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Systematic review

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The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis.

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Journal BMC musculoskeletal disorders
Year 2017
Links Pubmed DOI PubMed Central

This article includes 30 Primary studies 30 Primary studies (30 references)

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BACKGROUND: Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens. METHODS: We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline. RESULTS: Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = -0.76; -0.98 to -0.53, 95% CI, P < 0.00001, and SMD = -0.36; -0.63 to -0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2-4 injection subgroups. CONCLUSION: Overall, 2-4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.

Systematic review

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Clinical benefit of intra-articular saline as a comparator in clinical trials of knee osteoarthritis treatments: A systematic review and meta-analysis of randomized trials.

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Journal Seminars in arthritis and rheumatism
Year 2016
Links Pubmed DOI

This article includes 40 Primary studies 40 Primary studies (40 references)

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OBJECTIVES: Hyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA. METHODS: MEDLINE and Embase databases were searched for articles published up to and including August 14th, 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (≤3 months) and long-term (6-12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null effect in a comparator group) that were combined and weighted using a random effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics. RESULTS: From 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1705 patients (SMD = -0.68; 95% CI: -0.78 to -0.57; P < 0.001; I(2) = 50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD = -0.61; 95% CI: -0.76 to -0.45; P < 0.001) with a substantial degree of inconsistency (I(2) = 74%). Overall, 29 of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline. CONCLUSIONS: Pain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a "placebo."

Systematic review

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Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis.

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Journal Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society
Year 2016
Links Pubmed DOI www.epistemonikos.org

This article includes 73 Primary studies 73 Primary studies (73 references)

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PURPOSE: Intra-articular (IA) hyaluronic acid (HA) is considered a safer alternative to oral NSAIDs and opioids for knee osteoarthritis. A recent review raised potential safety concerns about HA, warranting further review of safety outcomes. We examined the risks of HA compared with IA placebo and investigated whether the risks vary among individual HA preparations. METHODS: We searched all relevant databases from inception to October 2015 and sought unpublished data. We included all knee osteoarthritis trials which compared any of the 18 HA products and reported on adverse events and withdrawals. We calculated Odds Ratios for safety data reported at the longest follow-up. Network meta-analysis was performed using a Bayesian hierarchical random effects model for mixed multiple treatment comparisons. RESULTS: We identified 74 studies involving 13,032 participants aged between 45-75 years. The proportion of women ranged from 28% -100%. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported adverse events were transient local reactions, such as pain, swelling and arthralgia, which subsided rapidly. None of the HA products were statistically significantly different from IA placebo or from each other with regard to incidence of adverse events. Three treatment-related serious adverse events were reported among 9,214 participants. CONCLUSIONS: Given the very low incidence of any particular adverse events, we conclude that HA products are relatively well tolerated. These products have a similar safety profile compared to each other. This information along with the comparative effectiveness profile and relative cost would be helpful for clinicians in delivering individualized patient care.

Systematic review

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Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials.

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Journal Annals of internal medicine
Year 2015
Links Pubmed DOI

This article includes 145 Primary studies 147 Primary studies (145 references)

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BACKGROUND: Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials. OBJECTIVE: To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data. STUDY SELECTION: 149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos. DATA EXTRACTION: Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool. DATA SYNTHESIS: Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior. LIMITATIONS: Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos. CONCLUSION: All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Systematic review

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Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: A systematic review and meta-analysis of randomized, saline-controlled trials

Journal Journal of pain research
Year 2015
Links Pubmed DOI PubMed Central

This article is included in 1 Broad synthesis 29 Broad syntheses (1 reference)

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

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Background: Intra-articular injection of hyaluronic acid is a common, yet controversial, therapeutic option for patients with knee osteoarthritis (OA). The purpose of this research was to determine the safety and efficacy of US-approved viscosupplements for symptomatic knee OA. Methods: We searched MedLine and EMBase for randomized, sham-controlled trials evaluating safety and/or clinical efficacy of US-approved viscosupplements in patients with symptomatic knee OA. Knee pain severity and knee joint function were assessed at 4 to 13 weeks and 14 to 26 weeks. Safety outcomes included serious adverse events, treatment-related serious adverse events, patient withdrawal, and adverse event-related patient withdrawal occurring at any time during follow-up. Results: A total of 29 studies representing 4,866 unique patients (active: 2,673, control: 2,193) were included. All sham-controlled trials used saline injections as a control. Viscosupplementation resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to preinjection values, with standardized mean difference values ranging from 1.07 to 1.37 (allP<0.001). Compared to controls, standardized mean difference with viscosupplementation ranged from 0.38 to 0.43 for knee pain and 0.32 to 0.34 for knee function (all P<0.001). There were no statistically significant differences between viscosupplementation and controls for any safety outcome, with absolute risk differences of 0.7% (95% confidence interval [CI]: –0.2 to 1.5%) for serious adverse events, 0% (95% CI: –0.4 to 0.4%) for treatment-related serious adverse events, 0% (95% CI: –1.6 to 1.6%) for patient withdrawal, and 0.2% (95% CI: –0.4 to 0.8%) for adverse event-related patient withdrawal. Conclusion: Intra-articular injection of US-approved viscosupplements is safe and efficacious through 26 weeks in patients with symptomatic knee OA.

