Osteoporosis, Postmenopausal
Conditions
Keywords
Breast cancer, postmenopausal, bone mineral density, Zoledronic acid, Letrozole, extended adjuvant treatment., Postmenopausal women with primary hormone receptor positive breast cancer
Brief summary
This was a prospective, randomized, open-label, two arm phase III trial designed to evaluate the efficacy and safety of zoledronic acid in preventing bone loss in postmenopausal women with operable breast cancer who had received 4 to 6 years of adjuvant tamoxifen therapy after resection of the tumor. Patients were treated with letrozole 2.5 mg orally per day or letrozole 2.5 mg orally per day in combination with zoledronic acid 4 mg/6 months as an infusion. This trial did not recruit patients in the United States.
Interventions
DRUGLetrozole
2.5 mg/day for 3 years
DRUGZoledronic acid
4 mg every 6 months
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Compliant postmenopausal women with primary operable breast cancer after 4 to 6 years of therapy with tamoxifen (end of tamoxifen therapy within last 6 months) * Performance status 0-2 (Eastern Cooperative Oncology Group) * Patients without severe osteoporosis at study entry * No evidence of relapse at the time of randomization * Adequate function of bone marrow, kidney, and liver
Exclusion criteria
* Estrogen- and progesterone-receptor status negative or unknown * Completion of adjuvant tamoxifen therapy more than 6 months prior to study start * Inflammatory breast cancer * Current/active dental problems including infection of the teeth or jawbone, dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw, of exposed bone in the mouth, or of slow healing after dental procedures. * Recent (within 6 weeks) or planned dental or jaw surgery * History of diseases with influence on bone metabolism such as Paget's disease and primary overactive parathyroid * Prior or concomitant therapies: chemotherapy within the last 12 months, intravenous or oral bisphosphonates, systemic corticosteroids, anabolic steroids or growth hormones, Tibolone, parathyroid hormone, systemic sodium fluoride or any drugs known to affect the skeleton (such as calcitonin, mithramycin, or gallium nitrate) * Patients with previous or concomitant cancers (not breast cancer) within the past 5 years EXCEPT adequately treated basal or squamous cell skin cancers or in situ cancer of the cervix. Patients with previous other cancer(s) must have been disease-free for at least 5 years. * Patients currently receiving oral bisphosphonates must discontinue these at least 3 weeks prior to study start. Additional protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Mineral Density (BMD) From Baseline to Month 36 | at 36 months as compared to baseline | Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD\*100. |
| Percent Change in Bone Mineral Density (BMD) From Baseline to Month 36 | Baseline, Month 36 | Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA) scan. ANCOVA model was used in the analysis where: Variable = Baseline, Center, Treatment BMD = (Month 36 BMD-Baseline BMD)/Baseline BMD\*100. |
| Change in T-score From Baseline to Month 36 | Baseline and Month 36 | BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman. |
| Change in Z Score From Baseline to Month 36 | Baseline, month 36 | Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Mineral Density From Baseline to 12 Months | Baseline, 12 months | Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD\*100. |
| Change in Z-Score From Baseline to Month 12 | Baseline, Month 12 | (DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis |
| Number of Participants With Any Kind of Fractures, by Visit. | Baseline, Month 6, 12, 18, 24 , 30 and 36 | Number of participants with fractures of any type since the last visit |
| Median Disease Free Survival (DFS) | 36 months | Disease Free Survival is measured in days and represents the number of days participants were progression free. Progression free survival is defined as the time from randomization to the date of the first documented progression or recurrence of disease or death from any cause. Median disease free survival is the time when 50% of the patients had a recurrence. |
| Change in T-Score From Baseline to Month 12 | Baseline, Month 12 | BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman. |
Countries
Germany
Participant flow
Pre-assignment details
Total Randomized participants were 83. 2 patients were enrolled but never received study medication. Hence, 81 were included in the safety population.
Participants by arm
| Arm | Count |
|---|---|
| Letrozole Letrozole 2.5 mg/day for 3 years | 37 |
| Letrozole + Zoledronic Acid Letrozole 2.5mg/day for 3 years plus Zoledronic acid 4mg every 6 months | 39 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal test procedure result | 1 | 0 |
| Overall Study | Administrative Problems | 0 | 3 |
| Overall Study | Adverse Event | 11 | 14 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Letrozole | Letrozole + Zoledronic Acid | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 39 Participants | 76 Participants |
| Age Continuous | 61.3 years STANDARD_DEVIATION 7.3 | 58.4 years STANDARD_DEVIATION 7.3 | 59.8 years STANDARD_DEVIATION 7.4 |
| Sex: Female, Male Female | 37 Participants | 39 Participants | 76 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 | 35 / 40 | 35 / 41 |
| serious Total, serious adverse events | 6 / 40 | 7 / 41 |
Outcome results
Primary
Change in Bone Mineral Density (BMD) From Baseline to Month 36
Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD\*100.
