Post Menopausal Osteoporosis
Conditions
Brief summary
This study will compare the effectiveness of denosumab treatment every 6 months with once yearly zoledronic acid treatment on bone mineral density (BMD) at various skeletal sites.
Interventions
BIOLOGICALDenosumab
Denosumab 60 mg administered by subcutaneous injection once every 6 months.
DRUGZoledronic Acid
Zoledronic acid 5 mg administered by intravenous infusion once a year
Administered by subcutaneous injection once every 6 months
Administered by intravenous infusion once a year
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ambulatory postmenopausal women. * Age 55 years or older * Subject has provided informed consent prior to any study specific procedures * Received oral bisphosphonate therapy for osteoporosis at least 2 years prior to screening visit * Screening BMD (g/cm²) values at the lumbar spine, total hip or femoral neck values of equal to or less than those listed in the protocol. * At least 2 lumbar vertebrae and one hip must be evaluable by dual energy x-ray absorptiometry (DXA) at the screening visit
Exclusion criteria
* Received other osteoporosis treatment or bone active treatment * Evidence of history of any of the following: * hyperthyroidism (stable on antithyroid therapy is allowed) * hypothyroidism (stable on thyroid replacement therapy is allowed) * hypo- or hyperparathyroidism * hypo- or hypercalcemia based on the central laboratory reference ranges * Recent tooth extraction (within 6 months of screening visit) * Paget disease of bone (subject report or chart review) * other bone diseases which affect bone metabolism (eg, osteopetrosis, osteogenesis imperfecta) (chart review) * Abnormalities of the following per central laboratory reference ranges: * vitamin D deficiency (25\[OH\] vitamin D level \< 20 ng/mL), repletion will be allowed and subjects may be re-screened * hypercalcemia * elevated transaminases ≥ 2.0 x upper limits of normal (ULN) * History of any solid organ or bone marrow transplant * Malignancy (except nonmelanoma skin cancers, cervical or breast ductal carcinoma in situ) within the last 5 years * Known intolerance to calcium or vitamin D supplements * Self-reported alcohol or drug abuse within 12 months prior to screening * Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s) * History or evidence of any other clinically significant disorder, condition or disease that in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis | Baseline and Month 12 | Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging facility. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis | Baseline and Month 12 | BMD of the hip was measured by DXA. DXA scans were analyzed by a central imaging facility. |
| Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis | Baseline and Month 12 | — |
| Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis | Baseline and Month 12 | — |
Countries
Australia, Belgium, Canada, Denmark, Poland, Spain, United States
Participant flow
Recruitment details
This study was conducted at 37 centers in Belgium, Denmark, Poland, Spain, Canada, United States of America, and Australia. The first participant enrolled on 07 November 2012 and the last participant enrolled on 15 January 2014.
Pre-assignment details
Participants were randomized in a 1:1 allocation ratio to receive either denosumab or zoledronic acid. Randomization was stratified by screening serum type I collagen C-telopeptide (sCTX) values (\< 0.3 ng/mL, 0.3 to 0.5 ng/mL).
