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Systematic review

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Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: A systematic review and meta-analysis

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Journal Seminars in arthritis and rheumatism
Year 2014
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This article is included in 2 Broad syntheses 5 Broad syntheses (2 references)

This article includes 5 Primary studies 5 Primary studies (5 references)

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OBJECTIVE: To assess the relative efficacy of intra-articular hyaluronic acid (IAHA) in comparison with non-steroidal anti-inflammatory drugs (NSAIDs) for knee osteoarthritis (OA). METHODS: We searched Medline, EMBASE, Google Scholar, ISI Web of Science, and Cochrane Database from inception until February 2013. Randomized controlled trials comparing HA with NSAIDs for knee OA were included if they reported at least one pain outcome. Two reviewers abstracted data and determined quality. Outcomes included pain, function, and stiffness. Random-effects meta-analyses were performed. RESULTS: Five trials (712 participants) contributed to the pain analysis. Both groups showed improvement from baseline. The analysis found an effect size (ES) of −0.07 (95% CI: −0.24 to 0.10) at trial end, favoring neither treatment. There were no statistically significant differences between the groups at 4 and 12 weeks in function [ES = −0.08 (95% CI: −0.39 to 0.23)] or stiffness [ES = 0.03 (95% CI: −0.27 to 0.34)] analyses based on two trials. Injection site pain was the most common adverse event reported in the HA group, and gastrointestinal adverse events were more common in the NSAIDs group. CONCLUSION: This meta-analysis suggests that IAHA is not significantly different from continuous oral NSAIDs at 4 and 12 weeks. Our study detected no safety concerns; however, the included trials had only a short follow-up duration. Given the favorable safety profile of IAHA over NSAIDs, this result suggests that IAHA might be a viable alternative to NSAIDs for knee OA, especially for older patients at greater risk for systemic adverse events.

Systematic review

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Comparative Effectiveness of Platelet-Rich Plasma Injections for Treating Knee Joint Cartilage Degenerative Pathology: A Systematic Review and Meta-Analysis.

Journal Archives of physical medicine and rehabilitation
Year 2014
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This article is included in 1 Structured summary of systematic reviews 15 Structured summaries of systematic reviews (1 reference) 1 Broad synthesis 15 Broad syntheses (1 reference)

This article includes 16 Primary studies 15 Primary studies (16 references)

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Abstract: Objective: To explore the effectiveness of platelet-rich plasma (PRP) in treating cartilage degenerative pathology in knee joints. Data Sources: Electronic databases, including PubMed and Scopus, were searched from the earliest record to September 2013. Study Selection: We included single-arm prospective studies, quasi-experimental studies, and randomized controlled trials that used PRP to treat knee chondral degenerative lesions. Eight single-arm studies, 3 quasi-experimental studies, and 5 randomized controlled trials were identified, comprising 1543 participants. Data Extraction: We determined effect sizes for the selected studies by extracting changes in functional scales after the interventions and compared the PRP group pooled values with the pretreatment baseline and the groups receiving placebo or hyaluronic acid (HA) injections. Data Synthesis: PRP injections in patients with knee degenerative pathology showed continual efficacy for 12 months compared with their pretreatment condition. The effectiveness of PRP was likely better and more prolonged than that of HA. Injection doses ≤2, the use of a single-spinning approach, and lack of additional activators led to an uncertainty in the treatment effects. Patients with lower degrees of cartilage degeneration achieved superior outcomes as opposed to those affected by advanced osteoarthritis. Conclusions: PRP application improves function from basal evaluations in patients with knee joint cartilage degenerative pathology and tends to be more effective than HA administration. Discrepancy in the degenerative severity modifies the treatment responses, leading to participants with lower degrees of degeneration benefiting more from PRP injections.

