Effects of PTH Replacement on Bone in Hypoparathyroidism
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 (Omega) 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.
Objectives

 The primary objective of this study is to evaluate the skeletal effects of hormone
 replacement therapy with HPTH in hypoparathyroidism.

 Study Population

 This study will enroll up to 69 subjects with physician-diagnosed hypoparathyroidism.<TAB>

 Design

 This study will treat hypoparathyroid individuals with synthetic human PTH 1-34 (HPTH) 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.

 With respect to HPTH treatment, this study is a single group, within-subjects, repeated
 measures treatment trial. With respect to all bone biopsy analyses, the design is a parallel
 group design with each subject allocated to one of the 3 biopsy follow-up times: 1, 2 or 4
 years after initiation of HPTH therapy. Post-baseline biopsy timing will be randomly assigned
 (1:1.2:1.4, respectively) to each subject, stratified by gender and by menopausal status,
 when relevant. Changes from baseline (time 0) to 1, 2 and 4-years will be compared. Subjects
 who were on conventional therapy in the former version of the protocol will also be
 randomized into the new study design. In contrast to new subjects, whose biopsy is performed
 at the end of the conventional care run-in period, the pre-conventional care biopsy will be
 used as the baseline for the those subjects entering the new design after having been on
 conventional care in the older protocol. Because it is not known with certainty what effects
 duration of time on conventional therapy will have on biopsy results, randomization will also
 be stratified on status of prior study participation. The subjects who were on HPTH therapy
 at the time of the protocol redesign are followed as a separate group under this protocol.

 Outcome Measures

 Primary:

 Changes in static and dynamic bone histomorphometry after 1 year, 2 years, and 4 years of
 HPTH therapy. Primary outcome measurements include:

 -  Mineralized perimeter

 -  Bone formation rate

 -  Cortical width

 -  Cortical area

 -  Osteoid width

 -  Osteoid perimeter

 -  Mineral apposition rate

 Secondary:

 Changes in bone mineralization density distribution at 1, 2 and 4 years of HPTH therapy. The
 specific outcomes that will be measured include:

 -  Spectral calcium-mean

 -  Calcium-peak

 -  Calcium-width

 Changes from baseline will be assessed in the following outcomes:

 -  Biochemical markers of bone metabolism: osteocalcin, bone-specific alkaline phosphatase,
 collagen cross-linked N-telopeptide.

 -  Serum and urine calcium; 1,25-OH2-Vitamin D

 -  Bone density assessed by DXA and quantitative CT

 -  Nephrocalcinosis by ultrasound and CT

 -  Fatigue Symptom Inventory

 -  6-Minute Walk Test

 -  SF-36 Health Survey

 Tertiary:

 Changes in blood chemistries and FGF23, renal mineral handling, and PTH sensitivity with the
 initiation of HPTH, which include:

 -  Serum albumin, calcium, phosphorus, magnesium, sodium, potassium, chloride, Total CO2,
 creatinine, glucose, urea nitrogen, and FGF23

 -  Urine cAMP, creatinine, phosphorus, calcium, and pH
-  INCLUSION CRITERIA:

 1. Age eligibility at screening:

 1. Premenopausal 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.

 EXCLUSION CRITERIA:

 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 m(2), using
 the CKD-EPI equation(15).

 3. Allergy or intolerance to tetracycline antibiotics

 4. Pregnant or lactating or planning to become pregnant during the course of the study.
 (Women who are able to get pregnant must agree to use an effective form of birth
 control while in this study.).

 5. Perimenopausal 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 continuously at any time, prior to study
 entry

 16. Any cognitive impairment that limits the subject s ability to comply, independently or
 through the assistance of a legally authorized representative, with protocol
 procedures.

 17. Open epiphyses as determined by an X-ray of the hand and wrist in subjects < 21 years
 of age.