Beyond resorption: targeting osteoclast fusion and polarization to restore balanced bone remodeling

The prevalence of osteoporosis is increasing worldwide as populations age, creating a growing clinical burden of fragility fractures and highlighting limitations of current antiresorptive therapies. Conventional agents such as bisphosphonates and denosumab effectively reduce fracture risk but suppress osteoclast number and activity indiscriminately, potentially impairing bone remodeling dynamics and silencing osteoclast-derived anabolic and angiogenic coupling signals. Recent advances have redefined osteoclasts as multifunctional cells that not only resorb bone but also orchestrate osteoblast differentiation and type H angiogenesis through factors such as PDGF-BB, S1P, Wnt10b, BMP6, and CTHRC1. These insights underscore the need for therapeutic strategies that temper pathological resorption while preserving beneficial coupling. This review integrates emerging molecular mechanisms regulating two key functions of osteoclasts, progenitor cell fusion and functional polarization, and evaluates their translational potential as selective antiresorptive targets. Fusion is driven by fusogen (DC-STAMP, OC-STAMP, Atp6v0d2, CD9, integrins), recognition systems (DC-STAMP, Siglec-15-sialylated TLR2), and alterations in membrane-cortical adhesion mediated by phosphatidylserine exposure, annexin A5, ERM, and BAR proteins. Osteoclast polarization relies on integrin αvβ3-Src-Pyk2 signaling, Rho-family GTPases. Recently, leucine-rich repeat kinase (LRRK1) has attracted attention as a factor that integrates both c-Src signaling and Rho-family GTPase signaling. Therapeutically, multiple modalities such as neutralizing antibodies against DC-STAMP/OC-STAMP, Siglec-15 inhibitors, small molecules such as E8431 (DC-STAMP antagonist) and C21 (Dock5 inhibitor), and LRRK1 inhibitors demonstrate the feasibility of selectively modulating fusion or polarization while maintaining osteoblast-coupling pathways. These strategies may complement conventional antiresorptives to provide safer, more physiologically balanced osteoporosis treatments. Collectively, emerging evidence positions osteoclast fusion and polarization as highly selective and clinically promising targets. A future therapeutic framework may integrate: (i) modest suppression of osteoclast number, (ii) targeted fusion inhibition to preserve preosteoclast-derived blood vessel formation, and (iii) polarization-directed modulation to reduce resorption while sustaining bone formation.