Osteopenia, Osteoporosis
Conditions
Keywords
Osteoporosis, Osteopenia, AMG 162, Fracture - hip, Postmenopausal
Brief summary
The purpose of this study is to determine whether in postmenopausal women with low bone mineral density, the mean percent change in total hip BMD in subjects receiving denosumab is not less than that observed in subjects receiving alendronate sodium by more than a pre-specified non-inferiority margin.
Interventions
DRUGAlendronate
ALN; 70 mg; oral; once weekly
DRUGDenosumab
60 mg; SC; every 6 months
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Patient is an ambulatory postmenopausal woman - Patient has BMD value that corresponds to a T-score of less than or equal to -2.0 (g/cm2) at the lumbar spine OR total hip within range specific to the study protocol.
Exclusion criteria
o Any disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures * Evidence of any of the following per subject report, chart review or central laboratory result: 1. Hyper- or hypothyroidism; however, subjects on stable thyroid hormone replacement therapy may be allowed per the following criteria: * If TSH level is normal, subject is eligible for the study. * If TSH level is below normal range, subject is not eligible for the study. * If TSH level is elevated (\> 5.5 mIU/mL to 10.0 mIU/mL), serum T4 should be measured. If serum T4 is within normal range, subject is eligible. If serum T4 is outside of normal range, subject is not eligible for the study. * If TSH level is above 10.0 mIU/mL, subject is not eligible. 2. Current hyper- or hypoparathyroidism 3. Elevated transaminases * Serum aspartate aminotransferase (AST; serum glutamate-oxaloacetic transaminase \[SGOT\]) ³ 2.0 x upper limits of normal (ULN) * Serum alanine aminotransferase (ALT; serum glutamate-pyruvate transaminase \[SGPT\]) ³ 2.0 x ULN 4. Significantly impaired renal function as determined by serum creatinine ³ 2.0 mg/dL 5. Current hypo- or hypercalcemia based on the central laboratory reference ranges 6. Active gastric or duodenal ulcer; history of significant gastrointestinal bleed requiring hospitalization or transfusion, or dyspepsia or gastroesophageal reflux disease that is uncontrolled by medication 7. Rheumatoid Arthritis, Paget's disease, Cushing's disease, hyperprolactinemia, or cirrhosis of the liver 8. Known to have tested positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen 9. Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years 10. Any metabolic bone disease, eg, osteomalacia or osteogenesis imperfecta, which may interfere with the interpretation of the findings 11. Malabsorption syndrome or any gastrointestinal disorders that are associated with malabsorption * Received any solid organ or bone marrow transplant * Vitamin D deficiency (25(OH) vitamin D level \< 12 ng/mL). Vitamin D repletion will be permitted and subjects may be re-screened; see Section 7. * Any laboratory abnormality which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results * Contraindicated or poorly tolerant of ALN therapy; contraindications for ALN therapy include: 1. Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia. 2. Inability to stand or sit upright for at least 30 minutes. 3. Hypersensitivity to ALN or other constituents of ALN tablets o Known sensitivity to mammalian cell derived drug products * Known intolerance to calcium supplements * Administration of intravenous bisphosphonate, or fluoride (except for dental treatment) or strontium ranelate * Oral bisphosphonate treatment: * ³ 3 months cumulatively in the past 2 years, OR * ³ 1 month in the past year, OR * Any use during the 3-month period prior to randomization * PTH or PTH derivatives (eg, teriparatide) within the last year * Administration of any of the following treatments within 3 months of randomization: 1. Any SERM (eg, raloxifene) 2. Tibolone 3. Anabolic steroids or testosterone 4. Glucocorticosteroids (³ 5 mg prednisone equivalent per day for more than 10 days) 5. Systemic (oral, transdermal, topical) hormone replacement therapy (local vaginal estrogen preparation will be allowed) 6. Calcitonin 7. Calcitriol or vitamin D derivatives 8. Other bone active drugs including anti-convulsives (except benzodiazepines) and heparin 9. Chronic systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, gonadotropin-releasing hormone agonists 10. Height, weight or girth which may preclude accurate DXA measurements * Less than 2 lumbar vertebrae (L1-L4) evaluable for DXA measurements * Both hips not evaluable by DXA (eg, history of bilateral hip replacement or pins in both hips) * Currently enrolled in or has not yet completed at least 1 month since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s) * Any physical or psychiatric disorder which, in the opinion of the investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results * Evidence of alcohol or substance-abuse within the last 12 months which the investigator believes would interfere with understanding or completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 | 12 months | Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 | 12 months | Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. |
| Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 | 12 months | Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. |
| Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 | 12 months | Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. |
| Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 | 12 months | Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. |
Participant flow
Recruitment details
First Subject Enrolled: 26-Apr-2006 Last Subject Enrolled: 17-Nov-2006
Participants by arm
| Arm | Count |
|---|---|
| Alendronate 70 mg QW | 595 |
| Denosumab 60 mg Q6M | 594 |
| Total | 1,189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 8 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Ineligibility determined | 1 | 3 |
| Overall Study | Lost to Follow-up | 8 | 3 |
| Overall Study | Noncompliance | 2 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 18 | 17 |
Baseline characteristics
| Characteristic | Alendronate 70 mg QW | Denosumab 60 mg Q6M | Total |
|---|---|---|---|
| Age Continuous | 64.6 Years STANDARD_DEVIATION 8.3 | 64.1 Years STANDARD_DEVIATION 8.6 | 64.4 Years STANDARD_DEVIATION 8.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 8 Participants | 6 Participants | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 7 Participants | 16 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 69 Participants | 66 Participants | 135 Participants |
| Race/Ethnicity, Customized Japanese | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 7 Participants | 10 Participants |
| Race/Ethnicity, Customized White or Caucasian | 502 Participants | 502 Participants | 1004 Participants |
| Sex: Female, Male Female | 595 Participants | 594 Participants | 1189 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 | 261 / 586 | 270 / 593 |
| serious Total, serious adverse events | 37 / 586 | 34 / 593 |
Outcome results
Primary
Total Hip Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months
Population: Randomized subjects who have a nonmissing baseline and at least 1 nonmissing postbaseline evaluation at or prior to month 12. LOCF used as imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Alendronate 70 mg QW | Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 | 2.6 Percent Change from Baseline |
| Denosumab 60 mg Q6M | Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 | 3.5 Percent Change from Baseline |
p-value: <0.000195% CI: [0.7, 1.2]ANCOVA
Secondary
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Alendronate 70 mg QW | Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 | 0.6 Percent Change from Baseline |
| Denosumab 60 mg Q6M | Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 | 1.1 Percent Change from Baseline |
p-value: 0.000195% CI: [0.3, 0.9]ANCOVA
Secondary
Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Alendronate 70 mg QW | Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 | 1.8 Percent Change from Baseline |
| Denosumab 60 mg Q6M | Femoral Neck Bone Mineral Density Percent Change From Baseline at Month 12 | 2.4 Percent Change from Baseline |
p-value: <0.000195% CI: [0.3, 1]ANCOVA
Secondary
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Alendronate 70 mg QW | Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 | 4.2 Percent Change from Baseline |
| Denosumab 60 mg Q6M | Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 | 5.3 Percent Change from Baseline |
p-value: <0.000195% CI: [0.7, 1.4]ANCOVA
Secondary
Trochanter Bone Mineral Density Percent Change From Baseline at Month 12
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Alendronate 70 mg QW | Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 | 3.4 Percent Change from Baseline |
| Denosumab 60 mg Q6M | Trochanter Bone Mineral Density Percent Change From Baseline at Month 12 | 4.5 Percent Change from Baseline |
p-value: <0.000195% CI: [0.6, 1.4]ANCOVA