Can ozone therapy be used with hyaluronic acid (HA) injections?

Ozone Therapy with Hyaluronic Acid (HA) Injections for Osteoarthritis

Ozone therapy can be used with hyaluronic acid (HA) injections and may provide better long-term outcomes than either treatment alone, though neither treatment is strongly recommended by current guidelines for osteoarthritis management. 1, 2

Current Guideline Recommendations on HA Injections

• Intra-articular hyaluronic acid injections are conditionally recommended against in patients with knee and first carpometacarpal (CMC) joint osteoarthritis and strongly recommended against in patients with hip osteoarthritis according to the 2019 American College of Rheumatology/Arthritis Foundation guidelines 3
• The recommendation against HA is based on meta-analyses showing that when limited to trials with low risk of bias, the effect size of hyaluronic acid injections compared to saline injections approaches zero 3
• Despite the conditional recommendation against HA, guidelines acknowledge that clinicians may still consider HA injections when other treatments have failed to provide adequate symptom relief 3

Evidence on Combined Ozone and HA Therapy

• A randomized clinical trial comparing the combination of ozone and HA versus either treatment alone found that the combined therapy led to significantly better outcomes, especially at 2-month follow-up 2
• The combination of ozone with HA appears to provide complementary effects that may enhance therapeutic outcomes for patients with knee osteoarthritis 2

Comparative Effectiveness of Ozone vs. HA

• Ozone injections showed better early results (at 2 months) compared to HA in one randomized clinical trial, but HA demonstrated superior efficacy at 3 months onwards 4
• In a 6-month randomized trial, both ozone and HA treatments significantly improved pain, stiffness, and function with no statistically significant difference between the two treatments 5
• A long-term study found that while both treatments reduced pain, HA showed significantly lower pain scores at follow-up visits compared to ozone 6

Treatment Duration and Protocol

• Most studies used protocols of:
  • HA: 3-4 weekly injections 1, 4, 6
  • Ozone: 3-4 weekly injections of 10 mL of a 30 μg/mL ozone solution 4, 5
  • Combined therapy: Weekly injections for 5 consecutive weeks 2

Clinical Decision Algorithm

1. First-line treatments: Begin with non-pharmacologic therapies, topical and oral NSAIDs, and intra-articular steroids as recommended by guidelines 3
2. Consider HA and/or ozone when:
   • Patients have inadequate response to first-line treatments 3
   • Shared decision-making has been conducted regarding the limited evidence of benefit 3
3. Treatment selection:
   • For short-term relief (1-2 months): Ozone may provide faster effects 1, 4
   • For longer-term management (6-12 months): HA or combined therapy may be preferable 1, 6
   • For potentially enhanced outcomes: Consider combined therapy 2

Caveats and Pitfalls

• Neither ozone nor HA injections are strongly supported by current osteoarthritis treatment guidelines 3
• The quality of evidence for ozone therapy is limited compared to the more extensively studied HA 3, 1
• There is significant heterogeneity in ozone preparation and administration protocols across studies 1, 4, 2
• No major adverse events have been reported with either treatment in the available studies, suggesting a reasonable safety profile 1, 5