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Repurposing Metformin to Promote Fracture Callus Maturation via AMPK-Driven Metabolic Activation
Vasyl Pastukh1, Jianying Zhang1, Peter G Alexander2
1MechanoBiology Laboratory, Bethel Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Summary
Metformin, an anti-diabetic drug, significantly accelerates bone fracture healing in rats by improving callus maturation and structural consolidation. This repurposing strategy enhances bone repair through metabolic and inflammatory modulation.
Area of Science:
- Orthopedics
- Pharmacology
- Regenerative Medicine
Background:
- Femoral shaft fractures lead to significant disability with limited therapeutic options for accelerated bone repair.
- Repurposing existing drugs offers a promising avenue to address biological bottlenecks in fracture healing.
Purpose of the Study:
- To investigate the efficacy of systemic metformin administration in enhancing bone fracture repair.
- To evaluate metformin's effects on callus maturation, structural consolidation, and underlying mechanisms in a rat model.
Main Methods:
- A rat open femoral shaft fracture model was used, comparing metformin-treated and vehicle-treated groups.
- Analyses included histology, immunofluorescence, micro-computed tomography (micro-CT), and biomechanical testing at 6 weeks post-injury.
- Mechanistic investigations focused on p-AMPK, mitochondrial markers, and HMGB1 release.
Main Results:
- Metformin accelerated callus maturation, evidenced by earlier cartilage ossification and improved collagen organization.
- Micro-CT revealed enhanced tissue mineral density, trabecular thickness, and bone volume fraction in metformin-treated animals.
- Mechanistically, metformin increased p-AMPK and mitochondrial markers while reducing HMGB1, indicating improved metabolism and reduced inflammation.
Conclusions:
- Systemic metformin promotes earlier structural consolidation of fracture calluses via metabolic and inflammatory modulation.
- Metformin's effects are particularly significant during the cartilage-to-bone transition, highlighting the role of metabolic activation.
- Metformin shows potential as a safe, inexpensive adjunct therapy to enhance bone fracture repair.
