Cinacalcet Treatment in Dialysis Patients with Secondary Hyperparathyroidism: Effects and Open Issues

Abstract

The recent introduction of calcimimetics, a novel class of therapeutic agents, has led to a change in the treatment strategy of secondary hyperparathyroidism in patients with end-stage renal disease. In initial acute studies in chronic hemodialysis patients, the calcimimetic cinacalcet was shown to reduce plasma intact parathyroid hormone within hours, followed by a rapid, profound decrease in plasma calcium and a minor decrease in plasma phosphorus. Subsequent reports showed that the long-term administration of cinacalcet to such patients proved to be superior to standard therapy in controlling secondary uremic hyperparathyroidism, in that it was able to induce a decrease in both plasma intact parathyroid hormone and the calcium x phosphorus product, in contrast to the effects of active vitamin D sterols. This allowed the achievement of the guideline treatment targets proposed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative in a much larger proportion of dialysis patients than standard therapy did. Moreover, the effect of cinacalcet is long-lasting. An important question is that of cinacalcet's effects on patient outcomes, which is still lacking. A similar lack of information exists for most other treatment modalities given to correct the mineral and bone disorder of chronic kidney disease. A post-hoc analysis of four clinical trials combined done in hemodialysis patients showed that randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization. To obtain a definitive answer to this question, including patient survival, we will have to wait for the results of prospective, randomized controlled trials. In pre-clinical studies performed in rats with chronic renal failure, the administration of the calcimimetic NPS R-568 at the time of uremia induction allowed the prevention of parathyroid hyperplasia, and the reversal of already established hyperplasia as well. Perhaps more important from the clinical point of view, NPS R-568 also appeared to allow reversal of osteitis fibrosa in uremic rats and reduction of aortic calcification and atherosclerosis in uremic rats and mice. In conclusion, the clinical introduction of cinacalcet allows for better control of secondary hyperparathyroidism in dialysis patients as compared to standard therapy, based on surrogate biochemical markers. Hopefully, in the future, this improvement will be shown to be associated with better patient outcomes for the treatment of fractures and cardiovascular morbidity and mortality.