Risedronate in Preventing Bone Loss in Premenopausal Women Receiving Chemotherapy for Primary Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Preventing bone loss in patients who are receiving chemotherapy for breast cancer may decrease the risk of fractures and may help patients live more comfortably. It is not yet known whether calcium is more effective with or without risedronate in preventing bone loss. PURPOSE: This randomized phase III trial is studying two forms of calcium with or without risedronate to compare how well they work in preventing bone loss in premenopausal women who are receiving chemotherapy for primary stage I, stage II, stage IIIA, or stage IIIB breast cancer.

Detailed Description
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OUTLINE: This is a randomized, placebo-controlled, double-blind study. Patients are stratified according to planned tamoxifen therapy (yes vs no vs undecided), planned taxane therapy (yes vs no vs undecided), time from last menses (1-3 months vs longer than 3 months to 6 months), and age (under 40 vs 40 to 49 vs 50 and over). Patients are randomized to 1 of 2 treatment arms. In both arms, treatment begins during the first month of chemotherapy and continues for 1 year in the absence of unacceptable toxicity. For more information regarding the treatment arms, please see the Arms section below. Questionnaires about cessation of menses, ovarian failure, and menopausal symptoms are completed at baseline, monthly during chemotherapy, at 6 months, and then at 1 and 2 years. Patients are followed for 1 year. A summary of study goals is listed below. Goals: To evaluate the effectiveness of risedronate at a weekly oral dose of 35 mg versus placebo in the prevention of bone loss in premenopausal women undergoing adjuvant or neoadjuvant chemotherapy for primary breast cancer. To evaluate the degree of bone loss over one year in premenopausal women undergoing adjuvant chemotherapy for primary breast cancer according to menopausal status at one year after therapy begins. To evaluate the relationship of current climacteric symptoms, menstrual and reproductive history, and chemotherapy regimen with ovarian failure (permanent cessation of menses) in premenopausal women undergoing adjuvant or neoadjuvant chemotherapy for primary breast cancer. To evaluate the relationship of baseline serum estradiol levels with ovarian failure in premenopausal women undergoing adjuvant or neoadjuvant chemotherapy for primary breast cancer.

Official Title
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A Phase III Randomized, Placebo-Controlled, Double-Blind Trial Of Risedronate (Actonel) For Prevention Of Bone Loss In Premenopausal Women Undergoing Chemotherapy For Primary Breast Carcinoma

Conditions
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Breast Cancer, Osteoporosis

Intervention / Treatment
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* Dietary Supplement: calcium carbonate
* Dietary Supplement: vitamin D
* Drug: risedronate sodium
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Required Characteristics Premenopausal women ≤ 6 months since last menstrual period no prior bilateral oophorectomy not on estrogen replacement therapy if TAH is performed, with at least one intact ovary, or if > 3 months since last menstrual period, then patients must have premenopausal estrogen levels ≤ 1 month of study entry Scheduled to undergo adjuvant or neoadjuvant chemotherapy for primary breast cancer (stages I-IIIB) ≥ 18 years of age ECOG performance status (PS) 0 or 1 Contraindications Hypercalcemia (calcium level > 1mg/dL above UNL ≤ 6 months Hypocalcemia (calcium level > 0.5 mg/dL below UNL ≤ 6 months Inability to stand or sit upright for at least 30 minutes Known swallowing disorder Bone mineral density T score of ≤ - 2.0 at the hip or lumbar spine a patient with a T score of - 2.1 is ineligible a patient with a T score of - 1.9 is eligible History of vertebral compression fracture Exception: traumatic fracture of the coccyx would not exclude a patient from participation Corticosteroids at doses > 5 mg daily of prednison or equivalent for > 2 weeks in the past 6 months Previous treatment with bisphosphonates Diseases affecting bone metabolism (hyperthyroidism, hyperparathyroidism, and hypercortisolism) History of severe renal impairment or creatinine > 2.0 mg/dL Malabsorption syndrome Estrogen replacement therapy Oral contraceptive use Prior bilateral oophorectomy Pregnant women Nursing women Women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, injections, intrauterine device [IUD], surgical sterilization, abstinence, etc.) This study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown Dental extraction, root canal, or implants ≤ 3 months prior to registration or planned during study treatment

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: calcium carbonate, vitamin D and risedronate<br>Patients receive calcium carbonate 600 mg daily, vitamin D 400 U daily and risedronate 35 mg weekly. | Dietary Supplement: calcium carbonate<br>* calcium 600 mg daily administered orally for one year<br>Dietary Supplement: vitamin D<br>* vitamin D 400 U daily administered orally for one year<br>Drug: risedronate sodium<br>* risedronate 35 mg weekly administered orally<br>|
| Placebo Comparator: calcium carbonate, vitamin D and placebo<br>Patients receive calcium carbonate 600 mg daily, vitamin D 400 U daily and placebo weekly. | Dietary Supplement: calcium carbonate<br>* calcium 600 mg daily administered orally for one year<br>Dietary Supplement: vitamin D<br>* vitamin D 400 U daily administered orally for one year<br>Other: placebo<br>* placebo tablet weekly administered orally for one year<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average intra-patient change in lumbar spine (L2-L4, PA) bone mineral density (BMD) from baseline to one year after study entry |  | 1 year post study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average intra-patient change in femoral neck and total hip BMD from baseline to one year after study entry |  | 1 year post study entry | 
| Incidence of osteopenia in the risedronate vs placebo groups at one year after study entry |  | 1 year post study entry | 
| Incidence of osteoporosis in the risedronate vs placebo groups at one year after study entry |  | 1 year post study entry | 
| Incidence of a 5% difference in intra-patient BMD scores at baseline |  | Baseline | 
| Serum and urine N-telopeptide and serum alkaline phosphatase at baseline and 6 months |  | Up to 6 months | 
| Frequency and severity of toxicity as measured by NCI CTC version 2.0 |  | Up to 1 year post study treatment | 
| Menopausal symptoms as measured by the Greene Climacteric Scale (GCS) at baseline, monthly during chemotherapy, at 6 months, 1 year, and 2 years after study entry |  | Up to 2 years post study entry | 
| Association of baseline serum estradiol levels with permanent cessation of menses |  | Baseline | 
| Relationship between the subscales of the GCS (psychological, vasomotor, somatic and sexual) with type of chemotherapy, duration of chemotherapy, and menstrual cycle changes |  | Up to 2 years post study entry | 

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