Advances in hyaluronic acid therapy for knee osteoarthritis: monotherapy and combination strategies: an evidenced based review

Knee osteoarthritis (KOA) is a chronic degenerative joint disease that lead to cartilage loss, inflammation, and disability. Intra-articular hyaluronic acid (HA) is widely used for its viscoelastic, anti-inflammatory, and chondroprotective properties; however clinical outcomes remain inconsistent. Recent studies have explored combining HA with biologic or pharmacologic agents, such as platelet-rich plasma (PRP), corticosteroids (CS), fibrinogen, botulinum toxin A, polydeoxyribonucleotide (PDRN), and stem cells, to enhance efficacy through multimodal mechanisms. Despite this, the comparative benefits and safety profiles of these emerging strategies remain unclear. This review aims to evaluate the clinical efficacy of intra-articular HA, used either alone or in combination with adjunctive agents, for the management of KOA. A comprehensive literature search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science, covering the period from January 2010 to April 2025. A total of 70 studies were included, comprising 50 randomized controlled trials (RCTs) and 20 meta-analyses. High-quality evidence supports the modest yet clinically significant efficacy of HA monotherapy, especially in the early to moderate stages of KOA. Outcomes appear to be affected by factors such as molecular weight, crosslinking, and injection protocols. Among combination strategies, the combination of HA and PRP demonstrates the most consistent synergistic benefits across various outcome domains. Short-term improvements are also observed with the combination of HA and CS. Emerging combinations involving fibrinogen, botulinum toxin A, peripheral blood stem cells and polydeoxyribonucleotide show early promise but remain under investigation.