Dear Editor, Viscosupplementation injections have been used for over 50 years with no cumulative evidence of safety concerns. The authors' conclusion that “Strong conclusive evidence indicates that viscosupplementation is associated with an increased risk of serious adverse events (SAEs)”(1) is incorrect, or at best an inaccurate representation of the evidence. In a clinical trial, the reporting of SAEs is taken very seriously, ALL adverse events are recorded, whether these are related to the treatment or not. There is a definitive difference between the reporting of SAEs in clinical trials and the likelihood of these events occurring in the real world (2). Ewer and Herson(2) submit that, as has happened here, these differences lead to over-zealous surveillance if not understood. When considering the safety of a treatment, only those events considered to be related to treatment are safety concerns. Despite the analysis of SAEs in this review, the authors failed to state that not a single paper identified any causal relationship between SAEs and the use of viscosupplementation. Whilst one could argue that a pooled analysis of SAEs may overcome the bias of decisions regarding causality, even a ‘careful re-adjudication’ of the SAEs reported would not lead to the conclusion that these were treatment related. An evaluation of all the original studies in this systematic review found that of the 12 published studies quoted, 11 studies (91.6%) state that SAEs were not related to the hyaluronic acid (HA) being studied. In the one study that did not equivocally state this (3) they reported “injection site reactions seen with HA were generally minor and resulted in 6 premature terminations. General or systemic reactions were uncommon, and serious reactions rare”. I would challenge the authors to identify any SAEs they have identified in the review that could be substantiated as likely to be causal that would support their statement that “Strong conclusive evidence indicates that viscosupplementation is associated with an increased risk of serious adverse events”(1). It should be noted that a previous meta-analysis from this group published by Rutjes et al., in 2012(4), reported similar concerns related to small effect sizes and significant safety issues. The authors claim that by using studies with greater than 100 participants per group they have reduced reporting bias but have included studies with less than 100 patients in the control group (5)(6). In addition, the inclusion of unpublished data that has not been non-peer reviewed increases the risk of bias. This publication utilizes a cumulative ‘z score’ with boundaries of equivalence of approximately +/-0.38 (1). The authors report a 38-year cumulative ‘z score’ of 0.37 that is within 0.01 of the boundaries of superiority. For the authors to claim that “Strong conclusive evidence” for their conclusion is not supported by the evidence they have presented.

Recently, Concoff et al, (2019)(7) analyzed a similar dataset, accurately accounting for heterogeneity in PROMs scores and finding the effect size for viscosupplementation was 0.34, not 0.2 as reported by these authors. The effect size was also reported using the more widely used definitions for molecular weight, finding a smaller effect size for low molecular weight HA of 0.23 and 0.57 for high molecular weight HA. It is unfortunate that methodological differences and misunderstanding of serious adverse event reporting in clinical trials have led to an invalid conclusion, rather than that which the data concludes: That there is NO evidence that viscosupplementation is associated with any treatment related risk of SAEs and the findings support the use of viscosupplementation for the treatment of knee osteoarthritis.

References 1. Pereira TV, Ju ni P, Saadat P, Xing D, Yao L, Bobos P, et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis. BMJ. 2022;378(jul06 19):E69722. 2. Ewer MS, Herson J. Cardiovascular adverse events in oncology trials: understanding and appreciating the differences between clinical trial data and real-world reports. Cardiooncology. 2022 Jul 19;8. 3. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol. 1998 Nov 1;25(11):2203–12. 4. Rutjes AWS, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012 Jul 8;157(3):180–91. 5. Pham T, Le Henanff A, Ravaud P, Dieppe P, Paolozzi L, Dougados M. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis. 2004 Dec 1;63(12):1611–7. 6. Hangody L, Szody R, Lukasik P, Zgadzaj W, Lénárt E, Dokoupilova E, et al. 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 Jul 1;9(3):276–83. 7. Concoff A, Rosen J, Fu F, Bhandari M, Boyer K, Karlsson J, et al. A Comparison of Treatment Effects for Nonsurgical Therapies and the Minimum Clinically Important Difference in Knee Osteoarthritis. JBJS Rev. 2019 Aug 1;7(8):E5.

Competing interests: Jane Fitzpatrick has received consultancy fees from Novartis, Zimmer Biomet and Bioventus Inc. in the last 5 years and organizational financial interests in the form of research grants from Orthocell and Zimmer Biomet.