Intra-articular hyaluronic acid for osteoarthritis

Letter

We read with interest the recent review by Pisaniello and colleagues examining intra-articular hyaluronic acid (HA) for osteoarthritis.¹ The authors conclude that HA provides no clinically meaningful benefit and may confer harm; however, several aspects of the interpretation warrant clarification.

First, the article presents the evidence as unequivocal, describing 'conclusive evidence' of no benefit based largely on pooled estimates from large placebo-controlled trials. Interpretation of clinical relevance, however, depends on assumptions regarding minimal clinically important difference, management of heterogeneity, and exclusion of smaller trials. While concerns regarding small-study effects and publication bias are valid, absence of benefit in pooled data means does not preclude clinically meaningful responses within specific phenotypes or patient subgroups, which remain insufficiently explored.

Second, the article reports a higher rate of serious adverse events with HA (3.7 versus 2.5%). Yet most events were considered unrelated to treatment. Presenting relative risk increases without parallel absolute risk context may inadvertently amplify perceived harm and therefore requires careful clinical interpretation.

Third, the discussion of platelet-rich plasma (PRP), another intra-articular therapy, relies on a single randomised trial.² PRP is not a uniform intervention; preparations vary considerably in platelet dose, leukocyte composition, activation method and injection protocol. Extrapolating findings from one preparation, particularly a low-dose protocol, to the broader class of autologous biologics risks oversimplification. Importantly, recent evidence indicates that treatment outcomes may vary with platelet dose and cellular composition.^3,4

While guideline recommendations against HA are noted, international positions remain heterogeneous, reflecting ongoing uncertainty in interpretation of the evidence base. Osteoarthritis management would therefore benefit from nuanced appraisal rather than categorical dismissal of entire therapeutic classes. Future research should prioritise phenotype-stratified trials, biologic dose–response evaluation and transparent reporting standards.

Jeannie Devereaux
Scientific Officer, High Tech Medical, Queensland; Owner, Regenerative Medicine Australia, Victoria

Amit Lakkaraju
Radiologist, Meridian Vein and Pain, Victoria

Zane Sherif
Radiologist, Mermaid Beach Radiology, Queensland

Don Buford
Orthopaedic surgeon, Texas Orthobiologics, Texas, USA

Conflicts of interest: Jeannie Devereaux is employed as a consultant by High Tech Medical, the Australian distributor of a platelet-rich plasma (PRP) product, and owns Regenerative Medicine Australia, an educational platform providing training in regenerative medicine, including PRP products. Amit Lakkaraju, Zane Sherif and Don Buford own clinics that provide intra-articular therapies. Don Buford is President of the Interventional Orthobiologics Foundation and a member of the Board of Directors, Arthroscopy Association of North America.

 

References

1. Pisaniello HL, Goh S, Buchbinder R. Intra-articular hyaluronic acid (viscosupplementation) for osteoarthritis: is it effective? Australian Prescriber 2026;49:16-21.
2. Bennell KL, Paterson KL, Metcalf BR, Duong V, Eyles J, Kasza J, et al. 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;326:2021-30.
3. Belk JW, Lim JJ, Keeter C, McCulloch PC, Houck DA, McCarty EC, et al. Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis. Arthroscopy 2023;39:1714-34.
4. Berrigan W, Tao F, Kopcow J, Park AL, Allen I, Tahir P, et al. The Effect of Platelet Dose on Outcomes after Platelet Rich Plasma Injections for Musculoskeletal Conditions: A Systematic Review and Meta-Analysis. Curr Rev Musculoskelet Med 2024;17:570-88.

 

Authors' response

Huai Leng Pisaniello, Shyan Goh and Rachelle Buchbinder, the authors of the article, comment:

We thank Devereaux and colleagues for their interest in our review on intra-articular hyaluronic acid (HA) use in osteoarthritis.¹

We stand by our interpretation of the evidence indicating a clinically irrelevant benefit of viscosupplementation with intra-articular HA. It was based on a high-quality systematic review that pooled data from 24 placebo-controlled trials with minimum 100 participants (total 8702 participants) with knee osteoarthritis,² and additional trials of viscosupplementation performed for other osteoarthritic joints. While we agree absence of benefit in pooled data does not theoretically preclude a clinically meaningful response within a subgroup, another subgroup would have to be clinically meaningfully worse off for a null effect, a scenario not reflected in the available data. This type of speculation is commonly used to counter evidence-based medicine.³

We agree that the clinical relevance of the higher rate of serious adverse events reported in Pereira et al. is unclear; while 11 of 15 trials included in this analysis reported that none of the serious adverse events were treatment related,² attribution of causality to adverse events in clinical trials is potentially unreliable.⁴ The true rate of serious adverse events that have been reported, such as septic and severe inflammatory arthritis and severe cutaneous reactions, are unlikely to be estimable from randomised trials.

Our review primarily addressed intra-articular HA use in osteoarthritis; hence a comprehensive review of evidence regarding platelet-rich plasma (PRP) therapy in osteoarthritis was not intended. We agree that there is wide variability in PRP preparation techniques across trials. There are also integrity issues with some large trials reporting implausibly large treatment effects.⁵ Our ongoing Cochrane review of PRP for knee osteoarthritis is investigating these issues.⁶

Further viscosupplementation trials should only be conducted if they will materially alter the conclusions from existing evidence. To be ethically justifiable they should be of high quality and only include patient subgroups with the potential to benefit.

Conflicts of interest: Huai Leng Pisaniello and Shyan Goh declared no conflicts of interest. Rachelle Buchbinder is a member of the expert group for Therapeutic Guidelines: Rheumatology, and Chair of the Australia and New Zealand Musculoskeletal Clinical Trials Network (ANZMUSC)–Australian Rheumatology Association (ARA) Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis. Rachelle was awarded National Health and Medical Research Council (NHMRC) grants for 'Better evidence more rapidly implemented to optimise health for people with musculoskeletal conditions' (2021 to 2025), 'Wiser healthcare: better value care for all Australians' (2022 to 2026), and 'Better outcomes in inflammatory arthritis' (2022 to 2026). She received funding from the NHMRC for the Cochrane Musculoskeletal Australian Editorial Base (2020 to 2025).

 

References 2

1. Pisaniello HL, Goh S, Buchbinder R. Intra-articular hyaluronic acid (viscosupplementation) for osteoarthritis: is it effective? Australian Prescriber 2026;49:16-21.
2. Pereira TV, Juni P, Saadat P, Xing D, Yao L, Bobos P, et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis. BMJ 2022;378:e069722.
3. Cohen AM, Stavri PZ, Hersh WR. A categorization and analysis of the criticisms of Evidence-Based Medicine. Int J Med Inform 2004;73:35-43.
4. Le-Rademacher J, Hillman SL, Meyers J, Loprinzi CL, Limburg PJ, Mandrekar SJ. Statistical controversies in clinical research: Value of adverse events relatedness to study treatment: analyses of data from randomized double-blind placebo-controlled clinical trials. Ann Oncol 2017;28:1183-90.
5. Pereira TV, Saadat P, Bobos P, Iskander SM, Bodmer NS, Rudnicki M, et al. Effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis based on large randomized trials: A systematic review and network meta-analysis. Osteoarthritis Cartilage 2025;33:207-17.
6. Whittle SL, Johnston RV, McDonald S, Paterson KL, Buchbinder R. Autologous blood product injections including platelet-rich plasma for osteoarthritis of the knee (Cochrane review protocol). Cochrane Database Syst Rev 2019; 2019.

 

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