Harnessing energy metabolism for enhanced bone defect repair: Mechanisms and therapeutic strategies

Abstract Bone defect repair remains a significant challenge in clinical orthopedics, primarily due to the limitations of traditional techniques, such as insufficient osteogenic efficiency and non‐functional bone regeneration. Recently, the regulation of energy metabolism has emerged as a promising avenue for bone regeneration. This review systematically examines the critical yet underexplored role of energy metabolism in bone regeneration, focusing on the dynamic regulatory mechanisms in osteoblasts and bone marrow mesenchymal stem cells across various metabolic pathways, and clarifies the influence of glucose metabolism and mitochondrial function on cellular proliferation and differentiation. Besides, three complementary strategies are proposed: leveraging cell derivatives (e.g., mitochondria, exosomes) to provide metabolic support; employing active factors (e.g., ions, enzymes) to target key metabolic pathways; and designing biomimetic scaffolds to reconstruct a favorable metabolic microenvironment. Furthermore, deficiencies in current research—such as the lack of systematic analysis of metabolic networks, clinical validation, and multidisciplinary collaborative innovation—are noted. Future directions should explore the interplay between metabolism and epigenetics, the development of responsive metabolic regulatory materials, and advancements in clinical translation, ultimately advocating for a new paradigm in precise bone defect repair to significantly enhance patient outcomes.