Systematic review

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US-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: Systematic review and meta-analysis of randomized, saline-controlled trials

Authors Miller LE , Block JE
Journal Clinical medicine insights. Arthritis and musculoskeletal disorders
Year 2013
Links Pubmed DOI PubMed Central

This article is included in 1 Structured summary of systematic reviews 29 Structured summaries of systematic reviews (1 reference) 3 Broad syntheses 29 Broad syntheses (3 references)

This article includes 29 Primary studies 29 Primary studies (29 references)

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We conducted a systematic review and meta-analysis of randomized saline-controlled trials to determine the safety and effcacy of US-approved intra-articular hyaluronic acid (IAHA) injections for symptomatic knee osteoarthritis. A total of 29 studies representing 4,866 unique subjects (IAHA: 2,673, saline: 2,193) were included. IAHA injection resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to pre-injection values, with standardized mean difference (SMD) values ranging from 1.07-1.37 (all P< 0.001). Compared to saline controls, SMDs with IAHA ranged from 0.38-0.43 for knee pain and 0.32-0.34 for knee function (all P<0.001). There were no statistically significant differences between IAHA and saline controls for any safety outcome, including serious adverse events (SAEs) (P = 0.12), treatment-related SAEs (P = 1.0), study withdrawal (P = 1.0), and AE-related study withdrawal (P = 0.46). We conclude that intra-articular injection of US-approved HA products is safe and efficacious in patients with symptomatic knee osteoarthritis. © the author(s), publisher and licensee Libertas Academica Ltd.

Systematic review

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Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products.

Journal BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
Year 2012
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This article is included in 3 Broad syntheses 74 Broad syntheses (3 references)

This article includes 74 Primary studies 74 Primary studies (74 references)

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BACKGROUND: Although accepted as a conservative treatment option for knee osteoarthritis, the debate about the effectiveness of intra-articular treatment with hyaluronic acid (HA) is still ongoing because of contrasting outcomes in different clinical studies. Several well designed clinical studies showed a significant improvement in pain at follow-up compared with baseline but no significant improvement comparing the efficacy of HA with placebo (saline) or with other conservative treatment options. Notwithstanding the effectiveness of different types of intra-articular HA products, the question of whether one HA product is better than another is still unanswered. In this systematic review we compare the effects of intra-articularly administered HA with intra-articularly administered placebo in general and, more specifically, the effects of individual HA products with placebo. We also compare the efficacy of different HA products. METHODS: A systematic review of randomized controlled trials (RCTs) was conducted using databases including MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trial Register and EMBASE. RESULTS: Seventy-four RCTs were included in this systematic review. HA improves pain by approximately 40-50% compared with baseline levels. However, when compared with saline the difference in efficacy is not that large. Due to a large 'placebo effect' of saline (approximately 30% pain reduction, persisting for at least 3 months) we determined a weighted mean difference between the efficacy of HA and saline of just 10.20 using the visual analog scale for pain. It is debatable whether this difference reaches the minimum clinically important difference. Comparing the different HA products, which vary in the molecular weight, concentration, and volume of HA, we were not able to conclude that one brand has a better efficacy than another due to the heterogeneity of the studies and outcomes. DISCUSSION: In the future it will be important to determine the exact mechanism of action of placebo as this may give us an idea of how to treat osteoarthritis more efficiently. Due to the limitations of this review (follow-up of just 3 months and large heterogeneity of the included studies), it is also important to compare the different HA products to determine which product(s), or which molecular weight range, concentration, or volume of HA is the best option to treat osteoarthritis. Our recommendation is to start large (multicenter) RCTs to give us more evidence about the efficacy of the different HA products.

Systematic review

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Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis.

Journal Annals of internal medicine
Year 2012
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This article is included in 3 Broad syntheses 85 Broad syntheses (3 references)

This article includes 86 Primary studies 85 Primary studies (86 references)

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BACKGROUND: Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis. PURPOSE: To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis. DATA SOURCES: MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources. STUDY SELECTION: Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis. DATA EXTRACTION: Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression. DATA SYNTHESIS: Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, -0.37 [95% CI, -0.46 to -0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of -0.03 (CI, -0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of -0.11 (CI, -0.18 to -0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]). LIMITATIONS: Trial quality was generally low. Safety data were often not reported. CONCLUSION: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events. PRIMARY FUNDING SOURCE: Arco Foundation.

