Osteoporosis, Postmenopausal Osteoporosis
Conditions
Keywords
Osteoporosis, Parathyroid hormone, Teriparatide, Bone formation, Bone resorption
Brief summary
Parathyroid hormone (PTH) increases bone formation and thereby improves bone density and bone strength in postmenopausal women with osteoporosis. However, prolonged PTH treatment increases bone formation less and less over time. This study will test whether increasing the daily dose of PTH sustains its ability to improve bone formation, and optional sub-studies will test several potential reasons why PTH's effects on bone formation decline over time.
Detailed description
In women with postmenopausal osteoporosis, PTH increases bone mineral density more than anti-resorptive agents, and its use markedly reduces the incidence of new spine and non-spine fractures. Still, PTH is not a cure for osteoporosis in many patients because PTH-stimulated bone formation declines as PTH therapy continues. Biochemical analyses suggest that bone formation and resorption peak after 6 to 9 months of daily PTH therapy and then decline progressively. The study will last 18 months. Blood, urine, and bone density tests will occur at screening. At the start of the study, participants will be randomly assigned to one of two PTH dose regimens. Patients will go to Massachusetts General Hospital at Months 0, 3, 6, 9, 12, 15, and 18 for blood and urine collection. In addition, bone density tests by DXA will be performed at Months 0, 6, 12, and 18, and by quantitative CT scans at Months 0 and 18. Approximately 6 weeks after any change in PTH dose, each participant's blood calcium will be checked 4 to 6 hours after that day's PTH injection, and her 24-hour urine calcium excretion will also be checked. Participants may enroll in optional substudies that will test whether reduced skeletal responses to long-term treatment with PTH are accompanied by changes in its absorption and/or destruction and whether reduced skeletal responses to long-term treatment with PTH are accompanied by parallel reductions in kidney responses to PTH.
Interventions
DRUGsynthetic hPTH 1-34
Either daily treatment with self-injected hPTH 1-34 or ascending dose treatment at 6-month intervals of hPTH 1-34
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
46 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Three or more years after menopause * Bone mineral density T-score \< or = -2.0 by dual-energy x-ray absorptiometry (DXA) of vertebrae or femoral neck, or by quantitative computerized tomography (QCT) of vertebral body trabeculae
Exclusion criteria
* Cannot walk without assistance * Significant heart, kidney, liver, or malignant disease * Current alcohol abuse * Major psychiatric disorders * Other current or past disorders known to affect bone * Use of medications known to affect bone for \> 7 days in the past 12 months * Use of bisphosphonates or fluoride * Abnormal blood calcium, PTH, 25-hydroxy vitamin D, creatinine, liver function tests, or complete blood count * Elevated calcium levels in 24-hour urine collection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Indices of Bone Turnover | Each index of bone turnover was measured at study month 0, 1.5, 3, 6, 7.5, 9, 12, 13.5, 15, and 18. | Change from month 0 (pre-treatment) baseline serum aminoterminal propeptide of type I collagen (PINP), osteocalcin (OC), and C-terminal telopeptide (CTX), expressed as an area under the curve (AUC). Each marker measurement result was multiplied by the corresponding subject-specific elapsed study time interval using the trapezoidal rule, and these products were summed to generate a subject-specific AUC (months\*ng/ml) for the marker. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Mineral Density (BMD) | baseline and 18 months (12 months in 4 subjects) | Percent change in BMD of the spine, femur, radius, and ulna, and subtotal body, calculated as 100\*\[(final - month 0)/month 0\] in subjects who took study therapy for at least 12 months. |
Countries
United States
Participant flow
Recruitment details
Postmenopausal women with low bone density were recruited from 2004-2007 to participate in this study at a single academic medical center. Recruitment letters were sent to women in the Greater Boston area and the trial was also posted on clinicaltrials.gov.
