Clinical Efficacy and Safety of Two Cycles of Intra-Articular Injection of Porcine Atelocollagen Versus Hyaluronic Acid in Knee Osteoarthritis

(1) <b>Background:</b> Knee osteoarthritis (KOA) induces pain, stiffness, and impaired mobility, particularly in aging populations. Despite providing symptom relief, the long-term efficacy of intra-articular hyaluronic acid (HA) injections remains unclear. With its longer intra-articular residence time and potential chondroprotective effects, porcine-derived atelocollagen is an alternative to HA. We aimed to compare the safety and efficacy of collagen versus HA injections in symptomatic KOA. (2) <b>Methods:</b> This retrospective observational study included 40 patients with KOA who received either two cycles of collagen or HA injections at 6-month intervals. Clinical outcomes were assessed using the visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline and 6 months after the first and second injections (Cycle 1 and Cycle 2, respectively). Patient satisfaction and adverse events were recorded. Non-inferiority analysis was conducted for VAS and WOMAC score changes. (3) <b>Results:</b> Significant intragroup improvements in VAS and WOMAC scores were noted after each injection cycle (<i>p</i> < 0.05), albeit without significant between-group differences, non-inferiority of collagen to HA based on predefined margins, and comparable patient-reported satisfaction (>85% reported improvement after each cycle), with similar incidence of mild adverse events (collagen: 20%, HA: 25%, <i>p</i> = 0.705). (4) <b>Conclusions:</b> Intra-articular collagen injections were clinically non-inferior to HA in reducing pain and improving function in patients with KOA across two treatment cycles. Given its favorable safety profile and potential structural benefits, collagen may serve as a viable alternative injectable therapy for the non-surgical management of KOA.