Background Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. Objectives To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). Search strategy MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched. Selection criteria RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). Data collection and analysis Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer. Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR). Main results Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. Authors' conclusions Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

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Viscosupplementation for the treatment of osteoarthritis of the knee

Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis.

Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis

ContextIntra-articular hyaluronic acid is a US Food and Drug Administration–approved
treatment for knee osteoarthritis (OA); however, its efficacy is controversial.ObjectiveTo evaluate whether intra-articular hyaluronic acid is efficacious in
treating knee OA.Data SourcesWe searched for human clinical trials in MEDLINE (1966 through February
2003) and the Cochrane Controlled Trials Register, using the search terms
(osteoarthritis, osteoarthrosis, or degenerative arthritis) and (hyaluronic acid, Hyalgan, Synvisc, Artzal, Suplasyn, BioHy, or Orthovisc).
We also hand searched manuscript bibliographies that met inclusion criteria,
selected rheumatic disease journals, and abstracts from scientific meetings.Study SelectionIncluded were published or unpublished, English and non-English, single-
or double-blinded, randomized controlled trials comparing intra-articular
hyaluronic acid with intra-articular placebo injection for the treatment of
knee OA. Trials also were required to have extractable data on pain reported
by 1 of the outcome measures recommended by the Osteoarthritis Research Society.Data ExtractionTwo reviewers independently performed data extraction using standardized
data forms. For each trial, we calculated an effect size (small-effect sizes,
0.2-0.5; large-effect sizes, 1.0-1.8, equivalent to a total knee replacement).
We used a random-effects model to pool study results, the Cochrane Q test
to evaluate heterogeneity, and a funnel plot and the Egger test to evaluate
publication bias.Data SynthesisThe overall dropout rate in the 22 selected trials was 12.4%. The pooled
effect size for hyaluronic acid was 0.32 (95% confidence interval [CI], 0.17-0.47).
There was significant heterogeneity among studies (P<.001).
Two outlier trials, both evaluating the highest-molecular-weight hyaluronic
acid, had effect sizes in excess of 1.5. However, the third trial of the same
compound showed a nearly null effect. When the 3 trials of this compound were
removed, heterogeneity was no longer significant (P =
.58), and the pooled effect size for intra-articular hyaluronic acid decreased
to 0.19 (95% CI, 0.10-0.27). There was evidence of publication bias with an
asymmetric funnel plot, a positive Egger test, and identification of 2 unpublished
trials whose pooled effect size was 0.07 (95% CI, − 0.15 to 0.28).ConclusionIntra-articular hyaluronic acid has a small effect when compared with
an intra-articular placebo. The presence of publication bias suggests even
this effect may be overestimated. Compared with lower-molecular-weight hyaluronic
acid, the highest-molecular-weight hyaluronic acid may be more efficacious
in treating knee OA, but heterogeneity of these studies limits definitive
conclusions.

Intra-articular Hyaluronic Acid in Treatment of Knee Osteoarthritis: A Meta-analysis

HYALURONIC ACID IS A LARGE glycosaminoglycan composed of repeating disaccharides of glucuronic acid and N-acetylglucosamine that is naturally occurring in synovial fluid. There has been a long history of injecting hyaluronic acid intra-articularly into the joints of arthritic animals to improve their performance. This treatment has been approved by the US Food and Drug Administration as a device for the treatment of osteoarthritis (OA) in humans since 1997, with 3 to 5 weekly injections costing between $100 and $200 for each injection, not including the physician visit during which the injection is given. Despite Food and Drug Administration approval, the efficacy of intraarticular hyaluronic acid in the treatment of OA remains controversial. In 1998, a task force for the European League of Associations of Rheumatologists (EULAR) Standing Committee for Clinical Trials described intraarticular hyaluronic acid as being “probably effective in knee OA” in a statement issued after a systematic evaluation of the existing literature. There was insufficient evidence to allow a more definitive statement about the efficacy of hyaluronic acid in the treatment of knee OA. Furthermore, a survey conducted by EULAR of a group of rheumatologists and orthoAuthor Affiliations are listed at the end of this article. Corresponding Author and Reprints: Grace H. Lo, MD, 715 Albany St, A203, Boston, MA 02118 (e-mail: grace .lo@bmc.org). Context Intra-articular hyaluronic acid is a US Food and Drug Administration– approved treatment for knee osteoarthritis (OA); however, its efficacy is controversial.

Intra-articular Hyaluronic Acid in Treatment of Knee Osteoarthritis

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 anti-inflammatory 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.

Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis

Objective. To compare the efficacy and safety of intra-articular injections of two different hyaluronan preparations and placebo in patients with knee osteoarthritis. Methods. In a randomized, patient- and observer-blind, placebo-controlled and multicentre trial with parallel groups, 210 patients, aged 60 yr or above, with knee osteoarthritis were included in a per protocol analysis. The patients were treated with three injections, once weekly, of either native high-molecular-weight hyaluronan (Artzal) or cross-linked hyaluronan (Synvisc) or with placebo and were followed for 52 weeks. The primary efficacy measures were weight-bearing pain during study weeks 026 and the duration of clinical benefit measured with KaplanMeier survival analysis for weeks 052. The secondary outcome measures were resting and maximum pain, Lequesne index, WOMAC (Western Ontario and McMaster University Osteoarthritis Index) and SF-36 (Medical Outcomes Study Short Form Health Survey) scores. Results. The intra-articular injections produced a significant reduction in weight-bearing pain, resting pain, maximum pain and Lequesne and WOMAC scores after 26 weeks. There were no significant differences in outcome between any of the three study groups during the first 26 weeks. In direct comparison against placebo for weeks 052, neither hyaluronan treatment (Artzal or Synvisc) showed a significantly longer duration of clinical benefit than placebo. However, when data for the two hyaluronan-treated groups were pooled, treatment with hyaluronan had a significantly longer duration of benefit compared with placebo (P = 0.047). Conclusion. Patients with knee osteoarthritis who were treated by injection into the knee of either of two hyaluronan preparations or placebo showed clinical improvement during the first 26 weeks of treatment, though neither hyaluronan preparation gave a longer duration of clinical benefit than placebo. However, when data for the two hyaluronan treatments were pooled, there was a significantly longer duration of clinical benefit for hyaluronan treatment than for placebo. (Less)

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Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double‐blind, parallel‐design multicentre study

L S Lohmander

Papers

Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double‐blind, parallel‐design multicentre study