Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. The effect of 5 years of treatment with anastrozole on bone mineral density (BMD) was previously reported (Eastell R. J Clin Oncol 26:1051-1058, 2008). However, the effect of long-term (more than 2 years) therapy with exemestane (EXE) on BMD is still unknown. We assessed changes in BMD from baseline to 5 years of treatment in patients receiving EXE as initial adjuvant therapy with/without oral bisphosphonates (Bis). Methods: Postmenopausal women with endocrine-responsive breast cancer receiving EXE as adjuvant therapy at our hospital since 2005 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48, and 60 months. Oral Bis (risedronate or alendronate) treatment was initiated when patients were diagnosed with osteoporosis with a T-score of 2.5 or lower. Observation was censored when treatment of EXE was stopped because of relapse or other diseases. Results: Eighty-one patients were enrolled in the study between 2005 and 2010. Patients’ median age was 67 years, and the median follow-up period was 60 months. Forty-two patients were administered Bis (upfront use of Bis: 28 patients; delayed use of Bis: 14 patients). Within 6 months of hormone therapy, BMD increased by 2.4% from baseline in the lumbar spine and decreased by 0.5% in the femoral neck. After 5 years of treatment, however, BMD had increased by 7.8% in the lumbar spine and by 3.4% in the femoral neck. In patients treated with upfront Bis (n = 28), a 5.7% increase in BMD from baseline was noted in the lumbar spine, whereas in those without Bis (n = 39), BMD decreased by 1.8% from baseline within 12 months (P < 0.0001). Fractures were observed in 10 patients (12.3%), and 8 (9.9%) had fragility-related fractures. Conclusions: Oral Bis improves BMD in the lumbar spine among patients with osteoporosis. Treatment with EXE for 5 years with proper use of Bis maintains BMD in the lumbar spine and femoral neck. Clinical trial information: UMIN000020499.