The Effect of Ozone (O3) versus Hyaluronic Acid on Pain and Function in Patients with Knee Osteoarthritis: A Systematic Review and Meta-Analysis



1 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran- Rothman Institute, Thomas Jefferson University, Philadelphia, USA

3 Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

4 Iran University of Medical Sciences, Tehran, Iran


Background: Of the pharmacological modalities for knee osteoarthritis (OA), intra-articular injections including ozone
(O3) and hyaluronic acid (HA) are commonly used for reducing pain and improving function. In this systematic review
and meta-analysis, we aimed to compare the effect of O3 versus HA in reducing pain and increasing function in patients
with knee OA.
Methods: After searching databases, we included 6 randomized controlled trials on patients with knee OA that
compared the effects of intra-articular injection of ozone versus HA. The primary outcome was visual analogue scale
(VAS) of pain. The secondary outcome was Western Ontario and McMaster Universities Arthritis Index (WOMAC)
Results: There was a total of 237 patients in the HA group and 230 patients in the Ozone group. Of 6 studies, 4 were
in English, 1 was in Persian, and 1 was in German language. The overall Standardized Mean Difference (SMD) for VAS
pain did not show a significant difference between the groups although it favored HA injection (1.27 [95%CI: (-0.12)-
2.66]). Total WOMAC score showed a significant difference over the time favoring HA injection (4.5 [95%CI: 1.1-8]).
However, no single time point showed any significant difference between groups.
Conclusion: This meta-analysis showed no significant difference between HA and ozone in reducing pain and
improving function in patients with knee OA, although the overall results favored HA over ozone. Since previous studies
have shown comparable results between HA and placebo, ozone seems to fall in the same category with more placebo
effect rather than a real disease-modifier.
Level of evidence: I