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

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.

the effect of intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee. In contrast to 2 previous metaanalyses on this subject, 8,9 we used a different approach to data synthesis and interpretation: instead of analyzing a composite effect size over time, we allocated trial data, when possible, to 3 outcome groups that we assumed would be relevant for patients with osteoarthritis. We specifically looked at pain at rest, pain during exercise and joint function as distinct outcomes, measured repeatedly over time. In addition, we assessed adverse events and the impact of both trial quality and molecular mass of the product. This analysis allows us to provide important additional insight into the effects of intra-articular administration of hyaluronic acid for the treatment of osteoarthritis of the knee.

Methods
We identified all randomized controlled trials comparing various preparations of hyaluronic acid with placebo in patients with osteoarthritis. We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004. The search string was [(osteoarthritis) or (degenerative arthritis) or (gonarthrosis) or (knee near arthralgia) or (knee near pain) or (patella near pain) or (patellofemoral near pain) or (patello near femoral pain) or (retropatellar near pain) or (femoropatellar near pain) or (femoro-patellar near pain)] and [(hyaluronan) or (hyaluronate) or (viscosupplementation) or (visco near supplementation) or (hyaluronic acid)]. For the MEDLINE and EMBASE searches we used validated search terms to identify randomized controlled trials (see Appendix 1). 10, 11 We predefined a variety of clinical outcomes: pain at rest, pain during or immediately after movement, joint function and adverse events. We also predefined time points of assessment in broad categories: 2-6 weeks, 10-14 weeks, 22-30 weeks and 44-60 weeks.
Two reviewers (J.A. and P.M.) independently abstracted data from each trial and entered the data on a predefined form. We compared the results and resolved disagreement by discussion among 3 reviewers (J.A., P.M., M.M.).
We determined whether concealment of allocation to treatment was reported, the degree of blinding (doctor blinded to the intervention, patient blinded to the intervention, assessor of the end point blinded to the intervention) and whether an intentionto-treat analysis was reported.
We extracted estimates of the effect of the intervention and its variance from the figures in the article, if these values were not explicitly reported in the text or tables. If a trial did not report measures of variability, we calculated them from p values or confidence intervals. For one trial 12 we took the median to be representative of the mean and converted the interquartile range into a standard deviation by dividing it by 1.35. 13 With one exception, all trials with data that could be extracted for quantitative analysis reported on loss to follow-up.
We used random-effects models to pool the data. Continuous outcomes were combined by either weighted mean differences or standardized mean differences, as appropriate. 13 We used summary risk ratios to combine adverse events. We calculated 95% confidence intervals (CIs) for all point estimates.
We used Cochrane's Q for heterogeneity, together with the resulting degrees of freedom (df), to calculate the proportion of variation due to unexplained heterogeneity: I 2 = (Q -df)/Q. 14 A value of less than 20% is consistent with little variability between studies, and 20% to 50% can be considered to represent a moderately large degree of variation. Regression methods were used to assess the presence of publication bias. 15 We used multivariate meta-regression analysis to assess whether an effect had been influenced by allocation concealment (blinding of randomization, yes versus no or unclear), blinded outcome assessment (blinded treating physician, patient and outcome assessor, explicitly reported versus not explicitly reported or unclear) and intention-to-treat analysis (explicitly reported versus not explicitly reported or unclear). We repeated the analyses for only those trials that fulfilled all 3 criteria.
We assessed the impact of the molecular mass of the hyaluronic acid on efficacy. We used molecular mass as an ordinal category and then collapsed categories of molecular mass into 2 categories (≤ 900 kDa and > 900 kDa) and repeated the analysis.

Results
The electronic search of databases resulted in 1159 hits, and we retrieved 42 publications for closer inspection (Fig. 1). Of these, 24 studies were potentially eligible. 12, The clinical and methodologic characteristics of the trials that reported at least one of the end points of interest are presented in Table 1 and Table 2.

Pain at rest
Eight trials (with a total of 10 comparisons) reported reduction of pain at rest for the treatment group (n = 231) relative to the control group (n = 237) at 2-6 weeks. 12,17,20,21,[24][25][26]31 Unexplained statistical heterogeneity was excessive (I 2 = 94%), and we could not identify a particular trial causing this excess variability (Fig. 2). Pooling in the face of such a high degree of heterogeneity of unknown cause is not advisable. If the data were pooled, the mean difference in the visual analogue scale was in favour of hyaluronic acid (-8.7 mm, 95% CI -17.2 to -0.2 mm, p = 0.046) ( Table 3). For trials in which allocation concealment was unclear or there was no intention-to-treat analysis, the effect was overestimated by 15.6 mm (95% CI -3.2 to 34.4, p = 0.11). For trials in which outcome assessment was not blinded, the effect was also overestimated, by 13.6 mm (95% CI -0.6 to 27.7, p = 0.06).
Two high-quality trials 12,33 assessed pain at rest at 10-14 and 22-30 weeks, and 2 trials (1 of which was of high quality) 12,24 at 44-60 weeks; there were no significant effects at these time points (Table 3).

