➢ The body of evidence surrounding the use of viscosupplementation in knee osteoarthritis is extensive and fraught with heterogeneous trials with conflicting conclusions.
➢ Attempts to aggregate the evidence through systematic reviews, meta-analyses, and guidelines have also resulted in unclear, discordant recommendations. Closer examination reveals that the evidence around viscosupplementation favors clinically important reductions in pain among higher-molecular-weight and cross-linked formulations and is a safe option in patients with knee osteoarthritis.
➢ Further large trials assessing the use of viscosupplementation across various formulations in knee osteoarthritis may confirm subgroup findings from meta-analyses; however, immediate focus on improved knowledge translation is required to ensure evidence-based approaches to the treatment of knee osteoarthritis.
The Global Burden of Osteoarthritis
Osteoarthritis is the most common form of articular disease in the world and is a leading cause of pain and disability1. Characterized by progressive degeneration of cartilage, osteoarthritis clinically manifests as joint pain, stiffness, and dysfunction1. It is estimated to affect approximately 27 million adults in the United States2. Symptomatic osteoarthritis most commonly affects the knee and is prevalent among nearly 17% of American adults older than 45 years of age2. Nearly half of all adults will have symptoms of osteoarthritis by the age of 85 years3. Chronic, abnormal, and/or excessive joint loading, varus alignment, joint injury, and obesity are all harbingers of disease development4,5, leading to substantial disability in activities of daily living and declines in health-related quality of life6,7. In the United Kingdom, half of adults with osteoarthritis report some level of disability8, and in the United States, osteoarthritis is second only to back pain as a cause of lost productivity9. Globally, the burden of osteoarthritis will continue to rise as life expectancy increases and patients remain active later in life. By 2025, the prevalence of knee osteoarthritis is expected to increase to 40%, largely because of an aging population and the obesity epidemic10. This will have substantial implications for both health systems and economies11,12. In 2003, total osteoarthritis-related annual costs in the United States, including medical care and lost wages, exceeded $128 billion13. Direct medical costs accounted for $80.8 billion, and more than $47 billion in costs were indirect expenditures13.
Treatment of Knee Osteoarthritis
The treatment of knee osteoarthritis consists of a combination of treatment options aimed at alleviating pain and improving function14. Evidence-based management begins with conservative measures, including weight loss, strengthening, and aerobic exercise, and then progresses to analgesic medications such as topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs)15,16. As knee osteoarthritis progresses beyond the effectiveness of these treatments, options become limited. Total knee arthroplasty has been shown to achieve excellent pain relief and long-term functional outcomes in older patients with severe osteoarthritis17. However, outcomes in younger patients are often suboptimal, as rates of aseptic loosening requiring a revision surgical procedure are increased18. Revision total knee arthroplasty carries inherent surgical risks for infection, fracture, implant failure, extended hospitalization, functional disability, and perioperative mortality19. Bridging the gap between systemic analgesics and arthroplasty for these patients is a challenge and has been an area of intense research. Glucosamine, chondroitin sulfate, bracing, and orthoses have all been explored as possible options; however, the evidence to support their efficacy has been limited, and their use remains controversial16. Periarticular osteotomies and unicondylar knee arthroplasty may be reasonable options for certain candidates, but they pose surgical risks to the patient20. Arthroscopy has demonstrated modest benefits in patients with symptomatic meniscal abnormalities; however, arthroscopic lavage and debridement have been clearly shown to have no benefit in isolated knee osteoarthritis21.
Few orthopaedic interventions have gained as much research attention recently as viscosupplementation; however, considerable controversy still persists regarding its clinical effectiveness and safety. In this review, we will examine the body of evidence surrounding viscosupplementation, which has been largely synthesized into discordant meta-analyses and clinical practice guidelines. We consider the reasons for disparate findings in the literature and translate the vast body of evidence to determine the role of viscosupplementation in current clinical practice.
Intra-Articular Hyaluronic Acid Injections (Viscosupplementation)
Normally, healthy adult knees contain approximately 2 mL of synovial fluid that acts as a lubricant for articular cartilage and medium for nutrient transport to chondrocytes22. Hyaluronic acid is a naturally occurring polysaccharide within synovial fluid produced by type-B synoviocytes, fibroblasts, and chondrocytes23. It is made up of repeating N-acetyl-glucosamine and glucuronic acid units and has a mean molecular weight of approximately 5 × 106 Da22,24. In healthy joints, hyaluronic acid has a concentration of 2.5 to 4 mg/mL and acts as a viscoelastic shock absorber during high shear and as a lubricant during slow movement25,26. It is also thought to have protective effects on the cartilage matrix, as well as anti-inflammatory and anti-nociceptive properties25,26. Hyaluronic acid acts as an anti-inflammatory by inhibiting the fibroblast release of arachidonic acid, impairing leukocyte activity, and reducing synovial levels of prostaglandin, fibronectin, and cyclic adenosine monophosphate25. It works as an analgesic by inhibiting nociceptors, bradykinin synthesis, and substance P signaling27.
