Effectiviteit en veiligheid van behandeling met cinacalcet bij patiënten met primaire hyperparathyreoïdie door een MEN-I mutatie.

This study will look at the efficacy and safety of cinacalcet in patients with PHPT due to a MEN-1 mutation.

Efficacy will be evaluated on the basis of clinical and biochemical data.

Safety will be evaluated on the basis of neurocognitive function tests, biochemical data and radiological data.
Patients will be treated with cinacalcet for 1 year at a starting dose of 30 mg once daily and a maximum dose of 30 mg twice daily.



Patients will be recruited from medical centers in the Netherlands.

Patients with MEN-1 have a high risk of developing primary hyperparathyroidism (PHPT). Surgical removal of all pathological parathyroid glands is the only approach that provides definitive cure, however, the recurrence rate in patients with a MEN-1 mutation is reported to be 50% 8-12 years after subtotal parathyroidectomy. Revision neck explorations are technically more challenging than initial surgery and associated with an up to a 3-fold increase in morbidity. The potential of non-invasive approaches such as the use of calcimimetics has been explored in patients with PHPT who cannot or will not have surgery and was found to be promising. The use of these agents would be particularly beneficial in patients with MEN-1 where recurrence and persistence of hyperparathyroidism is common after initial parathyroidectomy.

In addition to the parathyroid glands, the CaSR has also been identified in cells of the kidneys, bone, colon, thyroid, brain, pancreas and gastrinoma cells of the stomach. Stimulation of the CaSR by cinacalcet has been reported to increase urine calcium excretion and increase bone turnover, without having a significant effect on the bone mineral density. In contrast to patients with sporadic PHPT, patients with PHPT due to a MEN-1 mutation have a 33-50% chance of developing pituitary tumors, insulinomas, gastrinomas and other pancreatic tumors. The effect of cinacalcet on these associated endocrine pathologies has not been previously studied.

Primary Endpoints:

1. Specific and non-specific symptoms will be assessed using the validated Pasieka’s “Parathyroid Assessment of Symptoms Score (PAS)” before and 1, 2, 3, 6 and 12 months after start of cinacalcet;

2. Global cognitive function will be assessed using a battery of neuropsychological tests before and 1, 2, 3, 6 and 12 months after start of cinacalcet;

3. Quality of life will be assessed using the SF-36 questionnaire before and 12 months after the start of cinacalcet;

4. Blood will be collected to measure for serum calcium, PTH, phosphate, creatinine, albumin, 25OH vitamin D, alkaline phosphatase, B-crosslaps, P1NP, TSH, FT4, gastrin, insulin, prolactin, testosterone, FSH and LH before and 1, 2, 3, 6 and 12 months after the start of cinacalcet;

5. Two times 24-hrs urine will be collected to measure for calcium, phosphate and creatinine (TMP/GFR) before and 1, 2, 3, 6 and 12 months after the start of cinacalcet.



Secondary Endpoints:

1. BMD will be measured using dual energy X-ray absorptiometry (DXA, Hologic QDR 4500; Waltham, MA, USA) before and 12 months after the start of cinacalcet;

2. Lateral X-rays of spine will be performed before and 12 months after the start of cinacalcet;

3. An ultrasound of the kidneys will be performed before and 12 months after the start of cinacalcet;

4. An MRI of the abdomen and the brain will be performed before and 12 months after the start of cinacalcet;

5. CaR and VDR expression on pathological parathyroid samples will be determined and DNA analysis for somatic and germline mutations of the following genes will be performed; PTH, MEN-1, HRPT2, CaSR including newly identified gene targets.

Treatment with Cinacalcet (Primpara ®). Patients will be treated with cinacalcet for 1 year at a starting dose of 30 mg once daily and a maximum dose of 30 mg twice daily.