Denosumab in Breast Cancer: Immunobiology, Clinical Evidence and Future Perspectives

Bone is the most common site of distant relapse in breast cancer, and skeletal-related events (SREs) remain a major source of morbidity and reduced quality of life in patients with bone-metastatic disease. Denosumab, a fully human IgG2 monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), interrupts osteoclast-driven bone resorption upstream of the bisphosphonate mechanism of action and has demonstrated superiority over zoledronic acid in preventing SREs in pivotal phase III trials. Beyond this well-established antiresorptive role, RANK/RANKL signaling has been implicated in mammary tumorigenesis and modulation of the tumor immune microenvironment, and recent window-of-opportunity studies have shown that short-term denosumab increases tumor-infiltrating lymphocytes in human breast tumors—a translational finding that has not yet been linked to a demonstrated clinical benefit. This narrative review synthesizes the pharmacology of denosumab; the biological rationale linking RANKL to immune-cell function in the breast; the pivotal and contemporary clinical evidence in metastatic and early breast cancer, including the divergent D-CARE and ABCSG-18 adjuvant trials and the 2026 REDUSE dosing-interval data; and practical considerations distinguishing denosumab’s evidentiary position in metastatic disease, cancer treatment-induced bone loss, and adjuvant disease modification. We also discuss why preclinical immune synergy has not been reproduced clinically and outline priorities for biomarker-selected trials, immunotherapy combinations, dose de-escalation, and MRONJ risk stratification. Throughout, we distinguish established clinical applications from translational and hypothesis-generating findings, and highlight methodological limitations—including small subgroup sizes, retrospective design, and unpublished congress data—that should temper interpretation of several recent findings before they inform clinical practice or future trial design.