In contrast, knees affected by osteoarthritis are found to be deficient in hyaluronic acid, secondary to degradation, reduced production, and increased clearance attributed to elevated levels of free radicals, inflammatory cytokines, and cleavage enzymes25,28. This leads to elevated serum markers for hyaluronic acid, reduced viscoelasticity of synovial fluid, cartilage damage, and osteoarthritis progression4,24. Peyron and Balazs first proposed supplementation of exogenous intra-articular hyaluronic acid for osteoarthritis in 197429. This was meant to replace the abnormal synovial fluid with a product that held properties similar to those found in a normal knee. Intra-articular hyaluronic acid was developed to restore the viscoelastic properties of synovial fluid, hence the term “viscosupplementation.”9 Unfortunately, this term focuses most of the attention on the lubricating actions and less so on other critically important properties. For example, intra-articular hyaluronic acid has been theorized to reduce inflammation and to promote the synthesis of normal hyaluronic acid, all with the overall aim of decreasing knee pain and restoring mobility9.
Intra-articular hyaluronic acid was approved as a biologic device for use in humans in Canada in 1992 and in the United States in 199723,30. Current commercial hyaluronic acid preparations are either harvested from rooster combs (synthetic avian-based) or synthesized by means of in vitro bacterial fermentation (biofermented, non-avian)31. Although the former is easier to manipulate through cross-linking to increase molecular weight and provides a theoretical advantage associated with higher-molecular-weight preparations32, non-avian formulations have emerged more recently in an attempt to avoid the potential risks from poultry and egg protein allergies31. Several preparations of commercial hyaluronic acid are currently available in North America. They each vary by molecular weight, method of production, half-life, dosing regimen, and cost (Table I)9,30,33. Several formulations have evolved and have emerged over the past 2 decades, which has resulted in a plethora of randomized controlled clinical trials (RCTs) to assess the efficacy and safety of these products.
Many Conflicting Meta-Analyses
Decision-making that is informed by the integration of best available research, clinical expertise, and patient preferences and values is the foundation of evidence-based medicine34. To adequately interpret the litany of evidence surrounding viscosupplementation, surgeons must familiarize themselves with evidence-based medicine concepts and judiciously evaluate the effectiveness and integration of new technologies34,35. The ability to critically appraise empirical studies will allow surgeons to discern between novel drugs or devices that may either markedly improve patient lives or lead to patient morbidity and wasted resources35.
Given the mounting evidence from clinical trials evaluating the efficacy of hyaluronic acid in knee osteoarthritis, researchers have turned to meta-analysis, a statistical method to systematically combine and synthesize results from multiple trials. Meta-analyses are usually performed as part of an in-depth systematic review of the literature and serve to improve the power and precision of effect-size estimates by pooling data from smaller, individual studies36. If performed using high-quality trials and robust methodology, meta-analyses are the pinnacle of medical evidence. However, the inclusion of low-quality trials, inappropriate combination of heterogeneous studies, and failure to perform a comprehensive assessment of methodological quality may result in misleading findings from meta-analyses37,38. Viscosupplementation in knee osteoarthritis has been the subject of no fewer than 26 systematic reviews and meta-analyses from 2003 to 2015 (Fig. 1)39-65. Disparate results among these reviews have led to opposing views on its efficacy and safety.
Efficacy: Do Intra-Articular Hyaluronic Acid Injections Work?
In 2006, Bellamy et al. conducted an industry-sponsored Cochrane Review that compared 19 different hyaluronic acid formulations across 76 RCTs46. The sample sizes of the trials ranged from 12 to 495, and the median methodological quality was rated as 3 of 5 on the Jadad scale66. Despite considerable heterogeneity among trials with respect to inadequate sample sizes and the use of different hyaluronic acid products, comparisons, and trial designs, the authors still found hyaluronic acid to be an effective treatment with beneficial effects on pain, physical function, and patient global assessment scores that were most pronounced at 5 and 13 weeks after the injection. They also found the effect of hyaluronic acid to be comparable with that of oral NSAIDs. However, there were few head-to-head trials available, and firm conclusions with regard to the relative effect of each formulation could not be made. Furthermore, a variety of comparators were present among the included studies, including placebo, intra-articular corticosteroids, NSAIDs, physiotherapy, and arthroscopy, resulting in most of the comparisons being based on only a few small trials67.
