Ozone therapy for knee osteoarthritis: a literature visualization analysis of research hotspots and prospects

Abstract

Medical ozone is a molecule composed of three oxygen atoms with anti-inflammatory, analgesic, and antioxidant functions. Ozone therapy (O₃ or O₂– O₃) for knee osteoarthritis has gradually received increasing attention from researchers in recent years. Here, we discuss the research hotspots and development trends of ozone therapy for knee osteoarthritis through literature visualization and analysis. (1) From 2012 to the present, the overall trend of publications on ozone treatment for knee osteoarthritis has been increasing annually, and it has received widespread attention, especially in Iran and China. (2) Keyword analysis revealed that the keywords with the greatest number of citations for ozone treatment of knee osteoarthritis are “osteoarthritis,” “ozone,” “knee osteoarthritis,” “ozone therapy,” and “hyaluronic acid.” (3) The results of the cocitation analysis revealed that the themes of the cocited literature are concentrated in 11 directions: intra-articular injections, intra-articular oxygen ozone, treatment of knee osteoarthritis, rehabilitation studies, time effects, pain function, comprehensive review, growth factors, rheumatic diseases, ultrasound-guided corticosteroid injections, and placebo. (4) The hotspots of the available highly cited literature have focused mainly on the efficacy and safety of ozone or growth factors alone in the treatment of knee osteoarthritis. Most of the literature suggests that intra-articular injections are the most common form of ozone therapy, and the accuracy and safety of ozone injections can be ensured using ultrasound-guided techniques. Ozone therapy has a positive short-term effect on pain control and functional recovery within 6 months after injection, but how to maintain the long-term efficacy of ozone therapy has rarely been described. It is hypothesized that the combination of ozone and growth factors may be beneficial for prolonging the efficacy of ozone therapy. (5) Ozone therapy has no advantages over other therapies in terms of therapeutic efficacy. Compared with ozone therapy, platelet-rich plasma and growth factor-rich plasma have better long-term outcomes in the treatment of knee osteoarthritis, whereas stromal vascular components have the best effects on pain relief and functional improvement. Few studies address the combination of ozone and growth factors for the treatment of knee osteoarthritis, and a few clinical studies registered have explored other treatments (e.g., corticosteroids). (6) Future studies could further explore the specific mechanisms and optimal dosing regimens of ozone combined with different growth factors in the treatment of knee osteoarthritis to compensate for the short-term efficacy of ozone therapy and to validate the long-term efficacy and safety of this combination therapy. It is also imperative to develop international guidelines for ozone therapy for osteoarthritis of the knee as soon as possible.

Introduction

Ozone is a strong oxidizing agent with three oxygen atoms that has a wide range of biological effects, including anti-inflammatory, analgesic and antioxidant effects.1 Ozone can directly affect joints to reduce the inflammatory response, relieve pain and improve joint function in the treatment of knee osteoarthritis.2 In recent years, ozone therapy, an emerging noninvasive therapy, has gradually attracted the attention of researchers and provides new ideas for the treatment of knee osteoarthritis.

Since 2012, there has been a gradual increase in studies on ozone therapy for knee osteoarthritis, and its efficacy and safety have become popular research topics. An early study by Calunga et al.3 showed that ozone therapy could achieve intra-articular redox balance, significantly reduce pain, and improve knee function in the short term. Since then, several randomized controlled trials and systematic reviews have further validated the efficacy of ozone therapy in the treatment of knee osteoarthritis at different stages.2,4,5,6

Although some clinical studies have confirmed the potential efficacy of ozone in the treatment of knee osteoarthritis, its clinical application has not yet been fully popularized. The findings of many studies on the efficacy and safety of ozone in the treatment of knee osteoarthritis are controversial, and future developments in this field are not yet clear. To this end, we used literature visualization and bibliometric analysis to summarize and analyze the development trends, research hotspots and prospects in the field of ozone therapy for knee osteoarthritis, attempting to provide a reference basis for ozone therapy in the clinical treatment of knee osteoarthritis.

Methods

Retrieval analysis

The first author searched the Web of Science Core Collection database for relevant articles on ozone treatment of knee osteoarthritis on August 23, 2024.

Retrieval strategies

The retrieval strategies are shown in Table 1.

Table 1.

Literature search formula in the research field of ozone therapy for knee osteoarthritis (Web of Science Core Collection database)

#	Search formula	Results
1	TS=(“Osteoarthritis, Knee” OR “Knee Osteoarthriti*” OR “Osteoarthrit* of the Knee” OR “Osteoarthrit* of Knee”)	35217
2	TS=(Ozone OR Ozone (O3) OR oxygen ozone OR oxygen ozone (O2–O3))	112593
3	#2 AND #1	83

Limited conditions

Topic (TS) search (including title, abstract, keywords), with no limitation to search time.

