Acta Chir Orthop Traumatol Cech. 2025; 92(3):161-172 | DOI: 10.55095/achot2024/065
Intra-Articular Use of Hyaluronic Acid Preparations in the Treatment of Knee OsteoarthritisOriginal papers
- Ortopedická klinika Lékařské fakulty Univerzity Palackého a Fakultní nemocnice Olomouc
Purpose of the study: The knee is the most common peripheral site of osteoarthritis (KOA; knee osteoarthritis). The mainstay of non-operative treatment is education, exercise, weight reduction, and pharmacological therapy. Intra-articular hyaluronic acid (HA) injection is a non-operative treatment option. The aim of our study was to assess the most recent data on the efficacy of intra-articular administration of HA in KOA therapy and to compare it with intra-articular injections of platelet-rich plasma (PRP), corticosteroids (CS) and placebo (saline solution).
Material and methods: The PubMed and Cochrane Library databases were searched for randomized clinical trials (RCTs) conducted between 2012 and 2023 comparing the efficacy of HA with PRP, CS, or placebo. The efficacy was mostly assessed using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) and VAS (Visual Analogue Scale) for pain. The Rob2 (Risk of Bias 2) tool developed by the Cochrane Collaboration was used to assess the risk of bias.
Results: The data pooled from 29 studies (2032 patients treated with HA, 965 with PRP, 376 with CS and 697 with placebo) were analysed. The efficacy was assessed mostly at 1, 3, 6 and 12 months after the administration of the investigated substance. All types of interventions (HA, PRP, CS) were found to have a beneficial effect on the knee affected by KOA, namely through symptom relief. The greatest effect was achieved with PRP, which lasted longer than that of HA or CS. HA offered a moderate relief of symptoms, which was still apparent at 6 months after administration. The administration of CS resulted in a rapid onset of pain relief which was, however, of short duration and started to diminish as early as after the first month of follow-up. In placebo-controlled studies, the follow-up did not exceed 6 months.
Discussion and Conclusions: Intra-articular administration of HA continues to be the most common intra-articular therapy for patients with KOA. We should therefore take an interest in its outcomes. This intervention is recommended by the OARSI as 1B level treatment. The ACR, on the contrary, has turned from both the HA and PRP. The NICE in its opinion on non-surgical management of KOA also advises against HA. In our study, on the other hand, we concluded that all three active pharmaceutical ingredients (HA, PRP and CS) improved the KOA symptoms, with PRP showing the most significant, longest lasting and most consistent overall beneficial effects. This conclusion does not imply that HA offers no or only negligible effect. The particular size of effect of intra-articular administration of HA depends on a number of circumstances. Further research should therefore be conducted which would look into the HA benefit in relation to the specific patient, KOA phenotype, stage of inflammation, or healing processes.
Keywords: knee osteoarthritis, hyaluronic acid, platelet-rich plasma, corticoids, placebo, randomized clinical trials.
Received: October 11, 2024; Revised: October 29, 2024; Accepted: November 4, 2024; Published: July 1, 2025 Show citation
ACS | AIP | APA | ASA | Harvard | Chicago | Chicago Notes | IEEE | ISO690 | MLA | NLM | Turabian | Vancouver |
References
- Arden NK, Akermark C, Andersson M, Todman MG, Altman RD. A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin. 2014;30:279-286.
Go to original source...
Go to PubMed...
- Arden NK, Perry TA, Bannuru RR, Bruyere O, Cooper C, Haugen IK, Hochberg MC, McAlindon TE, Mobasheri A, Reginster JY. Non-surgical management of knee osteoarthritis: comparison of ESCEO and OARSI 2019 guidelines. Nat Rev Rheumatol. 2021;17:59-66.
Go to original source...
Go to PubMed...
- Askari A, Gholami T, NaghiZadeh MM, Farjam M, Kouhpayeh SA, Shahabfard Z. Hyaluronic acid compared with corticosteroid injections for the treatment of osteoarthritis of the knee: a randomized control trail. Springerplus. 2016;5:442.
Go to original source...
Go to PubMed...
- Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, Kraus VB, Lohmander LS, Abbott JH, Bhandari M, Blanco FJ, Espinosa R, Haugen IK, Lin J, Mandl LA, Moilanen E, Nakamura N, Snyder-Mackler L, Trojian T, Underwood M, McAlindon TE. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27:1578-1589.
