title: Hyaluronic acid and other conservative treatment options for osteoarthritis of the ankle.
abstract: BACKGROUND
  The cause of ankle osteoarthritis (OA) is usually trauma. Patients are relatively young, since ankle trauma occurs at a relatively young age. Several conservative treatment options are available, evidence of the benefits and harms of these options are lacking.
  
  
  OBJECTIVE
  To assess the benefits and harms of any conservative treatment for ankle OA in adults in order to provide a synthesis of the evidence as a base for future treatment guidelines.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, issue 9), MEDLINE (Ovid) (1946 up to 11 September 2014), EMBASE (1947 to September 2014), PsycINFO (1806 to September 2014), CINAHL (1985 to September 2014), PEDro (all years till September 2014), AMED until September 2014, ClinicalTrials.gov, Current Controlled Trials, The Dutch Register. To identify potentially relevant studies we screened reference lists in retrieved review articles and trials.
  
  
  METHODS
  We considered randomised or controlled clinical trials investigating any non-surgical intervention for ankle OA for inclusion.
  
  
  METHODS
  We used standard methodological procedures expected by Cochrane.
  
  
  RESULTS
  No other RCT concerning any other conservative treatment besides the use of hyaluronic acid (HA) for ankle OA was identified. Six randomised controlled trials (RCTs) were included.A total of 240 participants diagnosed with ankle OA were included in this review. The primary analysis included three RCTs (109 participants) which compared HA to placebo. One study compared HA to exercise therapy, one compared HA combined with exercise therapy to an intra-articular injection of botulinum toxin and one compared four different dosages of HA.Primary analysis: a pooled analysis of two trials (45 participants) found that the Ankle Osteoarthritis Scale (AOS) total score (measuring pain and physical function) was reduced by 12% (95% CI -24% to -1%) at six months (mean difference (MD) -12.53 (95% CI -23.84 to -1.22) on a scale of 0 to 100; number needed to treat for an additional beneficial outcome (NNTB) = 4 (95% CI 2 to 205); this evidence was graded as low quality, due to limitations in study design (unclear risk of selection bias for two studies and unclear risk for attrition bias for one study) and imprecision of results: a small population size (45 participants). It is not known if a mean difference of 12.53 points on a 100 point scale is clinically relevant. No minimal important clinical difference is known for this score. Pain and function outcomes were not reported separately. Radiographic joint structure changes were not investigated. For the mean quality of life at six months (two trials; 45 participants) no meta-analysis could be performed due to missing data. No serious adverse events (SAEs) were noted and no participants withdrew because of an adverse event. There were a few adverse events (AEs) 5/63 (8%) in the HA group and 2/46 (4%) in the placebo group. The Peto odds ratio (Peto OR) to have an adverse event was 2.34 higher compared to the control group (95% CI 0.45 to 12.11). This evidence is inconclusive because of a wide CI and a small number of events.For comparing HA to exercise therapy (30 participants) the results for pain on a Visual Analogue Scale (VAS 0 to 10) at 12 months are inconclusive (MD 0.70, 95% CI -2.54 to 1.14). The American Orthopedic Foot and Ankle Society score (AOFAS score) was 13.10 points (MD) higher in favour of HA (95% CI 2.97 to 23.23) on a scale of 0 to 100. The evidence was graded as low. No adverse events were found. Radiographic structure changes were not measured; no participants withdrew due to AEs; no SAEs were found.For the comparison of HA injection combined with exercise therapy to an intra-articular injection of botulinum toxin A (BoNT-A) (75 participants), the outcome of the AOS pain score of the affected joint at six months is inconclusive (MD 0.10, 95% CI -0.42 to 0.62). The physical function (the AOS disability score) at six months is inconclusive (MD 0.20, 95% CI -0.34 to 0.74). The same number of AEs were found in both groups; HA 2/37 (5.9%), BoNT-A 2/38 (5.8%) (risk ratio (RR) 1.03, 95% CI 0.15 to 6.91). Radiographic changes were not examined, no SAEs were found and no participants withdrew because of an AE. The evidence was graded as low.The RCT comparing four different dosing schedules for HA (26 participants) showed the best median decrease in pain on walking VAS (on a scale of 0 to 100) for 3 x 1 ml at 27 weeks with a median decrease of 30. Physical function, radiographic changes and quality of life were not measured.Twenty-seven percent of all participants had AEs, most of them in the 2ml group (57% in this group). No participants withdrew due to an AE and no SAEs were noted.Overall the quality of the evidence showed some serious limitations. The evidence was graded low for the primary analysis comparing HA to placebo. This was based on a limitation in design and implementation: sample sizes were small (45 to 92 participants) and and imprecision in results: there was an unclear risk of bias for several items concerning the three studies used in the meta analysis.
  
  
  CONCLUSIONS
  Currently, there is insufficient data to create a synthesis of the evidence as a base for future guidelines for ankle OA. Since the aetiology of ankle OA is different, guidelines that are currently used for hip and knee OA may not be applicable for ankle OA. Simple analgesics as recommended for hip and knee OA seem however a reasonable first step to treat ankle OA. It is unclear if there is a benefit or harm for HA as treatment for ankle OA compared to placebo at six months based on a low quality of evidence. Inconclusive results were found comparing HA to other treatments. HA can be conditionally recommended if patients have an inadequate response to simple analgesics. It remains unclear which patients (age, grade of ankle OA) benefit the most from HA injections and which dosage schedule should be used.
authors.affiliation: Department of Orthopaedic Surgery, St Maartenskliniek, Hengstdal 3, Nijmegen, Netherlands, 6522JV.
authors.forename: Angelique G H
authors.initials: AG
authors.lastname: Witteveen
authors.forename: Cheriel J
authors.initials: CJ
authors.lastname: Hofstad
authors.forename: Gino M M J
authors.initials: GM
authors.lastname: Kerkhoffs
mesh_terms: D000843:Ankle Joint; D001905:Botulinum Toxins / Q000627:therapeutic use; D005081:Exercise Therapy; D006801:Humans; D006820:Hyaluronic Acid / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D010003:Osteoarthritis / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D055675:Viscosupplements / Q000627:therapeutic use*
chemical_list: D055675:Viscosupplements; D006820:Hyaluronic Acid; D001905:Botulinum Toxins