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid 5 mg Q12M Participants received zoledronic acid 5 mg by intravenous infusion once every 12 months (Q12M) on Day 1 and placebo to denosumab by subcutaneous injection on Day 1 and at Month 6. | 322 |
| Denosumab 60 mg Q6M Participants received denosumab 60 mg subcutaneous injection once every 6 months (Q6M) for 12 months and placebo to zoledronic acid by intravenous infusion on Day 1. | 321 |
| Total | 643 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Decision by Sponsor | 2 | 2 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Denosumab 60 mg Q6M | Zoledronic Acid 5 mg Q12M | Total |
|---|---|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 7.1 | 69.5 years STANDARD_DEVIATION 7.7 | 69.0 years STANDARD_DEVIATION 7.4 |
| Body Mass Index (BMI) | 24.27 kg/m² STANDARD_DEVIATION 3.99 | 24.31 kg/m² STANDARD_DEVIATION 4.18 | 24.29 kg/m² STANDARD_DEVIATION 4.08 |
| Femoral Neck BMD T-score | -2.17 T-score STANDARD_DEVIATION 0.66 | -2.17 T-score STANDARD_DEVIATION 0.68 | -2.17 T-score STANDARD_DEVIATION 0.67 |
| Historical Fractures Any prior fracture | 169 participants | 159 participants | 328 participants |
| Historical Fractures Prior osteoporotic fracture | 120 participants | 121 participants | 241 participants |
| Lumbar Spine Bone Mineral Density (BMD) T-score | -2.74 T-score STANDARD_DEVIATION 0.83 | -2.64 T-score STANDARD_DEVIATION 0.86 | -2.69 T-score STANDARD_DEVIATION 0.84 |
| Prior Oral Bisphosphonate Duration | 6.21 years STANDARD_DEVIATION 3.84 | 6.35 years STANDARD_DEVIATION 3.68 | 6.28 years STANDARD_DEVIATION 3.76 |
| Race/Ethnicity, Customized Asian | 5 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Multiple | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Other | 4 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized White | 309 participants | 314 participants | 623 participants |
| Screening serum CTX < 0.3 ng/mL | 239 participants | 242 participants | 481 participants |
| Screening serum CTX ≥ 0.3 ng/mL | 82 participants | 78 participants | 160 participants |
| Screening serum CTX Missing | 0 participants | 2 participants | 2 participants |
| Sex: Female, Male Female | 321 Participants | 322 Participants | 643 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Total Hip BMD T-score | -1.93 T-score STANDARD_DEVIATION 0.74 | -1.93 T-score STANDARD_DEVIATION 0.8 | -1.93 T-score STANDARD_DEVIATION 0.77 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 320 | 15 / 320 |
| serious Total, serious adverse events | 29 / 320 | 25 / 320 |
Outcome results
Primary
Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis
Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging facility.
Time frame: Baseline and Month 12
Population: The primary efficacy analysis set includes all randomized participants who have a baseline BMD measurement and at least one postbaseline BMD measurement. Any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, last observation carried forward \[LOCF\]).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Zoledronic Acid 5 mg Q12M | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis | 1.1 percent change |
| Denosumab 60 mg Q6M | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 - Non-inferiority Analysis | 3.2 percent change |
Comparison: A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%.p-value: <0.000195% CI: [1.6, 2.6]ANCOVA
Secondary
Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis
Time frame: Baseline and Month 12
Population: The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Zoledronic Acid 5 mg Q12M | Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis | 1.1 percent change |
| Denosumab 60 mg Q6M | Percent Change From Baseline in Lumbar Spine BMD at Month 12 - Superiority Analysis | 3.2 percent change |
Comparison: A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%.p-value: <0.000195% CI: [1.6, 2.6]ANCOVA
Secondary
Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis
BMD of the hip was measured by DXA. DXA scans were analyzed by a central imaging facility.
Time frame: Baseline and Month 12
Population: The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Zoledronic Acid 5 mg Q12M | Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis | 0.6 percent change |
| Denosumab 60 mg Q6M | Percent Change From Baseline in Total Hip BMD at Month 12 - Non-inferiority Analysis | 1.9 percent change |
Comparison: A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the non-inferiority analysis the 1-sided significance level was 2.5%.p-value: <0.000195% CI: [1, 1.7]ANCOVA
Secondary
Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis
Time frame: Baseline and Month 12
Population: The primary efficacy analysis set; any postbaseline BMD value obtained at the early termination visit was carried forward as the month 12 value (ie, LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Zoledronic Acid 5 mg Q12M | Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis | 0.6 percent change |
| Denosumab 60 mg Q6M | Percent Change From Baseline in Total Hip BMD at Month 12 - Superiority Analysis | 1.9 percent change |
Comparison: A step-down sequential testing procedure was used in order to maintain the overall type I error rate at 5% for the tests of primary and secondary BMD endpoints. For the superiority analysis the 2-sided significance level was 5%.p-value: <0.000195% CI: [1, 1.7]ANCOVA