Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism

The design consists in a five-periods, two-treatments, open-label, randomized, crossover study with blind end-point evaluation.

Patients will come for an inclusion visit and will receive treatment with 0.5 µg/day alfacalcidol for 4 weeks (28±3 days, run-in). They will be instructed to maintain dietary calcium intakes (1 g/day) for the duration of the study and will be supplemented throughout the study with native vitamin D in order to maintain the concentration of 25OH vitamin D ≥ 40 ng/L. Magnesium supplementation (100 mg/day) will be maintained throughout the study.

At inclusion, patients will be randomly assigned to receive at the end of run-in period, in cross-over either an association hydrochlorothiazide 25 mg/day (ESIDREX®) + amiloride 5 mg/day (MODAMIDE®) + 0.5 µg/day alfacalcidol (ALFACALCIDOL®) or 40 µg/day rhPTH(1-34) (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).

After a washout period of 28±3 days under 0.5 µg alfacalcidol /day, the patients will follow the second period of treatment. The study will end with a final period of 28±3 days under 0.5 µg alfacalcidol /day. Patients will ambulatory monitor serum calcium, sodium, potassium, and creatinine levels at days 15 of run in and run out periods and at day 7 and day 28 of each treatment period.

Inclusion criteria

• Patients aged from 18 to 80 years, of both sexes
• Patient with primary hypoparathyroidism related to a genetically proven ADH OR primary hypoparathyroidism related to other cause but complicated by hypercalciuria under treatment
• Affiliated to a French health insurance system, and who have consented to the study.

Exclusion criteria

• Pregnant and breastfeeding women;
• Women of childbearing age without contraception;
• For men aged from 18 to 20 years, presence of cartilage of growth on X-ray of left knee;
• Anuria;
• Kidney failure with plasmatic creatinine >125 mmol/l and urea >10 mmol/l;
• Long QT interval : QTc > 450 ms (men) or 470 ms (women);
• Hepatic failure;
• Metabolic bone diseases (Paget's disease of bone) other than primary osteoporosis or glucocorticoid-induced osteoporosis;
• Association to other potassium sparing diuretics;
• Hypokalemia (<3.5 mmol/l) without diuretic therapy;
• Hyperkalemia (>5.5 mmol/l);
• Hyponatremia (<135 mmol/l) without diuretic therapy;
• Hypercalcemia (>2.6 mmol/l);
• Severe hypomagnesemia (≤ 0.5 mmol/l);
• Vitamin D deficiency (25OH vit D < 20 ng/mL);
• Unexplained increase in alkaline phosphatase (>2N);
• Intolerance to sulfamide;
• Intolerance to amiloride or other component of the drug;
• Hypersensitivity to any active substance or excipient of one of the experimental drugs;
• Gluten intolerance;
• Bone break history within the three previous months;
• History of radiotherapy of the skeleton;
• History of bone cancer or metastasis.
• Personnal or familial (first degree relatives) of skin cancer