Drug repurposing for osteoarthritis disease modification in the early 21^st century

Osteoarthritis (OA) is a leading cause of disability worldwide, significantly impacting patient mobility and quality of life. Its increasing prevalence presents a growing socioeconomic burden. Despite extensive research, no FDA-approved disease-modifying osteoarthritis drugs (DMOADs) exist, leaving patients reliant on symptomatic treatments like NSAIDs, corticosteroids, and joint replacement surgeries. A major challenge in OA drug development is the heterogeneity of the disease. Traditional approaches that target single molecular pathways often fail to address the multifactorial nature of OA. Given the high failure rate and costs of novel drug development, drug repurposing has emerged as a promising alternative. Several repurposed drugs, predominantly those affecting inflammation (e.g. Methotrexate, Adalimumab), metabolism (e.g. Metformin, Liraglutide) and bone homeostasis (e.g. Risedronate, Clodronate) have been investigated for OA. However, inconsistent clinical trial results underscore the need for improved screening, patient stratification, and mechanistic understanding. Recent insights into OA pathophysiology, such as the role of cellular senescence, mitochondrial dysfunction, and translational alterations, highlight novel targets for repurposing efforts. The future of OA drug repurposing will likely be shaped by advancements in high-throughput screening, artificial intelligence-driven drug discovery, and strategies that align treatments with patient-specific disease mechanisms. By integrating these innovations, drug repurposing holds potential to deliver DMOADs and improve patient outcomes worldwide.