Inclusion criteria

After the title and abstract were read, the literature related to artificial intelligence (AI) research in the field of peripheral nerve injury and repair was analyzed without limiting the article style.

Retrieval results

A total of 83 articles were included.

Methodology

Introduction of visualization software

(1) CiteSpace 6.3.R1 (64-bit) Basic software: This tool was developed by Dr. Chaomei Chen, a scholar from Drexel University, via the JAVA language and has been applied to the visual analysis of scientific literature. Through co-occurrence and cocitation analyses of a large number of literature data in a certain field, the software can analyze and predict the research frontiers and trends in the field in an objective and quantitative way.7, 8

(2) VOSviewer 1.6.19 software: This software generates cocitation networks via network or bibliometric data that can be used to draw co-occurrence and density maps.9, 10

Data export and processing

Before text mining, a data cleaning procedure was used, including unification of the English writing styles, merging full and short forms of the keywords, unification of singular and plural keywords, and uniform replacement of synonyms of the keywords (replacing “platelet-rich plasma” and “platelet-rich plasma” with “platelet-rich plasma”) to ensure that the keywords in the atlas are not repeated if their meaning remains the same. The literature included in the Web of Science Core Collection database is set to full records with cited references in plain text form to export TXT files and is imported into VOSviewer 1.6.19 software and CiteSpace 6.3.R1 (64-bit) basic software is used to map scientific knowledge, which displays the developmental process and structural relationships of scientific knowledge and thus presents the development sequence of subject knowledge fields.

VOSviewer software parameter settings

This software was used to perform the co-occurrence analysis of author keywords, with the minimum frequency of an author keyword being 3, and displayed the keyword visualization map and density visualization map. Full counting was used for all the indicators; that is, each co-occurrence or cocitation indicator had the same weight. The detailed steps and standard guidelines for VOSveiwer 1.6.19 software were taken from previous literature,10,11,12 to generate visualization maps.

CiteSpace software parameter settings

Time slicing was set from January 2012 to December 2024, with the default of “1” year as a time zone split, and burst terms were selected as the term type. The node type was chosen as needed: keywords for co-occurrence analysis and literature or journals for cocitation analysis.13, 14 CiteSpace 6.3.R1 (64-bit) basic software generated a cocitation map of the literature for a cluster analysis, with nodes representing the literature, the size of nodes representing citation frequency, and the connecting line representing the cocitation relationship between the literature.15 The cocitation map contributes to understanding which literature in the research field is a hotspot of attention and citation by other scholars. The top N = 50 was selected for the threshold setting; PathFinder was selected for the author-institution scientific collaboration network analysis in the option of pruning; and the merged network was selected for the cocitation analysis of the literature.16 Burst detection is burst literature detection performed in CiteSpace via the algorithm proposed by Goldberg et al.16 for detecting innovative topic hotspots.

Search for clinical trials registered

Clinicaltrials.gov (https://classic.clinicaltrials.gov/) was searched for clinical registry research projects related to ozone treatment of knee osteoarthritis, and the hotspots of clinical trials registered with a high degree of relevance were analyzed.

Main outcome measures

A visualization map and the bibliometric function of the Web of Science Core Collection database were used to discuss and analyze the number of publications, countries, institutions, keywords, cocitations, and clinical registry items.

Results

Analyses of annual publications, countries, and institutions

As shown in Figure 1, publications on ozone therapy for knee osteoarthritis began in 2012 and increased annually from 2012–2021, with a peak of 16 articles in 2021 and 14 articles in 2023, showing a general upward trend. The top 5 countries with the greatest number of publications in this field were Iran, with 21 articles; China, with 12 articles; Italy, with 12 articles; the USA, with 8 articles; and Brazil, with 7 articles. The top 3 institutions with the greatest number of publications in this field were Shahid Beheshti University Medical Sciences in Iran, with 13 publications; Iran University of Medical Sciences in Iran, with 6 publications; and Iran University of Medical Sciences in Iran, with 6 publications.

Figure 1.

Graphical analysis of the number, countries and institutions of publications related to ozone therapy for knee osteoarthritis (Web of Science Core Collection database)

The data were created with Excel 2019 software.

Keyword analysis

As shown in Figure 2, the top 5 keywords were osteoarthritis (32 times), ozone (26 times), knee osteoarthritis (22 times), ozone therapy (18 times), and hyaluronic acid (17 times).

Figure 2.

