Effects of PTH Replacement on Bone in Hypoparathyroidism

Official Title: “Effects of PTH Replacement on Bone in Hypoparathyroidism”

Hypoparathyroidism is a rare condition associated with a low level of parathyroid hormone (PTH) in the blood. Hypoparathyroidism can be genetic and show up in childhood, or it can occur later in life. If it occurs later, it is usually due to damage or removal of the parathyroid glands during neck surgery. PTH helps control the amount of calcium in blood, kidneys, and bones. Low levels of calcium in the blood can cause a person to feel sick. It can cause cramping or tingling in the hands, feet, or other parts of the body. A very low blood calcium can cause fainting or seizures.

The standard treatment for hypoparathyroidism is a form of vitamin D (calcitriol) and calcium supplements. Keeping normal blood levels of calcium can be difficult. Sometimes there is too much calcium in the urine even if the calcium levels in the blood are low. High calcium in the kidneys and urine can cause problems such as calcium deposits in the kidney (nephrocalcinosis) or kidney stones. High levels of calcium in the kidney may keep the kidney from functioning normally. Treatment with PTH will replace the hormone you are missing. Your disease may be better controlled on PTH than on calcium and calcitriol.

Researchers at the NIH have conducted prior studies to establish synthetic human parathyroid hormone 1-34 (HPTH) as a treatment for hypoparathyroidism. Other studies have shown that PTH may improve calcium levels in blood and urine. The primary purpose of this research study is to evaluate the effects of synthetic human parathyroid hormone 1-34 (HPTH) replacement therapy on bone in adults and teenagers with hypoparathyroidism.

The study takes 5 years to complete and requires 12 inpatient visits to the National Institutes of Health Clinical Center in Bethesda, MD. The first visit will help the study team decide whether you are eligible. This visit will last 2 to 3 days. After taking calcium and calcitriol for 1 - 7 months you will return to the NIH Clinical Center for the baseline visit. The baseline visit is the visit that you will start your PTH; you will also undergo a bone biopsy during the visit. The baseline visit may last 7 to 10 days. You will then take PTH twice a day for 5 years. You will be asked to return to the NIH clinical center every 6 months for 10 follow-up visits. During one of the follow-up visits, you will have a second bone biopsy taken from the other hip. That second biopsy will be done after 1 year, 2 years, or 4 years of taking PTH; the researchers will assign the timing of the second biopsy randomly. You will be asked to go to your local laboratory for blood and urine tests between each follow up visit. At first the blood tests will occur at least once a week.

Later, you will need to go to your local laboratory for blood tests at least once a month and urine tests once every 3 months. The local laboratory visits and follow-up visits at the NIH Clinical Center will help the study team determine whether the HPTH treatment is controlling your hypoparathyroidism.

Hypoparathyroidism due to inadequate production or secretion of parathyroid hormone (PTH) is associated with hypocalcemia, hyperphosphatemia, suppressed bone turnover and, oftentimes, increased bone mass. It may be due to a variety of genetic disorders, autoimmune conditions and infiltrative diseases or as a result of parathyroid gland injury or removal during neck surgery. Unlike other hormone deficiencies where individuals are treated with replacement hormones, hypoparathyroid patients are typically treated with calcium and vitamin D analogues; however, both the treatment and the underlying disease can lead to hypercalciuria, nephrocalcinosis and decreased renal function.

Prior studies at the NIH have been important in establishing synthetic human parathyroid hormone 1-34 (HPTH) as a beneficial treatment for hypoparathyroidism, possibly superior to conventional therapy with calcium and calcitriol. These noninvasive studies suggest that, although there is no significant effect of long-term treatment with HPTH on bone mass, HPTH therapy leads to a chronic high bone turnover state. The primary goals of this study are to (1) better understand the effects of hypoparathyroidism on the skeleton, and (2) evaluate the skeletal effects of hormone replacement therapy with HPTH in hypoparathyroidism. To accomplish these goals, we will treat hypoparathyroid individuals with synthetic human PTH 1-34 for up to 5 years, periodically assessing skeletal changes through biochemical markers and iliac-crest bone biopsies, which will allow for ultrastructural, cellular, and molecular analyses. This study presents a unique opportunity, through the study of subjects with hypoparathyroidism and their treatment with HPTH, to assess the role of HPTH in human skeletal biology.

