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Pablo Ureña Torres
Service de Néphrologie et Dialyse
Clinique de l’Orangerie
Secondary hyperparathyroidism (HPTH-II) is a common complication in patients with chronic kidney disease (CKD). It affects more than 300,000 end-stage renal disease patients treated by dialysis and probably more than three million patients with CKD.(1) It is associated with an increased risk of cardiovascular calcifications and mortality.(2) Although surgical parathyroidectomy (PTX) remains the gold-standard therapy, it is not without risk. PTX exposes patients to anaesthesia risks, surgical complications and potentially permanent hypoparathyroidism.(3)
On the other hand, traditional therapies such as calcium salts and vitamin D are limited by hypercalcaemia, hyperphosphataemia and lack of long-term efficacy. Calcimimetics, a new class of drugs, amplify the sensitivity of the parathyroid calcium-sensing receptor (CaR) to calcium, thereby reducing the serum concentration of PTH.(4,5) This article briefly reviews the development of calcimimetics and the results of the principal clinical trials that have been carried out.
Principal mechanisms leading to renal HPTH-II
HPTH-II results from an abnormal regulation of calcium, phosphate and vitamin D metabolism. Several factors are involved in the development of this condition:
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.
The cloning of the CaR by Brown and colleagues in 1993 led to the development of calcimimetics.(4) Type I calcimimetics mimic the effects of calcium. They consist of polyvalent cations, such as gadolinium, calcium, magnesium and lanthanum. Type II calcimimetics change the conformation of the CaR and stereoselectively increase its sensitivity to calcium. They do not alter PTH secretion in the absence of calcium.
Several type II calcimimetics have been synthesised: a first generation, which includes NPS R-567 and NPS R-568; and a second generation, with compounds such as AMG-073 or cinacalcet HCl and calindol.(11–13) NPS R-568 is remarkably effective in reducing serum PTH; however, it was withdrawn from clinical trials because of its unpredictable pharmacokinetic profile, due to its catabolism by the variable P450 cytochrome CYP2D6.(14) Cinacalcet HCl (Sensipar) has been extensively studied and approved in the USA by the FDA for the treatment of HPTH-II in dialysis patients,(15) and for hypercalcaemia in patients with parathyroid carcinoma (see Resource).
Clinical utilisation of cinacalcet HCl
Cinacalcet HCl is formally indicated in dialysis patients with HPTH-II characterised by a serum PTH level >300 pg/ml. These patients must also have a serum albumin-corrected total calcium >2.10mM (8.4mg/dl). It is also indicated in cases of hypercalcaemia in patients with parathyroid carcinoma.
Cinacalcet HCl in the treatment of renal HPTH-II
In dialysis patients with HPTH-II, the optimal daily dose of cinacalcet HCl appears to be 60–120mg. However, severe cases may require the maximal daily doses of 180mg. Independently of the baseline value, PTH decreases by 60–70% two to four hours after its administration and remains lower for the next 24 hours. Serum total calcium follows the same trend, but delayed by two to four hours; it often decreases by 20–30% of its baseline value. The reduction in serum PTH seen during the first weeks of treatment can reach up to 90% of the baseline value, similar to a surgical PTX. A transient hypocalcaemia often occurs during this phase, which is in part due to the phenomenon of “hungry bone”,(16) and also to a decrease in the intestinal expression of the TRPV5 calcium transporter.(17) Correcting this problem requires an increase in the dietary calcium intake, or high doses of calcium salts alone or in combination with vitamin D.
Table 1 illustrates the main results obtained with cinacalcet HCl in phase III studies in dialysis patients with HPTH-II. Cinacalcet HCl at doses of 20–180mg/day reduced mean serum PTH levels by 33% and 65% after 18 weeks and three years of treatment, respectively.(15,18–22) Mean serum calcium ¥ phosphorus (Ca ¥ P) product showed a decrease of 6–15%. This treatment frequently allows achievement of the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommended targets values for serum calcium, phosphorus, PTH and Ca ¥ P product (see Table 2).
Cinacalcet HCl in the treatment of parathyroid carcinoma
Parathyroid carcinoma is a rare cause of hypercalcaemia due to excessive PTH secretion. Its medical treatment is a real challenge because these tumours are often resistant to chemotherapy and radiotherapy. Two recent studies in 40 patients with inoperable parathyroid carcinoma and serum calcium of 14.5–15.4mg/dl have shown that 30–90mg of cinacalcet HCl four times a day reduces mean serum calcium to 11.8mg/dl and maintains this reduction for up to three years.(23,24)
The most frequent side-effects of cinacalcet HCl treatment are gastrointestinal troubles: nausea, gastralgia and vomiting. The incidence of other side-effects is not greater in dialysis patients receiving cinacalcet HCl than in nontreated patients. The transient hypocalcaemia that often occurs during the first weeks of treatment also has to be considered as a complication, because it may lower the threshold for seizures.
The development of calcimimetics has changed the treatment of hyperfunctioning parathyroid glands. The results of short- and long-term studies with cinacalcet HCl in patients with uraemic HPTH-II are very promising. The safety profile of this drug, its effectiveness in controlling PTH secretion and the simultaneous reductions in serum Ca ¥ P product observed make this agent advantageous over traditional therapies. However, because of the lifelong potential duration of this treatment, its cost-effectiveness needs to be estimated.