Systematic review

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Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: A systematic review and meta-analysis

Journal Arthritis and rheumatism
Year 2009
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This article is included in 1 Structured summary of systematic reviews 7 Structured summaries of systematic reviews (1 reference) 3 Broad syntheses 7 Broad syntheses (3 references)

This article includes 7 Primary studies 7 Primary studies (7 references)

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Objective. To compare the efficacy of intraarticular hyaluronic acid with corticosteroids for knee osteoarthritis (OA). Methods. Our data sources were Medline, EMBASE, CINAHL, BIOSIS, and the Cochrane database, as well as hand-sarched reviews, manuscripts, and supplements. For unpublished data we used author contacts. Randomized trials that reported effects of intraarticular hyaluronic acid versus corticosteroids on knee OA were selected based on inclusion criteria. Two reviewers extracted data independently. Using a random-effects model, we computed effect sizes for pain change from baseline at 2, 4, 8, 12, and 26 weeks. We also performed multivariate analyses accounting for within and between-study covariance. We performed sensitivity analyses for trials that reported intent-to-treat (ITT) analysis and blinding, and directly compared Hyalgan with methylprednisolone. Results. The 7 eligible trials included 606 participants. Five reported ITT analyses. At week 2 the effect size was -0.39 (95% confidence interval [95% CI], -0.65, -0.12) favoring corticosteroids; at week 4 it was -0.01 (95% CI -0.23, 0.21) suggesting equal efficacy. At week 8 the effect size was 0.22 (95% CI -0.05, 0.49) favoring hyaluronic acid, and at week 12 it was 0.35 (95% CI 0.03, 0.66) favoring hyaluronic acid. At week 26 the effect size was 0.39 (95% CI 0.18, 0.59), favoring hyaluronic acid. The multivariate analyses and sensitivity analyses generated consistent results. Conclusion. From baseline to week 4, intraarticular corticosteroids appear to be relatively more effective for pain than intraarticular hyaluronic acid. By week 4, the 2 approaches have equal efficacy, but beyond week 8, hyaluronic acid has greater efficacy. Understanding this trend is useful to clinicians when treating knee OA. © 2009, American College of Rheumatology.

Systematic review

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Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis.

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Journal Arthritis and rheumatism
Year 2007
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This article is included in 1 Structured summary of systematic reviews 13 Structured summaries of systematic reviews (1 reference) 1 Broad synthesis 13 Broad syntheses (1 reference)

This article includes 13 Primary studies 13 Primary studies (13 references)

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OBJECTIVE: To compare the effectiveness and safety of intraarticular high-molecular hylan with standard preparations of hyaluronic acids in osteoarthritis of the knee. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing hylan with a hyaluronic acid in patients with knee osteoarthritis. Trials were identified by systematic searches of Central, Medline, EMBase, Cinahl, the Food and Drug Administration, and Science Citation Index supplemented by hand searches of conference proceedings and reference lists (last update November 2006). Literature screening and data extraction were performed in duplicate. Effect sizes were calculated from differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled standard deviation. Trials were combined using random-effects meta-analysis. RESULTS: Thirteen trials with a pooled total of 2,085 patients contributed to the meta-analysis. The pooled effect size was -0.27 (95% confidence interval [95% CI] -0.55, 0.01), favoring hylan, but between-trial heterogeneity was high (I(2) = 88%). Trials with blinded patients, adequate concealment of allocation, and an intent-to-treat analysis had pooled effect sizes near null. The meta-analyses on safety revealed an increased risk associated with hylan for any local adverse events (relative risk [RR] 1.91; 95% CI 1.04, 3.49; I(2) = 28%) and for flares (RR 2.04; 95% CI 1.18, 3.53; I(2) = 0%). CONCLUSION: Given the likely lack of a superior effectiveness of hylan over hyaluronic acids and the increased risk of local adverse events associated with hylan, we discourage the use of intraarticular hylan in patients with knee osteoarthritis in clinical research or practice.

Systematic review

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Viscosupplementation for the treatment of osteoarthritis of the knee

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Journal Cochrane database of systematic reviews (Online)
Year 2006
Links Pubmed DOI PubMed Central

This article is included in 7 Broad syntheses 49 Broad syntheses (7 references)

This article includes 52 Primary studies 49 Primary studies (52 references)

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Background: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. Objectives: To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). Search methods: MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched. Selection criteria: RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). Data collection and analysis: Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer. Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR). Main results: Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. Authors' conclusions: Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

Systematic review

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Hyaluronic acid injections relieve knee pain.

