Calcium-sensing receptor and calcimimetic agents

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostas is. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles incl ude regulation of parathyroid hormone (PTH) secretion by small changes in i onized calcium (Ca2+) and control of urinary calcium excretion with small c hanges in blood Ca2+. The CaR also affects the renal handling of sodium, ma gnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of m utations causing the CaR to be less sensitive to extracellular Ca2+ cause f amilial hppocalciuric hypercalcemia, while the homozygous form results in s evere infantile hyperparathyroidism. Mutations causing increased sensitivit y of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyr oidism. Disorders, such as primary and secondary hyperparathyroidism. may e xhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. I n animals and humans with hyperparathyroidism, this agent produces a dose-d ependant fall in PTH and blood Ca2+, with larger doses causing more sustain ed effects. The treatment has been short-term except for one patient follow ed for more than 600 days for parathyroid carcinoma; nonetheless the drug d id not cause major side-effects and appears to be safe. Further longterm co ntrolled studies are needed with calcimimetic agents of this type.