Prevention of uremic bone disease using calcimimetic compounds

The discovery, characterization, and cloning of the calcium-sensing recepto r (CaR) in 1993 was soon followed by the creation of a new type of drug, th e calcimimetics-NPS R-568 and NPS R-467-which are small phenylalkylamine de rivative compounds that act as CaR agonists and increase the sensitivity of the CaR to activation by extracellular calcium (Ca2+). As expected, these compounds turned out to have a significant effect on the Ca2+/parathyroid h ormone (PTH) relationship, resulting in a dramatically greater suppression of the PTH level than would otherwise occur at the actual extracellular Ca2 + levels. Renal osteodystrophy (RO) due to secondary hyperparathyroidism (H PT) in chronic renal failure was an obvious target for studying the effects of NPS R-568. In a study on experimental animals, the results clearly show ed that this first generation of calcimimetics, NPS R-568, had an acute dos e-dependent and short-lived suppressive effect on PTH secretion from the pa rathyroid glands. A similar effect was found in patients with chronic renal failure and secondary HPT. At the same time, the calcimimetics induced a s light degree of hypocalcemia. Such a significant suppressive effect on PTH secretion would be expected to result in therapeutic potential for a preven tive or therapeutic effect on the RO accompanying chronic uremia. Administr ation would probably be in close concert with present strategies, phosphate binders and vitamin D analogs. A wide distribution of CaRs have now been d emonstrated in the body, and an important question is how calcimimetics wil l affect the function of different tissues and organs when used for long-te rm treatment or prevention of secondary HPT and RO. Although relatively few experimental and clinical investigations have been completed, they clearly confirm the suppressive effect of calcimimetics on PTH secretion. In rats with experimental chronic renal failure, a significant and beneficial effec t on the prevention of RO has been demonstrated. The effect of calcimimetic compounds is presently being evaluated in humans. Besides induction of hyp ocalcemia, the adverse effects in these mainly short-term studies have been few. Future studies with calcimimetics will further define the physiology and pathophysiology of the CaR and the long-term benefit of calcimimetic co mpounds in patients with chronic renal failure.