Calcimimetic agents and secondary hyperparathyroidism: treatment and prevention

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR) in the parathyroid glands and other tissues. They lower the threshold for CaSR activa- tion by extracellular calcium ions and diminish parathyroid hormone (PTH) release from parathyroid cells. By targeting the molecular mechanism that modulates PTH secretion on a minute-to-minute basis, calcimimetic compounds offer a novel approach to managing excess PTH secretion in several clinical disorders w1x. Despite abundant in vitro and in vivo experimental work, experience with calcimimetic agents in humans is rather limited. Preliminary reports describe their use in small numbers of patients with primary hyper- parathyroidism and in somewhat larger numbers of patients with secondary hyperparathyroidism due to end-stage renal disease w2- 4x. Although the duration of treatment in published studies has been confined to 1 or 2 weeks, calcimimetic compounds consistently and reproducibly lower plasma PTH levels when given to normal volunteers or to patients with either primary or secondary hyperparathyroidism. Results from early clinical trials in humans are consistent, therefore, with data obtained in experimental animals w5x. Apart from their effect to diminish PTH secretion, calcimimetic compounds may fundamentally influence the process of parathyroid gland hyperplasia, and their administration to experimental animals can favorably affect skeletal calcium balance. If confirmed by studies in humans, these ancillary features of calcimimetics broaden their appeal as a therapeutic approach to secondary hyperparathyroidism due to chronic renal failure. Mechanism of action In parathyroid cells, increases in extracellular calcium concentration activate the CaSR and diminish the release of PTH that is stored within secretory granules w6x. In contrast, decreases in extracellular calcium concentration inactivate the CaSR and promote PTH release. These interactions are summarized by the inverse sigmoidal curve that describes the relationship between ionized calcium and PTH concentrations in vivo and in vitro w6,7x. By lowering the threshold for activation of the CaSR by extracellular calcium ions, calcimimetic agents modify this relationship across a range of extracellular calcium concentrations. In effect, calcimimetic compounds lower the set point for calcium-regulated PTH release rendering para- thyroid cells more sensitive to the inhibitory action of calcium. Changes in PTH release that are mediated through the CaSR occur within seconds or minutes, whereas other more widely recognized modifiers of PTH secre- tion in vivo lower plasma PTH levels over many hours or several days w8x. Both vitamin D and calcium inhibit pre-pro-PTH gene transcription directly by interacting with distinct upstream negative regulatory elements within DNA. The exogenous administration of vitamin D or calcium can also diminish PTH secre- tion indirectly by raising serum calcium concentrations, but the effects of these interventions on serum calcium and plasma PTH levels typically unfold over several days. In contrast, calcimimetic agents abruptly lower plasma PTH levels without an antecedent rise in serum calcium concentration. Calcimimetic agents probably alter signal trans- duction by inducing conformational changes in the CaSR. They do not appear to compete with calcium for binding to the extracellular domain of the CaSR nor do they activate the receptor in the absence of extracellular calcium ions w9x.