Viscosupplementation

Effectiveness and Harms in Primary OA of the Knee. Results from 42 trials (N=5,843), all but one synthesized in various combinations in six meta-analyses, generally show positive effects of viscosupplementation on pain and function scores compared to placebo. However, the evidence on viscosupplementation is accompanied by considerable uncertainty due to variable trial quality, potential publication bias, and unclear clinical significance of the changes reported.

The pooled effects from poor quality trials were as much as twice those obtained from higher quality ones. Pooled results from small trials (≤100 patients) showed effects up to twice those of larger trials, a finding consistent with selective publication of underpowered positive trials. Among trials of viscosupplementation, those that have not been published in full text comprise approximately 25 percent of the total patient population.

Most RCTs reported results as mean changes in pain and function. Interpreting the clinical significance of pooled mean effects from the meta-analyses is difficult; mean changes do not quantify proportions responding. Numbers needed to treat cannot be calculated from mean changes. It would be more informative to report response rate, i.e., comparison of the proportion of patients achieving a clinically important improvement.

Trials of hylan G-F 20, the highest molecular weight cross-linked product, generally reported larger effects than other trials.

Minor adverse events accompanying intra-articular injections are common, but the relative risk accompanying hyaluronan injections over placebo appears to be small. Pseudoseptic reactions associated with hyaluronans appear relatively uncommon, but can be severe.

Differences in Outcomes Among Subpopulations. Four RCTs were identified examining any of the specified subgroups. None examined race/ethnicity, disease duration, or prior treatment. In one trial, randomization was stratified by disease severity; all other subgroup results were obtained in post-hoc analyses. There was no evidence for differential effects according to subgroups defined by age, sex, primary/disease, body mass index/weight, or disease severity. One positive post-hoc subgroup analysis found greater efficacy among older individuals with more severe disease, but was not confirmed in a subsequent trial.

Glucosamine, Chondroitin, Alone or in Combination

Effectiveness and Harms in Primary OA of the Knee. The best evidence comes from the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT; Clegg, Reda, Harris, et al., 2006), a large (n=1,583), good quality, NIH-funded, multicenter RCT. GAIT compared glucosamine hydrochloride, chondroitin sulfate, or the combination of these agents, with placebo or celecoxib in patients with primary osteoarthritis of the knee. After 24 weeks of treatment, intention-to-treat analysis showed no significant difference in symptomatic relief between glucosamine hydrochloride, chondroitin sulfate, or glucosamine hydrochloride plus chondroitin sulfate compared to placebo. Substantiating this result was that celecoxib, the active control, was effective.

Six study-level meta-analyses (MAs) assessed glucosamine or chondroitin in OA of the knee. All but one of the MAs reported statistically significant differences between treatment and placebo. However, these MAs had limitations in the quality of the primary studies that were pooled. Limitations of the primary literature included small study size, inclusion of studies that assessed joints other than knee, and failure to report intent to treat analysis. In general, the MAs did not perform adequate quality appraisal of the primary studies.

Glucosamine sulfate has been reported to be more effective than glucosamine hydrochloride, however, the evidence is not sufficient to draw conclusions. A subgroup analysis in the largest MA (Towheed, Maxwell, Anastassiades, et al., 2006) significantly favored glucosamine sulfate. The results of GUIDE (Herrero-Beaumont, Roman, Trabado, et al., 2007), a European placebo-controlled RCT (n=318), sponsored by Rotta, a glucosamine sulfate manufacturer, report favorable results for glucosamine sulfate. While the overall results of GAIT show no benefit, in the subgroup of knee OA patients with moderate-to-severe pain at baseline, the combination of glucosamine hydrochloride and chondroitin sulfate significantly improved pain. Together, this evidence suggests an independent trial of glucosamine sulfate would be useful to definitively establish whether there is benefit.

In general, adverse events with glucosamine or chondroitin treatment were no greater than placebo. There has been some concern from in vitro and preclinical studies that glucosamine supplementation could have a deleterious effect on glucose metabolism and glycemic control. However, available clinical studies are short-term, or if longer (e.g., 3 years), excluded patients with metabolic disorders.

