Abstract Background: Aromatase inhibitors (AIs) are widely used as postoperative endocrine therapy in patients with postmenopausal hormone receptor-positive breast cancer. The main side effect of AIs is bone loss, which is called cancer treatment-induced bone loss (CTIBL), and the use of bone resorption inhibitors are recommended when the risk of fracture is high. However, we do not yet have clear data on the preventive effects of bone resorption inhibitors and their safety in patients with normal bone density. In this study, we aimed to evaluate the preventive effects of denosumab on suppressing bone loss associated with postoperative endocrine therapy for Japanese breast cancer patients with normal bone mineral density. Methods: A multicenter, open-label, randomized controlled trial was conducted. Patients with postmenopausal hormone receptor-positive breast cancer of stage ≦IIIA with normal bone density meeting lumbar spine T-score ≧-1.0 and femoral neck T-score ≧-1.0 were included. Patients were assigned in a 1:1 ratio to receive the hormone alone (control group) or an additional 60 mg of denosumab every 6 months (denosumab group). The primary endpoint was the percentage change in lumbar spine (L1-L4) bone mineral density (BMD) at 12 months. Secondary endpoints included the percentage change in lumbar spine BMD (2-5 years later), femoral neck BMD change, pathological fracture incidence, adverse events, progression-free survival, and overall survival. Results: A total of 83 cases were registered, and 66 were included in the primary analysis. At 12 months, the mean percentage change in lumbar spine BMD was +4.56% in the denosumab group (N=32) and -3.66% in the control group (N=34), yielding a significant improvement of +8.1% (95%CI: 6.2%-10.1%, p0.01) in analyses adjusting for several covariates in a linear model. Within three years, there were no fractures in the denosumab group and one in the control group (p=0.53). Adverse events of any grade occurred in 13 cases (33.3%) in the denosumab group and 12 (31.6%) in the control group; there were no cases of osteonecrosis of the jaw or atypical femoral fractures. No significant differences were observed in disease-free survival or overall survival. Conclusion: In Japanese breast cancer patients with normal bone density, the combination of denosumab and postoperative adjuvant endocrine therapy significantly prevented the decline in lumbar spine BMD. This intervention showed a good safety profile without severe adverse events and the potential to prevent the occurrence of fractures. These findings support the consideration of denosumab as part of a comprehensive strategy for preserving bone health in a broader range of patients, including those with initially normal BMD who are receiving endocrine therapy for breast cancer. Future research should aim to explore long-term fracture outcomes, cost-effectiveness, and the integration of bone health strategies into standard oncology care. Citation Format: M. Morita, A. Watanabe, K. Sakaguchi, I. Takashi, Y. Hasegawa, A. Sato, S. Takao, K. Tane, M. Takahashi, K. Watanabe, M. Kato, Y. Ouchi, N. Kono, T. Kubota, M. Suzuki, J. Horiguchi, K. Narui, D. Miura, K. Terata, K. Imai, R. Takekawa, I. Yokota, A. Naito, S. Sakabayashi, Y. Naoi, T. Taguchi. A Multicenter Randomized Controlled Trial to Verify the Preventive Effect of Denosumab against Cancer Treatment-Induced Bone Loss (CTIBL) in Breast Cancer Patients Receiving Postoperative Endocrine Therapy with Normal Bone Density abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-05-27.
Morita et al. (Tue,) studied this question.