MEN1-related hyperparathyroidism: response to cinacalcet and its relationship with the calcium-sensing receptor gene variant Arg990Gly

Abstract

Objective: Primary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine neoplasia (MEN1) due to the high postsurgery recurrence rate. The aim was to evaluate the efficacy of cinacalcet in MEN1 patients in comparison with patients with sporadic PHPT (sPHPT) and the effect of Arg990Gly calcium-sensing receptor (CASR) polymorphism on the response to treatment. Design: This is a randomized, crossover, double-blind study carried out in the University Hospitals. Methods: Fifteen MEN1 patients with PHPT were randomized to two groups, one administered with 30 mg daily cinacalcet, titrated until calcium normalization, and one with placebo. After 3 months, patients were reassessed and after washout switched to the other treatment. For comparison, 20 sPHPT patients with similar calcium levels were administered with cinacalcet for 3 months. Ionized and total calcium, phosphate, and parathyroid hormone (PTH) were evaluated. CASR Arg990Gly was genotyped on blood DNA by direct sequencing. Results: Cinacalcet normalized calcium, increased phosphate, and reduced PTH levels in all patients. Cinacalcet dosage required to normalize calcium in MEN1 and sPHPT was not significantly different (45G21 vs 54G25 mg/day). Few mild adverse events, not requiring drug withdrawal, were observed in both the groups. No association between Arg990Gly CASR polymorphism and response to cinacalcet was found. Conclusions: This short-term prospective study demonstrated that the efficacy profile of cinacalcet in patients with MEN1-related PHPT and in those with sPHPT was similar and was not influenced by the 990 CASR variant. Although long-term safety and efficacy data are required, cinacalcet might be considered a treatment option in MEN1 patients who have contraindications to surgery or persistent PHPT after surgery.

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

“…The rs1501899 likely determines a reduction of the CASR expression, while the 990G causes a gain of function of the CASR (83). By contrast, in a small cohort of MEN1-related PHPT patients, the presence of the 990G allele did not influence the efficacy profile of cinacalcet (84). Lastly, recent data highlighted the role of proinflammatory cytokine like IL-1β and IL-6 in regulating the expression levels of CASR on kidney cells.…”

Medical Management of Primary Hyperparathyroidism

“…Filopanti et al carried out a randomized, crossover, double-blind study in 15 patients with MEN1-PHPT, who met the EMA criteria for cinacalcet therapy. 87 Mean total serum calcium and PTH concentrations were 11.5 ± 0.2 mg/dL and 97.8 ± 18.9 pg/ mL, respectively. Patients were randomly assigned to treatment with cinacalcet (30 mg daily, with dosage increase until normalization of serum calcium), or placebo.…”

“…Eight additional studies (four prospective, open label, [85][86][87][88] and four retrospective data collection [89][90][91][92] have been recently published in selected patients with sporadic PHPT (failed parathyroidectomy, or parathyroidectomy contraindicated, inappropriate or refused). Two studies also included patients who received cinacalcet to decrease serum calcium while awaiting parathyroidectomy.…”

“…Serum phosphate increased in all but one study and the changes were statistically significant compared with baseline values in four studies. 85,[87][88][89] Markers of bone turnover were occasionally measured and the results were inconsistent. BMD was evaluated at lumbar spine and hip in three studies and did not change.…”

Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel <i>CDC73</i> mutation

“…Although HPT-JT is a rare tumor syndrome, it cannot be overlooked because parathyroid carcinoma develops more frequently in this syndrome than other selected for MEN1 (12 articles, 30 patients) [12][13][14][15][16] and HPT-JT (9 articles, 35 patients) [17][18][19][20]. Serum calcium levels ranged from 10.8 to 17.5 mg/dL (mean 12.3 mg/dL, median 13.2 mg/dL) at 25-35 years old in MEN1 cases, and 12.0 to 16.8 mg/dL (mean 13.7 mg/dL, median 11.5 mg/dL) in HPT-JT cases (Fig.…”