Differences in Outcomes Among Subpopulations. GAIT found that glucosamine plus chondroitin produced a statistically and clinically significant improvement of pain in patients with moderate-to-severe OA of the knee. Although the effect of celecoxib treatment in a similar group of patients was not statistically significant, the magnitude and direction of the response were consistent with clinical benefit. The nonsignificant statistical result in the celecoxib arm may be a function of insufficient power due to the small number of patients. Although this subgroup analysis was not explicitly prespecified in the GAIT protocol, the stratified randomization by disease severity yields statistically valid comparisons. A trial of glucosamine sulfate would be useful to definitively establish whether there is benefit.

Arthroscopic Lavage and Debridement

Effectiveness and Harms in Patients With Primary OA. The best available evidence, a single placebo-controlled RCT, found arthroscopic lavage with or without debridement was not superior to placebo. The evidence base does not definitively show that arthroscopy is no more effective than placebo. However, additional high-quality RCTs would be necessary to refute the existing trial, which suggests equivalence between placebo and arthroscopy.

No other study besides Moseley, O'Malley, Petersen, et al. (2002) addressed the potential contribution of placebo effects to apparent improvement in outcome after arthroscopy. The primary limitations of the Moseley, O'Malley, Petersen, et al. (2002) trial are lack of details describing the patient sample, the use of a single surgeon, and enrollment of patients at a single Veterans Affairs Medical Center. These concerns call into question the generalizability of this trial's findings. Since OA of the knee affects a large population, uncertainty about arthroscopy's effectiveness should be resolved with further well-conducted and well-reported RCTs.

Major methodologic shortcomings in non-placebo RCTs, an administrative database analysis and case series preclude resolution of uncertainties raised by the trial of Moseley, O'Malley, Petersen, et al. (2002).

Evidence on the harms after arthroscopic lavage and debridement comes primarily from an administrative database analysis and case series reports. Potential harms include infection, prolonged drainage from arthroscopic portals, effusion, hemarthrosis and deep vein thrombosis. To determine whether the risk of such harms is acceptable, it is important to establish whether the effectiveness of arthroscopic lavage and debridement surpasses placebo.

Differences in Outcome Among Subpopulations. Subgroup analyses for mechanical symptoms, alignment and OA stage were performed in the Moseley placebo-controlled RCT. No differences in results were observed within subgroups. Subgroup analyses were also performed in a quasi-experimental study, an administrative database and several case series. In these studies, different outcomes were observed according to age, presence of mechanical symptoms, and severity of OA. However, since these studies did not include placebo controls, it cannot be concluded that arthroscopy has greater effectiveness in specific patient subgroups.

All Interventions

Effectiveness and Harms in Secondary OA of the Knee. We identified no studies that enrolled patients with only secondary OA of the knee, or that reported separately on secondary OA of the knee.

Comparison of Interventions. We did not find any direct comparative studies in which glucosamine, chondroitin, or glucosamine plus chondroitin were compared with arthroscopy or viscosupplementation to treat OA of the knee. A single, small, underpowered, poor quality trial found no difference in outcome measures comparing intra-articular hyaluronan to arthroscopy and debridement over a 1-year followup.

Discussion and Future Research

OA of the knee is a common condition and the three interventions reviewed in this report are widely used in the treatment of OA of the knee. Yet the best available evidence reports that glucosamine/chondroitin and arthroscopic surgery are no more effective than placebo. The Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) (n=1,583) found that neither glucosamine hydrochloride, chondroitin sulfate nor the combination was superior to placebo and that all were inferior to celecoxib. The double blind randomized controlled trial by Moseley, O'Malley, Petersen, et al. (2002, n=180) found that arthroscopic lavage with or without debridement was not superior to sham arthroscopy. Results from 42 RCTs, all but one of which were synthesized in various combinations in six meta-analyses, generally show positive effects of viscosupplementation on pain and function scores compared to placebo. However, the evidence on viscosupplementation is accompanied by considerable uncertainty due to variable trial quality, potential publication bias, and unclear clinical significance of the changes reported.

For viscosupplementation, higher-quality trials are in the minority and show smaller effects; there are numerous patients lost to follow-up, and a substantial portion of studies (25 percent of total patients) have not been published as full articles. The clinical significance of reported changes in pain and function scores is uncertain, as almost all studies compare only mean difference between arms. Although the overall pooled estimate suggests that hylan G-F 20 may have a larger effect than other hyaluronans, whether this represents a meaningful clinical effect or limitations in the quality and completeness of study reporting is unknown. A rigorous RCT that showed strong evidence of improvement in pain and function would be necessary to conclude that viscosupplementation is beneficial.

