Regulating Glucose Metabolism Enzymes for Osteoporosis Therapy: Current and Future Approaches

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, microarchitectural deterioration, and an increased risk of fracture. Its pathogenesis is closely associated with disturbances in energy metabolism, particularly glucose metabolic reprogramming in bone cells. Under osteoporotic conditions, the balance between osteoblasts and osteoclasts is disrupted, accompanied by impaired oxidative phosphorylation, dysregulated glycolysis, and reduced tricarboxylic acid cycle efficiency, ultimately leading to mitochondrial dysfunction. These metabolic alterations result in an insufficient energy supply and accelerate bone loss. Accordingly, the modulation of key enzymes involved in glucose metabolism has emerged as a promising therapeutic strategy. Strategies include the use of natural compounds, traditional Chinese medicine formulas, and specific inhibitors to modulate glucose metabolism processes and related pathways, thereby restoring cellular energy homeostasis and bone remodeling balance. This review summarizes pharmacological agents regulating glucose metabolism and proposes a hierarchical framework for therapeutic prioritization: first, inhibiting pathological glycolysis in osteoclasts (particularly via LDHA and PKM2). Second, restoring oxidative phosphorylation in osteoblasts (e.g., via COX I–V or ATP synthase). And third, employing multi-target traditional Chinese medicine formulas as complementary strategies. By establishing this cell-type-specific and pathway-specific hierarchy, the review aims to provide a theoretical basis for future research on metabolic interventions in bone diseases.