For physiotherapists managing knee osteoarthritis (OA), the landscape of intra-articular injections is constantly evolving. While Hyaluronic Acid (HA) viscosupplementation is a staple in conservative management, its efficacy is often debated due to the rapid degradation of HA by reactive oxygen species (ROS) within the inflamed joint capsule. A promising solution involves combining HA with mannitol, a potent free radical scavenger, to extend the residence time and therapeutic effect of the injection.
A recent 2026 randomized controlled trial published in The Knee investigates this specific formulation, marketed as JETKNEE, to determine if the biochemical theory translates to superior clinical outcomes.
The Biochemical Rationale: Why Add Mannitol?
The premise of the JETKNEE formulation is the stabilization of non-crosslinked HA (20 mg/ml) using 0.5% mannitol. In the pathophysiology of osteoarthritis, oxidative stress plays a significant role. ROS depolymerize HA, reducing its molecular weight and subsequently its viscoelastic properties. By neutralizing these free radicals, mannitol is hypothesized to protect the HA chains, theoretically prolonging the shock-absorbing and lubricating effects of the injection. However, until recently, high-quality evidence supporting this specific combination has been limited.
Study Design: JETKNEE vs. Saline
To test this hypothesis, Chen et al. conducted a double-blind, randomized clinical trial involving 132 patients with symptomatic knee OA, specifically classified as Kellgren-Lawrence grades 2 and 3. The participants were randomized to receive either a single 2 ml intra-articular injection of the mannitol-combined HA (JETKNEE) or a saline placebo.
The researchers tracked patients over a six-month period, utilizing the Visual Analog Scale (VAS) for pain as the primary outcome measure. Secondary outcomes were robust, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Lequesne index, and ultrasound evaluations of cartilage and muscle thickness.
Divergent Results: The Pain vs. Function Paradox
The results of this trial provide a nuanced perspective essential for clinicians referring patients for injections. Regarding the primary outcome—VAS pain at 6 months—the study did not find a statistically significant difference between the intervention and the placebo. Both groups experienced significant pain reduction, highlighting the formidable placebo effect often seen in intra-articular injection trials.
However, for physiotherapists focusing on rehabilitation and movement, the secondary outcomes tell a more compelling story. The JETKNEE group demonstrated significantly greater improvements in the WOMAC scores (covering pain, stiffness, and physical function) compared to the control group across all time points (P < 0.05). Furthermore, the Lequesne index showed more rapid improvements in the early stages of the follow-up for the treatment group.
Clinical Implications for Rehabilitation
While the failure to beat placebo on the VAS scale is notable, the superior functional outcomes measured by WOMAC suggest that mannitol-combined HA may offer benefits that purely pain-focused scales miss. For patients undergoing physiotherapy, the improvement in joint stiffness and function is often the gateway to better compliance with therapeutic exercise.
Clinicians should note that adverse events were slightly more frequent in the intervention group, though these were mostly mild. While this injection may not be a “magic bullet” for pain elimination compared to placebo, its capacity to improve functional indices makes it a relevant adjunct to mechanical loading and exercise therapy.
References
Chen, C. Y., Lu, C. C., Liou, I. H., Huang, M. H., Ding, R. S., & Sun, S. F. (2026). Efficacy and safety of a single intra-articular injection of mannitol-combined hyaluronan in patients with knee osteoarthritis – A double-blinded randomized clinical study. The Knee. https://pubmed.ncbi.nlm.nih.gov/41385821/