Pre-assignment details
Must satisfy inclusion and exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Constant Dose PTH Participants received constant dose synthetic hPTH 1-34 (30 mcg/day). | 40 |
| Ascending Dose PTH Participants received ascending dose synthetic hPTH 1-34 (20-30-40 mcg/day). | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 10 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Ascending Dose PTH | Constant Dose PTH | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 14 Participants | 27 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 26 Participants | 53 Participants |
| Age Continuous | 62.1 years STANDARD_DEVIATION 8.9 | 63.3 years STANDARD_DEVIATION 7.6 | 62.7 years STANDARD_DEVIATION 8.2 |
| Region of Enrollment United States | 40 participants | 40 participants | 80 participants |
| Sex: Female, Male Female | 40 Participants | 40 Participants | 80 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 40 | 8 / 40 |
| serious Total, serious adverse events | 0 / 40 | 2 / 40 |
Outcome results
Primary
Changes in Indices of Bone Turnover
Change from month 0 (pre-treatment) baseline serum aminoterminal propeptide of type I collagen (PINP), osteocalcin (OC), and C-terminal telopeptide (CTX), expressed as an area under the curve (AUC). Each marker measurement result was multiplied by the corresponding subject-specific elapsed study time interval using the trapezoidal rule, and these products were summed to generate a subject-specific AUC (months\*ng/ml) for the marker.
Time frame: Each index of bone turnover was measured at study month 0, 1.5, 3, 6, 7.5, 9, 12, 13.5, 15, and 18.
Population: Because this was a physiologic study evaluating the impact of stepwise increases in teriparatide, per protocol analysis was performed as was pre-specified in our analysis plan. Outcomes data were analyzed in women who remained on teriparatide throughout the first stepwise increase (i.e. until month 12 or later).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Constant Dose PTH | Changes in Indices of Bone Turnover | PINP | 4418 months*(ng/ml - baseline ng/ml) | Standard Deviation 2732 |
| Constant Dose PTH | Changes in Indices of Bone Turnover | OC | 956 months*(ng/ml - baseline ng/ml) | Standard Deviation 416 |
| Constant Dose PTH | Changes in Indices of Bone Turnover | CTX | 22 months*(ng/ml - baseline ng/ml) | Standard Deviation 11 |
| Ascending Dose PTH | Changes in Indices of Bone Turnover | OC | 822 months*(ng/ml - baseline ng/ml) | Standard Deviation 312 |
| Ascending Dose PTH | Changes in Indices of Bone Turnover | PINP | 3696 months*(ng/ml - baseline ng/ml) | Standard Deviation 1735 |
| Ascending Dose PTH | Changes in Indices of Bone Turnover | CTX | 19 months*(ng/ml - baseline ng/ml) | Standard Deviation 9 |
Secondary
Change in Bone Mineral Density (BMD)
Percent change in BMD of the spine, femur, radius, and ulna, and subtotal body, calculated as 100\*\[(final - month 0)/month 0\] in subjects who took study therapy for at least 12 months.
Time frame: baseline and 18 months (12 months in 4 subjects)
Population: Final BMD was measured after 18 months of study therapy in 48 subjects and measured after 12 months of study therapy in 4 others who thereafter dropped out prematurely. Of the latter 4, 3 were in the ascending dose arm and 1 was in the constant dose arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Constant Dose PTH | Change in Bone Mineral Density (BMD) | Femoral neck BMD | 1.7 percent change | Standard Deviation 3 |
| Constant Dose PTH | Change in Bone Mineral Density (BMD) | Subtotal BMD | -1.6 percent change | Standard Deviation 0.8 |
| Constant Dose PTH | Change in Bone Mineral Density (BMD) | Spine BMD | 5.9 percent change | Standard Deviation 4.6 |
| Constant Dose PTH | Change in Bone Mineral Density (BMD) | Total hip BMD | 1.4 percent change | Standard Deviation 3.1 |
| Constant Dose PTH | Change in Bone Mineral Density (BMD) | 1/3 Radius BMD | -4.6 percent change | Standard Deviation 2.8 |
| Ascending Dose PTH | Change in Bone Mineral Density (BMD) | Total hip BMD | 1.3 percent change | Standard Deviation 2.5 |
| Ascending Dose PTH | Change in Bone Mineral Density (BMD) | 1/3 Radius BMD | -3.1 percent change | Standard Deviation 3.3 |
| Ascending Dose PTH | Change in Bone Mineral Density (BMD) | Femoral neck BMD | 3.5 percent change | Standard Deviation 2.7 |
| Ascending Dose PTH | Change in Bone Mineral Density (BMD) | Spine BMD | 7.4 percent change | Standard Deviation 3.8 |
| Ascending Dose PTH | Change in Bone Mineral Density (BMD) | Subtotal BMD | -0.9 percent change | Standard Deviation 0.5 |