This study will determine whether a synthetic form of human parathyroid hormone (PTH) can control hypoparathyroidism and will examine the drug's effects on bone. Blood calcium and phosphate levels in patients with hypoparathyroidism are difficult to control with the current standard treatment of calcitriol and calcium supplementation. Calcium levels in the urine may be elevated at the same time that blood calcium levels are normal. This spilling of excessive calcium into the urine can lead to kidney damage.

Patients between 9 and 55 years of age with hypoparathyroidism may be eligible for this study. Participants

take standard calcitriol therapy for the first year of the study and start PTH after 1 year. After 1 year on PTH, they are given the option to continue the drug for an additional 3 years.

Patients are admitted to the NIH Clinical Center for 4-6 days at the start of the study, at the end of the first year, and at the end of the second year (and at year 5 for those who continue on PTH for an additional 3 years) for the following procedures:

" Daily 24-hour urine collection.

" Daily blood draw for calcium and phosphorous levels and for calcium-regulating hormones.

" Blood draw every 2 hours for 24 hours to measure blood calcium, phosphorus, and magnesium levels (admission 3 only). For this test blood samples are collected through a catheter (plastic tube) placed in a vein in the arm or hand to avoid multiple needle sticks.

" Questionnaire and 6-minute walk test to determine fatigue

" Bone biopsy to test treatment response. Before the biopsy, patients are given a regimen of the antibiotic tetracycline or demeclocycline. The drug is absorbed by the bone, "labeling" it in a way that permits investigators to learn more about the bone's biology. For the biopsy, the patient is given a sedative to cause drowsiness. The skin over the hipbone is numbed with an injection of anesthetic into the skin, through the underlying tissues, and onto the surface of the bone. A larger needle is then inserted into the bone itself, and a sample of bone tissue is withdrawn through the needle. More sedative or anesthetic may be given to lessen any pain.

Every week for the first month of the study and then twice a month, patients go to a laboratory for a 24-hour urine collection. Every 6 months, they come to the NIH outpatient clinic for a physical exam, blood and urine tests, and a dual energy X-ray absorptiometry (DXA) scan to measure bone density.

Prior studies (92-CH-0011) have been important in establishing synthetic human parathyroid hormone 1-34 (PTH) as a beneficial treatment for hypoparathyroidism, superior to conventional therapy with calcium and calcitirol. This study will examine the effects of hypoparathyroidism and two different parathyroid hormone (PTH) replacement regimens on the skeleton of children and adults with hypoparathyroidism. Our prior noninvasive studies of bone mass and turnover suggested that although there was no significant effect of long-term treatment with PTH on bone mass, PTH therapy leads to a chronic high bone turnover state. Ultrastructural, cellular, and molecular analyses are now needed to further examine and characterize both the effect of hypoparathyroidism and treatment with replacement PTH on bone. The primary goals of this study are to (1) understand the effect of absent or low levels of PTH (hypoparathyroidism) and its therapeutic replacement by way of PTH (for the maintenance of calcium homeostasis) on the hypoparathyroid skeleton and (2) characterize bone growth both in the absence of PTH in children with hypoparathyroidism and to then compare the same children on replacement doses of PTH. In the first year of the study, patients will receive conventional (calcitriol plus calcium) therapy, during the second year subjects will be treated with PTH (twice daily vs three times daily), and at the end of the second year subjects will be allowed to continue on PTH for up to an additional three additional years. This study presents a unique opportunity, through the study of subjects with hypoparathyroidism and their treatment with PTH, to assess the role of PTH in human skeletal biology.

• Chan JC, Young RB, Alon U, Mamunes P. Hypercalcemia in children with disorders of calcium and phosphate metabolism during long-term treatment with 1,25-dihydroxyvitamin-D3. Pediatrics. 1983 Aug;72(2):225-33. No abstract available.
• Chan JC, Young RB, Hartenberg MA, Chinchilli VM. Calcium and phosphate metabolism in children with idiopathic hypoparathyroidism or pseudohypoparathyroidism: effects of 1,25-dihydroxyvitamin D3. J Pediatr. 1985 Mar;106(3):421-6.
• Christiansen C, Rodbro P, Christensen MS, Hartnack B, Transbol I. Deterioration of renal function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol. Lancet. 1978 Sep 30;2(8092 Pt 1):700-3.

• INCLUSION CRITERIA:

This study will include patients of both genders (ages 9-55) with biochemically confirmed chronic hypoparathyroidism of at least one year duration. Eighty subjects (30 children and 50 adults) will be enrolled.

EXCLUSION CRITERIA:

Subjects who meet any of the following criteria are not eligible for the study:

• Presence of significant hepatic or kidney disease (GFR less than 25 mL/min).
• Allergy to tetracycline antibiotics.
• Pregnancy.
• Chronic disease that might effect growth or mineral metabolism such as GI disorders.
• Cushing's syndrome or disease and adrenal insufficiency.
• Use of systemic or inhaled corticosteroids within the last 6 months.
• Patients who are calcium infusion dependent and/or do not respond to calcitriol therapy to maintain normal levels of serum calcium will be excluded.
• Seizure disorder requiring antiepileptic medications.
• Treatment with PTH for more than 2 weeks within the two years prior to study entry.