Exercise in a Pill: Emerging Therapeutics for Age-Related Orthopedic Diseases

Significance: The global aging population has led to an increasing burden of age-related orthopedic diseases, seriously imposing social and economic pressures. Although exercise has been proven to have a protective effect on the musculoskeletal system, diseases themselves often restrict patients from engaging in physical activity. Exercise mimetics, as a pharmacological intervention that can simulate or enhance the benefits of exercise, offer new treatment options for such patients. Recent Advances: Exercise mimetics modulate oxidative stress, inflammatory responses, and apoptosis to enhance bone mineral density, improve trabecular microarchitecture, facilitate cartilage nourishment, and augment muscular strength and endurance. They have shown promising therapeutic potential in disease models such as osteoarthritis, intervertebral disc degeneration, osteoporosis, and sarcopenia. Some compounds such as metformin and resveratrol have been used in clinical research. Critical Issues: This review summarizes the mechanism of action and the latest research progress on exercise mimetics in degenerative orthopedic diseases and analyzes the current translational challenges and limitations in the research. Future Directions: Future research should further clarify the tissue-specific effects of exercise mimetics, the long-term safety of their use, and individual differences in their therapeutic efficacy. Meanwhile, developing targeted delivery systems, optimizing bioavailability, and promoting more rigorously designed clinical studies will help achieve wide application of exercise mimetics in the treatment of orthopedic diseases. Antioxid. Redox Signal. 44, 488–527.