Effects of PTH Replacement on Bone in Hypoparathyroidism

Phase 3TerminatedNCT00395538

National Institute of Dental and Craniofacial Research (NIDCR)46 enrolled

Overview

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

* 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.

Outcomes

Primary Outcomes

Change in Bone Biopsy Cancellous Bone Volume (Cn.BV/TV)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, so the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.BV/TV is one of 8 primary endpoints measured from the bone biopsy. The changes in Cn.BV/TV outcome between two time-points are being reported. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Total Number of Cortical Pores Per mm^2 (Ct.Po.N)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, so the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Po.N is a bone biopsy measure that assess the amount of holes in the cortical bone within a predetermined area of cortical bone. The changes in Cn.BV/TV outcome between two time-points are being reported. Cortical bone with a higher number of holes may be at greater risk of fracture. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Bone Formation Rate Per Unit of Bone Surface (Cn.BFR/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.BFR/BS, measured from the bone biopsy, is the cancellous bone formation rate per unit of bone surface where cancellous refers to the spongy structure of the bone. The changes in Cn.BFR/BS between two time-points are being reported. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Mineralizing Surface (Bone Surface Based)(Cn.MS/BS)

Following their baseline bone biopsy, 5, 5, and 2 participants were randomized to receive their second bone biopsy at years 1, 2, and 4 after the start of HPTH therapy, respectively. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced in size due to withdrawal and the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Cn.MS/BS between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Bone Formation Rate Per Unit of Bone Surface (Ec.BFR/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.BFR/BS is measured from the bone biopsy. This measures the rate of new bone formation per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.BFR/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Mineralizing Surface (Bone Surface Based) (Ec.MS/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the endocortical bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Ec.MS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Bone Formation Rate Per Unit of Bone Surface (Ic.BFR/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.BFR/BS is measured from the bone biopsy. This measures the rate of new bone formation between the two cortical surfaces (intracortical) in a predefined region of cortical bone. The changes in Ic.BFR/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Mineralizing Surface (Bone Surface Based) (Ic.MS/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the intracortical bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Ic.MS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Secondary Outcomes

Change in Trabecular Thickness (Tb.Th)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Tb.Th is measured from the bone biopsy. Tb.Th is the mean thickness of trabeculae, assessed using direct 3D methods. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Tb.Th between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Trabecular Number (Tb.N)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Tb.N is measured from the bone biopsy. Tb.N is the measure of the average number of trabeculae per unit length. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Tb.N between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Trabecular Separation (Tb.Sp)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Tb.Sp is measured from the bone biopsy. Tb.Sp is the mean distance between trabeculae, assessed using direct 3D methods. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Tb.Sp between two time-points are being reported.

Change in Average Thickness of Inner and Outer Cortices (Ct.Th)

Participants (Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Th, measured from the bone biopsy, is the average thickness of the inner and outer cortices. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Ct.Th between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Total Area of Inner and Outer Cortices (Ct.Ar)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.AR is measured from the bone biopsy. This measure defines the area of the outer cortex and inner cortex within a predefined section of cortical bone. The changes in Ct.Ar between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Total Area of Cortical Porosity (Ct.Po.Ar)

