Multi‐Core Functional Microspheres for Osteoporotic Bone Defects Therapy: From Local Treatment to Systematic Relief

Abstract Bone repair in patients with osteoporosis is a major challenge. In this study, multi‐enhanced bioactive microsphere scaffolds (abbr. GMA MSs) composed of a gelatin framework with alendronate (ALN) and magnesium (Mg) spheres encapsulants are developed for repairing osteoporotic bone defects. The GMA MSs prepared via the reverse microemulsion method and a photocuring process have a uniform morphology. Hydrogen (H ₂ ) generated from GMA MSs scavenged reactive oxygen species (ROS), regulated macrophage phenotype, inhibited the phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt) and nuclear factor kappa‐B (NF‐κB) signaling pathways, and decreased the expression of pro‐inflammatory factors, thereby improving the inflammatory microenvironment. Concurrently, the alkaline enhancement of ALN release from GMA MSs inhibited osteoclast activity, and the released Mg ²⁺ promoted osteogenic differentiation, which synergistically restored the balance of bone metabolism alongside ALN. After filling into osteoporotic skull defects, GMA MSs significantly improved the inflammatory response and promoted notable bone tissue repair in osteoporotic skull defects of ovariectomized (OVX) mice. Notably, the local treatment with GMA MSs significantly relieved systemic osteoporosis and reduced overall bone loss in these mice, highlighting the substantial potential of the GMA MSs scaffold in the clinical treatment of osteoporotic bone defects.