Go to original source...
Go to PubMed...
- Bennell KL, Paterson KL, Metcalf BR, Duong V, Eyles J, Kasza J, Wang Y, Cicuttini F, Buchbinder R, Forbes A, Harris A, Yu SP, Connell D, Linklater J, Wang BH, Oo WM, Hunter DJ. Effect of intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: The RESTORE Randomized Clinical Trial. JAMA. 2021;326:2021-2030.
Go to original source...
Go to PubMed...
- Bensa A, Albanese J, Boffa A, Previtali D, Filardo G. Intra-articular corticosteroid injections provide a clinically relevant benefit compared to placebo only at short-term follow-up in patients with knee osteoarthritis: a systematic review and meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2024;32:311-322.
Go to original source...
Go to PubMed...
- Bisicchia S, Bernardi G, Tudisco C. HYADD 4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up. Clin Exp Rheumatol. 2016;34:857-863.
- Brophy RH, Fillingham YA. AAOS Clinical Practice Guideline Summary: Management of Osteoarthritis of the Knee (Nonarthroplasty), Third Edition. J Am Acad Orthop Surg. 2022;30:e721-e729.
Go to original source...
Go to PubMed...
- Buendia-Lopez D, Medina-Quiros M, Fernandez-Villacanas Marin MA. Clinical and radiographic comparison of a single LP-PRP injection, a single hyaluronic acid injection and daily NSAID administration with a 52-week follow-up: a randomized controlled trial. J Orthop Traumatol. 2018;19:3.
Go to original source...
Go to PubMed...
- Cerza F, Carni S, Carcangiu A, Di Vavo I, Schiavilla V, Pecora A, De Biasi G, Ciuffreda M. Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med. 2012;40:2822-2827.
Go to original source...
Go to PubMed...
- Ciapini G, Simonettii M, Giuntoli M, Varchetta G, De Franco S, Ipponi E, Scaglione M, Parchi PD. Is the Combination of Platelet-Rich Plasma and Hyaluronic Acid the Best Injective Treatment for Grade II-III Knee Osteoarthritis? A Prospective Study. Adv Orthop. 2023;2023:1868943.
Go to original source...
Go to PubMed...
- Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339-346.
Go to original source...
Go to PubMed...
- Davalillo CAT, Vasavilbaso CT, Alvarez JMN, Granado PC, Jiménez OAG, del Sol MG, Orbezo FG. Clinical efficacy ofintra-articular injections in knee osteoarthritis: a prospective randomized study comparing hyaluronic acid and betamethasone. Open Access Rheumatol. 2015;7:9-18.
Go to original source...
Go to PubMed...
- De Lucia O, Jerosch J, Yoon S, Sayre T, Ngai W, Filippou G. One-year efficacy and safety of single or one to three weekly injections of Hylan G-F 20 for knee osteoarthritis: a systematic literature review and meta-analysis. Clin Rheumatol. 2021;40:2133-2142.
Go to original source...
Go to PubMed...
- Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med. 2019;47:347-354.
Go to original source...
Go to PubMed...
- Dorio M, Pereira RMR, Luz AGB, Deveza LA, de Oliveira RM, Fuller R. Efficacy of platelet-rich plasma and plasma for symptomatic treatment of knee osteoarthritis: a double-blinded placebo-controlled randomized clinical trial. BMC Musculoskelet Disord. 2021;22:822.
Go to original source...
Go to PubMed...
- Driban JB, Harkey MS, Barbe MF, Ward RJ, MacKay JW, Davis JE, Lu B, Price LL, Eaton CB, Lo GH, McAlindon TE. Risk factors and the natural history of accelerated knee osteoarthritis: a narrative review. BMC Musculoskelet Disord. 2020;21:332.
Go to original source...
Go to PubMed...
- Dulic O, Rasovic P, Lalic I, Kecojevic V, Gavrilovic G, Abazovic D, Maric D, Miskulin M, Bumbasirevic M. Bone marrow aspirate concentrate versus platelet rich plasma or hyaluronic acid for the treatment of knee osteoarthritis. Medicina (Kaunas). 2021;57:1193.
Go to original source...
Go to PubMed...
