Initial Denosumab Versus Sequential Bisphosphonate-to-Denosumab for Prevention of Skeletal-Related Events in Breast Cancer with Bone Metastases: A Retrospective, Single-Center Study

Background: Skeletal-related events (SREs), including pathological fractures, spinal cord compression, radiotherapy to bone, and bone surgery, substantially worsen quality of life in breast cancer with bone metastases. Denosumab, a monoclonal antibody targeting RANKL, mechanistically differs from bisphosphonates and is not renally cleared, offering potential clinical advantages. In practice, an increasing number of patients transition from bisphosphonates to denosumab. However, the comparative effectiveness of sequential therapy versus initial denosumab remains unclear. Methods: We retrospectively analyzed 165 patients with breast cancer and radiologically confirmed bone metastases treated between 1 January 2019 and 30 April 2024 at a tertiary center in China. Patients were categorized into an initial denosumab group (n = 67) or a sequential bisphosphonate-to-denosumab group (n = 98). The primary endpoint was time to first on-treatment SRE; the 12-month first on-treatment SRE rate was also reported as a descriptive summary measure. Secondary endpoints included cumulative SRE incidence and safety. Kaplan–Meier and log-rank tests compared SRE-free survival; Cox regression explored prognostic factors. Results: The median age at bone-metastasis diagnosis was 54.7 years. Median time from diagnosis to bone-targeted agents (BTAs) initiation was 0.9 months in both groups; median follow-up was longer in the sequential group (22.5 vs. 11.3 months). At diagnosis, 46 of 165 patients (27.9%) presented with synchronous SREs, more frequent in the initial denosumab group (37.3% vs. 21.4%; p = 0.040). During follow-up, 31 patients (18.8%) developed SREs: 25 of 98 (25.5%) in the sequential group versus 6 of 67 (9.0%) in the initial denosumab group (p = 0.008). After BTA initiation, on-treatment SREs occurred in 28 of 165 patients (17.0%): 25 of 98 (25.5%) in the sequential group versus 3 of 67 (4.7%) in the initial denosumab group (p < 0.001). The 12-month first on-treatment SRE rate was 15.7% (95% CI 8.1–22.7) for sequential therapy and 5.9% (0–12.3) for initial denosumab. In Cox analysis, second-line systemic therapy increased SRE risk (HR = 2.651, p = 0.021). Safety outcomes were generally manageable and consistent with known class effects, with no clear exposure-adjusted safety advantage of one strategy over another. Conclusions: Initial denosumab was associated with fewer and delayed SREs compared with sequential bisphosphonate-to-denosumab therapy, supporting early denosumab initiation as a potentially preferable BTA strategy. Prospective studies are warranted to confirm these findings.