Steroid-induced Osteopor, Glucocorticoid-induced Ostepor
Conditions
Keywords
GIOP, Glucocorticoid, osteporosis, denosumab, BMD, Bone Mineral Density
Brief summary
This is a 2-year study to evaluate the effect of denosumab versus risedronate in adults with glucocorticoid-induced osteoporosis.
Interventions
DRUGDenosumab
Administered by subcutaneous injection once every 6 months
DRUGPlacebo for risendronate
Administered orally once a day
DRUGRisendronate
Administered orally once a day
DRUGPlacebo for denosumab
Administered by subcutaneous injection once every 6 months
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Men and women 18 years of age or older who have been taking glucocorticoid treatment. Men and women who are less than 50 years of age must have had a fracture as an adult to be eligible. Men and women who are 50 years of age or older who have been taking glucocorticoids must meet protocol-specific BMD criteria.
Exclusion criteria
Use of agents affecting bone metabolism, use of more than one biologic agent for inflammatory disease, history of bone disease (except osteoporosis), low vitamin D level (one can enter the trial after vitamin D levels are corrected), abnormalities of blood calcium, an underactive or overactive thyroid condition that is not treated and stable, Addison's disease, any abnormality of the parathyroid glands (the glands that control blood calcium), currently pregnant or planning a pregnancy, currently breast feeding, and other criteria may apply.
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 at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis) | Baseline and month 12 | Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). |
| Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12 | Baseline and month 12 | Bone mineral density at the total hip was measured by dual-energy x-ray absorptiometry (DXA). |
| Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24 | Baseline and month 24 | Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA). |
| Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24 | Baseline and month 24 | Bone mineral density at the total hip was measured by dual-energy x-ray absorptiometry (DXA). |
Countries
Argentina, Belgium, Canada, Colombia, Czechia, Denmark, France, Germany, Hungary, Mexico, Netherlands, Poland, Russia, South Korea, Spain, United States
Participant flow
Recruitment details
Participants were enrolled at 79 centers in Europe, North America, Latin America, and Korea from 28 March 2012 to 30 June 2015. Participants who had been taking glucocorticoids for at least 3 months were classed as glucocorticoid continuing; those who were taking glucocorticoids for less than 3 months were classed as glucocorticoid initiating.
Pre-assignment details
Eligible patients were randomly assigned in a 1:1 ratio to receive 60 mg denosumab every 6 months or 5 mg oral risedronate daily for 24 months within each subpopulation. Randomization was stratified by sex within each subpopulation.
Participants by arm
| Arm | Count |
|---|---|
| Risedronate: Glucocorticoid-initiating Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18. | 145 |
| Denosumab: Glucocorticoid-initiating Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months. | 145 |
| Risedronate: Glucocorticoid-continuing Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18. | 252 |
| Denosumab: Glucocorticoid-continuing Participants received 60 mg denosumab by subcutaneous injection on day 1 and at months 6, 12, and 18. Participants also received placebo to risedronate orally once a day for 24 months. | 253 |
| Total | 795 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative decision | 1 | 1 | 1 | 0 |
| Overall Study | Adverse Event | 7 | 7 | 9 | 12 |
| Overall Study | Death | 3 | 2 | 8 | 9 |
| Overall Study | Lost to Follow-up | 1 | 3 | 13 | 5 |
| Overall Study | Noncompliance | 1 | 2 | 4 | 3 |
| Overall Study | Other | 0 | 0 | 4 | 2 |
| Overall Study | Protocol deviation | 0 | 1 | 0 | 1 |
| Overall Study | Requirement for Alternative Therapy | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 15 | 20 | 34 | 34 |
Baseline characteristics
| Characteristic | Risedronate: Glucocorticoid-initiating | Denosumab: Glucocorticoid-initiating | Risedronate: Glucocorticoid-continuing | Denosumab: Glucocorticoid-continuing | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 10 | 67.5 years STANDARD_DEVIATION 10.1 | 61.3 years STANDARD_DEVIATION 11.1 | 61.5 years STANDARD_DEVIATION 11.6 | 63.1 years STANDARD_DEVIATION 11.1 |
| Age, Customized 50 - 64 years | 75 Participants | 55 Participants | 130 Participants | 114 Participants | 374 Participants |
| Age, Customized < 50 years | 5 Participants | 2 Participants | 26 Participants | 33 Participants | 66 Participants |
| Age, Customized 65 - 74 years | 38 Participants | 50 Participants | 62 Participants | 73 Participants | 223 Participants |
| Age, Customized ≥ 75 years | 27 Participants | 38 Participants | 34 Participants | 33 Participants | 132 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 20 Participants | 54 Participants | 43 Participants | 135 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 127 Participants | 125 Participants | 198 Participants | 210 Participants | 660 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Lumbar Spine Bone Mineral Density (BMD) T-score Glucocorticoid-continuing Subpopulation | — | — | -1.96 T-score STANDARD_DEVIATION 1.38 | -1.92 T-score STANDARD_DEVIATION 1.38 | -1.94 T-score STANDARD_DEVIATION 1.38 |
| Lumbar Spine Bone Mineral Density (BMD) T-score Glucocorticoid-initiating Subpopulation | -1.06 T-score STANDARD_DEVIATION 1.57 | -0.92 T-score STANDARD_DEVIATION 1.86 | — | — | -0.99 T-score STANDARD_DEVIATION 1.72 |
| Menopausal Status Postmenopause | 83 Participants | 82 Participants | 157 Participants | 159 Participants | 481 Participants |
| Menopausal Status Premenopause | 7 Participants | 10 Participants | 25 Participants | 24 Participants | 66 Participants |
| Menopausal Status Unknown | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 9 Participants | 12 Participants | 6 Participants | 36 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 4 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 12 Participants | 11 Participants | 13 Participants | 47 Participants |
| Race/Ethnicity, Customized White | 123 Participants | 122 Participants | 223 Participants | 230 Participants | 698 Participants |
| Sex: Female, Male Female | 93 Participants | 93 Participants | 185 Participants | 185 Participants | 556 Participants |
| Sex: Female, Male Male | 52 Participants | 52 Participants | 67 Participants | 68 Participants | 239 Participants |
