Bone Loss, Breast Cancer
Conditions
Keywords
Bone Loss, Osteopenia, Breast cancer, letrozole, zoledronic acid, postmenopausal
Brief summary
Post-menopausal breast cancer patients will receive letrozole 2.5 mg daily for the treatment of breast cancer and will be randomized to a treatment group to receive either upfront zoledronic acid 4 mg IV 15-minute infusion every 6 months or delayed start zoledronic acid 4 mg IV 15-minute infusion every 6 months. Delayed start zoledronic acid will be initiated when either the Bone Mineral Density T-score is below -2 Standard Deviations at either the lumbar spine or hip or any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the month 36 scheduled visit. Letrozole 2.5 mg will be given daily for 5 years.
Interventions
DRUGZoledronic acid
Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months.
DRUGLetrozole
Letrozole tablets 2.5 mg/day taken orally for 5 years.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
* Stage I-IIIa breast cancer * Postmenopausal or recently postmenopausal * Recent surgery for breast cancer * Estrogen Receptor positive and/or progesterone receptor positive hormone receptor status * No prior treatment with letrozole Other protocol-defined inclusion criteria may apply.
Exclusion criteria
* Metastatic disease * Invasive bilateral disease * Clinical or radiological evidence of existing fracture in spine or hip * Prior treatment with IV bisphosphonates in the past 12 months * Current treatment with oral bisphosphonates ( must be discontinued within 3 weeks of baseline evaluation) * Use of Tibolone within 6 months * Prior use of parathyroid hormone for more than 1 week * Previous or concomitant malignancy * Abnormal renal function * History of disease effecting bone metabolism Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 12 Months of Therapy. | Baseline, 12 months | Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by energy x-ray absorptiometry (DXA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | Baseline, 2 years. Baseline, 3 years. Baseline, 4 years. Baseline, 5 years. | Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by dual energy x-ray absorptiometry (DXA) |
| Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | Baseline, 5 years. | Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L1-L4)as measured by dual energy x-ray absorptiometry (DXA) |
| Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | Baseline, 12 months. Baseline, 2 years. Baseline, 3 years. Baseline, 4 years. Baseline, 5 years. | Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by dual energy x-ray absorptiometry (DXA) |
| Percentage of Participants With Clinical Fractures at 3 Years of Therapy Which Were Not Present at Baseline | Baseline,3 years | At 3 years of therapy the percentage of participants with fractures as detected by X-ray and/ or bone scan. |
Countries
Argentina, Australia, Belgium, Brazil, Chile, China, Colombia, Czechia, Egypt, Finland, France, Germany, Guatemala, Hong Kong, Italy, Mexico, Netherlands, New Zealand, Peru, Philippines, Portugal, South Korea, Spain, Switzerland, Taiwan, Thailand, United Kingdom, Venezuela
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid 4 mg Upfront Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1. | 532 |
| Zoledronic Acid 4 mg Delayed Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1. | 533 |
| Total | 1,065 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Laboratory Results | 2 | 0 |
| Overall Study | Abnormal Test Procedure Results | 6 | 11 |
| Overall Study | Administrative Problems | 5 | 2 |
| Overall Study | Adverse Event | 46 | 42 |
| Overall Study | Death | 6 | 6 |
| Overall Study | Lack of Efficacy | 29 | 41 |
| Overall Study | Lost to Follow-up | 0 | 5 |
| Overall Study | No Longer Required Study Drug | 1 | 1 |
| Overall Study | Protocol Violation | 7 | 8 |
| Overall Study | Withdrawal by Subject | 22 | 19 |
Baseline characteristics
| Characteristic | Zoledronic Acid 4 mg Upfront | Zoledronic Acid 4 mg Delayed | Total |
|---|---|---|---|
| Age Continuous | 57 Years | 58 Years | 57 Years |
| Sex: Female, Male Female | 532 Participants | 533 Participants | 1065 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 | 477 / 525 | 486 / 535 |
| serious Total, serious adverse events | 133 / 525 | 124 / 535 |
Outcome results
Primary
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 12 Months of Therapy.
Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by energy x-ray absorptiometry (DXA).
Time frame: Baseline, 12 months
Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 12 Months of Therapy. | 2.208 Percentage change in BMD | Standard Deviation 3.4194 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 12 Months of Therapy. | -3.617 Percentage change in BMD | Standard Deviation 4.2151 |
Secondary
Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy.
Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L1-L4)as measured by dual energy x-ray absorptiometry (DXA)
Time frame: Baseline, 5 years.
Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication. n in each of the categories is the number of participants who had safety data at baseline and the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 2 years (n=339,343) | 3.300 Percentage change in BMD | Standard Deviation 4.07 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 4 years (n=290,294) | 3.529 Percentage change in BMD | Standard Deviation 5.541 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 3 years (n=313,311) | 3.521 Percentage change in BMD | Standard Deviation 4.5936 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 5 years (n=264,264) | 3.898 Percentage change in BMD | Standard Deviation 5.7995 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 12 months (n=360,369) | 2.128 Percentage change in BMD | Standard Deviation 3.2106 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 5 years (n=264,264) | -5.427 Percentage change in BMD | Standard Deviation 7.4818 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 12 months (n=360,369) | -3603 Percentage change in BMD | Standard Deviation 4.1808 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 2 years (n=339,343) | -4.521 Percentage change in BMD | Standard Deviation 5.2624 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 3 years (n=313,311) | -4.869 Percentage change in BMD | Standard Deviation 6.031 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. | At 4 years (n=290,294) | -5.148 Percentage change in BMD | Standard Deviation 6.8803 |
Secondary
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy.
Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by dual energy x-ray absorptiometry (DXA)
Time frame: Baseline, 2 years. Baseline, 3 years. Baseline, 4 years. Baseline, 5 years.
Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication. n in each of the categories is the number of participants who had safety data at baseline and the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 2 years (n=339,343) | 3.463 Percentage change in BMD | Standard Deviation 4.2691 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 3 years (n=313,311) | 3.730 Percentage change in BMD | Standard Deviation 4.884 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 4 years (n=290,294) | 3.782 Percentage change in BMD | Standard Deviation 5.73 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 5 years (n=264,264) | 4.308 Percentage change in BMD | Standard Deviation 6.0242 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 5 years (n=264,264) | -5.414 Percentage change in BMD | Standard Deviation 7.6185 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 2 years (n=339,343) | -4.601 Percentage change in BMD | Standard Deviation 5.5273 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 4 years (n=290,294) | -5.154 Percentage change in BMD | Standard Deviation 7.1079 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. | At 3 years (n=313,311) | -4.871 Percentage change in BMD | Standard Deviation 6.271 |
Secondary
Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy.
Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by dual energy x-ray absorptiometry (DXA)
Time frame: Baseline, 12 months. Baseline, 2 years. Baseline, 3 years. Baseline, 4 years. Baseline, 5 years.
Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication. n in each of the categories is the number of participants who had safety data at baseline and the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 2 years (n=394,393) | 1.649 Percentage change in BMD | Standard Deviation 2.7333 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 4 years (n=336,349) | 1.716 Percentage change in BMD | Standard Deviation 3.5228 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 3 years (n=376,365) | 1.754 Percentage change in BMD | Standard Deviation 3.1375 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 5 years (n=306,314) | 1.615 Percentage change in BMD | Standard Deviation 3.749 |
| Zoledronic Acid 4 mg Upfront | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 12 months (n=419,434) | 1.222 Percentage change in BMD | Standard Deviation 2.3257 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 5 years (n=306,314) | -4.162 Percentage change in BMD | Standard Deviation 6.027 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 12 months (n=419,434) | -2.239 Percentage change in BMD | Standard Deviation 3.3614 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 2 years (n=394,393) | -2.990 Percentage change in BMD | Standard Deviation 4.4318 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 3 years (n=376,365) | -3.302 Percentage change in BMD | Standard Deviation 4.8942 |
| Zoledronic Acid 4 mg Delayed | Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. | At 4 years (n=336,349) | -3.922 Percentage change in BMD | Standard Deviation 5.6505 |
Secondary
Percentage of Participants With Clinical Fractures at 3 Years of Therapy Which Were Not Present at Baseline
At 3 years of therapy the percentage of participants with fractures as detected by X-ray and/ or bone scan.
Time frame: Baseline,3 years
Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid 4 mg Upfront | Percentage of Participants With Clinical Fractures at 3 Years of Therapy Which Were Not Present at Baseline | 0.6 Percentage of Participants |
| Zoledronic Acid 4 mg Delayed | Percentage of Participants With Clinical Fractures at 3 Years of Therapy Which Were Not Present at Baseline | 1.5 Percentage of Participants |