Chemotherapy for breast cancer causes early-onset menopause for most women older than age 40 and is associated with accelerated bone loss. The primary objective of this study was to compare the effects of intravenous (IV) zoledronic acid versus prescribed physical activity (PA) on changes in bone mineral density (BMD) for women between the ages of 40 and 55 years receiving chemotherapy for breast cancer. A randomized controlled trial of 62 patients with breast cancer during chemotherapy compared IV zoledronic acid and oral calcium/vitamin D (ZO group) versus a PA program and oral calcium/vitamin D (PA group). ZO group participants received zoledronic acid IV every 3 months for 5 treatments. PA group participants were enrolled in a home-based exercise program and received motivational counseling, pedometers, and exercise tapes. BMD measurements from dual-energy x-ray absorptiometry (DEXA) scanning were completed at baseline and at 12 months. BMD significantly decreased in the PA group but not in the ZO group. Although spine, total hip, and total body BMD increased in the ZO group by 1.6%, 0.8%, and 0.8%, respectively, BMD decreased in the PA group by 6.0%, 3.4%, and 3.3%, respectively (P values < 0.0001 for all group comparisons). Zoledronic acid protected patients with breast cancer against bone loss during initial treatment, whereas home-based PA interventions were less effective in preventing bone loss.