title: Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials.
abstract: The aim was to identify factors explaining inconsistent observations concerning the efficacy of intra-articular hyaluronic acid compared to intra-articular sham/control, or non-intervention control, in patients with symptomatic osteoarthritis, based on randomized clinical trials (RCTs).
  
  
  
  A systematic review and meta-regression analyses of available randomized trials were conducted. The outcome, pain, was assessed according to a pre-specified hierarchy of potentially available outcomes. Hedges׳s standardized mean difference [SMD (95% CI)] served as effect size. REstricted Maximum Likelihood (REML) mixed-effects models were used to combine study results, and heterogeneity was calculated and interpreted as Tau-squared and I-squared, respectively.
  
  
  
  Overall, 99 studies (14,804 patients) met the inclusion criteria: Of these, only 71 studies (72%), including 85 comparisons (11,216 patients), had adequate data available for inclusion in the primary meta-analysis. Overall, compared with placebo, intra-articular hyaluronic acid reduced pain with an effect size of -0.39 [-0.47 to -0.31; P < 0.001], combining very heterogeneous trial findings (I(2) = 73%). The three most important covariates in reducing heterogeneity were overall risk of bias, blinding of personnel and trial size, reducing heterogeneity with 26%, 26%, and 25%, respectively (Interaction: P ≤ 0.001). Adjusting for publication/selective outcome reporting bias (by imputing "null effects") in 24 of the comparisons with no data available reduced the combined estimate to -0.30 [-0.36 to -0.23; P < 0.001] still in favor of hyaluronic acid.
  
  
  
  Based on available trial data, intra-articular hyaluronic acid showed a better effect than intra-articular saline on pain reduction in osteoarthritis. Publication bias and the risk of selective outcome reporting suggest only small clinical effect compared to saline.
authors.affiliation: The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospitaler, Nordre Fasanvej 57, DK-2000, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Johansen
authors.affiliation: The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospitaler, Nordre Fasanvej 57, DK-2000, Copenhagen, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Bahrt
authors.affiliation: Division of Rheumatology and Immunology, David Geffen School of Medicine, University of California, Los Angeles, CA 90024.
authors.forename: Roy D
authors.initials: RD
authors.lastname: Altman
authors.affiliation: The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospitaler, Nordre Fasanvej 57, DK-2000, Copenhagen, Denmark.
authors.forename: Else M
authors.initials: EM
authors.lastname: Bartels
authors.affiliation: Department of Sports Science and Clinical Biomechanics, SEARCH, Research Unit for Muscusloskeletal Function and Physiotherapy, University of Southern Denmark, Odense, Denmark; Department of Orthopedics, Copenhagen University Hospital, Herlev and Gentofte Hospitaler, Copenhagen, Denmark.
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Juhl
authors.affiliation: The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospitaler, Nordre Fasanvej 57, DK-2000, Copenhagen, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Bliddal
authors.affiliation: Department of Sports Science and Clinical Biomechanics, SEARCH, Research Unit for Muscusloskeletal Function and Physiotherapy, University of Southern Denmark, Odense, Denmark; Centre for Evidence-Based Practice, Bergen University College, Bergen, Norway.
authors.forename: Hans
authors.initials: H
authors.lastname: Lund
authors.affiliation: The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospitaler, Nordre Fasanvej 57, DK-2000, Copenhagen, Denmark. Electronic address: Robin.Christensen@regionh.dk.
authors.forename: Robin
authors.initials: R
authors.lastname: Christensen
mesh_terms: D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D020370:Osteoarthritis, Knee / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D016896:Treatment Outcome
chemical_list: D006820:Hyaluronic Acid
keywords: Bias; Efficacy; Hyaluronic acid; Inconsistency; Osteoarthritis; Pain