Calcimimetics normalize the phosphate-induced stimulation of PTH secretion in vivo and in vitro

Hyperphosphatemia is a key pathogenic factor in the development of secondary hyperparathyroidism and precludes its treatment with vitamin D. Calcimimetics are therapeutic drugs demonstrated to lower parathyroid hormone (PTH) levels through an increase in the intracellular calcium of parathyroid cells. The mechanism by which high phosphate levels stimulate PTH secretion is related to its ability to prevent the elevation of intracellular calcium. The aim of this study was to assess whether calcimimetics are able to normalize the phosphate-induced stimulation of PTH secretion. In vivo experiments studied PTH-calcium curves, and were carried out by hypocalcemic or hypercalcemic clamp, in normal rats and those with hyperphosphatemic renal failure treated with the calcimimetic NPS R-568. For in vitro studies, parathyroid glands from normal rats were incubated in normal (1 mM) and high (4 mM) phosphate media with calcimimetic. PTH-Ca curves showed that the calcimimetics produced a marked reduction in PTH secretion in both the hyperphosphatemic and control rats; maximal suppression of PTH was achieved with calcium of 0.9 mM vs. 0.7 mM, respectively. No effect was observed with calcium 0.6 mM. In vitro experiments showed that the addition of calcimimetic to medium with high phosphate concentration reduced PTH to values similar to those obtained from glands incubated in normal phosphate concentration. Calcimimetics overcome the stimulatory effect of high phosphate on PTH secretion in vivo and in vitro. Thus, calcimimetics should be effective in patients with secondary hyperparathyroidism whose phosphorus levels would contraindicate vitamin D treatment alone.