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Effectiveness of Zoledronic Acid in the Prevention of Osteoporosis in Early Breast Cancer Patients Receiving Letrozole

Primary Purpose

Breast Cancer

Status
Completed
Phase
Phase 3
Locations
Israel
Study Type
Interventional
Intervention
zoledronic acid
Sponsored by
Soroka University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Breast Cancer focused on measuring breast cancer, postmenopausal, letrozole, zoledronic acid, adjuvant,bone mineral density

Eligibility Criteria

18 Years - 82 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Postmenopausal women with histologically documented early (non-metastatic) breast cancer
  • Previous treatment with tamoxifen for at least 2.5 years and not more than 3.5 years
  • Assigned to receive letrozole treatment
  • Karnofsky performance status ≥ 70
  • Life expectancy ≥ 16 weeks
  • Signed informed consent after full explanation of study by participating clinician and prio to any study specific procedures
  • Adjuvant or neoadjuvant chemotherapy is allowed
  • No clinical and/or radiologic evidence of distant metastases
  • No prior treatment with an aromatase inhibitor
  • Able to comply with treatment and scheduled follow-up visits
  • Age between 18 and 82 years

Exclusion Criteria:

  • Pregnant or lactating women or women with child bearing potential
  • Patients with other malignancies except except adequately treated basal cell carcinoma of the skin or in-situ cervix carcinoma
  • Active infection or other serious underlying medical condition which would impair the ability of the patient to receive protocol treatment
  • Clinical and/or radiological evidence of distant metastases.
  • Evidence of pathological fracture
  • Prior treatment with an aromatase inhibitor
  • Prior administration of any intravenous bisphosphonate during the last year.
  • Oral bisphosphonate must be discontinued within 4 weeks of enrollment
  • Administration of long-term systemic corticosteroids within the last 12 months (short term steroid treatment is allowed.)
  • Prior use of parathyroid hormone treatment for more than 1 week
  • Use of any drug known to affect the skeleton (calcitonin, mithramycin, gallium nitrate) within two weeks prior to enrollment
  • Abnormal renal function: creatinine clearance must be above 30 ml/min (calculated by Cockroft formula)
  • Evidence of metabolic bone disease( Paget's, osteogenesis imperfecta, hyperparathyroidism within the 12 months prior to enrollment)
  • Baseline lumbar spine and or total hip Bone Mineral Density T score below -2
  • Known hypersensitivity to zoledronic acid
  • Psychological, familial, sociologic, or geographic conditions which do not permit medical follow-up and compliance with the study protocol
  • White blood cell ≤ 3.0 x 10exp9 /L or granulocytes ≤ 1.5 x 10exp9/L or platelets ≤100 x 10exp9
  • Total bilirubin> 1.5 x upper normal limit, SGOT and SGPT > 2.5 x upper normal limit
  • Unable to undergo DXA bone density scanning (spine deformity, severe scoliosis, lumbar sacral spine surgery)

Sites / Locations

  • Soroka University Medical Center
  • Tel Aviv Sourasky Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Immediate zoledronic acid

Delayed zoledronic acid

Arm Description

Patients on this arm will receive zoledronic acid every 6 months during 2.5 years of letrozole therapy starting within 3 months of the start of letrozole therapy. (5 doses of zoledronic acid)

Patients on this arm will receive zoledronic acid during the 2.5 years of letrozole treatment only after the T-score on bone mineral density testing falls below minus 2.0.

Outcomes

Primary Outcome Measures

bone mineral density
bone events
renal function
liver function

Secondary Outcome Measures

Full Information

First Posted
September 14, 2006
Last Updated
August 22, 2011
Sponsor
Soroka University Medical Center
Collaborators
Tel-Aviv Sourasky Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT00376740
Brief Title
Effectiveness of Zoledronic Acid in the Prevention of Osteoporosis in Early Breast Cancer Patients Receiving Letrozole
Official Title
Phase 3 Study of the Effect of Zoledronic Acid in the Prevention of Osteoporosis in Early Breast Cancer Patients Receiving the Aromatase Inhibitor, Letrozole, in the Adjuvant Setting
Study Type
Interventional