Keyword visualization analysis and frequency statistics of studies related to ozone therapy for knee osteoarthritis (Web of Science Core Collection database)

(A) Keyword network visualization; (B) Keyword density visualization; (C) Keyword frequency statistics. Created with VOSviewer_1.6.19 (A, B) and Excel 2019 (C). The larger keyword nodes in the graph represent a higher keyword frequency, the thicker the connecting line represents a greater number of cooccurrences between keywords, and different colors in the graph represent different keyword clusters.

Literature cocitation analysis

CiteSpace 6.3. R1 (64-bit) basic software was used to generate the literature cocitation map (Figure 3). The network consisted of the 11 largest clusters of all the literature mapping clusters, representing the 11 main research directions of the cocited literature: #0 intra-articular injections, #1 intra-articular oxygen ozone, #2 treatment of knee osteoarthritis, #3 rehabilitation studies, #4 time effects, #5 pain function, #6 comprehensive reviews, #7 growth factors, #10 rheumatic diseases, #11 ultrasound-guided corticosteroid injections, and #13 placebo, as shown in Table 2.

Figure 3.

Literature cocitation mapping of studies related to ozone treatment of knee osteoarthritis (Web of Science Core Collection database).

The block color of a cluster in the figure indicates the year in which the cocitation relationship first occurred in that cluster; the citation time color is 2012–2024 from left to right, with the blue block of literature representing the earliest publication year (2012) and the red block representing the latest publication year (2024). The nodes represent the cited literature (indicated by the first author’s name and the year of publication), and there are 11 clusters in the figure.

Table 2.

Summary of the 11 largest clusters.

Cluster ID	Silhouette	Label (LLR)
#0	0.892	Intra-articular injection
#1	0.930	Intra-articular oxygen ozone
#2	0.942	Treating knee osteoarthritis
#3	0.854	Rehabilitation research
#4	0.947	Temporal effect
#5	0.854	Pain function
#6	0.892	Comprehensive review
#7	0.933	Growth factor
#10	0.931	Rheumatic diseases
#11	0.978	Ultrasound-guided corticosteroid injection
#13	1.000	Placebo

The silhouette is the average profile value of clustering. If silhouette = 0.7, clustering is efficient and convincing; if silhouette > 0.5, clustering is generally regarded as reasonable. Label (LLR) is a clustering algorithm.

The top 10 cocited studies related to ozone treatment of knee osteoarthritis are shown in Table 3.

Table 3.

Top 10 cocited studies related to ozone treatment of knee osteoarthritis

Cited References	Count	Centrality	Main content of the article	Cluster ID
Sconza et al.17	24	0.05	Oxygen ozone therapy for knee osteoarthritis improves pain and knee joint function in short-term period.	#0 Intra-articular injection
Raeissadat et al.5	23	0.11	At 6-mon follow-up, both ozone and HA were effective in improving function and reducing pain in patients with osteoarthritis in specific knee joints, with no significant differences.	#7 Growth factor
Lopes de Jesus et al.18	22	0.02	The study confirmed the efficacy of ozone in relieving pain and improving function and quality of life in patients with knee osteoarthritis.	#0 Intra-articular injection
Duymus et al.4	20	0.16	In the treatment of mild-to-moderate knee osteoarthritis, PRP is more effective and provided better analgesia than HA and ozone injections.	#4 Temporal effect
Raeissadat et al.6	15	0.12	In the treatment of mild or moderate knee osteoarthritis, ozone can be recommended as an effective nonsurgical therapy and the therapeutic effect lasts for at least 3–6 mon.	#7 Growth factor
Manoto et al.19	15	0.01	Ozone therapy has been shown to have positive results in the treatment of osteoarthritis; however, there is controversy about the use of ozone therapy as a therapeutic agent.	#3 Rehabilitation research
Giombini et al.20	15	0.17	In patients with knee osteoarthritis, the combination of HA and oxygen ozone is more effective than HA or oxygen ozone alone	#0 Intra-articular injection
Noori-Zadeh et al.21	12	0.06	Intra-articular ozone therapy is an effective treatment for chronic pain in osteoarthritis of the knee.	#0 Intra-articular injection
Babaei-Ghazani et al.22	11	0.34	Oxygen-ozone injections have a longer duration of action on the knee compared with steroid injections.	#1 Intra-articular oxygen ozone
Oliviero et al.2	9	0.04	Ozone increases knee mobility, relieves pain, and reduces oozing. The amount and concentration of ozone injected varies among the various published treatment protocols.	#0 Intra-articular injection

Count represents the number of cocitations. HA: Hyaluronic acid; PRP: platelet-rich plasma.