Following their baseline bone biopsy, 5, 5, and 2 participants were randomized to receive their second bone biopsy at years 1, 2, and 4 after the start of HPTH therapy, respectively. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced in size due to withdrawal and the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Po.Ar is measured from the bone biopsy. This measure defines the area of the cortical bone with holes within a predefined section of cortical bone. The changes in Tb.Sp between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Osteoid Thickness (Cn.O.Th)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.O.Th measured from the bone biopsy. This measures the thickness of the unmineralized bone (osteoid) in a predefined region of cancellous bone. The changes in Cn.O.Th between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Bone Mineral Apposition Rate (Cn.MAR)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.MAR is measured from the bone biopsy. This measures the rate mineral is being laid down per day in a predefined region of the cancellous bone. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Cn.MAR between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Osteoid Surface / Bone Surface (Cn.OS/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.OS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that contains unmineralized bone (osteoid). The region of interest is the predefined area of total bone that is being measured. The changes in Cn.OS/BS between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Eroded Surface / Bone Surface (Cn.ES/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.ES/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that contains unmineralized bone (osteoid). The region of interest is the predefined area of total bone that is being measured. The changes in Cn.ES/BS between two time-points are being reported.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cancellous Adjusted Apposition Rate (Cn.AjAR)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.AjAR is measured from the bone biopsy. Cn.AjAR represents the Cn.MAR averaged over the entire osteoid surface.The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes. The changes in Cn.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Osteoid Thickness (Ec.O.Th)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.O.Th is measured from the bone biopsy. This measures the thickness of the unmineralized bone (osteoid) on the inner side of the cortex(endocortical). The changes in Cn.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Bone Mineral Apposition Rate (Ec.MAR)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose.Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.MAR is measured from the bone biopsy. This measures the rate mineral is being laid down per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Osteoid Surface / Bone Surface (Ec.OS/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.OS/BS is measured from the bone biopsy. This measures the rate mineral is being laid down per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.OS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Eroded Surface / Bone Surface (Ec.ES/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4- year biopsies were collapsed into one biopsy year group. Ec.ES/BS is measured from the bone biopsy. This measure demonstrates the percentage of the endocortical bone surface that is resorbed (eroded). The region of interest is the predefined area of total bone that is being measured. The changes in Ec.ES/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Endocortical Adjusted Apposition Rate (Ec.AjAR)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.AjAR is measured from the bone biopsy. Ec.AjAR represents the endocortical mineral apposition rate (Ec.MAR) averaged over the entire osteoid surface. This is another histomorphometric way to evaluate the rate at which bone is laid down on the inner cortical surface per day. The changes in Ec.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Osteoid Thickness (Ic.O.Th)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.O.Th is one of 21 secondary endpoints measured from the bone biopsy. This measures the thickness of the unmineralized bone (osteoid) within the middle of the cortex (intracortical). The changes in Ic.O.Th between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Bone Mineral Apposition Rate (Ic.MAR)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.MAR is measured from the bone biopsy. This measures the rate mineral is being laid down per day within the middle of the cortex (intracortical) surface in a predefined region of cortical bone. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Osteoid Surface / Bone Surface (Ic.OS/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.OS/BS measured from the bone biopsy. This measure demonstrates the percentage of the intracortical bone surface that is not mineralized (osteoid). The region of interest is the predefined area of total bone that is being measured. The changes in OS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Eroded Surface / Bone Surface (Ic.ES/BS)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.ES/BS is measured from the bone biopsy. This measure demonstrates the percentage of bone surface within the middle of the cortex that is resorbed (eroded). The region of interest is the predefined area of total bone that is being measured. The changes in Ic.ES/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Intracortical Adjusted Apposition Rate (Ic.AjAR)

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.AjAR is one of 21 secondary endpoints measured from the bone biopsy. Ic.AjAR represents the intracortical mineral apposition rate (Ic.MAR) averaged over the the entire osteoid surface. This is another histomorphometric way to evaluate the rate at which bone is laid down within the middle of the cortex per day. The changes in Ic.AjAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline values)

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cortex 1 Spectral Calcium Mean From the Back-Scattered Electron Imaging of Bone-Biopsies

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Mean is a measure of mean bone calcium content of the bone cortex 1 based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cortex 1 Spectral Calcium Peak From the Back-Scattered Electron Imaging of Bone-Biopsies

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Peak is a measure of the most frequent calcium content of the bone cortex 1 based on the bone mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cortex 1 Spectral Calcium Width From the Back-Scattered Electron Imaging of Bone-Biopsies

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Low is a measure of the area of low bone cortex 1 mineralization based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cortex 1 Spectral Calcium Low From the Back-Scattered Electron Imaging of Bone-Biopsies

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium Low is a measure of the area of low bone cortex 1 mineralization based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Change in Cortex 1 Spectral Calcium High From the Back-Scattered Electron Imaging of Bone-Biopsies

Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. The Cortex 1 Spectral Calcium High is a measure of the area of high bone cortex 1 mineralization based on the mineralization density distribution (BMDD) from the back-scattered electron imaging scan of the bone biopsies. The changes in Ic.MAR between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Raw 1/3 Radius Bone Mineralization Density (BMD) Assessed by DXA.

Time frame: 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)

Raw AP Spine Bone Mineralization Density (BMD) Assessed by DXA

Time frame: 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)

Raw Femoral Neck Bone Mineralization Density (BMD) Assessed by DXA

Time frame: 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)

Raw Lateral Spine Bone Mineralization Density (BMD) Assessed by DXA

Time frame: 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)

Raw Total Hip Bone Mineralization Density (BMD) Assessed by DXA

Time frame: 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)

Raw Whole Body Bone Mineralization Density (BMD) Assessed by DXA

Time frame: 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)

Perceived Interference (PI) of the Fatigue Symptom Inventory (FSI)

Perceived interference is measured using seven separate items that assess the degree to which fatigue in the past week was judged to interfere with general level of activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood. The interference ratings were summed to yield a total interference score ranging from 0 (no perceived interference due to fatigue) to 70 (maximum possible perceived interference due to fatigue).

