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e11625 Background: Aromatase inhibitors (AIs) reduce tumor cell proliferation and improve breast cancer survival. Recent evidence from in vivo models and the ABCSG-12 Trial suggests that bisphosphonates such as zoledronic acid add to the inhibitory effect of AIs but the mechanism is unclear. We assessed the effect of letrozole alone and in combination with zoledronic acid in a 14 day pre-surgical study in women with primary breast cancer. Methods: Postmenopausal women (n=109) aged 50–75 years with untreated estrogen receptor positive invasive breast cancer (no prior hormonal therapy) gave written informed consent to the study and were randomized to letrozole (2.5mg) or placebo tablets (2:1). Letrozole treated patients were randomized further to zoledronic acid 4mg intravenously or no treatment 2–4 days prior to surgery. Epithelial proliferation and apoptosis was measured pre and post treatment by immunohistochemistry for Ki67 and activated caspase 3 respectively counting at least 1,000 cells. Smooth Muscle Actin immunohistochemistry was also assessed pre and post treatment to determine fibroblast activation. Results: The study is powered to detect a 10% difference in epithelial proliferation with the combination arm (80% chance) compared to the letrozole alone arm. Conclusions: This preoperative biological study should provide important insight into the cellular mechanism or action of zoledronic acid in addition to AIs on primary breast cancer. [Table: see text]