A systematic review by Sconza et al.17 (cited 24 times) suggests that most studies on oxygen–ozone therapy for knee osteoarthritis are methodologically limited and significantly biased. Despite the poor quality of evidence, ozone therapy appears to be safe and may provide short-term pain relief and functional improvement. This literature is the most cocited one.

A randomized controlled trial by Raeissadat et al.5 (cited 23 times) compared ozone therapy with intra-articular injections of hyaluronic acid (HA) in the treatment of 174 patients with knee osteoarthritis and reported that both treatments resulted in significant improvements in pain, stiffness, and function, but no intergroup differences were found at the 6-month follow-up.

A randomized, double-blind, controlled clinical trial by Lopes de Jesus et al.18 (cited 22 times) enrolled 98 patients with symptomatic knee osteoarthritis who were treated with ozone or placebo for 8 weeks. The results showed that ozone was more effective than placebo in reducing pain, improving joint function and improving quality of life.

Duymus et al.4 (cited 20 times) compared three treatments: platelet-rich plasma (PRP), HA, and ozone gas for the treatment of patients with mild-to-moderate knee osteoarthritis. At the end of the 1^st month, significant improvements were observed in all the treatment groups. At the end of the 3^rd month, the PRP and HA groups showed similar improvements (WOMAC scores and pain), whereas the improvement in the ozone group was not significant. At the end of the 6^th month, the therapeutic efficacy persisted in the PRP and HA groups and disappeared in the ozone group. At the end of the 12^th month, PRP was considered statistically and clinically superior to HA. Thus, PRP is more effective than HA and ozone injections in the treatment of mild-to-moderate knee osteoarthritis, with a single injection providing pain relief for at least 12 months.

Raeissadat et al.6 (cited 15 times) systematically reviewed randomized controlled trials on intra-articular ozone injections for the treatment of knee osteoarthritis and reported that intra-articular ozone injections were superior to controls (e.g., HA, dextrose, and air injections) and lasted for at least 3–6 months. Thus, ozone can be used as an effective nonsurgical treatment for mild or moderate knee osteoarthritis.

Manoto et al.19 (cited 15 times) reported that ozone therapy has positive results in the treatment of osteoarthritis, but its use as a therapeutic agent is controversial. The mechanism of ozone therapy in the treatment of osteoarthritis is not fully understood, and this review summarizes the use of ozone therapy in the treatment of damaged articular cartilage after osteoarthritis.

A randomized controlled trial by Giombini et al.20 (cited 15 times) compared the short-term clinical efficacy of intra-articular injections of HA, oxygen ozone, or their combination in patients with knee osteoarthritis. Researchers reported that the combination of oxygen ozone and HA was significantly more effective than HA or oxygen ozone alone, especially at the 2-month follow-up.

Noori-Zadeh et al.21 (cited 12 times) assessed the effectiveness of intra-articular ozone therapy in relieving pain in patients with knee osteoarthritis through a systematic evaluation and meta-analysis, suggesting that intra-articular ozone therapy is an effective therapy for treating chronic pain in patients with knee osteoarthritis.

A randomized clinical trial by Babaei-Ghazani et al.22 (cited 11 times) compared ultrasound-guided corticosteroids with oxygen ozone injections for the treatment of osteoarthritis of the knee. The results revealed that both injections were effective, but oxygen–ozone injections improved visual analog scale (VAS) scores and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, and the effect of oxygen–ozone injections was greater than that of corticosteroid injections.

Oliviero et al.2 (cited 11 times) reported that ozone therapy relieves pain and improves physical function in patients with knee osteoarthritis; however, there is controversy about the dosage and concentration of ozone, and its long-term efficacy has not yet been clarified, which requires further research.

Literature hotspots related to growth factors in the ozone treatment of knee osteoarthritis

