Alendronate‐Conjugated Citrate‐Based Composite Microscaffolds Promote Osteoporotic Bone Regeneration via Activating Osteogenesis and Suppressing Osteoclastogenesis

ABSTRACT Healing of osteoporotic bone defects is profoundly compromised by the dysregulation of bone remodeling homeostasis, characterized by excessive osteoclastic resorption and diminished osteoblastic activity, thus conventional bioinert bone cements fail to modulate these aberrant conditions or restore physiological remodeling. To address this, alendronate‐conjugated citrate‐based composite microscaffolds, consisting of an alendronate (ALN) conjugated poly (octamethylene citrate) prepolymer mixed with hydroxyapatite (HA) (APOC‐HA), was developed followed by thermal post‐polymerization. Benefiting from the novel composite cylinder fabrication process using powder compression method in a custom‐designed three‐part split mold, and the chelation interaction between ALN and HA, the compression strength of the nonporous composite cylinders exceeded 250 MPa. Upon implantation, ALN conjugated on the polymer chains effectively inhibits osteoclast activity as the material degrades. Simultaneously, the sustained release of citrate, a key metabolic regulator, enhances the energy metabolism of bone marrow mesenchymal stem cells (BMSCs) via participating tricarboxylic acid (TCA) cycle, promoting osteogenic differentiation and mineralization. The crosslinked APOC‐HA scaffold provides robust mechanical support and excellent biocompatibility while improving bone homeostasis. Consequently, this dual‐functional biomaterial offers favorable conditions for regeneration in osteoporotic defects, representing a promising strategy for future clinical applications.