Systematic review

Unclassified

Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis.

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Journal Annals of internal medicine
Year 2015
Links Pubmed DOI

This article is included in 1 Broad synthesis 137 Broad syntheses (1 reference)

This article includes 133 Primary studies 137 Primary studies (133 references)

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BACKGROUND: The relative efficacy of available treatments of knee osteoarthritis (OA) must be determined for rational treatment algorithms to be formulated. PURPOSE: To examine the efficacy of treatments of primary knee OA using a network meta-analysis design, which estimates relative effects of all treatments against each other. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, Cochrane Central Register of Controlled Trials from inception through 15 August 2014, and unpublished data. STUDY SELECTION: Randomized trials of adults with knee OA comparing 2 or more of the following: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, intra-articular (IA) corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. DATA EXTRACTION: Two reviewers independently abstracted study data and assessed study quality. Standardized mean differences were calculated for pain, function, and stiffness at 3-month follow-up. DATA SYNTHESIS: Network meta-analysis was performed using a Bayesian random-effects model; 137 studies comprising 33 243 participants were identified. For pain, all interventions significantly outperformed oral placebo, with effect sizes from 0.63 (95% credible interval [CrI], 0.39 to 0.88) for the most efficacious treatment (hyaluronic acid) to 0.18 (CrI, 0.04 to 0.33) for the least efficacious treatment (acetaminophen). For function, all interventions except IA corticosteroids were significantly superior to oral placebo. For stiffness, most of the treatments did not significantly differ from one another. LIMITATION: Lack of long-term data, inadequate reporting of safety data, possible publication bias, and few head-to-head comparisons. CONCLUSION: This method allowed comparison of common treatments of knee OA according to their relative efficacy. Intra-articular treatments were superior to nonsteroidal anti-inflammatory drugs, possibly because of the integrated IA placebo effect. Small but robust differences were observed between active treatments. All treatments except acetaminophen showed clinically significant improvement from baseline pain. This information, along with the safety profiles and relative costs of included treatments, will be helpful for individualized patient care decisions. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Systematic review

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Are intra-articular injections of Hylan G-F 20 efficacious in painful osteoarthritis of the knee? A systematic review & meta-analysis.

Authors Pai SK , Allgar V , Giannoudis PV
Journal International journal of clinical practice
Year 2014
Links Pubmed DOI

This article includes 6 Primary studies 6 Primary studies (6 references)

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AIM: To systematically review evidence and perform a meta-analysis of the efficacy of intra-articular (IA) injections of Hylan G-F 20 for the treatment of painful osteoarthritis (OA) of the knee. METHODS: Systematic review of the Embase and PubMed databases up to July 2013 of randomised placebo-controlled trials studying the effect of Hylan G-F 20 in patients with painful knee OA, with a meta-analysis of trials reporting visual analogue scores (VAS) for weight-bearing pain in the knees of patients followed up for a minimum of 6 months. RESULTS: Six placebo-controlled randomised trials were identified on systematic review of which two studies met criteria for inclusion in the meta-analysis. Meta-analysis demonstrated that at 6-month follow up, there was no significant difference between Hylan G-F 20 and control in terms of reduction in VAS for weight bearing pain. (Mean Difference - 12.96 (95% CI: -35.48, 9.56). Z tests used to test for overall effect showed that the difference between the two groups was not significant (p = 0.26). DISCUSSION: A significant placebo effect exists for patients receiving IA injections for the treatment of painful knee OA. The withdrawal of fluid from the affected knee prior to any injectable therapy may itself have additional benefits which in isolation have not been studied. This may form the basis of future research. The authors' acknowledge that although limited conclusions can be drawn from the results of this study, the meta-analysis presented has not been performed previously and will further contribute to the knowledge on this subject. CONCLUSION: Although Hylan G-F 20 may produce improvement in VAS scores for weight-bearing pain at 6-month follow up in OA knees treated with it, patients should be informed that this may be equivalent to that seen with control treatments.

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

Unclassified

Conflict of interest in the assessment of hyaluronic acid injections for osteoarthritis of the knee: an updated systematic review.

Journal The Journal of arthroplasty
Year 2013
Links Pubmed DOI

This article is included in 1 Broad synthesis 48 Broad syntheses (1 reference)

This article includes 48 Primary studies 48 Primary studies (48 references)

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The search results of a recent systematic review of prospective, randomized, placebo-controlled trials on hyaluronic acid injections for knee arthritis were updated and reviewed for funding source and qualitative conclusions. Forty-eight studies were identified; 30 (62.5%) were industry funded, and 3 (6.25%) were not. Fifteen (31.3%) studies did not identify a funding source. An association was observed between a reported potential financial conflict of interest of the author and the qualitative conclusion (P=0.018). None of the studies with a reported financial conflict of interest of at least one author had an unfavorable conclusion; 11 (35%) of the 31 studies with no industry-affiliated authors indicated that hyaluronic acid injection for knee osteoarthritis was no more effective than a placebo injection.

Systematic review

Unclassified

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
Links Pubmed DOI

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.