Intervention(s) in this Clinical Trial

• Drug: Parathyroid Hormone 1-34
  • N/A

Primary Measures

• Vitamin D vs PTH effects on bone.
  • Time Frame: 5 years
    Safety Issue?: No

Secondary Measures

• Vitamin D vs PTH effects on calcium metabolism.
  • Time Frame: 5 years
    Safety Issue?: No

INCLUSION CRITERIA:

• 1. Age eligibility at screening:
• 1. Premeopausal women: aged 18 to 45 years, 2. Postmenopausal women: aged greater than or equal to 53 years to 70 years and 5 years since last menses. For women without a uterus, subjects must have a clinical history of menopause for at least 5 years and an FSH greater than 30 U/L.
• 3. Men: aged 18 to 70 years, 2. Physician-diagnosed hypoparathyroidism of at least 1-year duration, confirmed by medical record review. The investigators will confirm the diagnosis during the screening visit at which time the subject must have an intact PTH < 30 pg/mL.
• 3. Willing to provide informed consent

EXCLUSION CRITERIA:

Subjects meeting any of the following criteria will not be enrolled:

• 1. Moderate to severe hepatic disease defined as hepatic transaminases (ALT and AST) >
• 2 times the upper limit of normal
• 2. Severe renal insufficiency defined as a calculated GFR < 25 mL/min/1.73 m2, using the CKD-EPI equation15.
• 3. Allergy or intolerance to tetracycline antibiotics
• 4. Pregnant or lactating.
• 5. Peri-or post-menopausal as defined by no menses for 6 months to 5 years and an FSH >
• 20 U/L at the screening and/or baseline visits.
• 6. Chronic diseases that might affect mineral metabolism such as diabetes, celiac disease, Crohn's disease, Cushing's syndrome, or adrenal insufficiency
• 7. Concurrent treatment with doses of thyroid hormone intended to suppress thyroid stimulating hormone below the assay's detection limit or persistent thyroid cancer
• 8. History of a skeletal disease unrelated to hypoparathyroidism, such as osteoporosis or low bone density (defined as a DXA Z-Score < -2 in all subjects or T-score < -2 in subjects greater than or equal to 20 year old), osteosarcoma, Paget's disease, alkaline phosphatase > 1.5 times the upper limit of normal, or metastatic bone disease
• 9. History of retinoblastoma or Li-Fraumeni syndrome
• 10. History of treatment with bisphosphonates, calcitonin, tamoxifen, selective-estrogen receptor modulators, or directed skeletal irradiation
• 11. Use of oral or intravenous corticosteroids or estrogen replacement therapy for more than 3 weeks within the last 6 months
• 12. Use of depot medroxyprogesterone for contraception within the past 12 months
• 13. Chronic inadequate biochemical control with conventional therapy and/or calcium infusion dependent
• 14. Seizure disorder requiring antiepileptic medications
• 15. Treatment with PTH for more than 2 weeks prior to study entry
• 16. Any cognitive impairment that limits the subject's or the subject's legally authorized representative's ability to understand the protocol, provide informed consent, or to comply with the protocol procedures
• 17. Unwillingness or inability to comply with protocol procedures
• 18. Open epiphyses as determined by an X-ray of the hand and wrist in subjects < 21 years of age.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: National Institute of Dental and Craniofacial Research (NIDCR) NIH

Overall Clinical Trial Officials and Contacts

Overall Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00395538

Study ID Number: 070016

ClinicalTrials.gov Identifier: NCT00395538

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page