Time frame: at 36 months as compared to baseline
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Bone Mineral Density (BMD) From Baseline to Month 36 | -0.11 Percent | Standard Deviation 0.14 |
| Letrozole + Zoledronic Acid | Change in Bone Mineral Density (BMD) From Baseline to Month 36 | 0.03 Percent | Standard Deviation 0.08 |
Primary
Change in T-score From Baseline to Month 36
BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman.
Time frame: Baseline and Month 36
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy.Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in T-score From Baseline to Month 36 | -0.90 T-Score | Standard Deviation 1.03 |
| Letrozole + Zoledronic Acid | Change in T-score From Baseline to Month 36 | 0.46 T-Score | Standard Deviation 0.27 |
Primary
Change in Z Score From Baseline to Month 36
Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis.
Time frame: Baseline, month 36
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Z Score From Baseline to Month 36 | -0.31 Z-Score | Standard Deviation 0.35 |
| Letrozole + Zoledronic Acid | Change in Z Score From Baseline to Month 36 | 0.25 Z-Score | Standard Deviation 0.34 |
Primary
Percent Change in Bone Mineral Density (BMD) From Baseline to Month 36
Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA) scan. ANCOVA model was used in the analysis where: Variable = Baseline, Center, Treatment BMD = (Month 36 BMD-Baseline BMD)/Baseline BMD\*100.
Time frame: Baseline, Month 36
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Percent Change in Bone Mineral Density (BMD) From Baseline to Month 36 | -11.34 Percent Change in BMD | Standard Deviation 17.72 |
| Letrozole + Zoledronic Acid | Percent Change in Bone Mineral Density (BMD) From Baseline to Month 36 | 3.31 Percent Change in BMD | Standard Deviation 8.32 |
Secondary
Change in Bone Mineral Density From Baseline to 12 Months
Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD\*100.
Time frame: Baseline, 12 months
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Bone Mineral Density From Baseline to 12 Months | -0.04 g/cm^2 | Standard Deviation 0.04 |
| Letrozole + Zoledronic Acid | Change in Bone Mineral Density From Baseline to 12 Months | 0.02 g/cm^2 | Standard Deviation 0.05 |
Secondary
Change in T-Score From Baseline to Month 12
BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman.
Time frame: Baseline, Month 12
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations at both baseline and endpoint were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in T-Score From Baseline to Month 12 | -0.31 T-Score | Standard Deviation 0.35 |
| Letrozole + Zoledronic Acid | Change in T-Score From Baseline to Month 12 | 0.25 T-Score | Standard Deviation 0.34 |
Secondary
Change in Z-Score From Baseline to Month 12
(DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis
Time frame: Baseline, Month 12
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations at both baseline and endpoint were included in this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Letrozole | Change in Z-Score From Baseline to Month 12 | -0.26 Z-Score | Standard Deviation 0.35 |
| Letrozole + Zoledronic Acid | Change in Z-Score From Baseline to Month 12 | 0.37 Z-Score | Standard Deviation 0.38 |
Secondary
Median Disease Free Survival (DFS)
Disease Free Survival is measured in days and represents the number of days participants were progression free. Progression free survival is defined as the time from randomization to the date of the first documented progression or recurrence of disease or death from any cause. Median disease free survival is the time when 50% of the patients had a recurrence.
Time frame: 36 months
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. The median disease free survival was not observed because patients in the combination therapy did not have any recurrences.
Secondary
Number of Participants With Any Kind of Fractures, by Visit.
Number of participants with fractures of any type since the last visit
Time frame: Baseline, Month 6, 12, 18, 24 , 30 and 36
Population: (ITT) The study population will consist of post menopausal breast cancer patients who have completed 4 to 6 years of adjuvant Tamoxifen therapy after therapy. Participants with observations from baseline to month 36 were included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Month 12 | 0 Participants |
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Month 24 | 0 Participants |
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Month 6 | 0 Participants |
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Month 30 | 0 Participants |
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Month 18 | 0 Participants |
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Month 36 | 0 Participants |
| Letrozole | Number of Participants With Any Kind of Fractures, by Visit. | Baseline | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Month 36 | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Baseline | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Month 6 | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Month 12 | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Month 18 | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Month 24 | 0 Participants |
| Letrozole + Zoledronic Acid | Number of Participants With Any Kind of Fractures, by Visit. | Month 30 | 0 Participants |