Authors Modawal A , Ferrer M , Choi HK , Castle JA
Journal The Journal of family practice
Year 2005
Links Pubmed

This article is included in 1 Structured summary of systematic reviews 9 Structured summaries of systematic reviews (1 reference) 5 Broad syntheses 9 Broad syntheses (5 references)

This article includes 9 Primary studies 9 Primary studies (9 references)

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OBJECTIVE: To evaluate the efficacy of intra-articular viscosupplementation therapy with hyaluronic acid for pain relief of knee osteoarthritis, we conducted a meta-analysis of randomized, double-blinded, placebo-controlled trials. METHODS: We searched systematically for randomized, double-blinded, placebo-controlled trials of hyaluronic acid (hyaluronan and hylan G-F20) for pain relief of knee osteoarthritis. Studies reporting pain visual analogue scale (VAS) differences were included in the meta-analysis. Changes in pain were measured by VAS for placebo and treatment, and summary estimates of the differences between the 2 arms were calculated at 1 week, 5 to 7 weeks, 8 to 12, and 15 to 22 weeks after the last intra-articular injection. Sources of heterogeneity were assessed using information on quality score, type of viscosupplementation, and VAS change in pain with activity or rest. Heterogeneity across the studies was significant in all analyses (P<.01); therefore a random effect model was used. Pain was measured either on activity or at rest. RESULTS: Eleven trials (9 hyaluronan and 2 hylan G-F 20) allowed calculation of the summary estimate of difference in change of VAS pain at 1 week, 6 of the 11 allowed the estimation between 5 to 7 weeks and 8 to 12 weeks, and only 3 at 15 to 22 weeks. The summary estimates of VAS differences between therapy and placebo injection: at 1 week, 4.4 (95% confidence interval [CI], 1.1-7.2); at 5 to 7 weeks, 17.7 (7.5-28.0); at 8 to 12 weeks, 18.1 (6.3-29.9) and at 15 to 22 weeks, 4.4 (-15.3 to 24.1). CONCLUSION: Intra-articular viscosupplementation was moderately effective in relieving knee pain in patients with osteoarthritis at 5 to 7 and 8 to 10 weeks after the last injection but not at 15 to 22 weeks.

Systematic review

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Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis.

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Journal CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne
Year 2005
Links Pubmed DOI PubMed Central

This article is included in 1 Structured summary of systematic reviews 22 Structured summaries of systematic reviews (1 reference) 4 Broad syntheses 22 Broad syntheses (4 references)

This article includes 22 Primary studies 22 Primary studies (22 references)

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BACKGROUND: Osteoarthritis of the knee affects up to 10% of the elderly population. The condition is frequently treated by intra-articular injection of hyaluronic acid. We performed a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of this treatment. METHODS: We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004 using a combination of search terms for knee osteoarthritis and hyaluronic acid and a filter for randomized controlled trials. We extracted data on pain at rest, pain during or immediately after movement, joint function and adverse events. RESULTS: Twenty-two trials that reported usable quantitative information on any of the predefined end points were identified and included in the systematic review. Even though pain at rest may be improved by hyaluronic acid, the data available from these studies did not allow an appropriate assessment of this end point. Patients who received the intervention experienced a reduction in pain during movement: the mean difference on a 100-mm visual analogue scale was -3.8 mm (95% confidence interval [CI] -9.1 to 1.4 mm) after 2-6 weeks, -4.3 mm (95% CI -7.6 to -0.9 mm) after 10-14 weeks and -7.1 mm (95% CI -11.8 to -2.4 mm) after 22-30 weeks. However, this effect was not compatible with a clinically meaningful difference (expected to be about 15 mm on the visual analogue scale). Furthermore, the effect was exaggerated by trials not reporting an intention-to-treat analysis. No improvement in knee function was observed at any time point. Even so, the effect of hyaluronic acid on knee function was more favourable when allocation was not concealed. Adverse events occurred slightly more often among patients who received the intervention (relative risk 1.08, 95% CI 1.01 to 1.15). Only 4 trials explicitly reported allocation concealment, had blinded outcome assessment and presented intention-to-treat data. INTERPRETATION: According to the currently available evidence, intra-articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events. Large trials with clinically relevant and uniform end points are necessary to clarify the benefit-risk ratio.