The purpose of this paper was to evaluate the efficacy of intra-articular (AI) injections of Hyaluronic Acid (HA) versus Oxygen-Ozone (O2O3) in relieving pain and reducing disability in patients affected by knee osteoarthritis (KOA).
Methods
People with painful KOA for at least three months were randomly allocated to receive three IA injections, once a week, of HA (Group A) vs O2O3 (Group B). They were evaluated at baseline (T0), at 1 (T1), 3 (T2), 6 (T3), and 12 months (T4) after the treatment, using as outcomes: WOMAC pain score, WOMAC LK 3.1, Numeric Rating Scale (NRS), and KOOS.
Results
Of the 122 patients assessed for eligibility, 112 participants were enrolled. Both groups A and B showed significant improvements in all outcomes measures from 1 month after the treatment (HA Group: 6.77 ± 2.53 vs 3.66 ± 2.57; O2O3 Group: 6.50 ± 2.24 vs 3.45 ± 2.30). In contrast, at T2 and T3, the HA-treated group showed significant pain and functional improvement compared to O2O3 group.
Conclusion
Both HA and O2O3 might be considered safe and potential effective treatments for KOA, due to their anti-inflammatory effects. O2O3 seems to have a faster effect; rather, HA showed superior efficacy at 3 months onwards from the end of the treatment.
Martel-PelletierJBoileauCPelletierJ-P, et al.Cartilage in normal and osteoarthritis conditions. Best Pract Res Clin Rheumatol2008; 22: 351–384.
2.
TonuttiAGranataVMarrellaV, et al.The role of WNT and IL-1 signaling in osteoarthritis: therapeutic implications for platelet-rich plasma therapy. Front Aging2023; 4: 1201019.
3.
DillonCFRaschEKGuQ, et al.Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. J Rheumatol2006; 33: 2271–2279.
4.
NeogiT. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage2013; 21: 1145–1153.
5.
NichollsMAFierlingerANiaziF, et al.The disease-modifying effects of hyaluronan in the osteoarthritic disease state. Clin Med Insights Arthritis Musculoskelet Disord2017; 10: 117954411772361.
6.
MonticoneMSconzaCPortogheseI, et al.Cross-cultural adaptation, reliability and validity of the Fremantle Knee Awareness Questionnaire in Italian subjects with painful knee osteoarthritis. Health Qual Life Outcomes2021; 19: 114.
7.
De SireAStagnoDMinettoMA, et al.Long-term effects of intra-articular oxygen-ozone therapy versus hyaluronic acid in older people affected by knee osteoarthritis: a randomized single-blind extension study. J Back Musculoskelet Rehabil2020; 33: 347–354.
8.
RabiniAde SireAMarzettiE, et al.Effects of focal muscle vibration on physical functioning in patients with knee osteoarthritis: a randomized controlled trial. Eur J Phys Rehabil Med2015; 51: 513–520.
9.
RichmondJHunterDIrrgangJ, et al.Treatment of osteoarthritis of the knee (nonarthroplasty). J Am Acad Orthop Surg2009; 17: 591–600.
10.
SconzaCLeonardiGCarfìC, et al.Intra-Articular injection of Botulinum toxin for the treatment of knee osteoarthritis: a systematic review of randomized controlled trials. Int J Mol Sci2023; 24: 1486.
11.
GhoshP. The role of hyaluronic acid (hyaluronan) in health and disease: interactions with cells, cartilage and components of synovial fluid. Clin Exp Rheumatol1994; 12: 75–82.
12.
AmielDToyoguchiTKobayashiK, et al.Long-term effect of sodium hyaluronate (Hyalgan) on osteoarthritis progression in a rabbit model. Osteoarthritis Cartilage2003; 11: 636–643.
13.
PunziL. The complexity of the mechanisms of action of hyaluronan in joint diseases. Clin Exp Rheumatol2001; 19: 242–246.
14.
SconzaCRomanoDScaturroD, et al.Safety and efficacy of hybrid cooperative complexes of sodium hyaluronate and sodium chondroitin for the treatment of patients with symptomatic knee osteoarthritis. Rheumatol Ther2024; 11: 381–395.