While the overall results of GAIT show no benefit, a subgroup analysis found that the combination of glucosamine hydrochloride and chondroitin sulfate significantly improved pain in patients with moderate-to-severe OA of the knee. Although this subgroup analysis was not explicitly prespecified in the GAIT protocol, the stratified randomization by disease severity yields statistically valid comparisons. The nonsignificant statistical result in the celecoxib arm in the same patient subgroup may be a function of insufficient power. Given the small number of patients in the moderate-to-severe subgroup, and the large number of such patients in the general population, a further trial can be justified. However, these subgroup results do not override the overall results of GAIT, which must stand unless confirmed in a rigorous RCT.

The existing evidence does not definitively show that arthroscopic lavage with or without debridement is no more effective than placebo. However, additional placebo-controlled RCTs showing clinically significant advantage for arthroscopy would be necessary to refute the Moseley results, which show equivalence between placebo and arthroscopy. The recently published Spine Patient Outcomes Research Trial (SPORT) offers an alternative study design that could be informative, a rigorous RCT comparing surgery to conservative management, rather than sham (Weinstein, Tosteson, Lurie, et al., 2006).

Overall, our recommendations for future research reach beyond the specific treatments addressed in this report, and are intended broadly to improve the quality of research and reporting on interventions for osteoarthritis of the knee. However, our population is aging, there is increasing prevalence of obesity, and increasing burden of knee osteoarthritis, together with inconsistent evidence regarding disease treatments. Given the public health impact, research on new approaches to prevention and treatment should be given high priority.

Minimally Clinically Important Improvement in Pain and Function Should be the Measure of Success for All Trials. Clinically meaningful results require outcome measures establishing that patients experience improvement that is important to them—meaningful clinically important improvement. The range of magnitude of improvement clinically important to patients has been estimated for VAS pain and WOMAC measures, while to a lesser degree for the Lequesne Index (see Methods). Common measures and intervals for measurement will produce a more robust body of cumulative evidence and improve the ability to compare and pool results among trials.

Unpublished Studies Should be Made Available as Full Text Publications. Among RCTs of viscosupplementation, those that have not been published in full text comprise approximately 25 percent of the total patient population. Several meta-analyses of glucosamine report that trials of the Rotta product, glucosamine sulfate, show outcomes superior to trials of glucosamine hydrochloride; yet key trials have not been published as full-text studies. Existing studies should be published in full. And all trials should be registered at inception at ClinicalTrials.gov along with anticipated date for full release of results.

The Pitfalls of Meta-Analysis Should be More Widely Recognized and Acknowledged. Our evidence report draws heavily on six study-level meta-analyses of glucosamine/chondroitin and five of viscosupplementation. While we used a validated instrument to appraise the quality of the systematic reviews, the instrument does not address the question of when meta-analysis is appropriate to a systematic review. Meta-analysis is a technique with underlying assumptions that may or may not hold when a particular collection of results are pooled. Furthermore, meta-analyses may fail to convey the real uncertainty and potential bias accompanying pooled estimates.

Uncertainty in the magnitude of effects pooled is influenced by factors intrinsic to the underlying trials. Among these are variable patient characteristics, trial characteristics, and the indication that a few trial results were outliers and influential on pooled estimates. The meta-analyses frequently reported high inter-trial heterogeneity. Random effects models were used in the face of high heterogeneity, but a consequence is to increase the influence of smaller trials on the pooled results. The meta-analyses did not address a threshold question, one that has not been clearly resolved by practitioners of meta-analysis: when is heterogeneity too high to justify pooling trial results. A related concern is the practice of reporting on multiple outcome measures and time intervals, which may be represented by a small portion of studies, thus potentially introducing bias.

Conclusions

Osteoarthritis of the knee is a common condition. The three interventions reviewed in this report are widely used in the treatment of OA of the knee, yet the best available evidence does not clearly demonstrate clinical benefit. Uncertainty over clinical benefit can be resolved only by rigorous, multicenter RCTs. In addition, given the public health impact of OA of the knee, research on new approaches to prevention and treatment should be given high priority.