- Duymus TM, Mutlu S, Dernek B, Komur B, Aydogmus S, Kesiktas FN. Choice of intra-articular injection in treatment of knee osteoarthritis: platelet-rich plasma, hyaluronic acid or ozone options. Knee Surg Sports Traumatol Arthrosc. 2017;25:485-492.
Go to original source...
Go to PubMed...
- Elsawy SA, Hamdy, M., Ahmed, M.S. Intra-articular injection of hyaluronic acid for treatment of osteoarthritis knee: comparative study to intra-articular corticosteroids. Egypt Rheumatol Rehabil. 2017;44:143-146.
Go to original source...
- Fallacara A, Baldini E, Manfredini S, Vertuani S. Hyaluronic acid in the third millennium. Polymers (Basel). 2018;10:701.
Go to original source...
Go to PubMed...
- Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A, Fornasari P, Marcacci M, Kon E. Platelet-Rich Plasma Intra-articular Knee Injections Show No Superiority Versus Viscosupplementation: a Randomized Controlled Trial. Am J Sports Med. 2015;43:1575-1582.
Go to original source...
Go to PubMed...
- Gilat R, Haunschild ED, Knapik DM, Evuarherhe A, Jr., Parvaresh KC, Cole BJ. Hyaluronic acid and platelet-rich plasma for the management of knee osteoarthritis. Int Orthop. 2021;45:345-354.
Go to original source...
Go to PubMed...
- Gupta RC, Lall R, Srivastava A, Sinha A. Hyaluronic acid: molecular mechanisms and therapeutic trajectory. Front Vet Sci. 2019;6:192.
Go to original source...
Go to PubMed...
- Hangody L, Szody R, Lukasik P, Zgadzaj W, Lenart E, Dokoupilova E, Bichovsk D, Berta A, Vasarhelyi G, Ficzere A, Hangody G, Stevens G, Szendroi M. Intraarticular injection of a cross-linked sodium hyaluronate combined with triamcinolone hexacetonide (Cingal) to provide symptomatic relief of osteoarthritis of the knee: a randomized, double-blind, placebo-controlled multicenter clinical trial. Cartilage. 2018;9:276-283.
Go to original source...
Go to PubMed...
- Henrotin Y, Berenbaum F, Chevalier X, Marty M, Richette P, Rannou F. Reduction of the Serum Levels of a Specific Biomarker of Cartilage Degradation (Coll2-1) by Hyaluronic Acid (KARTILAGE(R) CROSS) Compared to Placebo in Painful Knee Osteoarthritis Patients: the EPIKART Study, a Pilot Prospective Comparative Randomized Double Blind Trial. BMC Musculoskelet Disord. 2017;18:222.
Go to original source...
Go to PubMed...
- Henrotin Y, Tits C, Paul J, Gramme P, Helleputte T, Migliore A, Richette P, Chevalier X, Monfort J, Diracoglu D, Bard H, Jerosch J, Baron D, Raghu R, Conrozier T. Retreatment with hyaluronic acid viscosupplementation in knee osteoarthritis: agreement between EUROVISCO Guidelines and current medical practice. Cartilage. 2021;13:1696S-1701S.
Go to original source...
Go to PubMed...
- Huang Y, Liu X, Xu X, Liu J. Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis : A prospective randomized controlled study. Orthopade. 2019;48:239-247.
Go to original source...
Go to PubMed...
- Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen G, Zimmerman-Gorska I, Dougados M, Standing Committee for International Clinical Studies Including Therapeutic Trials E. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145-1155.
Go to original source...
Go to PubMed...
- Khongwir W, Saha, S., Khonglah, T. . A comparative study of the results of conservative therapy, intra-articular steroid injection therapy and intra-articular hyaluronic acid injection therapy in primary osteoarthritis of knee: a prospective study in Eastern Indian population. . National Journal of Clinical Orthopaedics 2018;2:81-86.
Go to original source...
- Kim MS, Koh IJ, Choi KY, Sung YG, Park DC, Lee HJ, In Y. The Minimal Clinically Important Difference (MCID) for the WOMAC and factors related to achievement of the MCID after medial opening wedge high tibial osteotomy for knee osteoarthritis. Am J Sports Med. 2021;49:2406-2415.
Go to original source...
Go to PubMed...
