Breast Cancer, Osteoporosis
Conditions
Keywords
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, osteoporosis
Brief summary
RATIONALE: Zoledronate may reduce bone loss in patients receiving letrozole for breast cancer. PURPOSE: This clinical trial is studying how well zoledronate works in treating osteopenia or osteoporosis in postmenopausal women receiving letrozole for stage I, stage II, or stage IIIA primary breast cancer.
Detailed description
OBJECTIVES: Primary * Assess changes in total lumbar spine bone mineral density (BMD) from baseline to 12 months in postmenopausal women treated with zoledronate for osteopenia or osteoporosis and letrozole for hormone receptor-positive, stage I-IIIA primary breast cancer. Secondary * Determine changes in total lumbar spine BMD from baseline to 2, 3, 4, and 5 years in these patients. * Determine changes in femoral neck BMD from baseline to 1, 2, 3, 4, and 5 years in these patients. * Determine time to disease progression in these patients. OUTLINE: This is an open-label, multicenter study. * Adjuvant aromatase inhibitor therapy: Patients receive oral letrozole daily for up to 5 years in the absence of disease progression or unacceptable toxicity. * Osteoporosis management: Patients receive zoledronate IV over 15 minutes on day 1. Patients also receive oral elemental calcium twice daily and oral vitamin D daily for 6 months. Treatment repeats every 6 months for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients undergo total lumbar spine and hip (femoral neck) bone density testing by dual energy x-ray absorptiometry (DXA) at baseline and annually for 5 years. After completion of study therapy, patients are followed at 4 weeks. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.
Interventions
DRUGzoledronic acid
zoledronic acid
PROCEDURELetrozole as adjuvant therapy
standard care
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of localized breast cancer * Stage I-IIIA disease * Adequately treated breast cancer * No clinical or radiological evidence of recurrent or metastatic disease * Baseline total lumbar spine or femoral neck bone mineral density T-score \< -2.0 standard deviation (e.g., a patient with a T score of -2.1 is eligible) * Hormone-receptor status: * Estrogen receptor and/or progesterone receptor-positive breast cancer PATIENT CHARACTERISTICS: * Female * Postmenopausal, defined by 1 of the following criteria: * Age \> 55 years with cessation of menses * Age ≤ 55 years with spontaneous cessation of menses for \> 1 year * Age ≤ 55 years with spontaneous cessation of menses for ≤ 1 year, but amenorrheic (e.g., spontaneous or secondary to hysterectomy), AND has postmenopausal estradiol levels * Bilateral oophorectomy * ECOG performance status 0-2 * Life expectancy ≥ 5 years * WBC ≥ 3,000/mm³ OR granulocyte count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Alkaline phosphatase ≤ 3 times upper limit of normal (ULN) * AST ≤ 3 times ULN * Creatinine \< 2.0 mg/dL * Creatinine clearance ≥ 45 mL/min * No hypercalcemia (i.e., calcium level \> 1 mg/dL above ULN) OR hypocalcemia (i.e., calcium level \> 0.5 mg/dL below lower limit of normal) within the past 6 months * No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix * No other nonmalignant systemic diseases, including any of the following: * Uncontrolled infection * Uncontrolled diabetes mellitus * Uncontrolled thyroid dysfunction * Disease affecting bone metabolism (hyperparathyroidism, hypercortisolism, Paget's disease, osteogenesis imperfecta) * Malabsorption syndrome * No uncontrolled seizure disorders associated with falls * No known hypersensitivity to zoledronate or other bisphosphonates, letrozole, calcium, or vitamin D * No concurrent active dental problems, including any of the following: * Infection of the teeth or jawbone (maxillary or mandibular) * Dental or fixture trauma * Prior or current diagnosis of osteonecrosis of the jaw * Exposed bone in the mouth * Slow healing after dental procedures * No contraindication to spine dual energy x-ray absorptiometry (DXA) as defined by any of the following: * History of surgery at the lumbosacral spine, with or without implantable devices * Scoliosis with a Cobb angle \> 15 degrees at the lumbar spine * Immobility, hyperostosis, or sclerotic changes at the lumbar spine, or evidence of sclerotic abdominal aorta sufficient to interfere with DXA scan * Disease of the spine that would preclude the proper acquisition of a lumbar spine DXA * No condition that would preclude study follow-up or compliance * No psychiatric illness that would preclude giving informed consent PRIOR CONCURRENT THERAPY: * More than 3 weeks since prior and no other concurrent oral bisphosphonates * No prior intravenous bisphosphonates * No prior aromatase inhibitor therapy * More than 6 months since prior anabolic steroids or growth hormone * More than 2 weeks since prior and no concurrent inhibitor of osteoclastic bone resorption (e.g., calcitonin, mithramycin, or gallium nitrate) * More than 30 days since prior systemic investigational drug and/or device * More than 7 days since prior topical investigational drug * More than 6 weeks since prior and no concurrent dental or jaw surgery (e.g., extraction, implants) * Concurrent short-term corticosteroid therapy allowed * No concurrent sodium fluoride, parathyroid hormone, or tibolone * No other concurrent investigational drug or device
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) | Baseline and 1 year | Change: BMD values at twelve months post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 3 Post Study Entry | Baseline and 3 year | Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 4 Post Study Entry | Baseline and 4 year | Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 5 Post Study Entry | Baseline and 5 year | Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 1 Post Study Entry | Baseline and 1 year | Change: BMD values at year 1 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 2 Post Study Entry | Baseline and 2 year | Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 2 Post Study Entry | Baseline and 2 year | Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 4 Post Study Entry | Baseline and 4 year | Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 5 Post Study Entry | Baseline and 5 year | Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
| Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | 5 years | Adverse events were assessed per NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1=Mild, Grade 2=Moderate. |
| Time to Disease Progression | Up to 5 years | Time to disease progression was defined as the time from date of randomization to the documentation of disease progression. |
| Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 3 Post Study Entry | Baseline and 3 year | Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value. |
Countries
United States
Participant flow
Recruitment details
Sixty participants were recruited between June 2006 and July 2007 at 6 individual sites participating in the Mayo Clinic Cancer Research Consortium (MCCRC).