Time frame: 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)

Average Severity Score of the Fatigue Symptom Inventory (FSI)

Severity is measured using four separate items of the FSI questionnaire that assesses how the participant felt on their most, least, and average fatigue days in the past week as well as current fatigue. Participants score their level of fatigue for each item on an 11-point scale (0=not at all fatigued, 10=as fatigued as I could be). An average is taken of sum of these 4 scores. The average severity score can range from 0 to 10. A higher average severity score indicates that the participant is experiencing more severe fatigue.

Time frame: 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)

Composite Severity Score of the Fatigue Symptom Inventory (FSI)

Severity is measured using four separate items of the FSI questionnaire that assesses how the participant felt on their most, least, and average fatigue days in the past week as well as current fatigue. Participants score their level of fatigue for each item on an 11-point scale (0=not at all fatigued, 10=as fatigued as I could be). The composite severity score reflects the sum of these 4 scores. The composite severity scores can range from 0 to 40. A higher composite severity scores indicates that the participant is experiencing more severe fatigue.

Time frame: 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)

SF36 Bodily Pain Domain

The Bodily Pain (BP) domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical domains: physical function, physical role limitations, bodily pain, and general health, and 4 mental domains: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool derives SF36 domain scores for each of the eight domains. These domain scores are scaled to range from 0 to 100 with a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The BP domain scores indicate to what extent a participant's bodily pain hinders their performance of daily activities.

Time frame: 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)

SF36 Emotional Role Limitations Domain

Emotional Role Limitations (RE) Domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical domains: physical function, physical role limitations, bodily pain, and general health, and 4 mental domains: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool derives SF36 domain scores for each of the eight domains. These domain scores are scaled to range from 0 to 100 with a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The RE Domain score assesses the extent to which the emotional condition of the participant, e.g. feeling depressed or anxious, limits his/her daily functioning and ability to perform roles, such as in cutting down on the amount of time spent on work or other activities and accomplishing less than he/she would like to.

Time frame: 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)

SF36 General Health Domain

General Health (GH) Domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical domains: physical function, physical role limitations, bodily pain, and general health, and 4 mental domains: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool derives SF36 domain scores for each of the eight domains. These domain scores are scaled to range from 0 to 100 with a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The GH domain score assesses a participant's perception of their general health in terms of concepts such as excellent, very good, good, fair or poor, getting ill easier than other people, and just as healthy as anyone he/she knows.

Time frame: 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)

SF36 Mental Health Domain

Mental Health (MH) Domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical domains: physical function, physical role limitations, bodily pain, and general health, and 4 mental domains: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool derives SF36 domain scores for each of the eight domains. These domain scores are scaled to range from 0 to 100 with a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The MH domain assesses the extent to which the participant is, among other things, feeling full of pep, is happy, is feeling calm and peaceful, is very nervous, or is feeling worn out and tired.

Time frame: 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)

SF36 Physical Function Domain

Physical Function (PF) Domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical domains: physical function, physical role limitations, bodily pain, and general health, and 4 mental domains: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool derives SF36 domain scores for each of the eight domains. These domain scores are scaled to range from 0 to 100 with a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The PF domain assesses the extent to which the participant's perceptions of his/her ability to perform vigorous and moderate physical activities are influenced by his/her physical condition.

Time frame: 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)

SF36 Physical Role Limitations Domain

Physical Role Limitations (RP) Domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical domains: physical function, physical role limitations, bodily pain, and general health, and 4 mental domains: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool derives SF36 domain scores for each of the eight domains. These domain scores are scaled to range from 0 to 100 with a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The RP Domain assesses the extent to which a participant's' performance of his/her roles in daily activities is impeded by his/her physical state of health.

Time frame: 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)

SF36 Social Function Domain

Social Function (SF) Domain scores are derived from the SF36 Health Survey taken by the participant. The SF-36 is a validated questionnaire assessing 4 physical components: physical function, physical role limitations, bodily pain, and general health, and 4 mental components: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool is used to calculate each of the eight domain scores. The scoring tool transforms the score into a 0-100 scale on the assumption that each question carries equal weight. SF36 domain scores are scaled to have a population mean of 50 and a standard deviation of 10. The SF Domain assesses the level of a participant's social activities and interaction with significant others such as family members, friends, neighbours and other social relations. Lower scores indicate more disability; higher scores indicate less disability with respect to social function.

Time frame: 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)

SF36 Vitality Domain

Vitality (VT) Domain scores are derived from the SF36 Health Survey taken by the participant. SF36 domain scores are scaled to have a population mean of 50 and a standard deviation of 10. Higher scores reflect a better quality of life.The SF-36 is a validated questionnaire assessing 4 physical components: physical function, physical role limitations, bodily pain, and general health, and 4 mental components: vitality, emotional role limitations, social function and mental health. From the 36 questions asked, a scoring tool is used to calculate the eight domain scores. The scoring tool transforms the score into a 0-100 scale on the assumption that each question carries equal weight. SF36 domain scores are scaled to have a population mean of 50 and a standard deviation of 10. Lower scores indicate more disability; and, higher scores indicate less disability. The VT Domain assesses the participant's experience of feeling energetic and full of pep, or worn out and tired.

