Study to determine treatment effects of Denosumab in patients with Breast Cancer receiving Aromatase Inhibitor Therapy

Inclusion Criteria for Double Blinded Phase: - Histologically or cytologically confirmed adenocarcinoma of the breast; - Female subjects with non-metastatic disease who are estrogen receptor (ER) and/or progesterone receptor (PR) positive, and who have completed their treatment pathway; - Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting; - Postmenopausal woman, defined as a woman fulfilling any one of the following criteria: • Having undergone a bilateral oophorectomy; • Age ≥ 60 years; • Aged < 60 years meeting the following requirements: - Follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range; - A negative pregnancy test within 7 days prior to randomization. Subjects who have undergone a hysterectomy do not require a pregnancy test. -More criteria may apply. Exclusion Criteria for Double Blinded Phase: - Aromatase inhibitor therapy for more than 24 months; - Prior or concurrent treatment with Selective Estrogen Receptor Modulators (eg, tamoxifen); - Evidence of metastatic disease; - Current or prior intravenous (IV) bisphosphonate administration; - Oral bisphosphonate treatment greater than or equal to 3 years continuously OR greater than 3 months but less than 3 years unless there was a washout period of at least 1 year prior to randomization OR any use during the 3-month period prior to randomization; - Prior administration of denosumab; - Known liver or renal deficiency; - Recurrence of the primary malignancy (e.g., during the allowed interval of pretreatment with aromatase inhibitor); - Diagnosis of any second non-breast malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri; - Any kind of disorder that compromises the ability to give written informed consent and/or comply with study procedures. Inclusion Criteria to Receive Open-label Phase Denosumab: - Obtain signed and dated written informed consent prior to performing any study-specific procedure; - Subjects currently taking an approved non-steroidal AIT (eg, anastrazole) or who have completed or discontinued AIT within 12 months prior to participation in the OLP; - Randomized to placebo arm during the double-blind phase (as determined by unblinding procedures); Exclusion Criteria to Receive Open-label Phase Denosumab: - Current or prior IV bisphosphonate administration; - Subjects meeting the following criteria for oral bisphosphonate treatment: ∙ Greater than or equal to 3 years continuously, ∙ Greater than 3 months but less than 3 years unless subject has had a washout period of at least 1 year prior to participation in the OLP, ∙ Any use during the 3-month period prior to participation in the OLP; - Prior or concurrent treatment with SERMs (eg, tamoxifen); - Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase; Treatment with commercial denosumab (Prolia or Xgeva) prior to participation in the OLP. Eligibility for ZA substudy Inclusion Criteria -Obtain signed and dated written informed consent prior to performing any substudy-specific procedure -Subjects that received OLP denosumab and completed OLP treatment - Last OLP denosumab administration no longer than 9 months ago Exclusion Criteria -Current or prior ZA administration. -Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase and OL phase -Known sensitivity or intolerance to any of the products to be administered during the substudy (eg, ZA, calcium or vitamin D) - Known history of any of the following conditions either by subject self report or chart review • Paget’s disease (bone), Cushing’s disease, hyperprolactinemia or other active metabolic bone disease • Known history of hypocalcemia • Major surgery, or significant traumatic injury occurring within 4 weeks prior to randomization • Parathyroid glands in neck surgically removed. • Any sections of intestine removed. • Known human immunodeficiency virus infection • Active infection with hepatitis B or hepatitis C virus - Known liver or renal disease as determined by the investigator and indicated by the following criteria: • Aspartate aminotransferase ≥ 2.5 x ULN • Alanine transaminase ≥ 2.5 x ULN • Serum creatinine ≥ 2 x ULN • Creatine clearance < 35ml/min Subjects that are pregnant or breastfeeding • All subjects with reproductive potential must have a negative pregnancy test within 7 days before randomization -Subjects who are osteoporotic in baseline BMD