Out of 83 publications, 7 were retrieved with TS=(growth factor*), as shown in Table 4. These seven publications focused on the clinical efficacy of intra-articular injections of related drugs (growth factors, ozone, and PRP) in the treatment of knee osteoarthritis. Below is a summary of the main content of each author’s literature as well as commonalities and developmental trends. The most highly cited literature was Raeissadat et al.23 (51 citations), which compared the efficacy of PRP, plasma rich in growth factor (PRGF), HA, and ozone in patients with knee osteoarthritis and reported that PRP and PRGF were more effective in long-term management. Anil et al.24 (46 citations) conducted a network meta-analysis of randomized controlled trials comparing the efficacy of different intra-articular injections of medications and reported that the stromal vascular fraction (SVF) was the most effective in reducing pain and improving function. Liao et al.25 (7 citations) investigated the efficacy of intra-articular injections in conjunction with physiotherapy in patients with knee osteoarthritis and reported that the combination of dextrose prolotherapy (DxTP) with physiotherapy was the most effective in reducing pain and improving function. Xue et al.26 (5 citations) conducted a comparative study on the efficacy of intra-articular injections in the treatment of mild-to-moderate knee osteoarthritis and reported that PRP was more effective than HA or steroids in relieving pain, stiffness, and dysfunction. Fernandez-Cuadros et al.27 (5 citations) investigated the modulating effect of intra-articular ozone on inflammation in patients with knee osteoarthritis and the changes in interleukin-6 and insulin-like growth factor-1, which are proinflammatory and anabolic biomarkers. Raeissadat et al.28 (2 citations) conducted a cost-effectiveness analysis comparing the cost-effectiveness of PRP, PRGF, HA, and ozone in Iranian patients with knee osteoarthritis and reported that PRP performed best in terms of cost-effectiveness. Dubin et al.29 (0 citations) published an overview of the American Academy of Orthopedic Surgeons’ techniques for the treatment of knee osteoarthritis, systematically reviewing current evidence from clinical studies on PRP for the treatment of knee osteoarthritis. All of these studies focused on the efficacy of intra-articular injections of PRP, PRGF, HA, ozone, SVF, and DxTP in the treatment of knee osteoarthritis. The results of these studies generally indicate that PRP and PRP are more effective at relieving osteoarthritis pain and stiffness and improving function. Some studies have noted that the combination of intra-articular injections and physical therapy is more effective. These studies compared the efficacy of various intra-articular injectable drugs for the treatment of knee osteoarthritis, but no studies have focused on the combination of growth factors and ozone for the treatment of knee osteoarthritis.

Table 4.

Top 10 highly cited studies related to the comparative efficacy of ozone, growth factors and other drugs in the treatment of knee osteoarthritis (2021–2024)

Author	Source	Document type	Citations in WoS Core	Main content of the article
Raeissadat et al.23	BMC Musculoskeletal Disorders	Article	51	This study compared the short- and long-term efficacy of intra-articular injections of hyaluronic acid (HA), platelet-rich plasma (PRP), plasma rich in growth factor (PRGF), and ozone in patients with knee osteoarthritis.
Anil et al.24	Knee	Review	46	A total of 79 randomized controlled trials (RCTs) with 8761 patients were included in this systematic review. Intra-articular injections evaluated included autologous conditioned serum, bone marrow aspirate concentrate, botulinum toxin, corticosteroids (CS), HA, mesenchymal stem cells (MSCs), ozone, saline placebo, PRP, PRGF, and stromal vascular fraction (SVF). Current evidence suggests that SVF injections provide the greatest improvement in pain and function in patients with knee osteoarthritis within 1-year follow-up.
Liao et al.25	International Journal of Molecular Sciences	Article	7	This network meta-analysis study designed to determine the comparative efficacy of combination therapy [intra-articular injections (IAIs) and physical therapy (PT), IAI + PT] in patients with osteoarthritis of the knee found that of the identified medications (autologous conditioned serum, botulinum toxin type A, corticosteroids, hyaluronic acid, MSCs, ozone, PRP, PRGF, sphingomyelin), intra-articular injections + physiotherapy regimen was the best treatment option for pain relief and overall function recovery, while MSCs plus physiotherapy was the most effective option for improving recovery of walking ability.
Xue et al.26	Medicine	Review	5	In patients with mild to moderate knee osteoarthritis, IA injection PRP outperformed IA injection ozone, HA, CS, platelet-rich plasma-derived growth factor, and hyaluronic acid and platelet-rich plasma in terms of pain, stiffness, and dysfunction.
Fernandez-Cuadros et al.27	Processes	Article	5	Ozone has anti-inflammatory, metabolism-enhancing and anabolic properties, making it an effective option for treating knee osteoarthritis in a realistic rehabilitation seffing. Ozone reduces pro-inflammatory cytokine interleukin-6. Ozone has a metabolic/hypoglycemic effect on obese/diabetic knee osteoarthritis patients by lowering insulin growth factor 1 (IGF-1). Ozone has an anabolic effect in nondiabetic/nonobese patients by improving IGF-1. Ozone also reduces other inflammatory biomarkers (C-reactive protein, erythrocyte sedimentation rate and uric acid) and improves pain, function and quality of life.
Raeissadat et al.28	BMC Musculoskeletal Disorders	Article	2	The cost-effectiveness of PRP, PRGF, HA, and ozone as effective treatments for knee osteoarthritis was evaluated from the perspective of healthcare in Iran. The results of the study found that the cost associated with intraarticular injection of HA ($581.67/patient) was defined as the highest cost, followed by PRGF ($328.10/patient), PRP ($318.58/patient) and ozone ($103.20/patient). In terms of utility values, PRP and PRGF (0.68) had the same and highest utility values in the treatment of knee osteoarthritis.
Dubin et al.29	Journal of the American Academy of Orthopaedic Surgeons	Review	0	The efficacy of PRP in patients with knee osteoarthritis was assessed by analyzing the best current evidence. The results of PRP vs. control/placebo, acetaminophen, nonsteroidal anti-inflammatory drugs, corticosteroids, exercise, prolotherapy, autoregulatory serum, bone marrow aspirate concentrate, HA, and ozone therapy were presented.

