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

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:

1. 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.

2. 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.

3. 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.

4. To evaluate the relationship of baseline serum estradiol levels with ovarian failure in
premenopausal women undergoing adjuvant or neoadjuvant chemotherapy for primary breast
cancer.

1. Required Characteristics

1. 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

2. Scheduled to undergo adjuvant or neoadjuvant chemotherapy for primary breast
cancer (stages I-IIIB)

3. ≥ 18 years of age

4. ECOG performance status (PS) 0 or 1

2. Contraindications

1. Hypercalcemia (calcium level > 1mg/dL above UNL ≤ 6 months

2. Hypocalcemia (calcium level > 0.5 mg/dL below UNL ≤ 6 months

3. Inability to stand or sit upright for at least 30 minutes

4. Known swallowing disorder

5. 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

6. History of vertebral compression fracture

- Exception: traumatic fracture of the coccyx would not exclude a patient
from participation

7. Corticosteroids at doses > 5 mg daily of prednison or equivalent for > 2 weeks
in the past 6 months

8. Previous treatment with bisphosphonates

9. Diseases affecting bone metabolism (hyperthyroidism, hyperparathyroidism, and
hypercortisolism)

10. History of severe renal impairment or creatinine > 2.0 mg/dL

11. Malabsorption syndrome

12. Estrogen replacement therapy

13. Oral contraceptive use

14. Prior bilateral oophorectomy

15. 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

16. Dental extraction, root canal, or implants ≤ 3 months prior to registration or
planned during study treatment