is not attempted. Malignancy-related hypercalcemia has only been reported in two pregnant patients, with maternal demise occurring within 4months postpartum in both cases (94,95).
Parathyroid carcinoma
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Jesse T. Davidson, Alicia Diaz-Thomas
Management in recurrent disease focuses on medical agents to reduce symptoms and prolong life by mitigating hypercalcemia and its effects. Selective calcium-sensing receptor agonists (e.g., cinacalcet) and bisphosphonates are the primary treatment, but they tend to lose efficacy over time (22,23). Denosumab, an antibody to the receptor activator of nuclear factor-ΚB ligand (RANKL) that blocks osteoclast development, has demonstrated considerable efficacy in managing hypercalcemia in adult parathyroid cancer (24) and thus may be a valuable palliative tool in children as well. Its use as a palliative agent in recurrent pediatric parathyroid cancer should be considered (authors’ experience). Additionally, a recent adult case report suggests a chemotherapeutic agent, temozolomide, could also be considered as salvage therapy in tumors that express high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive temozolomide treatment response in other tumors (25). Molecular profiling of parathyroid cancers can thus lead to identification of actionable therapeutic targets once other treatments have failed.
Inflammasomes: a preclinical assessment of targeting in atherosclerosis
Published in Expert Opinion on Therapeutic Targets, 2020
Jeremiah Stitham, Astrid Rodriguez-Velez, Xiangyu Zhang, Se-Jin Jeong, Babak Razani
The role of increased intracellular Ca2+ is thought to facilitate mitochondrial damage by overloading the mitochondrial matrix, increase oxidative stress (enhance NADH dehydrogenase activity) and ROS formation that, ultimately, causes loss of membrane potential and release of mtDNA into the cytosol [77]. P2RX7, along with other plasma membrane channels like TRPM2 and TRPM7 (transient receptor potential cation channel subfamily M member 2 and 7) have been linked to Ca2+ influx and NLRP3 inflammasome activation [78]. Ca2+ influx has also been associated with endoplasmic reticulum (ER) stress and apoptosis [79,80]. A number of studies have shown that inhibition of Ca2+ influx, at both the level of the ER and extracellular membrane-mediated entry, attenuated IL-1β production, suggesting it to be a requisite process for NLRP3 inflammasome activation that may be contingent upon ER stress-related apoptosis [28,77,81]. However, others have shown that NLRP3 inflammasome activation can occur independently from Ca2+ mobilization, suggesting more of a modulatory role [57]. Stimulation with an allosteric agonist to the calcium-sensing receptor (CaSR), a G-protein coupled receptor (GPCR) that triggered by extracellular Ca2+ has also been shown to activate the NLRP3 through both Gαq-mediated Ca2+ increase and with Giα-mediated inhibition of cAMP [82].
Calcilytics: a non-steroidal replacement for inhaled steroid and SABA/LABA therapy of human asthma?
Published in Expert Review of Respiratory Medicine, 2020
The extracellular calcium-sensing receptor (CaSR) is a G-protein coupled receptor originally identified as the body’s master controller for extracellular calcium homeostasis. The CaSR, as might be anticipated, is expressed in cells concerned with global calcium metabolism, including the parathyroid glands, cells of the renal cortex and osteocytes. In the parathyroid gland the receptor plays a role in regulating the release of parathyroid hormone to maintain normocalcaemia, and this in turn means that it is a potential therapeutic target for the regulation of parathyroid hormone secretion and the clinical sequelae of excessive secretion, for example as a result of primary or secondary hyperparathyroidism. Thus agonists of the CaSR, termed calcimimetics, have long been on the market as a treatment for hyperparathyroidism [6]. Conversely, antagonists of the CaSR, termed calcilytics, increase the secretion of parathyroid hormone. Several calcilytic compounds have been evaluated as orally active anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because they lacked clinical efficacy [7]. More recently the efficacy of systemic calcilytics has been also tested in Phase 2 clinical trials for the treatment of hypoparathyroidism and for a rare form of autosomal dominant hypocalcemia with hypercalciuria caused by gain-of-function mutations in the CaSR gene [8].
Hypercalcemic crisis in third trimenon: evaluating the optimal treatment strategy
Published in Gynecological Endocrinology, 2018
Julie Refardt, Patricia Farina, Irene Hoesli, Christian Meier
PHPT is the most common cause of hypercalcemia during pregnancy [5,10] and has been described in several case reports and reviews of the literature. However, it is essential to rule out other causes of hypercalcemia, as this determines the further management. The most important differential diagnosis to an elevated PTH with only mild hypercalcemia is the benign familial hypocalciuric hypercalcemia [11], an autosomal dominant condition caused by a loss-of-function mutation in the calcium-sensing receptor gene (CASR) requiring no further interventions. In patients with low PTH-levels, secondary causes of hypercalcemia due to hyperthyroidism, vitamin D-intoxication, granulomatous disease and malignancy must be considered [6]. In case of suspected malignancy, parathyroid hormone-related peptide PTHrP should be measured [12]. PTHrP-related hypercalcemia is mostly caused by solid organ malignancy (e.g. lung, ovarian and renal cell carcinoma) but some cases have also been described of placental origin during pregnancy [13–15].