Secondary hyperparathyroidism disease stabilization following calcimimetic therapy

Abstract

Standard therapy for secondary hyperparathyroidism (SHPT) includes dietary calcium supplementation, active vitamin D, and phosphate binders; however, these are often insufficient to allow patients to achieve their serum parathyroid hormone (PTH), calcium and calcium-phosphorus product (Ca × P) targets. Recent preclinical studies have demonstrated that treatment with type II calcimimetics that increase the sensitivity of the calcium-sensing receptor (CaR) to calcium can reverse the alterations in CaR and vitamin D receptor expression and parathyroid cell proliferation that are associated with SHPT. These data suggest that calcimimetic treatment could stabilize disease progression and improve maintenance of treatment goals. In clinical trials involving SHPT patients, the calcimimetic cinacalcet has been shown to decrease PTH, calcium, phosphorus and Ca × P. Significant improvements were seen regardless of initial disease severity, and benefits were maintained over the course of long-term therapy (up to 4 years), indicating effective disease stabilization. In conclusion, preclinical and clinical data provide both theoretical and empirical support for the use of calcimimetics in moderate and advanced SHPT to effectively stabilize disease.

Keywords: calcimimetic; calcium-sensing receptor; cinacalcet; secondary hyperparathyroidism.

Fig. 1.

The effect of the calcimimetic R-568 on rat parathyroid gland VDR mRNA in vivo. Rats were treated with R-568 (1 mg/kg intravenously 3 and 6 h before euthanasia; n = 22), calcitriol (10 pmol/kg intraperitoneally every 30 min for 5.5 h before euthanasia; n = 22), or a combination of R-568 and calcitriol (n = 22) before euthanasia and measurement of VDR mRNA by quantitative real-time polymerase chain reaction. A control group (n = 20) received no treatment. Mean serum concentrations of ionized calcium and PTH are also included. ^*P < 0.01 versus control; ^aP < 0.05 versus calcimimetic; ^bP < 0.05 versus control. Data are mean ± standard error. Adapted with permission from Rodriguez et al. [15].

Fig. 2.

Percentage change in (A) iPTH and (B) Ca × P by disease severity. Patients were treated with cinacalcet (beginning at 30 mg with possible titration up to 180 mg; n = 546) or placebo (n = 408) for 26 weeks. Patients were divided into groups according to baseline iPTH levels (pg/mL). Bars represent the mean (SE) percentage change from baseline for iPTH. SE, standard error. Adapted with permission from Frazão et al. [23].

Fig. 3.

Proportion of patients achieving serum iPTH ≤300 pg/mL and Ca × P <55 mg²/dL² during treatment with either cinacalcet (n = 122) or placebo (n = 126). (A) Achievement of serum iPTH ≤300 pg/mL and Ca × P <55 mg²/dL² after 1 year. (B) Maintenance of serum iPTH ≤300 pg/mL after 6 and 12 months of treatment. (C) Maintenance of combined serum iPTH and Ca × P target after 6 and 12 months of treatment. Adapted with permission from Frazão et al. [25].

Fig. 4.

Effect of long-term cinacalcet treatment on serum iPTH in dialysis patients. Patients received double-blind treatment with either cinacalcet (n = 9) or placebo (n = 12) for 1 year followed by a 3-year open-label extension treatment with cinacalcet. SE, standard error. Adapted with permission from Cunningham et al. [28].