Ureña P, Legoupil N, de Vernejoul M C
Service de néphrologie-dialyse, Clinique de l'Orangerie, Aubervilliers (93).
Presse Med. 2005 Sep 10;34(15):1095-100. doi: 10.1016/s0755-4982(05)84125-9.
The extracellular calcium-sensing receptor (CaR) on the parathyroid cell surface negatively regulates secretion of parathyroid hormone (PTH). Its activation by small changes in the extracellular concentration of ionized calcium (ec[Ca2+]) decreases PTH secretion and secondarily bone turnover. CaR is an ideal target for compounds that may be developed to modulate its activity - activating calcimimetics and inhibiting calcilytics. Calcimimetics can amplify the sensitivity of the CaR to ec(Ca2+), thereby suppressing PTH levels and in turn reducing blood Ca++. They dose-dependently reduce the secretion of PTH in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia when given at the onset of the disease and stop cell proliferation if they are administered afterwards, when the hyperplasia already exists. They normalize plasma PTH levels and bone remodeling. In uremic patients undergoing hemodialysis, calcimimetics reduce plasma PTH concentrations in the short (12 weeks) and long (2 years) terms. They also reduce serum levels of calcium-phosphorus product. Calcimimetics are therefore an alternative for the treatment of secondary hyperparathyroidism, particularly in dialysis patients, when increased serum levels of calcium-phosphorus product, the attendant risk of cardiovascular calcification, and its lack of efficacy limit use of the standard treatment.
甲状旁腺细胞表面的细胞外钙敏感受体（CaR）对甲状旁腺激素（PTH）的分泌起负调节作用。细胞外游离钙（ec[Ca2+]）浓度的微小变化激活该受体后，会减少PTH分泌，进而降低骨转换。CaR是可能开发的用于调节其活性的化合物的理想靶点——激活剂为拟钙剂，抑制剂为拟钙解剂。拟钙剂可增强CaR对ec（Ca2+）的敏感性，从而抑制PTH水平，进而降低血钙浓度。它们在培养的甲状旁腺细胞、动物模型和人体中呈剂量依赖性地减少PTH分泌。在尿毒症动物中，这些化合物在疾病发作时给药可预防甲状旁腺细胞增生，在增生已经存在时给药则可阻止细胞增殖。它们可使血浆PTH水平和骨重塑恢复正常。在接受血液透析的尿毒症患者中，拟钙剂在短期（12周）和长期（2年）内均可降低血浆PTH浓度。它们还可降低血清钙磷乘积水平。因此，当血清钙磷乘积水平升高、随之而来的心血管钙化风险以及标准治疗缺乏疗效限制了其使用时，拟钙剂是治疗继发性甲状旁腺功能亢进的一种替代方法，尤其适用于透析患者。
