Clinical trial NCT00395538: Effects of PTH Replacement on Bone in Hypoparathyroidism
Official title: Effects of PTH Replacement on Bone in Hypoparathyroidism
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hypoparathyroidism
DiGeorge Syndrome
Keywords: Parathyroid
Bone Biopsy
Calcium-Sensing Receptor
Bone Density
Bone Turnover
Hypoparathyroidism
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2006-11-03
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: * 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.

Primary outcomes:
measure: Change in Bone Biopsy Cancellous Bone Volume (Cn.BV/TV)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Total Number of Cortical Pores Per mm^2 (Ct.Po.N)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Bone Formation Rate Per Unit of Bone Surface (Cn.BFR/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Mineralizing Surface (Bone Surface Based)(Cn.MS/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Bone Formation Rate Per Unit of Bone Surface (Ec.BFR/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Mineralizing Surface (Bone Surface Based) (Ec.MS/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Bone Formation Rate Per Unit of Bone Surface (Ic.BFR/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Mineralizing Surface (Bone Surface Based) (Ic.MS/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
Secondary outcomes:
measure: Change in Trabecular Thickness (Tb.Th)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Trabecular Number (Tb.N)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Trabecular Separation (Tb.Sp)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Average Thickness of Inner and Outer Cortices (Ct.Th)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Total Area of Inner and Outer Cortices (Ct.Ar)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Total Area of Cortical Porosity (Ct.Po.Ar)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Osteoid Thickness (Cn.O.Th)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Bone Mineral Apposition Rate (Cn.MAR)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Osteoid Surface / Bone Surface (Cn.OS/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Eroded Surface / Bone Surface (Cn.ES/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cancellous Adjusted Apposition Rate (Cn.AjAR)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Osteoid Thickness (Ec.O.Th)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Bone Mineral Apposition Rate (Ec.MAR)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Osteoid Surface / Bone Surface (Ec.OS/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Eroded Surface / Bone Surface (Ec.ES/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Endocortical Adjusted Apposition Rate (Ec.AjAR)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Osteoid Thickness (Ic.O.Th)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Bone Mineral Apposition Rate (Ic.MAR)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Osteoid Surface / Bone Surface (Ic.OS/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Eroded Surface / Bone Surface (Ic.ES/BS)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Intracortical Adjusted Apposition Rate (Ic.AjAR)
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cortex 1 Spectral Calcium Mean From the Back-Scattered Electron Imaging of Bone-Biopsies
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cortex 1 Spectral Calcium Peak From the Back-Scattered Electron Imaging of Bone-Biopsies
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cortex 1 Spectral Calcium Width From the Back-Scattered Electron Imaging of Bone-Biopsies
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cortex 1 Spectral Calcium Low From the Back-Scattered Electron Imaging of Bone-Biopsies
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Change in Cortex 1 Spectral Calcium High From the Back-Scattered Electron Imaging of Bone-Biopsies
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Raw 1/3 Radius Bone Mineralization Density (BMD) Assessed by DXA.
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Raw AP Spine Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Raw Femoral Neck Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Raw Lateral Spine Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Raw Total Hip Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Raw Whole Body Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Perceived Interference (PI) of the Fatigue Symptom Inventory (FSI)
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Average Severity Score of the Fatigue Symptom Inventory (FSI)
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Composite Severity Score of the Fatigue Symptom Inventory (FSI)
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Total Distance Walked During a 6-minute Walk
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Bodily Pain Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Emotional Role Limitations Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 General Health Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Mental Health Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Physical Function Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Physical Role Limitations Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Social Function Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: SF36 Vitality Domain
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Serum Alkaline Phosphatase
timeFrame: Baseline, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Serum Calcium
timeFrame: Baseline, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Serum Osteocalcin
timeFrame: Baseline, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Serum Phosphorus
timeFrame: Baseline, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: 24 Hour Urine NTX Telopeptide
timeFrame: Baseline, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Number of Participants With Nephrolithiasis/Nephrocalcinosis
timeFrame: Baseline, 12-Month Visit, 24-Month Visit, 36-Month Visit, 48-Month Visit, and 60-Month Visit
measure: Primary Bone Biopsy Measures Adjusted for HPTH Dose
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Sensitivity Analyses of Female Menopause Status in the Primary Bone Biopsy Efficacy Models
timeFrame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies
measure: Z-score of 1/3 Radius Bone Mineralization Density (BMD) Assessed by DXA.
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH (up to 5 years), and post-HPTH follow-up visit (6 months post last visit on HPTH)
measure: Z-score of AP Spine Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits
measure: Z-score of Femoral Neck Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits
measure: Z-score of Lateral Spine Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits
measure: Z-score of Total Hip Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits
measure: Z-score of Whole Body Bone Mineralization Density (BMD) Assessed by DXA
timeFrame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Dental and Craniofacial Research (NIDCR)
name: Rachel I Gafni, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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. doi: 10.1016/s0022-3476(85)80668-5.
citation: 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. doi: 10.1016/s0140-6736(78)92702-2.