Rosuvastatin in Combination With Bortezomib Promotes Osteogenesis in Myeloma Bone Disease by Inhibiting the Secretion of CCL3

Background: Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM) and a primary cause of disability in affected patients. Its pathogenesis is driven by an imbalance in bone remodeling, largely attributed to the overexpression of C-C motif chemokine ligand 3 (CCL3). While both bortezomib and statins have been reported to inhibit CCL3, their combined effect on promoting osteogenesis in MBD remains unexplored. This study aimed to investigate the therapeutic potential and underlying mechanism of rosuvastatin in combination with bortezomib for MBD. Methods: Bone marrow samples from MBD patients were analyzed to correlate CCL3 levels with bone turnover markers. Human myeloma cell lines (IM9, XG-1) were treated with bortezomib and/or rosuvastatin. Cell viability was assessed by CCK-8 assay, and CCL3 expression was measured by ELISA and Western blot. A NOD/SCID mouse model of MBD was established to evaluate the in vivo effects on tumor growth, CCL3 secretion (by immunohistochemistry), and bone remodeling (by ALP and TRAP double staining). Results: CCL3 levels were significantly elevated in MBD patients and positively correlated with the severity of bone destruction. The combination of bortezomib and rosuvastatin synergistically inhibited CCL3 secretion in vitro and in vivo more effectively than either monotherapy. Consequently, the combination treatment significantly enhanced osteoblast activity, suppressed osteoclast formation, and improved survival in the murine model. Conclusion: The combination of rosuvastatin and bortezomib exerts a synergistic effect by inhibiting CCL3, thereby rebalancing bone remodeling and promoting osteogenesis. This strategy represents a promising novel therapeutic approach for mitigating MBD.