Statement: Patients diagnosed with osteonecrosis are eligible for the primary trial but excluded from the secondary trial.
Primary_evidence: Inclusion criteria:   Female patients  18 years of age.   Written informed consent given.   Histologically confirmed Stage IV breast cancer with at least one bone metastasis radiologically confirmed.   Previous treatment with zoledronic acid every 3-4 weeks, for 9-12 infusions over no more than 15 months.   Eastern Cooperative Oncology Group (ECOG) performance status 2 .   Life expectancy  1 year. Exclusion criteria:   More than 3 months since last infusion of Zoledronic Acid (Zometa®).   Treatments with other bisphosphonate than Zoledronic Acid (Zometa®) at any time prior to study entry.   Serum creatinine > 3 mg/dL (265 μmol/L) or calculated (Cockcroft-Gault formula) creatinine clearance (CLCr) < 30 mL/min CrCl = ({[140-age (years)] x weight(kg)}/ [72 x serum creatinine (mg/dL)])x 0.85   Corrected (adjusted for serum albumin) serum calcium < 8 mg/dl (2 mmol/L) or > 12 mg/dL ( 3.0 mmol/L).   Current active dental problem including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a recurrent or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.   Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants).   Pregnant patients (with a positive pregnancy test prior to study entry) or lactating patients. Women of childbearing potential not using effective methods of birth control (e.g. abstinence, oral contraceptives or implants, IUD, vaginal diaphragm or sponge, or condom with spermicide).   History of non-compliance to medical regimens or potential unreliable behavior.   Known sensitivity to study drug(s) or class of study drug(s).   Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study   Use of any other investigational agent in the last 30 days.
Secondary_evidence: Inclusion Criteria:   Post-menopausal women at high risk for development of breast cancer   On a stable dose of hormone replacement therapy   have cytomorphologic evidence of hyperplasia +/- atypia and Ki-67 expression >1.5% in benign breast epithelial cells acquired by RPFNA   Serum level of 25-OH vitamin D of at least 30 ng/ml prior to study entry   Willing to have a repeat random periareolar fine needle aspiration (RPFNA) and mammogram at 6 months and 12 months (if participating in the open label portion of the study) following initiation of study drug Exclusion Criteria:   Prior history of osteoporosis or osteoporotic fracture.   Prior history of invasive breast cancer or other invasive cancer within five years from date of study entry.   Current and chronic use of cyclooxygenase-2 (COX-2) specific inhibitors or NSAIDs   Receiving treatment for rheumatoid arthritis or fibromyalgia   Current history of poorly controlled migraines or perimenopausal symptoms   Currently receiving other investigational agents.   Receipt of more than 6 months of an aromatase inhibitor (anastrozole, exemestane, letrozole, etc.) at any time in the past.