Knee osteoarthritis (OA) is one of the major causes of disability throughout the world. OA was designated as the fourth leading cause of years lived with disability at global level reporting for 3.0% of total global years lived with disability (YLDs) in 2000 according to the World Health Report. The loss of hyaluronan in the synovial fluid and cartilage of the knee cause joint pain and stiffness in knee OA patients.

HA CW et al. executed a randomized, multi-center, double-blind, non-inferiority study to investigate the efficacy and safety of a cross-linked hyaluronate (XLHA, single injection form) distinguished with a linear high molecular hyaluronate (HMWHA, thrice injection form) in symptomatic knee osteoarthritis patients.

A total of 287 patients with osteoarthritis (Kellgren-Lawrence grade I to III) were randomized to each group. To maintain double-blindeness, three weekly injections were given in both groups but two times of saline injections preceded the XLHA injection. Twelve weeks after last injection, the primary endpoint revealed the change of weight-bearing pain (WBP). As per the secondary outcomes, Western Ontario and McMaster Universities Osteoarthritis index; pain at rest, at night, or in motion; OMERACT-OARSI responder rate; proportion of patients attaining at least 20 mm or 40% reduction in WBP; and rate of rescue medicine use and its total consumption were considered.

Non-inferiority of XLHA to HMWHA as the lower bound of 95% CI (-1.9 mm, 10.1 mm) was well above the predefined margin (-10 mm) as the mean changes of WBP at 12 weeks after the final injection was -33.3 mm and -29.2 mm with XLHA and HMWHA. No significant between-group differences were observed in all the secondary endpoints. The most common adverse event was pain at the injection site and with no major safety concerns. 

These findings revealed that the single cross-linked hyaluronate injection was non-inferior to three injections of linear high molecular hyaluronate with respect to WBP reduction. Hence, XLHA is an effective and safe treatment for knee osteoarthritis.