Search

The inhibitory effect of cinacalcet hydrochloride (cinacalcet) on blood phosphorus (P) levels is widely-accepted. However, this effect is only observed in patients on dialysis. Reduction in parathyroid hormone (PTH) induced by cinacalcet increases blood P levels with decreased urinary P excretion in pre-dialysis patients with chronic kidney disease (CKD). Similar results observed in normal and CKD rats provide a pharmacological validation of the trade-off hypothesis. The lowering effect of cinacalcet on blood P levels in dialysis patients is attributed to decreased P mobilization from the bone caused by the decreased PTH secretion. It is unlikely that this P-lowering effect of cinacalcet would bring any benefits on the enhanced parathyroid gland function and bone metabolism. On the other hand, the P-lowering effect of this drug is considered to contribute to its inhibitory effects on the development and progression of vascular calcification in dialysis patients. Further studies should examine this beneficial cinacalcet effect would lead to the reduction of the mortality risk.

Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% +/- 21% and 61% +/- 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy.

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.

Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic kidney disease (CKD). Rats were fed a diet containing adenine for 4 weeks to establish CKD. Animals were then offered a diet containing sevelamer hydrochloride (sevelamer) or a normal diet for alternating 2 week periods over 8 weeks. Adenine-treated rats showed marked elevations of serum phosphorus, PTH and FGF23 levels associated with parathyroid hyperplasia and aortic calcification. Serum phosphorus, PTH and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, intermittent treatment with sevelamer successfully inhibited parathyroid hyperplasia and aortic calcification. In conclusion, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CKD. Setting up a period of reduced serum phosphorus levels, even if it is intermittent, is worthwhile for the inhibition of the development of parathyroid hyperplasia and aortic calcification.

Calcimimetics are positive allosteric modulators that activate the parathyroid calcium receptor (CaR) and thereby immediately suppress parathyroid hormone (PTH) secretion. Preclinical studies have demonstrated that calcimimetics inhibit PTH secretion and parathyroid gland hyperplasia and ameliorates bone qualities in rats with chronic renal insufficiency. Clinical trials with cinacalcet hydrochloride, a calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum phosphorus levels in dialysis patients with secondary hyperparathyroidism (2HPT). Thus, calcimimetics have considerable potential as an innovative medical approach to manage 2HPT. In this review, the similarities are extrapolated between the pharmacological effect of calcimimetics on the set point of Ca-regulated PTH secretion and clinical observations in affected subjects with activating CaR mutations.

Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with early chronic kidney disease (CKD) and are postulated to cause low blood levels of 1,25-dihydroxyvitamin D, as well as normal phosphate levels. In order to provide more direct evidence for the pathophysiological role of FGF23 in the settings of mineral ion homeostasis typically seen in early CKD, we studied rats with progressive CKD treated with anti-FGF23 neutralizing antibody. Without antibody treatment, rats with CKD exhibited high circulating levels of FGF23 and parathyroid hormone, low 1,25-dihydroxyvitamin D, and normal serum phosphate levels, accompanied by increased fractional excretion of phosphate. Antibody treatment, however, lessened fractional excretion of phosphate, thus increasing serum phosphate levels, and normalized serum 1,25-dihydroxyvitamin D by increased 1α-OHase and decreased 24-OHase expressions in the kidney. These antibody-induced changes were followed by increased serum calcium levels, leading to decreased serum parathyroid hormone. Hence, our study shows that FGF23 normalizes serum phosphate and decreases 1,25-dihydroxyvitamin D levels in early-stage CKD, and suggests a pathological sequence of events for the development of secondary hyperparathyroidism triggered by increased FGF23, followed by a reduction of 1,25-dihydroxyvitamin D and calcium levels, thereby increasing parathyroid hormone secretion. [ABSTRACT FROM AUTHOR]

High serum parathyroid hormone levels are associated with vascular calcification. Cinacalcet is a calcimimetic agent that inhibits parathyroid hormone secretion and is used to treat patients with secondary hyperparathyroidism. Here we measured the effects of oral cinacalcet on calcification of the aorta and heart in rats with a remnant kidney (5/6 nephrectomy) model of uremia that were fed a high-phosphate diet containing lactose to accelerate the process of aortic calcification. Alizarin red staining showed that the smooth muscle in the aortic arch of rats with a remnant kidney was calcified. The tissue levels of calcium and phosphorus in the aorta and hearts of these rats were significantly increased compared to sham-operated rats. Expression of the osteoblastic lineage genes osteocalcin, osteopontin and runt-related gene 2 were also increased in the aorta of these rats. Cinacalcet suppressed these calcification-related changes by reducing serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Parathyroidectomy also suppressed calcification in this model. We suggest that cinacalcet inhibits calcification of the aorta and heart in uremic patients with secondary hyperparathyroidism by decreasing serum parathyroid hormone levels.Kidney International (2008) 74, 1270–1277; doi:10.1038/ki.2008.407; published online 27 August 2008 [ABSTRACT FROM AUTHOR]

