TSA, PXD, and MGCD function as dual-action therapeutics by regulating macrophage polarization and enhancing osteogenesis, thereby establishing a pro-regenerative microenvironment and reversing inflammatory bone loss. These findings provide mechanistic insight into the epigenetic control of immune-bone crosstalk and support a drug-repurposing strategy that utilizes clinically available HDAC inhibitors to accelerate the development of osteoimmunomodulatory therapies.