15.
HemshekharMThusharaRMChandranayakaS, et al.Emerging roles of hyaluronic acid bioscaffolds in tissue engineering and regenerative medicine. Int J Biol Macromol2016; 86: 917–928.
16.
McAlindonTEBannuruRRSullivanMC, et al.OARSI Guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage2014; 22: 363–388.
17.
PeckJSlovekAMiroP, et al.A comprehensive review of viscosupplementation in osteoarthritis of the knee. Orthop Rev2021; 13: 25549. Epub ahead of print 10 July 2021. DOI: https://doi.org/10.52965/001c.25549
18.
MiglioreAGigliucciGAlekseevaL, et al.Systematic literature review and expert opinion for the use of viscosupplementation with hyaluronic acid in different localizations of osteoarthritis. Orthop Res Rev2021; 13: 255–273.
19.
de SireABaricichAMinettoMA, et al.Low back pain related to a sacral insufficiency fracture: role of paravertebral oxygen-ozone therapy in a paradigmatic case of nociplastic pain. Funct Neurol2019; 34: 119–122.
20.
SconzaCBraghettoGRespizziS, et al.Ultrasound-guided periradicular oxygen-ozone injections as a treatment option for low back pain associated with sciatica. Int Orthop2021; 45: 1239–1246.
21.
De SireAMarottaNFerrilloM, et al.Oxygen-Ozone therapy for reducing pro-inflammatory cytokines serum levels in musculoskeletal and temporomandibular disorders: a comprehensive review. Int J Mol Sci2022; 23: 2528.
22.
BiazzoACorrieroASConfalonieriN. Intramuscular oxygen-ozone therapy in the treatment of low back pain. Acta Bio Medica Atenei Parm2018; 89: 41–46.
23.
SconzaCDi MatteoBQueirazzaP, et al.Ozone therapy versus hyaluronic acid injections for pain relief in patients with knee osteoarthritis: preliminary findings on molecular and clinical outcomes from a randomized controlled trial. Int J Mol Sci2023; 24: 8788.
24.
CostaTRodrigues-ManicaSLopesC, et al.Ozonoterapia na Osteoartrose do Joelho: revisão Sistemática. Acta Médica Port2018; 31: 576–580.
25.
LiQQiXZhangZ. Intra-articular oxygen-ozone versus hyaluronic acid in knee osteoarthritis: a meta-analysis of randomized controlled trials. Int J Surg2018; 58: 3–10.
26.
RaeissadatSATabibianERayeganiSM, et al.An investigation into the efficacy of intra-articular ozone (O2–O3) injection in patients with knee osteoarthritis: a systematic review and meta-analysis. J Pain Res2018; 11: 2537–2550.
27.
SconzaCRespizziSVirelliL, et al.Oxygen–ozone therapy for the treatment of knee osteoarthritis: a systematic review of randomized controlled trials. Arthrosc J Arthrosc Relat Surg2020; 36: 277–286.
28.
ConrozierTRamanRDiraçogluD, et al.EUROVISCO Consensus guidelines for the use of hyaluronic acid viscosupplementation in knee osteoarthritis based on patient characteristics. Cartilage2024; 20: 19476035241271970.
29.
GandekB. Measurement properties of the western Ontario and McMaster universities osteoarthritis index: a systematic review. Arthritis Care Res2015; 67: 216–229.
30.
OrnettiPDougadosMPaternotteS, et al.Validation of a numerical rating scale to assess functional impairment in hip and knee osteoarthritis: comparison with the WOMAC function scale. Ann Rheum Dis2011; 70: 740–746.
31.
AltmanRManjooAFierlingerA, et al.The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskelet Disord2015; 16: 321.
32.
ChengOTSouzdalnitskiDVroomanB, et al.Evidence-Based knee injections for the management of arthritis. Pain Med2012; 13: 740–753.
33.
PaoloniMDi SanteLCacchioA, et al.Intramuscular oxygen-ozone therapy in the treatment of acute back pain with lumbar disc herniation: a multicenter, randomized, double-blind, clinical trial of active and simulated lumbar paravertebral injection. Spine2009; 34: 1337–1344.