2. Study Status

Record Verification Date
August 2011
Overall Recruitment Status
Completed
Study Start Date
September 2005 (undefined)
Primary Completion Date
November 2010 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Soroka University Medical Center
Collaborators
Tel-Aviv Sourasky Medical Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine whether zoledronic acid given intravenously every 6 months can prevent reduction in bone mineral density in women with early stage breast cancer receiving adjuvant therapy with the aromatase inhibitor drug letrozole, after having received adjuvant tamoxifen.
Detailed Description
Letrozole is an aromatase inhibitor used in the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women.It has more recently been approved for use in many countries as adjuvant therapy for early breast cancer; and is often used in an adjuvant regimen following 2-3 years of tamoxifen treatment or as an extended adjuvant therapy after up to 5 years of tamoxifen. Letrozole inhibits the conversion of androgens to estrogens in vitro and in vivo. Plasma levels of estradiol and related estrogen compounds in postmenopausal patients receiving letrozole are suppressed up to 95% from baseline and are often undetectable.The estrogen deprivation in women receiving letrozole may cause increased bone resorption and bone loss.Studies comparing tamoxifen and aromatase inhibitors, in adjuvant therapy have shown an increase fracture rate, and decreased bone mineral density in patients receiving aromatase inhibitors. Zoledronic acid is an intravenously administered bisphosphonate that inhibits osteoclastic bone resorption. Intravenous bisphosphonates are effective in reducing the rate of skeletal complications, including fractures, in patients with metastatic breast cancer and other tumors when given every few weeks. Small clinical trials have given some evidence that osteoporosis can be effectively treated by one or two doses of intravenous zoledronic acid per year. This study will determine the effect of giving zoledronic acid every 6 months on the bone mineral density of patients receiving letrozole as adjuvant therapy for early breast cancer after having received adjuvant tamoxifen for at least 2.5 years. Patients will be randomized to receive zoledronic acid either at the start of letrozole therapy or when bone mineral density T score drops below - 2 standard deviation or at the occurrence of a non-trauma related fracture.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
breast cancer, postmenopausal, letrozole, zoledronic acid, adjuvant,bone mineral density

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Immediate zoledronic acid
Arm Type
Experimental
Arm Description
Patients on this arm will receive zoledronic acid every 6 months during 2.5 years of letrozole therapy starting within 3 months of the start of letrozole therapy. (5 doses of zoledronic acid)
Arm Title
Delayed zoledronic acid
Arm Type
Active Comparator
Arm Description
Patients on this arm will receive zoledronic acid during the 2.5 years of letrozole treatment only after the T-score on bone mineral density testing falls below minus 2.0.
Intervention Type
Drug
Intervention Name(s)
zoledronic acid
Other Intervention Name(s)
Zomera, zolendronate
Intervention Description
Zoledronic acid 4 mg IV every 6 months up to 2.5 years after the start of letrozole treatment.
Primary Outcome Measure Information:
Title
bone mineral density
Title
bone events
Title
renal function
Title
liver function

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
82 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Postmenopausal women with histologically documented early (non-metastatic) breast cancer Previous treatment with tamoxifen for at least 2.5 years and not more than 3.5 years Assigned to receive letrozole treatment Karnofsky performance status ≥ 70 Life expectancy ≥ 16 weeks Signed informed consent after full explanation of study by participating clinician and prio to any study specific procedures Adjuvant or neoadjuvant chemotherapy is allowed No clinical and/or radiologic evidence of distant metastases No prior treatment with an aromatase inhibitor Able to comply with treatment and scheduled follow-up visits Age between 18 and 82 years Exclusion Criteria: Pregnant or lactating women or women with child bearing potential Patients with other malignancies except except adequately treated basal cell carcinoma of the skin or in-situ cervix carcinoma Active infection or other serious underlying medical condition which would impair the ability of the patient to receive protocol treatment Clinical and/or radiological evidence of distant metastases. Evidence of pathological fracture Prior treatment with an aromatase inhibitor Prior administration of any intravenous bisphosphonate during the last year. Oral bisphosphonate must be discontinued within 4 weeks of enrollment Administration of long-term systemic corticosteroids within the last 12 months (short term steroid treatment is allowed.) Prior use of parathyroid hormone treatment for more than 1 week Use of any drug known to affect the skeleton (calcitonin, mithramycin, gallium nitrate) within two weeks prior to enrollment Abnormal renal function: creatinine clearance must be above 30 ml/min (calculated by Cockroft formula) Evidence of metabolic bone disease( Paget's, osteogenesis imperfecta, hyperparathyroidism within the 12 months prior to enrollment) Baseline lumbar spine and or total hip Bone Mineral Density T score below -2 Known hypersensitivity to zoledronic acid Psychological, familial, sociologic, or geographic conditions which do not permit medical follow-up and compliance with the study protocol White blood cell ≤ 3.0 x 10exp9 /L or granulocytes ≤ 1.5 x 10exp9/L or platelets ≤100 x 10exp9 Total bilirubin> 1.5 x upper normal limit, SGOT and SGPT > 2.5 x upper normal limit Unable to undergo DXA bone density scanning (spine deformity, severe scoliosis, lumbar sacral spine surgery)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tamar Safra, M.D.
Organizational Affiliation
Tel-Aviv Sourasky Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
Soroka University Medical Center
City
Beer Sheva
Country
Israel
Facility Name
Tel Aviv Sourasky Medical Center
City
Tel Aviv
Country
Israel

12. IPD Sharing Statement

Citations:
PubMed Identifier
22156381
Citation
Safra T, Bernstein-Molho R, Greenberg J, Pelles-Avraham S, Stephansky I, Sarid D, Inbar MJ, Stemmer SM, Geffen DB. The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: a prospective, randomized, phase II trial. Oncology. 2011;81(5-6):298-305. doi: 10.1159/000334456. Epub 2011 Dec 8.
Results Reference
derived

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Effectiveness of Zoledronic Acid in the Prevention of Osteoporosis in Early Breast Cancer Patients Receiving Letrozole

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