Pain during or immediately after exercise
Nine trials (with a total of 10 comparisons) reported pain reduction in the treatment group (n = 559) relative to the control group (n = 582) at 2-6 weeks. 16,[19][20][21]24,[26][27][28]31 The weighted mean difference was -3.8 mm on the visual analogue scale (95% CI -9.1 to 1.4 mm, p = 0.15) ( Table 3). Again, there was an excessive degree of unexplained statistical heterogeneity (I 2 = 81%). One trial had a qualitative interaction: among patients with less severe osteoarthritis (Kellgren and Lawrence grades I and II 39 ), those who received hyaluronic acid had better pain reduction than those who received placebo; however, among patients with more advanced disease (grades III and IV), pain increased with hyaluronic acid. 26 When this trial was excluded, the effect remained largely unchanged (weighted mean difference -4.2 mm), although the precision was higher (95% CI -7.5 to -0.8 mm, p = 0.015), and heterogeneity was acceptable (I 2 = 20%).
Only one trial followed patients until 44-60 weeks (47 intervention patients, 48 control patients), 24 and it showed no effect (Table 3).
Trial quality had no undue influence on the effect size at any point, but only one trial 33 was of high quality.

Joint function
Nine trials reported a measure of joint function at 2-6 weeks (489 intervention patients, 505 control patients). 12,18,[20][21][22]24,27,31,32 Because different measurement systems were used in these trials, we calculated standardized effects. The standardized weighted mean difference between the groups at 2-6 weeks was 0.00 (95% CI -0.23 to 0.23, p = 0.99) (Fig. 4A). There was a high degree of unexplained statistical heterogeneity (I 2 = 66%). Even though there was no statistically significant pooled effect, unclear or absent allocation concealment led to considerable inflation of the effect (by 2.6 points on the z score, 95% CI 1.2 to 3.9, p < 0.001). Other measures of quality did not influence the effect size.
Six trials (with a total of 7 comparisons) reported data on function at 10-14 weeks (533 intervention patients, 490 control patients). 12,18,22,27,29,32 The standardized weighted mean difference between the groups was -0.11 (95% CI -0.31 to 0.09, p = 0.28) (Fig. 4B). Heterogeneity was considerable (I 2 = 59%), but there were no obvious differences in study or patient characteristics that would explain this high degree of heterogeneity. Unclear or absent allocation concealment led to considerable inflation of the summary effect (by 3.0 points on the z score, 95% CI 1.1 to 4.9, p < 0.001). Other measures of quality did not influence the effect size.
Data from 22-30 weeks were available for 4 trials (with a total of 5 comparisons) (295 intervention patients, 247     †Binary data other than from adverse events could not be used for analysis.  *Continuous data are given as mean (standard deviation) except where indicated. †Continuous data are given as mean (standard error). ‡Continuous data are given as mean (range). §Data not presented as mean (standard deviation), mean (standard error), or mean (range). ¶No detailed data available for treatment and control groups.

Impact of molecular mass
The effect size is ordered in Fig. 2, Fig. 3 and Fig. 4 according to molecular mass, but no clear association is evi-dent. This lack of association was confirmed by the metaregression analyses.

Sensitivity analysis
We repeated the analyses for pain at rest, pain after movement and joint function at 2-6 weeks and 10-14 weeks for only those trials that reported allocation concealment, blinded outcome assessment and intention-to-treat analysis. There was no significant effect in favour of the intervention (Table 4).

Interpretation
The methodologic quality of most of the trials was poor. Treatment with intra-articular hyaluronic acid did not have a proven beneficial effect on osteoarthritis pain at rest. Pain during or after movement was slightly lower relative to placebo, but this effect is of borderline clinical relevance at best. Moreover, the effect appears to have been inflated by trials of low methodologic quality. Intra-articular hyaluronic acid did not lead to improvement in joint function but may have been associated with a higher rate of side effects than placebo.
Patients with chronic rheumatoid arthritis rated pain as "somewhat better" at a mean difference of 8 mm on a visual analogue scale and as "much better" at a 15-mm difference. 40 The summary estimates obtained in this metaanalysis fell short of being the difference defined as "somewhat better," and the confidence intervals sometimes