- Kim S, Kosorok MR, Arbeeva L, Schwartz TA, Callahan LF, Golightly YM, Nelson AE, Allen KD. Precision Medicine-Based Machine Learning Analyses to Explore Optimal Exercise Therapies for Individuals With Knee Osteoarthritis: Random Forest-Informed Tree-Based Learning. J Rheumatol. 2023;50:1341-1345.
Go to original source...
Go to PubMed...
- Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, Callahan L, Copenhaver C, Dodge C, Felson D, Gellar K, Harvey WF, Hawker G, Herzig E, Kwoh CK, Nelson AE, Samuels J, Scanzello C, White D, Wise B, Altman RD, DiRenzo D, Fontanarosa J, Giradi G, Ishimori M, Misra D, Shah AA, Shmagel AK, ThomaLM, Turgunbaev M, Turner AS, Reston J. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72:220-233.
Go to original source...
Go to PubMed...
- Liao CD, Chen HC, Huang MH, Liou TH, Lin CL, Huang SW. Comparative efficacy of intra-articular injection, physical therapy, and combined treatments on pain, function, and sarcopenia indices in knee osteoarthritis: a network meta-analysis of randomized controlled trials. Int J Mol Sci. 2023;24.
Go to original source...
Go to PubMed...
- Lisi C, Perotti C, Scudeller L, Sammarchi L, Dametti F, Musella V, Di Natali G. Treatment of knee osteoarthritis: platelet-derived growth factors vs. hyaluronic acid. A randomized controlled trial. Clin Rehabil. 2018;32:330-339.
Go to original source...
Go to PubMed...
- Louis ML, Magalon J, Jouve E, Bornet CE, Mattei JC, Chagnaud C, Rochwerger A, Veran J, Sabatier F. Growth factors levels determine efficacy of platelets rich plasma injection in knee osteoarthritis: a randomized double blind noninferiority trial compared with viscosupplementation. Arthroscopy. 2018;34:1530-1540 e1532.
Go to original source...
Go to PubMed...
- Marinho A, Nunes C, Reis S. Hyaluronic Acid: A Key Ingredient in the Therapy of Inflammation. Biomolecules. 2021;11.
Go to original source...
Go to PubMed...
- Migliore A, Blicharski T, Plebanski R, Zegota Z, Gyula G, Rannou F, Reginster JY. Knee osteoarthritis pain management with an innovative high and low molecular weight hyaluronic acid formulation (HA-HL): a randomized clinical trial. Rheumatol Ther. 2021;8:1617-1636.
Go to original source...
Go to PubMed...
- Monticone M, Frizziero A, Rovere G, Vittadini F, Uliano D, S LAB, Gatto R, Nava C, Leggero V, Masiero S. Hyaluronic acid intra-articular injection and exercise therapy: effects on pain and disability in subjects affected by lower limb joints osteoarthritis. A systematic review by the Italian Society of Physical and Rehabilitation Medicine (SIMFER). Eur J Phys Rehabil Med. 2016;52:389-399.
- Park YB, Kim JH, Ha CW, Lee DH. Clinical Efficacy of Platelet-Rich Plasma Injection and Its Association With Growth Factors in the Treatment of Mild to Moderate Knee Osteoarthritis: A Randomized Double-Blind Controlled Clinical Trial As Compared With Hyaluronic Acid. Am J Sports Med. 2021;49:487-496.
Go to original source...
Go to PubMed...
- Petterson SC, Plancher KD. Single intra-articular injection of lightly cross-linked hyaluronic acid reduces knee pain in symptomatic knee osteoarthritis: a multicenter, double-blind, randomized, placebo-controlled trial. Knee Surg Sports Traumatol Arthrosc. 2019;27:1992-2002.
Go to original source...
Go to PubMed...
- Porcello A, Hadjab F, Ajouaou M, Philippe V, Martin R, Abdel-Sayed P, Hirt-Burri N, Scaletta C, Raffoul W, Applegate LA, Allemann E, Jordan O, Laurent A. Ex vivo functional benchmarking of hyaluronan-based osteoarthritis viscosupplement products: comprehensive assessment of rheological, lubricative, adhesive, and stability attributes. Gels. 2023;9.
Go to original source...
Go to PubMed...
- Qiao X, Yan L, Feng Y, Li X, Zhang K, Lv Z, Xu C, Zhao S, Liu F, Yang X, Tian Z. Efficacy and safety of corticosteroids, hyaluronic acid, and PRP and combination therapy for knee osteoarthritis: a systematic review and network meta-analysis. BMC Musculoskelet Disord. 2023;24:926.