Time frame: 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)

Primary Bone Biopsy Measures Adjusted for HPTH Dose

The 8 primary bone biopsy measures were to be adjusted HPTH dose by fitting the primary bone biopsy model with both linear and quadratic dose covariates added to the model. However, the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively. To add additional linear and quadratic dose covariates to the statistical model with an already small sample sizes would highly risk over-parameterizing the model. Thus no new analysis was performed.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Sensitivity Analyses of Female Menopause Status in the Primary Bone Biopsy Efficacy Models

As a sensitivity analysis, the 8 primary bone biopsy measures were to be adjusted for female menopausal status, by fitting the primary bone biopsy model with a menopausal status covariate added to the model. However, the study was terminated early resulting in only 5, 5, and 2 participants having their biopsies at 1, 2, and 4 years respectively. Furthermore, 3 males would need to be removed from the model leaving 4, 3, 2 participants with bone biopsies with an additional degree of freedom consumed for the menopausal status covariate. Thus, the planned mixed models analysis was not performed since with such small samples sizes random fluctuations in the data could give misleading erroneous results.

Time frame: Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Z-score of 1/3 Radius Bone Mineralization Density (BMD) Assessed by DXA.

The DXA BMD measures were assessed every 6 months over 5 years, and at a follow-up visit post-HPTH therapy. Due to varying lengths of time on each participant was on HPTH, these BMD assessment times were collapsed for purposes of analysis to: baseline, 6-month on HPTH therapy, last visit on HPTH therapy, and the post-HPTH follow-up visit The 1/3 Radius BMD is one of 6 bone regions measurements of bone mineralization density assessed by DXA. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: 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)

Z-score of AP Spine Bone Mineralization Density (BMD) Assessed by DXA

The DXA BMD were assessed every 6 months over 5 years, and at a follow-up visit post-HPTH therapy. Due to varying lengths of time on each participant was on HPTH, these BMD assessment times were collapsed for purposes of analysis to: baseline, 6-month on HPTH therapy, last visit on HPTH therapy, and the post-HPTH follow-up visit. The AP Spine BMD is one of 6 bone regions measurements of bone mineralization density assessed by DXA. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits

Z-score of Femoral Neck Bone Mineralization Density (BMD) Assessed by DXA

The DXA BMD measures were assessed every 6 months over 5 years, and at a follow-up visit post-HPTH therapy. Due to varying lengths of time on each participant was on HPTH, these BMD assessment times were collapsed for purposes of analysis to: baseline, 6-month on HPTH therapy, last visit on HPTH therapy, and the post-HPTH follow-up visit. The Femoral BMD is one of 6 bone regions measurements of bone mineralization density assessed by DXA. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits

Z-score of Lateral Spine Bone Mineralization Density (BMD) Assessed by DXA

The DXA BMD were assessed every 6 months over 5 years, and at a follow-up visit post-HPTH therapy. Due to varying lengths of time on each participant was on HPTH, these BMD assessment times were collapsed for purposes of analysis to: baseline, 6-month on HPTH therapy, last visit on HPTH therapy, and the post-HPTH follow-up visit. The Lateral Spine BMD is one of 6 bone regions measurements of bone mineralization density assessed by DXA . The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits

Z-score of Total Hip Bone Mineralization Density (BMD) Assessed by DXA

The DXA BMD measures were assessed every 6 months over 5 years, and at a follow-up visit post-HPTH therapy. Due to varying lengths of time on each participant was on HPTH, these BMD assessment times were collapsed for purposes of analysis to: baseline, 6-month on HPTH therapy, last visit on HPTH therapy, and the post-HPTH follow-up visit. The Total Hip BMD is one of 6 bone regions measurements of bone mineralization density assessed by DXA. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits

Z-score of Whole Body Bone Mineralization Density (BMD) Assessed by DXA

The DXA BMD measures were assessed every 6 months over 5 years, and at a follow-up visit post-HPTH therapy. Due to varying lengths of time on each participant was on HPTH, these BMD assessment times were collapsed for purposes of analysis to: baseline, 6-month on HPTH therapy, last visit on HPTH therapy, and the post-HPTH follow-up visit. The Whole Body BMD is one of 6 bone regions measurements of bone mineralization density assessed by DXA. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

Time frame: Baseline, 6-months after start of HPTH, last visit on HPTH, and post-HPTH follow-up visits

Effects of PTH Replacement on Bone in Hypoparathyroidism

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes