Postmenopausal Osteoporosis
Conditions
Keywords
randomized controlled trial, osteoporosis, risedronate
Brief summary
The purpose of this trial is to study the efficacy of a single-dose monthly dosing regimen as compared to the standard daily dosing regimen of risedronate 5 mg daily.
Detailed description
The comparator arms of this risedronate study are 150 mg monthly and 5 mg daily.
Interventions
DRUGrisedronate
tablet, 5 mg risedronate, once a day for 2 years
Sponsors
Sanofi
Warner Chilcott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female: 50 years of age or older * \>5 years since last menses natural or surgical * have lumbar spine BMD (bone mineral density) more that 2.5 standard deviations (SD) below the young adult mean, or have 1-spine BMD more than 2.0 SD below the young adult female mean value and also have at least one prevalent vertebral body fracture
Exclusion criteria
* history of uncontrolled hyperparathyroidism, hyperthyroidism, osteomalacia * BMI (body mass index) \>32 kg/m\^2 * use of medications within 3 months of starting study drug that impact bone metabolism such as glucocorticoids, estrogens, calcitonin, calcitriol, other bisphosphonates and parathyroid hormone * hypocalcemia or hypercalcemia of any cause * markedly abnormal clinical laboratory measurements that are assessed as clinically significant by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 12-Endpoint in Women With Postmenopausal Osteoporosis, Primary Efficacy Population | Baseline to Month 12 - Endpoint | BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. LOCF - last observation carried forward (Last post-baseline measurement available to Month 12). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population | Baseline to Month 12 | BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. |
| Percent Change From Baseline in Lumbar Spine BMD at Month 24-Endpoint, Endpoint Population (Month 24) | Baseline to Month 24 - Endpoint | BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. LOCF - last observation carried forward (Last post-baseline measurement available to Month 24). |
| Percent Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population | Baseline to Month 24 | BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. |
| Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population | Baseline to Month 24 | BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. |
| Change From Baseline in Urine Type-1 Collagen Cross-linked-N-telopeptide Corrected for Creatinine Clearance (NTX/Cr) at Month 6, ITT Population | Baseline to Month 6 | Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24. nmol BCE / mmol Creatinine = nanomoles bone collagen equivalents / millimoles Creatinine |
| Percent Change From Baseline in Urine NTX/Cr at Month 6, ITT Population | Baseline to Month 6 | Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24. |
| Change From Baseline in Urine NTX/Cr at Month 24, ITT Population | Baseline to Month 24 | Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24. |
| Percent Change From Baseline in Urine NTX/Cr at Month 24, ITT Population | Baseline to Month 24 | Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24. |
| Change From Baseline in Serum Type-1 Collagen Cross-linked C-telopeptide (CTX) at Month 6, ITT Population | Baseline to Month 6 | ng / mL = nanograms / milliliter. Assayed by electrochemiluminescent immunoassay. |
| Percent Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population | Baseline to Month 12 | BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. |
| Change From Baseline in Serum CTX at Month 24, ITT Population | Baseline to Month 24 | Assayed by electrochemiluminescent immunoassay. |
| Percent Change From Baseline in Serum CTX at Month 24, ITT Population | Baseline to Month 24 | Assayed by electrochemiluminescent immunoassay. |
| Change From Baseline in Serum Bone-specific Alkaline Phosphatase (BAP) at Month 6, ITT Population | Baseline to Month 6 | ug / L = micrograms per liter, Assayed by ELISA (enzyme-linked immunosorbent assay) |
| Percent Change From Baseline in Serum BAP at Month 6, ITT Population | Baseline to Month 6 | Assayed by ELISA (enzyme-linked immunosorbent assay) |
| Change From Baseline in Serum BAP at Month 24, ITT Population | Baseline to Month 24 | Assayed by ELISA (enzyme-linked immunosorbent assay) |
| Percent Change From Baseline in Serum BAP at Month 24, ITT Population | Baseline to Month 24 | Assayed by ELISA (enzyme-linked immunosorbent assay) |
| Number of Participants With New Vertebral Fracture at Month 12, ITT Population | Baseline to Month 12 | At least 1 new fractured vertebra |
| Number of Participants With New Vertebral Fracture at Month 24, ITT Population | Baseline to Month 24 | At least 1 new fractured vertebra |
| Percent Change From Baseline in Serum CTX at Month 6, ITT Population | Baseline to Month 6 | Assayed by electrochemiluminescent immunoassay. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Estonia, Finland, France, Hungary, Lebanon, Norway, Poland, Spain, United States
Participant flow
Recruitment details
Screening period began 17 Oct '05
Participants by arm
| Arm | Count |
|---|---|
| 5 mg Risedronate 5 mg risedronate tablet, once daily for 2 years | 644 |
| 150 mg Risedronate 150 mg risedronate taken once a month for 2 years | 650 |
| Total | 1,294 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 85 | 80 |
| Overall Study | Did not take any study drug | 2 | 0 |
| Overall Study | Lost to Follow-up | 7 | 7 |
| Overall Study | Physician Decision | 6 | 3 |
| Overall Study | Withdrawal by Subject | 46 | 47 |
Baseline characteristics
| Characteristic | 5 mg Risedronate | 150 mg Risedronate | Total |
|---|---|---|---|
| Age Continuous | 64.4 years STANDARD_DEVIATION 7.7 | 65.5 years STANDARD_DEVIATION 7.2 | 64.9 years STANDARD_DEVIATION 7.5 |
| Age, Customized 65 - <75 years | 232 Partcipants | 268 Partcipants | 500 Partcipants |
| Age, Customized < 65 years | 335 Partcipants | 304 Partcipants | 639 Partcipants |
| Age, Customized > = 75 years | 75 Partcipants | 78 Partcipants | 153 Partcipants |
| Region of Enrollment Argentina | 302 participants | 304 participants | 606 participants |
| Region of Enrollment Australia | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Belgium | 13 participants | 14 participants | 27 participants |
| Region of Enrollment Canada | 19 participants | 19 participants | 38 participants |
| Region of Enrollment Estonia | 48 participants | 50 participants | 98 participants |
| Region of Enrollment Finland | 17 participants | 18 participants | 35 participants |
| Region of Enrollment France | 50 participants | 49 participants | 99 participants |
| Region of Enrollment Hungary | 22 participants | 22 participants | 44 participants |
| Region of Enrollment Lebanon | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Norway | 24 participants | 25 participants | 49 participants |
| Region of Enrollment Poland | 103 participants | 104 participants | 207 participants |
| Region of Enrollment Spain | 7 participants | 9 participants | 16 participants |
| Region of Enrollment United States | 24 participants | 23 participants | 47 participants |
| Sex: Female, Male Female | 644 Participants | 650 Participants | 1294 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 | 554 / 642 | 578 / 650 |
| serious Total, serious adverse events | 51 / 642 | 77 / 650 |
Outcome results
Primary
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 12-Endpoint in Women With Postmenopausal Osteoporosis, Primary Efficacy Population
BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. LOCF - last observation carried forward (Last post-baseline measurement available to Month 12).
Time frame: Baseline to Month 12 - Endpoint
Population: ITT (intent to treat) Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 12-Endpoint in Women With Postmenopausal Osteoporosis, Primary Efficacy Population | 3.425 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 12-Endpoint in Women With Postmenopausal Osteoporosis, Primary Efficacy Population | 3.540 Percent Change |
95% CI: [-0.505, 0.274]ANOVA
Secondary
Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population
BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment.
Time frame: Baseline to Month 12
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population | 0.0256 g/cm^2 |
| 150 mg Risedronate | Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population | 0.0261 g/cm^2 |
95% CI: [-0.0035, 0.0024]ANOVA
Secondary
Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population
BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment.
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population | 0.0309 g/cm^2 |
| 150 mg Risedronate | Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population | 0.0319 g/cm^2 |
95% CI: [-0.0048, 0.0029]ANOVA
Secondary
Change From Baseline in Serum BAP at Month 24, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay)
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Serum BAP at Month 24, ITT Population | -4.10 ug / L |
| 150 mg Risedronate | Change From Baseline in Serum BAP at Month 24, ITT Population | -4.22 ug / L |
95% CI: [-0.45, 0.7]ANOVA
Secondary
Change From Baseline in Serum Bone-specific Alkaline Phosphatase (BAP) at Month 6, ITT Population
ug / L = micrograms per liter, Assayed by ELISA (enzyme-linked immunosorbent assay)
Time frame: Baseline to Month 6
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Serum Bone-specific Alkaline Phosphatase (BAP) at Month 6, ITT Population | -5.31 ug / L |
| 150 mg Risedronate | Change From Baseline in Serum Bone-specific Alkaline Phosphatase (BAP) at Month 6, ITT Population | -5.48 ug / L |
95% CI: [-0.29, 0.64]ANOVA
Secondary
Change From Baseline in Serum CTX at Month 24, ITT Population
Assayed by electrochemiluminescent immunoassay.
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Serum CTX at Month 24, ITT Population | -0.22 ng / mL |
| 150 mg Risedronate | Change From Baseline in Serum CTX at Month 24, ITT Population | -0.20 ng / mL |
95% CI: [-0.06, 0.01]ANOVA
Secondary
Change From Baseline in Serum Type-1 Collagen Cross-linked C-telopeptide (CTX) at Month 6, ITT Population
ng / mL = nanograms / milliliter. Assayed by electrochemiluminescent immunoassay.
Time frame: Baseline to Month 6
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Serum Type-1 Collagen Cross-linked C-telopeptide (CTX) at Month 6, ITT Population | -0.36 ng / mL |
| 150 mg Risedronate | Change From Baseline in Serum Type-1 Collagen Cross-linked C-telopeptide (CTX) at Month 6, ITT Population | -0.34 ng / mL |
95% CI: [-0.05, 0]ANOVA
Secondary
Change From Baseline in Urine NTX/Cr at Month 24, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24.
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Urine NTX/Cr at Month 24, ITT Population | -28.88 nmol BCE / mmol Creatinine |
| 150 mg Risedronate | Change From Baseline in Urine NTX/Cr at Month 24, ITT Population | -29.87 nmol BCE / mmol Creatinine |
95% CI: [-2.54, 4.53]ANOVA
Secondary
Change From Baseline in Urine Type-1 Collagen Cross-linked-N-telopeptide Corrected for Creatinine Clearance (NTX/Cr) at Month 6, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24. nmol BCE / mmol Creatinine = nanomoles bone collagen equivalents / millimoles Creatinine
Time frame: Baseline to Month 6
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Change From Baseline in Urine Type-1 Collagen Cross-linked-N-telopeptide Corrected for Creatinine Clearance (NTX/Cr) at Month 6, ITT Population | -30.04 nmol BCE / mmol Creatinine |
| 150 mg Risedronate | Change From Baseline in Urine Type-1 Collagen Cross-linked-N-telopeptide Corrected for Creatinine Clearance (NTX/Cr) at Month 6, ITT Population | -30.26 nmol BCE / mmol Creatinine |
95% CI: [-2.83, 3.28]ANOVA
Secondary
Number of Participants With New Vertebral Fracture at Month 12, ITT Population
At least 1 new fractured vertebra
Time frame: Baseline to Month 12
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Risedronate | Number of Participants With New Vertebral Fracture at Month 12, ITT Population | 8 Participants |
| 150 mg Risedronate | Number of Participants With New Vertebral Fracture at Month 12, ITT Population | 8 Participants |
p-value: 195% CI: [0.36, 2.54]Fisher Exact
Secondary
Number of Participants With New Vertebral Fracture at Month 24, ITT Population
At least 1 new fractured vertebra
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Risedronate | Number of Participants With New Vertebral Fracture at Month 24, ITT Population | 14 Participants |
| 150 mg Risedronate | Number of Participants With New Vertebral Fracture at Month 24, ITT Population | 14 Participants |
p-value: 195% CI: [0.47, 2.03]Fisher Exact
Secondary
Percent Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population
BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment.