Go to original source...
Go to PubMed...
- Raeissadat SA, Ghazi Hosseini P, Bahrami MH, Salman Roghani R, Fathi M, Gharooee Ahangar A, Darvish M. The comparison effects of intra-articular injection of Platelet Rich Plasma (PRP), Plasma Rich in Growth Factor (PRGF), Hyaluronic Acid (HA), and ozone in knee osteoarthritis; a one year randomized clinical trial. BMC Musculoskelet Disord. 2021;22:134.
Go to original source...
Go to PubMed...
- Raeissadat SA, Rayegani SM, Hassanabadi H, Fathi M, Ghorbani E, Babaee M, Azma K. Knee osteoarthritis injection choices: platelet- rich plasma (PRP) versus hyaluronic acid (a one-year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord. 2015;8:1-8.
Go to original source...
Go to PubMed...
- Ranusa M, Ondra M, Rebenda D, Vrbka M, Gallo J, Krupka I. Effects of viscosupplementation on tribological behaviour of articular cartilage. Lubricants. 2022;10:361.
Go to original source...
- Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157:180-191.
Go to original source...
Go to PubMed...
- Safali S, Ertas ES, Ozdemir A, Catakli D. Evaluation of single and multiple hyaluronic acid injections at different concentrations with high molecular weight in the treatment of knee osteoarthritis. BMC Musculoskelet Disord. 2024;25:164.
Go to original source...
Go to PubMed...
- Sdeek M, Sabry D, El-Sdeek H, Darweash A. Intra-articular injection of Platelet rich plasma versus Hyaluronic acid for moderate knee osteoarthritis. A prospective, double-blind randomized controlled trial on 189 patients with follow-up for three years. Acta Orthop Belg. 2021;87:729-734.
Go to original source...
Go to PubMed...
- Su K, Bai Y, Wang J, Zhang H, Liu H, Ma S. Comparison of hyaluronic acid and PRP intra-articular injection with combined intra-articular and intraosseous PRP injections to treat patients with knee osteoarthritis. Clin Rheumatol. 2018;37:1341-1350.
Go to original source...
Go to PubMed...
- Tammachote N, Kanitnate S, Yakumpor T, Panichkul P. Intra-articular, single-shot hylan g-f 20 hyaluronic acid injection compared with corticosteroid in knee osteoarthritis: a double-blind, randomized controlled trial. J Bone Joint Surg Am. 2016;98:885-892.
Go to original source...
Go to PubMed...
- Taslakian B, Miller LE, Mabud TS, Macaulay W, Samuels J, Attur M, Alaia EF, Kijowski R, Hickey R, Sista AK. Genicular artery embolization for treatment of knee osteoarthritis pain: Systematic review and meta-analysis. Osteoarthr Cartil Open. 2023;5:100342.
Go to original source...
Go to PubMed...
- van der Weegen W, Wullems JA, Bos E, Noten H, van Drumpt RA. No difference between intra-articular injection of hyaluronic acid and placebo for mild to moderate knee osteoarthritis: a randomized, controlled, double-blind trial. J Arthroplasty. 2015;30:754-757.
Go to original source...
Go to PubMed...
- Wandel S, Juni P, Tendal B, Nuesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. 2010;341: c4675.
Go to original source...
Go to PubMed...
- Wang YC, Lee CL, Chen YJ, Tien YC, Lin SY, Chen CH, Chou PP, Huang HT. Comparing the efficacy of intra-articular single platelet-rich plasma(prp) versus novel crosslinked hyaluronic acid for early-stage knee osteoarthritis: a prospective, double-blind, randomized controlled trial. Medicina (Kaunas). 2022;58:1028.
Go to original source...
Go to PubMed...
- Webner D, Huang Y, Hummer CD, 3rd. Intraarticular hyaluronic acid preparations for knee osteoarthritis: are some better than others? Cartilage. 2021;13:1619S-1636S.
Go to original source...
Go to PubMed...
- Yu W, Xu P, Huang G, Liu L. Clinical therapy of hyaluronic acid combined with platelet-rich plasma for the treatment of knee osteoarthritis. Exp Ther Med. 2018;16:2119-2125.
Go to original source...
Go to PubMed...