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid 4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years) | 53 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 1 |
| Overall Study | Increased creatinine | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Personal conflicts of patient | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Treatment for polymyalgia rheumatic | 1 |
| Overall Study | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | Zoledronic Acid |
|---|---|
| Age, Continuous | 66.9 years STANDARD_DEVIATION 10 |
| Bone Mineral Density Measurement in Lumbar Spine | 0.86 g/cm2 STANDARD_DEVIATION 0.12 |
| Duration of tamoxifen use <=2 years | 4 participants |
| Duration of tamoxifen use >2 years | 20 participants |
| Duration of tamoxifen use Missing | 29 participants |
| Previous fracture by history or X-ray No | 46 participants |
| Previous fracture by history or X-ray Yes | 7 participants |
| Prior chemotherapy No | 33 participants |
| Prior chemotherapy Yes | 20 participants |
| Prior tamoxifen No | 29 participants |
| Prior tamoxifen Yes | 24 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 51 Participants |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 0 Participants |
| Time since tamoxifen ended <1 year | 20 participants |
| Time since tamoxifen ended >=1 year | 4 participants |
| Time since tamoxifen ended Missing | 29 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 52 |
| other Total, other adverse events | 45 / 52 |
| serious Total, serious adverse events | 1 / 52 |
Outcome results
Primary
Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD)
Change: BMD values at twelve months post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 1 year
Population: The primary analysis is performed on data where participants had the same baseline and 1 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) | 2.66 Percentage of the baseline value |
Comparison: A sample of 60 participants was estimated to provide percentage statistics accuracy to within 13% with 95% confidence.p-value: 0.01Kruskal-Wallis
Secondary
Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 1 Post Study Entry
Change: BMD values at year 1 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 1 year
Population: Analysis was performed on data where participants had the same baseline and 1 year BMD Femoral Neck measurement location (Left femoral, right femoral)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 1 Post Study Entry | 5.66 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 2 Post Study Entry
Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 2 year
Population: Analysis was performed on data where participants had the same baseline and 2 year BMD Femoral Neck measurement location (Left femoral, right femoral)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 2 Post Study Entry | 10.47 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 3 Post Study Entry
Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 3 year
Population: Analysis was performed on data where participants had the same baseline and 3 year BMD Femoral Neck measurement location (Left femoral, right femoral)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 3 Post Study Entry | 8.44 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 4 Post Study Entry
Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 4 year
Population: Analysis was performed on data where participants had the same baseline and 4 year BMD Femoral Neck measurement location (Left femoral, right femoral)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 4 Post Study Entry | 4.49 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 5 Post Study Entry
Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 5 year
Population: Analysis was performed on data where participants had the same baseline and 5 year BMD Femoral Neck measurement location (Left femoral, right femoral)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 5 Post Study Entry | 4.54 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 2 Post Study Entry
Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 2 year
Population: Analysis was performed on data where participants had the same baseline and 2 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 2 Post Study Entry | 4.94 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 3 Post Study Entry
Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 3 year
Population: Analysis was performed on data where participants had the same baseline and 3 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 3 Post Study Entry | 6.20 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 4 Post Study Entry
Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 4 year
Population: Analysis was performed on data where participants had the same baseline and 4 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 4 Post Study Entry | 6.99 Percentage of the baseline value |
Secondary
Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 5 Post Study Entry
Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time frame: Baseline and 5 year
Population: Analysis was performed on data where participants had the same baseline and 5 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Zoledronic Acid | Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 5 Post Study Entry | 11.71 Percentage of the baseline value |
Secondary
Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications
Adverse events were assessed per NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1=Mild, Grade 2=Moderate.
Time frame: 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 1 Arthralgia | 7 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 2 Arthralgia | 4 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 3 Arthralgia | 1 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 1 Creatinine Increase | 7 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 2 Creatinite increase | 2 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 2 Desquamating Rash | 1 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 2 Headache | 1 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 2 Hot flashes | 3 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 1 Nausea | 2 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 3 Pain in extremity | 1 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 1 Fever | 2 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 1 Vomiting | 1 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 1 Musculoskeletal disorder | 1 Participants |
| Zoledronic Acid | Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications | Grade 2 Urogenital disorder | 1 Participants |
Secondary
Time to Disease Progression
Time to disease progression was defined as the time from date of randomization to the documentation of disease progression.
Time frame: Up to 5 years
Population: None of the participants had disease progression.