Original article
Cinacalcet HCl: A Novel Treatment for Secondary Hyperparathyroidism Caused by Chronic Kidney Disease

https://doi.org/10.1053/j.jrn.2006.04.010Get rights and content

Secondary hyperparathyroidism (SHPT) develops as a result of impaired calcium homeostasis when the failing kidneys disturb the complicated interactions between parathyroid hormone (PTH), calcium, phosphorus, and vitamin D. Twelve years ago, the calcium-sensing receptor (CaR) of the parathyroid gland was first cloned and identified as the principal regulator of PTH secretion. The activation of the CaR by small changes in extracellular calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and ultimately, bone turnover. The CaR became an ideal target for the development of calcimimetics, which are able to amplify its sensitivity to ec(Ca2+) suppressing PTH secretion. Cinacalcet HCl, a first-in-class calcimimetic, approved in both the United States and the European Union, offers a new therapeutic approach to the treatment of SHPT. The efficacy of cinacalcet HCl in treating SHPT in dialysis patients (n = 1,136) was studied in three similarly designed phase III clinical trials comparing patients receiving standard SHPT therapy plus cinacalcet HCl or plus placebo. Cinacalcet HCl, dosed from 30 to 180 mg/day, significantly reduced PTH while simultaneously lowering calcium, phosphorus, and calcium–phosphorus product in each of the three studies. Respective to the National Kidney Foundation–Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI) recommended targets for bone and mineral metabolism, 41% of cinacalcet HCl-treated patients achieved both PTH and calcium–phosphorus product targets, compared with only 6% in the placebo group. Results from 2 recent phase IIIb studies (TARGET and CONTROL) conducted in the United States also showed that cinacalcet HCl can significantly reduce or maintain reduction in PTH while simultaneously lowering calcium, phosphorus, and calcium–phosphorus product. In addition, patients taking vitamin D at baseline of these 2 trials were able to see significant mean reductions in vitamin D dose. Further assessment of cinacalcet HCl trial data has shown some important effects in SHPT patient clinical outcomes. A combined post-hoc analysis of clinical events using data from 4 (n = 1,184) cinacalcet HCl phase II and III studies suggests that treatment with cinacalcet HCl has a beneficial effect on relative risks of parathyroidectomy, fracture, and hospitalization for cardiovascular complications. Nausea and vomiting occurred more often in patients taking cinacalcet HCl than in those taking a placebo. There were also transient episodes of hypocalcemia in 5% of cinacalcet HCl patients versus 1% of placebo patients. However, these episodes were rarely associated with symptoms. The development of calcimimetics has already changed the treatment of SHPT in renal patients. Its effectiveness on the control of PTH secretion, along with simultaneous reductions in calcium, phosphorus, and calcium–phosphorus product, give this agent an advantage over traditional therapies in all levels of severity of SHPT.

Section snippets

Principal Mechanisms Leading to Renal SHPT

SHPT results from an abnormal regulation of calcium, phosphate, and vitamin D metabolism. Several factors are involved in its development: (1) phosphate retention,6 (2) the subsequent increase in serum phosphate and in fibroblast growth factor-23 inhibits 1α-hydroxylase and calcitriol synthesis,7 (3) the hyperphosphaturic effect of PTH and its stimulatory effect on the 1α-hydroxylase are compromised by a reduced renal PTH receptor expression,8 (4) the net calcium balance becomes negative, the

Complications of Renal SHPT

The excess of PTH in patients with renal insufficiency has been considered for several decades as a potent uremic toxin.17 Aside from its known deleterious effects on a multitude of organs, including anemia, dyslipidemia, neuromyopathy, nervous depression, and impaired insulin secretion, certainly the most devastating effect is found on the cardiovascular system. A high serum PTH level is associated with decreased myocardial contractility, hypertrophy, fibrosis and myocardial calcium

Parathyroid CaR and the Development of Calcimimetics

The CaR of the parathyroid gland is the principal regulator of PTH secretion. When serum calcium decreases, the CaR is inhibited and PTH-containing vesicles move to the cell membrane and release PTH to the circulation. When serum calcium increases, the CaR is activated and the release of PTH is inhibited. As SHPT progresses and parathyroid hyperplasia gets more advanced, the parathyroid expression of the CaR is reduced.12, 13 Patients with SHPT show a rightward shift of the PTH-calcium sigmoid

Indications

Since early 2004, cinacalcet HCl has been formally indicated in dialysis patients with SHPT to achieve a target serum PTH concentration of between 150 and 300 pg/mL (15.9 o 31.8 pmol/L) in the intact PTH (iPTH) assay.29, 30 These patients must also have a serum albumin corrected total calcium concentration >2.10 mM (8.4 mg/dL). It is also indicated in the case of hypercalcemia in patients with parathyroid carcinoma.

Cinacalcet HCl in the Treatment of Renal SHPT

Phase I and II studies with the second-generation calcimimetic cinacalcet HCl in

Conclusions

The development of calcimimetics has changed the treatment of hyperfunctioning parathyroid glands states. The results of short-term and long-term studies with cinacalcet HCl in patients with uremic SHPT are very promising. Its safety profile, its effectiveness on the control of PTH secretion, and the simultaneous reductions in serum calcium–phosphorus product make this agent advantageous over the classic therapies. However, because of the lifelong potential duration of this treatment, its cost

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