Clinical use of calcimimetics in the treatment of hyperparathyroidisms

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium concentration (Ca(2+)ec) regulates parathormone (PTH) and calcitonin secretion, urinary calcium excretion and ultimately bone turnover. Cloning of CaR and discovery of mutations making the receptor less or more sensitive to calcium allowed a better understanding of several hereditary disorders characterized either by hyperparathyroidism or hypoparathyroidism. CaR became an ideal target for the development of compounds able to modulate the activity of CaR, activators (calcimimetics) as well as inhibitors (calcilytics). The calcimimetics are able to amplify the sensitivity of the CaR to Ca(2+)ec, suppressing PTH levels with a resultant fall in blood Ca2+. They dose-dependently reduce the secretion of PTH in vitro in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia, normalize plasma PTH levels and bone remodelling. In uremic patients undergoing hemodialysis, the calcimimetics reduce plasma PTH concentration at short-term (12 weeks) as well as at long-term (2 years), serum calcium-phosphorus product and bone remodelling. After one year of treatment, these patients show a gain of bone mass of 2-3% at the femoral neck and at the total body. Contrarily, the calcilytics, by inhibiting CaR, can intermittently stimulate the secretion and the serum concentration of PTH. This results in an skeletal anabolic effect with a substantial increase in bone mineral density. They are potentially very interesting for the treatment of post-menopausal osteoporosis.