Therefore, future studies may focus on the comparative efficacy of different intra-articular drug injections, as well as optimized regimens for combination therapy. More multicenter, large sample size studies may be needed to improve the reliability and generalizability of the results. Cost-effectiveness analysis may become an important research direction to guide clinical decision-making and policy formulation. Long-term follow-up studies may help to better understand the long-term efficacy and safety of different treatments. Further studies are needed to explore the differences in the effectiveness of different treatment options in specific populations (e.g., elderly individuals, diabetic patients, etc.).

Analysis of clinical registry protocols

Eight clinical study protocols of interventional studies of ozone therapy for knee osteoarthritis were retrieved from Clinicaltrials.gov, as shown in Table 5. Most of these studies investigated the efficacy (in terms of analgesia and functional restoration) and safety of intra-articular ozone therapy in the treatment of knee osteoarthritis. In addition, one study (NCT04830423) reported the efficacy of ultrasound-guided oxygen–ozone injections for treating knee osteoarthritis. Two studies reporting ozone combination therapy are of interest: one study (NCT06088706) compared the therapeutic effects of intra-articular ozone and corticosteroid injections in patients with knee osteoarthritis, and the other study (NCT05837494) reported the therapeutic effects of intra-articular ozone and corticosteroid injections versus PRGF in patients with knee osteoarthritis. The results of these two studies are more promising.

Table 5.

Clinical registry protocols for ozone treatment of knee osteoarthritis of the knee from Clinicaltrials.gov

NCT number	Study title	Study type	First posted	Study status
NCT04426721	Intraarticular oxygen–ozone therapy for the treatment of knee osteoarthritis compared with hyaluronic acid	Interventional	2020–06–11	Unknown
NCT05824052	Investigating the Impact of ex vivo ozone injection on synovial fluids in patients diagnosed with knee osteoarthritis	Interventional	2023–04–21	Completed
NCT04830423	The effectiveness of ultrasound guided ozone (O2–O3) injection with knee osteoarthritis	Interventional	2021–04–05	Unknown
NCT06088706	Evaluation of the effect of different doses of ozone therapy on pain and function of patients with knee osteoarthritis	Interventional	2023–10–18	Completed
NCT06328270	Comparison of the therapeutic effects of intra-articular injection of ozone and corticosteroid in knee osteoarthritis	Interventional	2024–03–25	Completed
NCT02833545	Safety and efficacy of intra-articular ozone injections for knee osteoarthritis	Interventional	2016–07–14	Completed
NCT00832312	Intraarticular ozone therapy for pain control in osteoarthritis of the knee	Interventional	2009–01–30	Terminated
NCT05837494	Intraarticular injection of ozone with corticosteroids us. prgf in knee osteoarthritis	Interventional	2023–05–01	Completed

Discussion

Analysis of study findings

This review indicates that ozone therapy for knee osteoarthritis is receiving increasing attention worldwide, especially in regions such as Iran and China. The top 5 keywords in terms of frequency are “osteoarthritis,” “ozone,” “knee osteoarthritis,” “ozone therapy,” and “hyaluronic acid.” These keywords reflect the core themes of the study. “Ozone therapy” appears more frequently as a keyword, indicating the importance of this therapy in the treatment of knee osteoarthritis.

The literature cocitation map shows 11 major research fields, including intra-articular injections, intra-articular oxygen ozone therapy, and treatment of knee osteoarthritis. These findings indicate that studies have focused primarily on ozone therapy for knee osteoarthritis and relevant techniques and management. In the growth factor-related literature, studies have focused on the clinical efficacy of intra-articular injections, including PRP, PRGF, HA, ozone, and other drugs, in the treatment of knee osteoarthritis. These findings generally suggest that PRP and PRGF are more effective at relieving osteoarthritic pain and stiffness and improving function. These studies provide diverse options for the treatment of knee osteoarthritis.

There are currently eight clinical registry protocols for interventional studies on ozone therapy for knee osteoarthritis, with the majority focusing on the efficacy and safety of ozone therapy. Some of these studies have explored the use of ozone combined with other treatments (e.g., corticosteroids, PRGF, etc.).

