Unraveling stress fractures: from cellular and molecular mechanisms to therapeutic approaches

Stress fractures are overuse injuries that develops in response to repetitive loads applied to bone with normal structural integrity and is highly prevalent among physically active populations, but their underlying mechanisms remain incompletely understood. This article reviews the complex pathogenesis and healing mechanisms of stress fractures. Stress fractures develop when repetitive mechanical loading on the bone exceeds its threshold for adaptive repair, leading to the progressive accumulation of microdamage and ultimately disrupting the physiological equilibrium between bone resorption and formation. The healing of stress fractures is characterized by intramembranous ossification, a process that begins with periosteal woven bone formation to stabilize the fracture and proceeds through subsequent bone remodeling to repair the cracks. The development and repair processes of stress fractures involve dynamic alterations in cell types and tissue constituents, along with active signaling activities within and among the involved cells involved.

Future research should prioritize the use of larger animal models such as rabbits and minipigs, and the development of stress fracture models that more accurately replicate the clinical pathogenesis of stress fractures. Although the efficacy of anti-osteoporotic agents, non-steroidal anti-inflammatory drugs (NSAIDs), and low-intensity pulsed ultrasound (LIPUS) have been reported, future research should explore additional physical therapy modalities to elucidate their specific role in the management of stress fractures and underlying mechanisms. Overall, by reviewing the latest research advances in the pathogenesis and treatment of stress fractures and exploring targeted therapeutic strategies, this article holds the promise to offer novel insights into their prevention and management, thereby driving improvements and innovations in clinical treatment approaches and demonstrating significant translational potential.