Time frame: Baseline to Month 12
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population | 3.522 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Lumbar Spine BMD at Month 12, ITT Population | 3.598 Percent Change |
95% CI: [-0.475, 0.323]ANOVA
Secondary
Percent Change From Baseline in Lumbar Spine BMD at Month 24-Endpoint, Endpoint Population (Month 24)
BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment. LOCF - last observation carried forward (Last post-baseline measurement available to Month 24).
Time frame: Baseline to Month 24 - Endpoint
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Lumbar Spine BMD at Month 24-Endpoint, Endpoint Population (Month 24) | 3.927 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Lumbar Spine BMD at Month 24-Endpoint, Endpoint Population (Month 24) | 4.166 Percent Change |
Comparison: The sample size of 1068 patients will provide approximately 90% power to demonstrate the noninferiority of the monthly regimen at month 24, using a 2% noninferiority margin and assuming a common SD of the percent change from baseline in lumbar spine BMD at month 24 of 5%, a 2-year dropout rate of 30%, and a true mean difference (uDaily-uMonthly) of 0.8%.95% CI: [-0.727, 0.249]ANOVA
Secondary
Percent Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population
BMD assessed using dual-energy x-ray absorptiometry (DXA) using Hologic or Lunar equipment.
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population | 4.217 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Lumbar Spine BMD at Month 24, ITT Population | 4.302 Percent Change |
95% CI: [-0.609, 0.439]ANOVA
Secondary
Percent Change From Baseline in Serum BAP at Month 24, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay)
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Serum BAP at Month 24, ITT Population | -25.84 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Serum BAP at Month 24, ITT Population | -25.07 Percent Change |
95% CI: [-3.96, 2.43]ANOVA
Secondary
Percent Change From Baseline in Serum BAP at Month 6, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay)
Time frame: Baseline to Month 6
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Serum BAP at Month 6, ITT Population | -33.34 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Serum BAP at Month 6, ITT Population | -34.66 Percent Change |
95% CI: [-0.85, 3.48]ANOVA
Secondary
Percent Change From Baseline in Serum CTX at Month 24, ITT Population
Assayed by electrochemiluminescent immunoassay.
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Serum CTX at Month 24, ITT Population | -29.33 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Serum CTX at Month 24, ITT Population | -23.63 Percent Change |
95% CI: [-12.04, 0.66]ANOVA
Secondary
Percent Change From Baseline in Serum CTX at Month 6, ITT Population
Assayed by electrochemiluminescent immunoassay.
Time frame: Baseline to Month 6
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Serum CTX at Month 6, ITT Population | -57.79 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Serum CTX at Month 6, ITT Population | -53.62 Percent Change |
95% CI: [-7.98, -0.36]ANOVA
Secondary
Percent Change From Baseline in Urine NTX/Cr at Month 24, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24.
Time frame: Baseline to Month 24
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Urine NTX/Cr at Month 24, ITT Population | -49.45 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Urine NTX/Cr at Month 24, ITT Population | -46.62 Percent Change |
95% CI: [-6.45, 0.8]ANOVA
Secondary
Percent Change From Baseline in Urine NTX/Cr at Month 6, ITT Population
Assayed by ELISA (enzyme-linked immunosorbent assay) for NTX and colorimetric assay for creatinine. Patient collected second urine voided between 6 and 9 am from day of clinic visit and day before clinic visit at Months 3, 6, 12 & 24.
Time frame: Baseline to Month 6
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 5 mg Risedronate | Percent Change From Baseline in Urine NTX/Cr at Month 6, ITT Population | -51.83 Percent Change |
| 150 mg Risedronate | Percent Change From Baseline in Urine NTX/Cr at Month 6, ITT Population | -50.26 Percent Change |
95% CI: [-4.47, 1.33]ANOVA