Time trends in the evolution of research hotspots

The literature cocitation analysis summarized the following timeline of classic literature research on ozone therapy for knee osteoarthritis:

In 2012, a study by Calunga et al.3 enrolling 42 patients with knee osteoarthritis revealed that comprehensive ozone therapy achieved intra-articular redox balance and significant pain reduction, which was the first study to assess the role of ozone therapy in oxidative stress parameters in the synovial fluid of patients with knee osteoarthritis, as well as its clinical evolution.

In 2017, Duymus et al.4 reported that PRP was superior to HA and ozone in the treatment of mild-to-moderate knee osteoarthritis. Raeissadat et al.5 demonstrated that ozone and HA improved knee function and reduced pain, but neither of them showed significant superiority at the 6-month follow-up.

In 2018, a Meta-analysis by Raeissadat et al.6 further confirmed that ozone is an effective nonsurgical therapy for the treatment of mild or moderate knee osteoarthritis, with efficacy lasting at least 3–6 months.

In 2019, a systematic review by Oliviero et al.2 noted the potential of ozone therapy in relieving the symptoms of acute and chronic knee osteoarthritis, but the dose and concentration of injections are controversial, and there is no clear protocol for use. In terms of ozone combination therapy, Dernek et al.30 reported that PRP alone and PRP combined with ozone therapy had similar efficacy, but ozone-treated patients recovered faster and experienced less pain.

In 2020, systematic reviews by Sconza et al.17 and Hedayatabad et al.31 further emphasized the safety and efficacy of oxygen ozone therapy, as well as the similar efficacy of oxygen–ozone and HA.

In 2023, several studies further confirmed the effectiveness of ozone therapy. Zhang et al.32 reported that intra-articular perfusion combined with ozone injection could effectively relieve clinical symptoms and improve bone metabolic indices in patients with knee osteoarthritis. Yang et al.33 also reported that the combination of ozone and sodium hyaluronate has a significant therapeutic effect on knee osteoarthritis.

In 2024, a randomized, double-blind controlled trial by Nazarieh et al.34 demonstrated that ozone injections are a nonsurgical therapy for the treatment of mild to moderate knee osteoarthritis and can reduce pain and improve patients’ ability to perform daily living in the short to medium term (3–6 months). Another systematic review by Lino et al.35 emphasized the beneficial effects and safety of ozone therapy in the treatment of knee osteoarthritis, especially in pain control.

Taken together, ozone therapy has positive effects on pain control and functional recovery in patients with knee osteoarthritis in the short term (within 6 months), but its long-term efficacy and optimal use regimen still need further research. Additionally, future studies should pay more attention to the long-term efficacy of ozone therapy, the optimization of injection regimens and the combined application of ozone therapy with other therapies. Moreover, research into the indications and contraindications of ozone therapy in the treatment of knee osteoarthritis at different stages will also be a hot topic.

Effects of different factors in ozone therapy for knee osteoarthritis

In a study comparing the efficacy of ozone therapy and other factors in the treatment of knee osteoarthritis, different factors, including PRP, PRGF, and HA, were used to treat knee osteoarthritis via intra-articular injection. The findings of the present study suggest that, compared with ozone therapy alone, these growth factors are more effective at relieving osteoarthritic pain and stiffness and improving function. Specifically, PRP and PRGF are more effective in long-term management than ozone therapy is, whereas stromal vascular components are effective in reducing pain and improving function. In addition, the combination of intra-articular injections of different factors (PRP, PRGF) with physiotherapy has the best results in reducing pain and improving function.

To date, few studies have investigated the combination of ozone and growth factors for the treatment of knee osteoarthritis. The available literature has focused on the efficacy and safety of treatment with ozone or growth factors alone, whereas relatively few studies have been conducted on the combination of the two. A number of clinical trials (NCT06088706, NCT05837494) are underway in interventional studies comparing the efficacy of intra-articular injections of ozone and corticosteroids in patients with knee osteoarthritis, and the results of these studies are relatively promising.

PRP and PRGF are more effective at relieving osteoarthritic pain and stiffness and improving function,36 whereas ozone therapy may also provide short-term pain relief and functional improvement. These findings provide a basis for future exploration of the combination of ozone and growth factors in the treatment of knee osteoarthritis. The combination of ozone and growth factors is promising for the treatment of knee osteoarthritis. Combination therapy may enhance therapeutic efficacy through synergistic effects. For example, ozone may stimulate the release and activity of growth factors, while growth factors may enhance the effects of ozone on cartilage repair and inflammation modulation. This combination therapy may provide a more comprehensive and long-lasting therapeutic effect against knee osteoarthritis.