Abstract: Circulating levels of calcium ion (Ca2+) are maintained within a narrow physiological range mainly by the action of parathyroid hormone (PTH) secreted from parathyroid gland (PTG) cells. PTG cells can sense small fluctuations in plasma Ca2+ levels by virtue of a cell surface Ca2+ receptor (CaR) that belongs to the superfamily of G protein-coupled receptors (GPCR). Compounds that activate the CaR and inhibit PTH secretion are termed ‘calcimimetics’ because they mimic or potentiate the effects of extracellular Ca2+ on PTG cell function. Preclinical studies with NPS R-568, a first generation calcimimetic compound that acts as a positive allosteric modulator of the CaR, have demonstrated that oral administration decreases serum levels of PTH and calcium, with a leftward shift in the set-point for calcium-regulated PTH secretion in normal rats. NPS R-568 also suppresses the elevation of serum PTH levels and PTG hyperplasia and can improve bone mineral density (BMD) and strength in rats with chronic renal insufficiency (CRI). Clinical trials with cinacalcet hydrochloride (cinacalcet), a compound with an improved metabolic profile, have shown that long-term treatment continues to suppress the elevation of serum levels of calcium and PTH in patients with primary hyperparathyroidism (1HPT). Furthermore, clinical trials in patients with uncontrolled secondary hyperparathyroidism (2HPT) have demonstrated that cinacalcet not only lowers serum PTH levels, but also the serum phosphorus and calcium×phosphorus product; these are a hallmark of an increased risk of cardiovascular disease and mortality in dialysis patients with end-stage renal disease. Indeed, cinacalcet has already been approved for marketing in several countries. Calcimimetic compounds like cinacalcet have great potential as an innovative medical approach to manage 1HPT and 2HPT. [Copyright &y& Elsevier]

The effects of sevelamer hydrochloride (Renagel[sup ®] ; hereafter referred to as sevelamer), a noncalcemic phosphate binder, on renal mineral handling were examined in rats. Normal rats were fed a diet containing 0.3, 1, 3, and 5% sevelamer for 8 days, and serum, urine, and the immunohistochemical localization of the type II Na/Pi cotransporter protein in the kidney were analyzed. Rats treated with 3 or 5% sevelamer showed significant decreases in serum phosphorus (P) and parathyroid hormone (PTH) levels, with no changes in serum calcium (Ca), magnesium (Mg), or 1,25(OH)[sub 2] D[sub 3] levels. Increases were observed in urinary excretions of Ca and Mg associated with a reduction in the PTH level in rats treated with 3 or 5% sevelamer. Rats treated with 1% or higher concentrations of sevelamer showed significant dose-dependent and marked reductions of the urinary P excretion, and the tubular reabsorption of P was maximized to almost 100% in the 5% sevelamer group. The hypophosphaturia in rats treated with 3 or 5% sevelamer was accounted for by the reductions in serum PTH and P per se, and immunohistochemical analysis showed that the expression of type II Na/Pi cotransporter protein was markedly increased at the brush border membranes of the deep and superficial nephrons in rats treated with 5% sevelamer as compared with rats given a normal diet. In conclusion, sevelamer rapidly lowered serum P and PTH levels in normal rats. Sevelamer treatment also produced a marked hypophosphaturia associated with translocation of type II Na/Pi cotransporter protein and increased urinary Ca and Mg excretions by the reduction of PTH.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Unlabelled: Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism.Background: Secondary hyperparathyroidism (secondary HPT) in chronic renal insufficiency (CRI) is characterized by multiglandular hyperplasia.Methods: In this study, we investigated the effects of the calcimimetic NPS R-568 on the parathyroid gland in rats with CRI induced by ligation of the renal arteries and severe secondary HPT induced by dietary phosphorus loading. Six days after surgery, high-phosphorus diet feeding was started, and NPS R-568 was administered to the rats for 56 days either by daily gavage (30 or 100 micromol/kg) or by continuous subcutaneous infusion (20 micromol/kg. day).Results: After 54 days, serum PTH levels in vehicle-treated CRI rats were 1019 vs. 104 pg/mL in sham-operated controls. Infusion of NPS R-568 maintained serum PTH at levels comparable with those of sham-operated controls, whereas daily gavage also prevented much of the increase in CRI controls and decreased PTH levels intermittently in a dose-dependent fashion. Parathyroid gland enlargement was caused predominantly by hyperplasia. Total cell number per kg body wt was 3.5-fold higher in vehicle-treated CRI rats than in sham-operated controls. Both infusion and high-dose gavage of NPS R-568 completely prevented the increase in parathyroid cell number.Conclusion: These results demonstrate that the calcimimetic compound NPS R-568 can prevent both the increase in serum PTH levels and parathyroid hyperplasia in rats with CRI and severe secondary HPT. Moreover, these changes occurred despite decreases in serum 1, 25(OH)2D3 and increases in serum phosphate, suggesting a dominant role for the calcium receptor in regulating parathyroid cell proliferation. [ABSTRACT FROM AUTHOR]

Osteitis fibrosa is a common bone injury associated with secondary hyperparathyroidism (2(o)HPT). NPS R-568 is a phenylalkylamine derivative that acts as an agonist at the cell-surface Ca2+ receptor ("calcimimetic") and inhibits parathyroid hormone (PTH) secretion. In the present study, we tested whether NPS R-568 could ameliorate osteitis fibrosa in partially nephrectomized (Nx) rats with 2(o)HPT. Six months after surgery, Nx rats had developed mild but progressive 2(o)HPT and osteitis fibrosa. Two groups of Nx rats received NPS R-568 (3 and 30 mg/kg body wt x day) by daily gavage for 30 days, which led to a dose-related decrease in serum PTH levels and to a marked reduction in peritrabecular fibrosis (0.96 +/- 0.49% to < 0.1%). Furthermore, 2(o)HPT was associated with decreases in volumetric cortical bone mineral density (vCtBMD) and in cortical bone stiffness at the femoral midshaft. NPS R-568 significantly restored the deficits in vCtBMD and stiffness. These results indicate that NPS R-568 has beneficial effects on bones with osteitis fibrosa by normalizing serum PTH levels. [ABSTRACT FROM AUTHOR]