| Total Hip BMD T-score Glucocorticoid-continuing Subpopulation | — | — | -1.56 T-score STANDARD_DEVIATION 0.96 | -1.66 T-score STANDARD_DEVIATION 0.96 | -1.61 T-score STANDARD_DEVIATION 0.96 |
| Total Hip BMD T-score Glucocorticoid-initiating Subpopulation | -0.98 T-score STANDARD_DEVIATION 1.07 | -1.14 T-score STANDARD_DEVIATION 1 | — | — | -1.06 T-score STANDARD_DEVIATION 1.04 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 385 | 13 / 394 |
| other Total, other adverse events | 76 / 385 | 77 / 394 |
| serious Total, serious adverse events | 98 / 385 | 92 / 394 |
Outcome results
Primary
Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis)
Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
Time frame: Baseline and month 12
Population: Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Risedronate: Glucocorticoid-initiating | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis) | 0.8 percent change |
| Denosumab: Glucocorticoid-initiating | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis) | 3.8 percent change |
| Risedronate: Glucocorticoid-continuing | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis) | 2.3 percent change |
| Denosumab: Glucocorticoid-continuing | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Non-inferiority Analysis) | 4.4 percent change |
Comparison: Analyses of the primary and secondary endpoints were performed independently within the glucocorticoid-continuing and glucocorticoid-initiating subpopulations. A fixed-sequence testing procedure was used to control the experiment-wise type 1 error rate at a two-sided 5% significance level within each subpopulation.~The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD, sex, machine type, and baseline BMD-by-machine type interaction.p-value: <0.00195% CI: [2, 3.9]ANCOVA
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use (\< 12 months vs ≥ 12 months).p-value: <0.00195% CI: [1.4, 3]ANCOVA
Secondary
Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis)
Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
Time frame: Baseline and month 12
Population: Randomized participants with a baseline and month 12 measurement for the lumbar spine BMD.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Risedronate: Glucocorticoid-initiating | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis) | 0.8 percent change |
| Denosumab: Glucocorticoid-initiating | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis) | 3.8 percent change |
| Risedronate: Glucocorticoid-continuing | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis) | 2.3 percent change |
| Denosumab: Glucocorticoid-continuing | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12 (Superiority Analysis) | 4.4 percent change |
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction.p-value: <0.00195% CI: [2, 3.9]ANCOVA
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use (\< 12 months vs ≥ 12 months).p-value: <0.00195% CI: [1.4, 3]ANCOVA
Secondary
Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24
Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
Time frame: Baseline and month 24
Population: Randomized participants with a baseline and month 24 measurement for the lumbar spine BMD.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Risedronate: Glucocorticoid-initiating | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24 | 1.7 percent change |
| Denosumab: Glucocorticoid-initiating | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24 | 6.2 percent change |
| Risedronate: Glucocorticoid-continuing | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24 | 3.2 percent change |
| Denosumab: Glucocorticoid-continuing | Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 24 | 6.4 percent change |
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction.p-value: <0.00195% CI: [3.2, 5.8]ANCOVA
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use (\< 12 months vs ≥ 12 months).p-value: <0.00195% CI: [2, 4.3]ANCOVA
Secondary
Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12
Bone mineral density at the total hip was measured by dual-energy x-ray absorptiometry (DXA).
Time frame: Baseline and month 12
Population: Randomized participants with a baseline and month 12 measurement for the total hip BMD.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Risedronate: Glucocorticoid-initiating | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12 | 0.2 percent change |
| Denosumab: Glucocorticoid-initiating | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12 | 1.7 percent change |
| Risedronate: Glucocorticoid-continuing | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12 | 0.6 percent change |
| Denosumab: Glucocorticoid-continuing | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12 | 2.1 percent change |
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction.p-value: <0.00195% CI: [0.8, 2.1]ANCOVA
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use (\< 12 months vs ≥ 12 months).p-value: <0.00195% CI: [1, 2.1]ANCOVA
Secondary
Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24
Bone mineral density at the total hip was measured by dual-energy x-ray absorptiometry (DXA).
Time frame: Baseline and month 24
Population: Randomized participants with a baseline and month 24 measurement for the total hip BMD.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Risedronate: Glucocorticoid-initiating | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24 | -0.0 percent change |
| Denosumab: Glucocorticoid-initiating | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24 | 3.1 percent change |
| Risedronate: Glucocorticoid-continuing | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24 | 0.5 percent change |
| Denosumab: Glucocorticoid-continuing | Percent Change From Baseline in Total Hip Bone Mineral Density at Month 24 | 2.9 percent change |
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-initiating subpopulation was analyzed using an ANCOVA model adjusting for treatment, baseline BMD value, sex, machine type, and baseline BMD value-by-machine type interaction.p-value: <0.00195% CI: [2.2, 3.9]ANCOVA
Comparison: Analyses of the primary and secondary endpoints were performed independently within each subpopulation using a fixed-sequence testing procedure to control the experiment-wise type 1 error rate at a two-sided 5% significance level.~The glucocorticoid-continuing subpopulation was analyzed using an ANCOVA model adjusted for treatment, baseline BMD, sex, machine type, baseline BMD-by-machine type interaction, and duration of prior glucocorticoid use (\< 12 months vs ≥ 12 months).p-value: <0.00195% CI: [1.7, 3.2]ANCOVA