Hyaluronic Acid

Three high-quality RCTs evaluated IA hyaluronic acid versus saline control with 1.5-6 month follow-up.^8–10 Cohen 2008 found saline superior to HA across multiple outcomes at 1.5, 3, and 6 months (AOS Total, WOMAC Total, Pain scores).⁸ DeGroot 2012 found no differences between HA and saline.⁹ Kubo 2022 showed DF-HA reduced adverse events but no improvement in patient-reported outcomes.¹⁰ Meta-analysis confirmed no benefit of HA over saline. 

Two high-quality RCTs compared combination IA therapy (HA + corticosteroid) to corticosteroid monotherapy.^11,12 Gomes 2023 found combination superior for VAS Pain at 1 month and for both AOFAS Total and VAS Pain at 3 months, with trends persisting at 6 months.¹¹ Woo 2025 found combination superior for AOS Total at 1.5 and 3 months.¹² Both studies consistently demonstrated combination therapy provides superior improvement in disease-specific ankle outcomes and pain scores versus corticosteroid alone at 1.5-3 months. However, neither study compared combination therapy to placebo, so absolute efficacy cannot be determined.

Benefits/Harms: 

Hyaluronic Acid Alone: No demonstrated benefit over saline placebo. Generally well-tolerated but multiple injections required (3-5 weekly), with potential for post-injection pain/effusion and false patient expectations. 

Hyaluronic Acid combined with Corticosteroid: Improved pain and ankle-specific function at 1.5-3 months versus corticosteroid alone. Combination of adverse events from both agents. Multiple Hyaluronic Acid combined with Corticosteroid: Improved pain and ankle-specific function at 1.5-3 months versus corticosteroid alone. Combination of adverse events from both agents. Multiple injections required (3 weekly), increased cost versus corticosteroid alone, and no long-term (>6 months) safety data.

Cost Effectiveness/Resource Utilization: 

Hyaluronic Acid Alone: HA costs $500-2000+ per injection series. Given lack of efficacy versus placebo, routine use represents poor resource utilization. 

Hyaluronic Acid combined with Corticosteroid: Significantly more expensive than corticosteroid alone (additional $500-2000+). Incremental benefit must be weighed against cost and lack of placebo comparison. Requires multiple clinic visits versus single corticosteroid injection.

Acceptability: 

Hyaluronic Acid Alone: Despite use in knee OA, ankle-specific evidence demonstrates lack of efficacy. Patients should be counseled that high-quality evidence does not support benefit over placebo. Stakeholder resistance expected given widespread HA marketing.

Hyaluronic Acid combined with Corticosteroid: May be acceptable to patients willing to undergo multiple injections for added benefit. Higher cost may limit accessibility, insurance coverage may be limited, and some hesitancy given HA alone showed no benefit versus placebo. Shared decision-making should emphasize incremental (not absolute) benefit, cost, and treatment burden.

Feasibility: 

Hyaluronic Acid Alone: Widely available and technically feasible, but feasibility does not override lack of efficacy. 

Hyaluronic Acid combined with Corticosteroid: Feasible in most practices performing IA injections. Requires availability of both agents and ability to schedule multiple visits. Less feasible in rural settings or for patients with transportation/scheduling limitations.

Future Research: 

Hyaluronic Acid Alone: Investigation of patient subgroups, different HA formulations, comparison to non-surgical interventions, longer-term outcomes, and mechanistic studies to understand ineffectiveness in ankle OA. 

Hyaluronic Acid combined with Corticosteroid: Critical need for comparison to placebo/control, comparative effectiveness versus other non-surgical interventions, optimal injection protocols, patient characteristics predicting response, long-term outcomes and safety, cost-effectiveness analyses, and stratification by OA severity.