Future studies are needed to explore the specific mechanisms and optimal ratios of different growth factors in combination with ozone, as well as the long-term efficacy and safety of such combination therapies. Rigorously designed randomized controlled trials can be used to assess the clinical effects of combination therapy more accurately and provide strong evidence in clinical practice.

Mechanisms of ozone therapy for osteoarthritis of the knee

Ozone therapy has emerged as an effective treatment for the repair of compromised articular cartilage in osteoarthritis. This therapeutic approach serves to mitigate the inflammatory environment that contributes to the degradation of the cartilaginous matrix and the programmed cell death of chondrocytes observed in osteoarthritis. The therapeutic benefits of ozone are realized through its capacity to restore the cellular redox equilibrium and via the modulation of cytokine activity.19 Nevertheless, additional in vitro research is imperative to elucidate the precise molecular mechanisms through which ozone stimulates cellular responses.

Limitations

This review included a relatively small number of studies in this field, with only 83 articles retrieved. We only retrieved one database (Web of Science Core Collection), and we failed to comprehensively retrieve all relevant literature from the major databases (PubMed, Embase, CNKI, etc.) due to the functional limitations of econometric software, which may have led to the retrieval of incomplete information. However, the literature in the Web of Science Core Collection also largely represents the majority of research perspectives in the field, and the databases will be expanded for further analysis in the future.

Ozone therapy for knee osteoarthritis, although promising, faces limitations, including variable efficacy, uncertain long-term benefits, potential for symptom recurrence, unclear mechanisms, procedural risks, and patient acceptance challenges. It lacks standardized protocols and may not be suitable for all cases, particularly severe cases, but its cost-effectiveness and safety need further validation.

Conclusions and prospects

The visualization analysis results indicate that ozone therapy typically acts through intra-articular injection to reduce joint inflammation and pain and may promote cartilage repair. Ozone therapy has shown some effectiveness in the treatment of knee osteoarthritis. It relieves pain and improves joint function, and for some patients, it may be an effective alternative to medication. However, the efficacy of ozone therapy may vary from person to person, and not all patients experience the same improvement. For severe cases of osteoarthritis, combination with other treatments, such as surgery or medication, may be necessary. In addition, ozone therapy is generally considered a relatively safe treatment, but like all medical procedures, it carries certain risks, including possible localized pain, infection or allergic reactions.37 Therefore, it is important to have the treatment performed under the supervision of a qualified medical professional. Growth factors are biomolecules that stimulate cell growth and repair, and combining ozone with growth factors may help to enhance therapeutic efficacy, promote cartilage regeneration and reduce the symptoms of arthritis.38 Research on the combination of ozone and growth factor therapy is currently underway.

Research hotspots in the field of ozone therapy for knee osteoarthritis have focused mainly on the use of ozone therapy alone and in combination with other therapies for the treatment of knee osteoarthritis. Although the current research results generally indicate that PRP and PRGF are more effective than ozone therapy in relieving osteoarthritic pain and stiffness and improving function, further investigations are warranted on the specific mechanism of ozone therapy, the optimal therapeutic program and the long-term efficacy and safety of ozone therapy. The combined application of ozone with other therapies is also a focus of future research. Future research directions in the field of ozone therapy for knee osteoarthritis include comparing the efficacy of different intra-articular injections, exploring optimized protocols for combined treatments, and conducting long-term follow-up studies to better understand the long-term efficacy and safety of different treatments. Considering the importance of cost-effectiveness in clinical decision-making and policy formulation, conducting cost-effectiveness analyses may also become a hot topic in the future.

Owing to its anti-inflammatory and analgesic properties, ozone therapy has potential in the treatment of a wide range of musculoskeletal disorders. Jeyaraman et al.39 have nonetheless raised concerns about their potential toxicity and emphasized the importance of adhering to strict dosing protocols to ensure safety. In addition, heterogeneity in patient responses and the hazards of oxidants have been observed. More high-quality clinical studies with long-term follow-up are needed to refine the indications, efficacy, and safety of ozone therapy. There is an existing study by de Sire et al.40 with up to 31 weeks of follow-up that evaluated the long-term efficacy and safety of oxygen–ozone therapy. These findings indicate that ozone therapy is comparable to hyaluronic acid in reducing pain but has superior long-term results. In conclusion, the development of international guidelines is necessary as soon as possible for more patients with knee osteoarthritis to accept and use ozone therapy.

Funding Statement

Funding: This study was supported by the National Key R&D Program of the Ministry of Science and Technology of the People’s Republic of China in the 14^th Five-Year Plan, No. 2022YFA1207504.

Data availability statement:

No additional data are available.