Ozone Therapy in Orthopaedics

Definition and Introduction

Chemistry and Preparation

• Ozone (O3) is an allotrope of oxygen - a triatomic, unstable molecule that readily releases nascent oxygen (O•)
• Generated by passing pure oxygen through an electrical corona discharge
• Concentration is expressed in micrograms per milliliter (mcg/mL)
• Therapeutic range: 1-40 mcg/mL depending on indication and route
• Must be used immediately after preparation (half-life ~40 minutes at room temperature)

Mechanism of Action

(Source: Ozone therapy in musculoskeletal medicine - Springer/European Journal of Medical Research, 2024)

1. Anti-inflammatory Action

• Ozone reacts with polyunsaturated fatty acids in biological fluids, generating Reactive Oxygen Species (ROS) and lipid oxidation products (LOPs)
• These LOPs act as signaling molecules that downregulate NF-κB pathway, reducing production of IL-1β, TNF-α, IL-6, and prostaglandins
• Reduces bradykinin and prostaglandin synthesis at pain receptor level

2. Antioxidant / Redox Regulation

• Paradoxically, controlled oxidative stress activates the Nrf2 pathway, upregulating the body's own antioxidant defenses (superoxide dismutase, catalase, glutathione peroxidase)
• Resets the cellular redox balance in chronically inflamed tissues

3. Enhanced Tissue Oxygenation

• Increases 2,3-diphosphoglycerate (2,3-DPG) in red blood cells, promoting oxygen release to hypoxic tissues
• Improves microcirculation in ischemic/degenerative tissues

4. Analgesic Mechanism

• Oxidizes arachidonic acid, blocking prostaglandin E2 synthesis
• Inactivates algogenic substances (bradykinin, substance P) at nerve endings
• Blocks NMDA receptor phosphorylation (reducing central sensitization)

5. Antimicrobial Action

• Ozone is a potent bactericidal, fungicidal, and virucidal agent
• Oxidizes and disrupts bacterial cell membranes and DNA
• Germicidal at concentrations as low as 0.1 mcg/mL

6. Tissue Healing and Regeneration

• Upregulates VEGF (vascular endothelial growth factor) and TGF-β
• Stimulates fibroblast proliferation and collagen synthesis
• Promotes angiogenesis and granulation tissue formation
• Supports bone regeneration

Routes of Administration

Orthopaedic Applications

1. Lumbar Disc Herniation (Strongest Evidence)

• Most extensively studied application
• Mechanism: Ozone oxidizes proteoglycans in nucleus pulposus (NP), causing disc shrinkage and dehydration ("chemonucleolysis"), reducing mechanical nerve compression
• Also reduces the inflammatory cascade around the nerve root
• Technique: CT/fluoroscopy-guided intradiscal + periradicular injection, 2-10 mL of O2/O3 at 20-30 mcg/mL

• Intradiscal ozone injections superior to steroid injections at ≥6 months (OR = 3.95, 95% CI 2.44-6.39)
• Comparable outcomes to microdiscectomy at 18 months (SMD = -0.05)
• Greater VAS reduction vs. steroids at 1 month (SMD = 2.53)

2. Knee Osteoarthritis

• Intra-articular ozone reduces chondrocyte apoptosis and cartilage degradation
• Decreases synovial inflammation and MMP (matrix metalloproteinase) activity
• Stimulates cartilage repair and proteoglycan synthesis

• Intra-articular ozone achieves similar VAS and WOMAC scores to hyaluronic acid at 4-6 months follow-up
• Combination of ozone + HA was shown to be more effective than either alone in some RCTs

3. Chronic Osteomyelitis

• Ozonated water lavage combined with vacuum-sealed drainage (VSD) provides:
  • Bacterial clearance (including MRSA)
  • Reduced biofilm formation
  • Stimulation of granulation tissue
• Effective adjunct to IV antibiotics, especially in antibiotic-resistant cases
• Route: Local irrigation with ozonated saline (3 cycles of ozonated gas in 100 mL saline)

4. Cervical Disc Herniation / Neck Pain

• Oxygen-ozone therapy shows benefit in cervical radiculopathy
• Periradicular and epidural routes used
• A 2024 review (Jandura et al., PMID 38541068) supports its use as a minimally invasive alternative

5. Soft Tissue Conditions

6. Wound Healing (Post-Operative / Diabetic Foot)

• Ozonated water/oil reduces bacterial load, promotes angiogenesis
• Reduces wound size, accelerates closure in chronic ulcers
• Valuable in post-operative wound complications

FLOWCHART: Ozone Therapy in Orthopaedics - Clinical Decision Algorithm

Contraindications

Complications and Safety

• Local: Post-injection pain, temporary flare of symptoms, hematoma
• Rare: Pneumocephalus (epidural route), gas embolism (IV route - AVOID direct IV injection)
• Ozone gas embolism is the most feared complication - prevented by using O2/O3 mixture and correct technique
• Overall: Very low complication rate when administered by trained practitioners with proper equipment
• No teratogenicity, nephrotoxicity, or hepatotoxicity at therapeutic doses

Advantages Over Conventional Treatments

Limitations and Current Status

• Lack of FDA approval - major barrier to mainstream acceptance
• No standardized protocols for concentration, volume, frequency, or technique
• Evidence quality: High-quality RCTs are limited; best evidence exists for lumbar disc herniation and knee OA
• Operator-dependent procedure requiring trained personnel and proper ozone generator
• Storage and stability issues (must be used immediately)
• The Frontiers in Physiology 2022 review notes that "lack of standardization in treatment protocols is the Achilles' heel of this technique"

Summary Table

Key Points for Exam

1. Ozone = O3 - unstable triatomic oxygen, generated from pure O2
2. Strongest evidence: Lumbar disc herniation (outperforms steroids at 6 months; comparable to surgery at 18 months) and knee OA (comparable to HA)
3. Mechanism in disc: Oxidizes proteoglycans in NP → disc shrinkage → nerve decompression
4. Mechanism in joints: Inhibits NF-κB, reduces IL-1β, TNF-α, MMPs, prevents chondrocyte apoptosis
5. Most feared complication: Gas embolism (prevented by proper technique)
6. Absolute contraindication: G6PD deficiency
7. Not FDA approved - used as complementary/alternative or when conventional therapy fails
8. Best results: Ozone combined with hyaluronic acid in knee OA; ozone combined with VSD in osteomyelitis

• Chang et al. 2024 (PMID 38905033) - Intradiscal ozone superior to steroids and comparable to microdiscectomy for HLD
• Migliorini et al. 2024 (PMID 39579218) - Ozone vs. HA intra-articular: comparable outcomes in knee OA (Level I evidence)
• Arias-Vázquez et al. 2026 (PMID 41496305) - 2026 meta-analysis confirms ozone injections reduce pain in knee OA