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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Osteoporosis
• Intervention / Treatment: Drug: zoledronic acid; Procedure: Letrozole as adjuvant therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic in Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: zoledronic acid; 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; zoledronic acid; Other Names: Zometa®; Procedure: Letrozole as adjuvant therapy; standard care; Other Names: Femara®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Stephanie Hines, MD, Mayo Clinic

Publications and helpful links

General Publications

• Hines SL, Sloan JA, Atherton PJ, Perez EA, Dakhil SR, Johnson DB, Reddy PS, Dalton RJ, Mattar BI, Loprinzi CL. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy. Breast. 2010 Apr;19(2):92-6. doi: 10.1016/j.breast.2009.12.001. Epub 2010 Jan 15.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2006
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): May 9, 2016

Study Registration Dates

• First Submitted: February 15, 2007
• First Submitted That Met QC Criteria: February 15, 2007
• First Posted (Estimate): February 19, 2007

Study Record Updates

• Last Update Posted (Actual): September 11, 2019
• Last Update Submitted That Met QC Criteria: August 28, 2019
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; osteoporosis; stage II breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Metabolic Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Musculoskeletal Diseases; Bone Diseases; Breast Neoplasms; Osteoporosis; Bone Diseases, Metabolic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Bone Density Conservation Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; Zoledronic Acid
• Other Study ID Numbers: MC05C8 (Other Identifier: Mayo Clinic Cancer Center); P30CA015083 (U.S. NIH Grant/Contract); 2330-05 (Other Identifier: Mayo Clinic IRB)