34.
De SireAAgostiniFLippiL, et al.Oxygen–ozone therapy in the rehabilitation field: state of the art on mechanisms of action, safety and effectiveness in patients with musculoskeletal disorders. Biomolecules2021; 11: 356.
35.
HashemiMHoseini KhamenehSMDadkhahP, et al.Effect of Intraarticular injection of ozone on inflammatory cytokines in knee osteoarthritis. J Cell Mol Anesth12 May 2017; 2: 37–42. DOI: https://doi.org/10.22037/jcma.v2i2.16016
36.
HigashiYSukhanovSAnwarA, et al.Aging, atherosclerosis, and IGF-1. J Gerontol A Biol Sci Med Sci2012; 67A: 626–639.
37.
SmithNWilsonAGandhiJ, et al.Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Med Gas Res2017; 7: 12.
38.
SconzaCLeonardiGKonE, et al.Oxygen-ozone therapy for the treatment of low back pain: a systematic review of randomized controlled trials. Eur Rev Med Pharmacol Sci2021; 25: 6034–6046.
39.
ZhaiPPengXLiB, et al.The application of hyaluronic acid in bone regeneration. Int J Biol Macromol2020; 151: 1224–1239.
40.
AnzillottiGIacomellaAGrancagnoloM, et al.Conservative vs. surgical management for femoro-acetabular impingement: a systematic review of clinical evidence. J Clin Med2022; 11: 5852.
41.
AltomareDFuscoGBertolinoE, et al.Evidence-based treatment choices for acute lateral ankle sprain: a comprehensive systematic review. Eur Rev Med Pharmacol Sci2022; 26: 1876–1884.
42.
Liu-BryanRTerkeltaubR. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol2015; 11: 35–44.
43.
AnilUMarkusDHHurleyET, et al.The efficacy of intra-articular injections in the treatment of knee osteoarthritis: a network meta-analysis of randomized controlled trials. Knee2021; 32: 173–182.
44.
IolasconGGimiglianoFMorettiA, et al.Early osteoarthritis: how to define, diagnose, and manage. A systematic review. Eur Geriatr Med2017; 8: 383–396.
45.
MadryHLuytenFPFacchiniA. Biological aspects of early osteoarthritis. Knee Surg Sports Traumatol Arthrosc2012; 20: 407–422.
46.
SoulJDunnSLAnandS, et al.Stratification of knee osteoarthritis: two major patient subgroups identified by genome-wide expression analysis of articular cartilage. Ann Rheum Dis2018; 77: 423–430.
47.
WoodMJMillerREMalfaitA-M. The genesis of pain in osteoarthritis: inflammation as a mediator of osteoarthritis pain. Clin Geriatr Med2022; 38: 221–238.
48.
RutjesAWSJüniPDa CostaBR, et al.Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med2012; 157: 180.
49.
FilardoGDi MatteoBDi MartinoA, et al.Platelet-Rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J SPORTS Med2015; 43: 1575–1582.
50.
InvernizziMStagnoDCardaS, et al.Safety of intra-articular oxygen-ozone therapy compared to intra-articular sodium hyaluronate in knee osteoarthritis: a randomized single blind pilot study. Int J Phys Med Rehabil2017; 5: 1. DOI: 10.4172/2329-9096.1000385
51.
DuymusTMMutluSDernekB, et al.Choice of intra-articular injection in treatment of knee osteoarthritis: platelet-rich plasma, hyaluronic acid or ozone options. Knee Surg Sports Traumatol Arthrosc Off J ESSKA2017; 25: 485–492.
52.
GiombiniAMenottiFDi CesareA, et al.Comparison between intrarticular injection of hyaluronic acid, oxygen ozone, and the combination of both in the treatment of knee osteoarthrosis. J Biol Regul Homeost Agents2016; 30: 621–625.
53.
AslanSGde SireAKöylüSU, et al.The efficacy of ultrasonography-guided oxygen-ozone therapy versus corticosteroids in patients with knee osteoarthritis: a multicenter randomized controlled trial. J Back Musculoskelet Rehabil2024; 37: 1455–1466.
