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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. © 2017 The Author(s).

Systematic review

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Effectiveness of 3 Weekly Injections Compared With 5 Weekly Injections of Intra-Articular Sodium Hyaluronate on Pain Relief of Knee Osteoarthritis or 3 Weekly Injections of Other Hyaluronan Products: A Systematic Review and Meta-Analysis.

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Journal Archives of Physical Medicine & Rehabilitation
Year 2017
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This article includes 24 Primary studies 24 Primary studies (24 references)

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Objective To investigate whether the number of hyaluronic acid (HA) injections in a sodium hyaluronate (Hyalgan) course of therapy alters effectiveness in reducing knee osteoarthritis (OA) pain. Data Sources Electronic databases, including PubMed and Embase, were searched from January 1980 until November 2015. Study Selection We included clinical studies that evaluated the effectiveness of a course of 3 or 5 weekly intra-articular injections of Hyalgan to treat knee OA pain. We also included clinical studies evaluating the effectiveness of a 3-week course of other Food and Drug Administration–approved HA treatments of knee OA pain. Twenty-four studies were identified, comprising 2168 study participants in 30 treated cohorts. Data Extraction We determined effect sizes for selected studies by extracting knee OA pain scores before and after HA or control treatments. Meta-regressions were implemented to determine whether the number of weekly injections in a course of Hyalgan therapy modified outcomes. Data Synthesis The pooled estimate for relief from baseline pain was −31.4 (SE, 5.46; 95% confidence interval [CI], −45.5 to −17.4) with a 3-week course of Hyalgan and −32.2 (SE, 5.25; 95% CI, −45.6 to −18.7) with a 5-week course of Hyalgan. Findings from the meta-analysis indicate relief of knee OA pain with a 3-week course of Hyalgan is similar to that with a 5-week course of Hyalgan ( P =.916). The pooled estimate for relief from baseline pain with a 3-week course of other HA products was −29.4 (SE, 4.98; 95% CI, −42.2 to −16.6), also indicating pain relief with a 3-week course of Hyalgan is similar to that with a 3-week course of other HA products ( P =.696). Conclusions There was no statistical difference between reduction in knee OA pain with a 3-week course of Hyalgan compared with reduction in knee OA pain with a 5-week course of Hyalgan or a 3-week course of other HA products. These findings demonstrate that comparable knee OA pain relief is achieved with a 3-week course of Hyalgan and the 2 control groups.

Systematic review

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The effectiveness of three weekly injections compared to five weekly injections of intra-articular sodium hyaluronate on pain relief of knee osteoarthritis or three weekly injections of other hyaluronan products: A Systematic Review and Meta-Analysis.

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Journal Archives of physical medicine and rehabilitation
Year 2017
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This article includes 24 Primary studies 24 Primary studies (24 references)

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OBJECTIVE: To investigate whether the number of hyaluronic acid (HA) injections in a Hyalgan(®) course of therapy alters effectiveness in reducing knee osteoarthritis (OA) pain. DATA SOURCES: Electronic databases, including PubMed and EMBase, were searched from January 1980 until November 2015. STUDY SELECTION: We included clinical studies that evaluated the effectiveness of a course of three or five weekly intra-articular injections of Hyalgan to treat knee OA pain. We also included clinical studies evaluating the effectiveness of a three-week course of other FDA-approved HA treatments of knee OA pain. Twenty-four studies were identified, comprising 2,168 study participants in 30 treated cohorts. DATA EXTRACTION: We determined effect sizes for selected studies by extracting knee OA pain scores before and after HA or control treatments. Meta-regressions were implemented to determine whether the number of weekly injections in a course of Hyalgan therapy modified outcomes. DATA SYNTHESIS: The pooled estimate for relief from baseline pain was -31.4 (5.46 SE; 95% confidence interval [CI], -45.5, -17.4) with a three-week course of Hyalgan and -32.2 (5.25; CI, -45.6, -18.7) with a five-week course of Hyalgan. Findings from the meta-analysis indicate relief of knee OA pain with a three-week course of Hyalgan is similar to that with a five-week course of Hyalgan (P = .916). The pooled estimate for relief from baseline pain with a three-week course of other HA products was -29.4 (4.98; CI, -42.2, -16.6), also indicating pain relief with a three-week course of Hyalgan is similar to that with a three-week course of other HA products (P = .696). CONCLUSIONS: There was no statistical difference between reduction in knee OA pain with a three-week course of Hyalgan compared to reduction in knee OA pain with a five-week course of Hyalgan or a three-week course of other HA products. These findings demonstrate that comparable knee OA pain relief is achieved with a three-week course of Hyalgan and the two control groups.

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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Product Differences in Intra-articular Hyaluronic Acids for Osteoarthritis of the Knee.

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Journal The American journal of sports medicine
Year 2016
Links Pubmed DOI

This article includes 68 Primary studies 68 Primary studies (68 references)

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BACKGROUND: Knee osteoarthritis (OA) is a common and often disabling joint disorder among adults that may result in impaired activity and daily function. A variety of treatment options are currently available and prescribed for knee OA depending on the severity of the disorder and physician preference. Intra-articular hyaluronic acid (IA-HA) injection is a treatment for knee OA that reportedly provides numerous biochemical and biological benefits, including shock absorption, chondroprotection, and anti-inflammatory effects within the knee. Clarity is needed as to whether the available IA-HA products should be considered for therapy as a group or whether there are significant differences in the products that need to be considered in treatment of OA of the knee. PURPOSE: To determine whether there are differences in efficacy and safety with respect to intrinsic properties of available IA-HA injections for knee OA. STUDY DESIGN: Meta-analysis. METHODS: A comprehensive literature search of the Medline, EMBASE, and PubMed databases was conducted for all existing randomized trials of IA-HA. The primary outcome measure analyzed was the mean pain score at the reported follow-up nearest to 26 weeks after injection. Pooled efficacy and safety results were recorded for subgroupings of HA product characteristics. RESULTS: A total of 68 studies were included for analysis. Products with an average molecular weight ≥3000 kDa provided favorable efficacy results when compared with products of an average molecular weight <3000 kDa. Products with a molecular weight ≥3000 kDa demonstrated significantly fewer discontinuations due to treatment-related adverse events than did ≤1500 kDa counterparts, while trial discontinuation rates were similar between biological fermentation-derived HA products and avian-derived HA. The results did not demonstrate a significant difference in the occurrence of effusion across molecular weight subgroups. Additionally, biological fermentation-derived HA had a significantly smaller incidence of effusion than did avian-derived HA. Biological fermentation-derived HA demonstrated fewer acute flare-ups at the injection site than did avian-derived HA products, while high-molecular-weight products demonstrated the highest rate of injection site flare-up. CONCLUSION: Despite similarities, IA-HA products should not be treated as a group, as there are differences in IA-HA products that influence both efficacy and safety. In the available literature, IA-HA products with a molecular weight ≥3000 kDa and those derived from biological fermentation relate to superior efficacy and safety-factors that may influence selection an IA-HA product for OA of the knee.

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 Non-Steroidal Antiinflammatory Drugs (NSAIDs) and opioids for knee osteoarthritis (OA). 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 OA trials which compared any of the 18 HA products and reported on adverse events (AEs) 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 and 75 years. The proportion of women ranged from 28% to 100%. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported AEs 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 AEs. Three treatment-related serious adverse events (SAEs) were reported among 9214 participants. Conclusions Given the very low incidence of any particular AEs, 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. © 2016 Osteoarthritis Research Society International

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

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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 antiinflammatory 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. © 2015 American College of Physicians.

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
Links Pubmed DOI

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.