What is intraarticular (within a joint) hyaluronic acid used for?

Intraarticular Hyaluronic Acid: Clinical Use and Evidence

Primary Indication

Intraarticular hyaluronic acid is FDA-approved for treating knee osteoarthritis pain, but current high-quality evidence does not support its routine use, and major guidelines recommend against it for most patients. 1

Evidence-Based Recommendations by Joint

Knee Osteoarthritis

• The American Academy of Orthopaedic Surgeons (AAOS) recommends against routine use of hyaluronic acid despite its common use, citing inconsistent evidence across 17 high-quality and 11 moderate-quality studies. 1
• The number needed to treat is 17 patients, meaning only 1 in 17 patients derives meaningful benefit, but current evidence cannot identify which subset of patients will respond. 1
• The American College of Rheumatology/Arthritis Foundation provides a conditional recommendation against hyaluronic acid injections because when analysis is restricted to low-bias trials, the effect size compared to saline injections approaches zero. 1
• The apparent benefits seen in earlier reviews were driven by studies with higher risk of bias; rigorous studies fail to demonstrate efficacy beyond placebo. 1, 2

Hip Osteoarthritis

• The American College of Rheumatology/Arthritis Foundation strongly recommends against hyaluronic acid for hip OA, reflecting higher-quality evidence of complete lack of benefit compared to the knee. 1, 2
• The evidence against hyaluronic acid is stronger for hip than knee, with effect sizes approaching zero in high-quality trials. 2

Shoulder (Glenohumeral) Osteoarthritis

• The AAOS provides a Grade C recommendation (Level IV evidence) that hyaluronic acid is an option for glenohumeral osteoarthritis, though this is based on limited evidence from only one industry-supported study. 3

Treatment Algorithm for Knee OA

First-Line Therapies (Use Before Considering Hyaluronic Acid)

• Non-pharmacologic interventions: exercise, weight loss, and physical therapy. 2, 4
• Oral NSAIDs (both nonselective and selective COX-2 inhibitors are effective, with no notable difference in gastrointestinal adverse events between them). 1
• Acetaminophen (effective but carries FDA black box warning requiring appropriate prescribing). 1
• Topical NSAIDs or capsaicin cream. 4

Second-Line: Intraarticular Corticosteroids

• Corticosteroid injections are the evidence-based choice for intraarticular therapy, supported by 19 high-quality and 6 moderate-quality studies. 1, 4
• Provide immediate symptom relief within 7 days with an effect size of 1.27. 2, 4
• Duration of benefit is typically 3 months. 1, 4
• Require only a single injection versus 3-5 weekly injections for hyaluronic acid. 2, 4
• Particularly effective for acute flares with effusion and local inflammation. 4

Third-Line: Consider Hyaluronic Acid Only After Failures

• Hyaluronic acid may be considered only when patients have failed non-pharmacologic therapies, topical/oral NSAIDs, and corticosteroid injections. 1, 4
• This requires shared decision-making that acknowledges the limited evidence of benefit. 1, 4
• The conditional recommendation against is consistent with using hyaluronic acid when other alternatives have been exhausted, particularly given the contextual effects (placebo response) of intraarticular injections. 1

Patient Selection Criteria (If Considering Hyaluronic Acid)

Favorable Characteristics

• Mild-to-moderate disease severity (Kellgren-Lawrence grades 1-3). 4, 5
• Age over 60 years with significant functional impairment. 4
• Patients with significant surgical risk factors who are not candidates for arthroplasty. 5

Unfavorable Characteristics (Avoid Treatment)

• Severe osteoarthritis with complete collapse of joint space or bone loss shows poor clinical response. 4, 5
• Patients with severe disease and baseline effusion respond poorly. 4
• Hip osteoarthritis (strong evidence of no benefit). 1, 2

Practical Considerations

Administration

• Typically given as 3-5 weekly injections (most commonly 3 injections over 3 weeks or single injection depending on formulation). 6
• High molecular weight preparations are used in 63.2% of studies, low molecular weight in 21%. 6
• Duration of symptom control when effective is approximately 6 months. 7, 6

Adverse Events

• Generally well-tolerated with very few adverse events. 7
• Local pain and swelling lasting a few days are the most common side effects. 7, 6
• Severe allergic reactions are extremely rare. 6
• One case of septic arthritis reported in 80 treated knees (1.25% risk). 5

Critical Caveats and Pitfalls

Publication Bias Concerns

• Benefit is restricted to studies with higher risk of bias, particularly industry-sponsored trials. 1, 4
• Discrepancies between industry-sponsored and publicly-funded studies raise serious concerns about publication bias. 1

Do Not Extrapolate Between Joints

• Never extrapolate the weak evidence for knee OA to hip OA, as the hip joint has distinct biomechanics and higher-quality evidence specifically showing lack of benefit. 2

Avoid Oral Narcotics

• Oral narcotics including tramadol should not be used in knee osteoarthritis treatment due to notable increase in medication-related adverse effects with no consistent improvement in pain and function. 1

Insurance Coverage

• The conditional recommendation against is not intended to influence insurance coverage decisions but reflects the limited evidence base. 1

Combination Therapies

• Hyaluronic acid combined with corticosteroids, platelet-rich plasma, or mesenchymal stem cells shows better results than hyaluronic acid alone in some studies. 6
• Platelet-rich plasma is supported by two high-quality studies showing reduced pain and improved function, though with inconsistency in severe knee OA and concerns about cost and safety. 1