Zoledronate in Treating Osteopenia or Osteoporosis in Postmenopausal Women Receiving Letrozole for Stage I, Stage II, or Stage IIIA Primary Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women With Primary Breast Cancer Undergoing Adjuvant Aromatase Inhibitor (Letrozole) Therapy

Conditions
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Breast Cancer, Osteoporosis

Intervention / Treatment
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* Drug: zoledronic acid
* Procedure: Letrozole as adjuvant therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zoledronic acid<br>4 mg 15 minutes IV infusion. If creatinine clearance is ≤ 60, dosage should be adjusted as follows:CrCl 50-60: 3.5 mg; CrCl 40-49: 3.3 mg; CrCl 30-39: 3.0 mg. | Drug: zoledronic acid<br>* zoledronic acid<br>* Other names: Zometa®;Procedure: Letrozole as adjuvant therapy<br>* standard care<br>* Other names: Femara®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 2 year | 
| 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. | Baseline and 3 year | 
| 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. | Baseline and 4 year | 
| 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. | Baseline and 5 year | 
| 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. | Baseline and 1 year | 
| 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. | Baseline and 2 year | 
| 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. | Baseline and 3 year | 
| 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. | Baseline and 4 year | 
| 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. | Baseline and 5 year | 
| 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. | 5 years | 
| Time to Disease Progression | Time to disease progression was defined as the time from date of randomization to the documentation of disease progression. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, osteoporosis