Favours intervention
Favours placebo included the range defined as "much better"; however, the latter were also compatible with increased pain. This finding was augmented by the sensitivity analyses, where the confidence intervals barely exceeded 15 mm (Table 4).
In several instances, only a few trials were available for a given end point at a particular time. A more significant problem, however, was the low methodologic reporting quality of the trials. Low-quality trials, particularly those    Data are presented as weighted mean difference for each study (boxes), 95% CIs (horizontal lines) and summary weighted mean difference with 95% CI (diamond). The trials are ranked according to the molecular mass of the hyaluronic acid preparation. A not reporting allocation concealment and those not reporting blinding, are known to favour interventions. 15,[41][42][43][44] Our data are compatible with these findings.
Another problem is the wide range of reported end points. We tried to compose clinically useful and comparable outcome categories for the trials. Within our selection algorithm we planned to categorize all reported end points (a total of 125) into 12 categories and to discard end points that could not be allocated. We analyzed only 4 of these 12 categories (the most relevant from a clinical perspective). The remaining 8 categories were global pain, pain on touch, joint effusion, joint stiffness, quality of life, pain medication, overall assessment by patient and overall assessment by observer.
Only 2 papers were excluded because there was no abstract available in English or German. From their titles, it was doubtful that these were randomized controlled trials, but we could not confirm study type. Including non-English studies and unpublished studies in a meta-analysis may even introduce bias. 43,45 It is difficult to determine the trade-off between detecting all of the available evidence and introducing bias through inclusion of inferior studies identified by a comprehensive search. 45 We applied multiple statistical tests, and a type 1 errordetecting an effect where none existed -is possible. This possibility should be borne in mind when interpreting the data.
Finally, there were only a limited number of trials for each end point and time point, which led to wide confidence intervals. Even so, the limits did not exceed a clinically meaningful difference in many instances. We could not detect publication bias (data not shown) except perhaps with regard to adverse event reporting. This does not necessarily exclude the possibility of such bias, but if there was any selection or publication bias, it would probably have exaggerated the effect.
We are aware of 3 relevant systematic reviews. 8,9,46 One of these was an update of the EULAR recommendations for management of knee osteoarthritis. 46 The literature search for that review was systematic, but it covered only 2 databases (MEDLINE and EMBASE). A summary quality score was used, and the median score was 20 out of 28. This high score is surprising, considering that the standard of reporting for the 3 most important items was poor. 41 Perhaps the high scores were the result of summing indi-vidual items. The use of such scores, however, is not advisable. 47 The task force that prepared the EULAR update 46 did not perform a quantitative summary but counted the number of positive trials, an approach that may be misleading. 48 The authors' conclusion that "there is evidence to support the efficacy of HA [hyaluronic acid]" is not, in our opinion, well supported by the information presented.
The second systematic review and meta-analysis 8 covered the same search period as ours. Lo and associates 8 chose a hierarchy of relevant end points and selected the highest-ranking end point in each trial. The time of assessment was 2-3 months, but if data for this time point were not available, data were extracted on pain at 1-4 months after the first intra-articular injection. This creative approach may lump together end points that are only weakly related. The authors also extracted data on change from baseline, choosing not to rely on the assumption that the groups were comparable before treatment began. Indeed, for 2 trials 24,26 the groups were not comparable at baseline. Nevertheless, trials are usually designed for simple betweengroup comparisons. Using such a change score might reduce the power or precision of an individual study. 49 The trials included in the analysis of Lo and associates 8 differed slightly from those in our analysis: we identified and included 4 published studies 17,19,25,38 not used by Lo and associates, whereas those authors included 3 studies that we did not (2 published only as abstracts 50,51 and 1 in which the patient's other knee served as the control [i.e., observations may not be independent] 52 ). Lo and associates concluded that at best there is a small effect. Unsurprisingly, their findings were similar to the results of our meta-analysis.
The third systematic review and meta-analysis 9 was published recently, but the search included only studies published up to 2001. Wang and colleagues 9 used 3 end points to calculate "efficacy scores," standardizing for different pain measures and summing efficacy scores over time. This approach transforms scores to a palatable size but makes clinical inferences very difficult. It is questionable if combining data from trials of highly variable length is reasonable. We found 7 additional studies, 12,19,22,28,29,31,33   adverse events. Even though some of their reported results were of statistical significance, they were certainly not of clinical relevance. Experimental studies and animal studies suggest that the molecular mass of hyaluronic acid may affect pain and the underlying inflammatory mechanisms in osteoarthritis. 2, 53 Lo and associates 8 observed that studies using the highest-molecular-weight hyaluronic acid had much greater effect sizes but also exhibited crucial heterogeneity, but another trial found no significant difference in clinical efficacy between 2 hyaluronic acid preparations. 29 We observed no association between molecular mass and effect of hyaluronic acid by informal methods (ranking the effects) or formal methods for indirect comparisons (meta-regression analysis).
The currently available evidence suggests that intraarticular hyaluronic acid is not clinically effective and may be associated with increased risk of adverse events. Therefore, this type of therapy should not be used for the treatment of painful osteoarthritis (except in clinical trials) until a large long-term trial with clinically relevant and uniform end points has clarified the benefit-risk ratio. Using predefined clinically important differences could further help in the assessment of its value for patients with knee osteoarthritis. Such an approach is of particular importance when considering the public health impact of the disease and its treatment.