Abstract
Osteoarthritis (OA) is a leading cause of physical disability, psychological distress, and a significant economic burden worldwide. Current treatments alleviate symptoms; however, disease progression remains largely uncontrolled, highlighting the urgent need for investigation of disease-modifying therapies. Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), such as glucosamine (GlcN), chondroitin sulfate (CS), and hyaluronic acid (HA), have gained increasing attention for their potential benefits in alleviating pain and mitigating the inflammatory and degenerative processes that characterize OA. These compounds modulate several homeostatic mechanisms, promoting anti-inflammatory, antioxidant, antiapoptotic, and anabolic countermensuring effects. Nevertheless, debates regarding their long-term efficacy and safety remain controversial, which explains why major osteoarthritis societies do not provide the same recommendations for the pharmacological treatment of OA. In this context, this review critically evaluates the current evidence surrounding HA, GlcN, and CS, highlighting their safety, mechanisms of action, and promising therapeutic perspectives for modifying the natural course of knee, hand, and hip OA.