REVIEW article
Front. Endocrinol.
Sec. Bone Research
This article is part of the Research TopicMetabolic and Biomechanical Factors in Bone Fragility: New Frontiers in Understanding and Managing OsteoporosisView all 8 articles
Macrophages in Osteoporotic Fractures: From Immunometabolic Mechanisms to Precision Therapeutic Approaches
Provisionally accepted
- 1Orthopedics and Traumatology Department of Integrated Traditional Chinese and Western Medicine, Tianjin Hospital, Tianjin, China
- 2Cardiothoracic Surgery Department, Tianjin Hospital, Tianjin, China
- 3Orthopedics and Traumatology Department of Integrated Traditional Chinese and Western, Tianjin Hospital, Tianjin, China
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Osteoporosis (OP) is a systemic bone disease characterized by reduced bone mass and deterioration of bone microarchitecture. Its critical complication, osteoporotic fractures (OPF), imposes a significant global disease burden. Macrophages, serving as central regulators within the osteoimmune microenvironment, dynamically modulate bone homeostasis and fracture healing through polarization (into pro-inflammatory M1 and reparative M2 phenotypes) and metabolic reprogramming. In OPF, OP-inducing factors (such as estrogen deficiency and aging) induce metabolic dysregulation in macrophages by disrupting the balance between glycolysis and oxidative phosphorylation (OXPHOS), causing aberrant succinate accumulation, and depleting NAD+ levels. This dysregulation disrupts the orderly transition from pro-inflammatory M1 to reparative M2 polarization, ultimately leading to insufficient inflammatory initiation in the early fracture phase and impaired osteogenic differentiation during later stages. Targeting this mechanism, innovative therapeutic strategies centered on macrophage metabolic reprogramming and polarization modulation are rapidly developing. These include nanocarriers for mitochondrial function restoration, bioactive coatings enabling time-programmed osseointegration, immunomodulatory smart hydrogels, and functionalized composite biomaterials. These strategies effectively promote osteoporotic bone regeneration by synergistically optimizing osteoimmune homeostasis and the osteoblast-osteoclast balance. This review systematically summarizes the immunometabolic mechanisms of macrophages in OPF and explores targeted intervention strategies, providing novel perspectives for the precision treatment of OPF.
Keywords: Osteoporotic Fractures, Macrophages, Immunometabolism, metabolic reprogramming, polarization, targeted therapy
Received: 03 Sep 2025; Accepted: 05 Nov 2025.
Copyright: © 2025 Xing, Li, Xia, Xia and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hongzhou Zhao, 13920233256@139.com
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