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

• ClinicalTrials.gov Identifier: NCT00436917
• Recruitment Status: Completed
• First Posted: February 19, 2007
• Results First Posted: August 12, 2011
• Last Update Posted: September 11, 2019
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Mayo Clinic

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Osteoporosis	Drug: zoledronic acid; Procedure: Letrozole as adjuvant therapy	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women With Primary Breast Cancer Undergoing Adjuvant Aromatase Inhibitor (Letrozole) Therapy
• Actual Study Start Date: April 2006
• Actual Primary Completion Date: June 2008
• Actual Study Completion Date: May 9, 2016

Arms and Interventions

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 Name: Zometa®; Procedure: Letrozole as adjuvant therapy; standard care; Other Name: Femara®

Outcome Measures

Primary Outcome Measures :

1. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) [ Time Frame: 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 Outcome Measures :

1. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 2 Post Study Entry [ Time Frame: 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.
2. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 3 Post Study Entry [ Time Frame: 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.
3. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 4 Post Study Entry [ Time Frame: 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.
4. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 5 Post Study Entry [ Time Frame: 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.
5. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 1 Post Study Entry [ Time Frame: 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.
6. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 2 Post Study Entry [ Time Frame: 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.
7. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 3 Post Study Entry [ Time Frame: 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.
8. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 4 Post Study Entry [ Time Frame: 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.
9. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 5 Post Study Entry [ Time Frame: 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.
10. Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications [ Time Frame: 5 years ]
    Adverse events were assessed per NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1=Mild, Grade 2=Moderate.
11. Time to Disease Progression [ Time Frame: Up to 5 years ]
    Time to disease progression was defined as the time from date of randomization to the documentation of disease progression.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Florida

Mayo Clinic in Florida

Jacksonville, Florida, United States, 32224

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

National Cancer Institute (NCI)

Investigators

• Study Chair: Stephanie Hines, MD; Mayo Clinic
• Principal Investigator: Charles L. Loprinzi, MD; Mayo Clinic

More Information

Publications of Results:

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.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00436917
• Other Study ID Numbers: MC05C8; P30CA015083 ( U.S. NIH Grant/Contract ); MC05C8 ( Other Identifier: Mayo Clinic Cancer Center ); 2330-05 ( Other Identifier: Mayo Clinic IRB )
• First Posted: February 19, 2007
• Results First Posted: August 12, 2011
• Last Update Posted: September 11, 2019
• Last Verified: April 2016

Keywords provided by Mayo Clinic:

stage I breast cancer; stage II breast cancer; stage IIIA breast cancer; osteoporosis

Additional relevant MeSH terms:

Breast Neoplasms; Osteoporosis; Bone Diseases, Metabolic; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Zoledronic Acid; Letrozole; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Bone Density Conservation Agents