Campbell et al.68 conducted a review comparing the results of 6 meta-analyses, all with conflicting results with respect to the efficacy of hyaluronic acid for knee osteoarthritis40,42-44,47,67. All 6 meta-analyses were found to have asked similar clinical questions; however, variations in search strategies and study eligibility criteria resulted in the inclusion of different primary trials in each of the reviews. Additionally, differences in assessment of study quality, selection of pooled outcome measures and outcome time points, and statistical model selection contributed to discordant findings. Overall, using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach69, Campbell et al. concluded that viscosupplementation provides a probable therapeutic benefit for physical function improvement and pain reduction, with a low risk for harm. They also suggested that further research would be unlikely to alter their confidence in the effect estimates68.
It was not long before the pendulum of consensus would swing back. In 2012, Rutjes et al. produced a large meta-analysis on viscosupplementation, where they assessed pain intensity, frequency of osteoarthritis flareups, and physical function across 89 trials involving 12,667 patients58. Trial size, use of blinded outcome assessment, industry support, and publication status were all factors found to be associated with treatment effect size. Rutjes et al. commented on the presence of publication bias, as an asymmetric funnel plot indicated that the majority of the included studies demonstrated an effect in favor of the intervention. Unique to their meta-analysis was the focus on clinically important reductions in knee pain over the standard statistically significant reductions in pain commonly reported in prior reviews. The most common reference point for the interpretation of patient-reported outcomes, such as pain and physical function, is the minimal clinically important difference (MCID), which describes the smallest change in the outcome of interest that informed patients would perceive as important, either beneficial or harmful, and that would lead the patient or clinician to consider a change in management70,71. Using a prespecified validated MCID set at an effect size of −0.37, the authors concluded that viscosupplementation demonstrated significant but clinically irrelevant pain relief (effect size, −0.37; 95% confidence interval [95% CI], −0.46 to −0.28). Using the same thresholds, those studies evaluating either high-molecular-weight or cross-linked formulations achieved both significant and clinically important pain reductions. Although subgroups are often exploratory, these findings appeared to support further exploration of the specific hyaluronic acid formulation and relying less on the overall class of viscosupplementation effect.
The most recent meta-analysis on viscosupplementation for knee osteoarthritis was performed in 2015 by Jevsevar et al., who similarly used the MCID approach to assess the effect of intra-articular hyaluronic acid injections on patient-reported pain and function65. The authors assessed a total of 19 RCTs, consisting of 4,485 patients; 14 of the studies were double-blind, placebo-controlled trials. Jevsevar et al. concluded that when considering only those trials that were adequately blinded, the use of hyaluronic acid did not provide a clinically important difference over placebo. The lack of double-blind placebo-controlled design, the use of hyaluronic acid cross-linking, and longer follow-up were all associated with increased treatment effects, which overlap or surpass the MCID in most cases65.
Upon closer inspection, inferences from the overall pooled analysis across 71 trials by Rutjes et al. that specifically assessed knee pain and 19 trials by Jevsevar et al. may be limited for several important reasons. First, heterogeneity was a serious issue in each meta-analysis, with individual trials varying with respect to concealment of allocation, blinding of patients, follow-up duration, number of injections, and structure and molecular weight of the formulation used. Second, viscosupplementation was compared with either sham treatment or non-sham treatment, but including active controls into these groups may have contaminated the analyses and resulted in an overall underestimation of the true effect size. Comparators included oral NSAIDs72, cyclooxygenase-2 inhibitors73, and physiotherapy74, in addition to intra-articular placebos and conventional treatment75,76. Further, there has been growing recognition that the effects of intra-articular saline solution in placebo-controlled trials may not be benign. In a 2008 meta-analysis, Zhang et al. quantified the extent of the placebo effect in RCTs of knee osteoarthritis. The authors concluded that placebo therapy is effective in the treatment of osteoarthritis, especially for pain, stiffness, and physical function. However, an important determinant of the magnitude of the placebo effect is the expected treatment effect of the active agent itself77. The placebo effect for pain in the knee was found to be 0.54 (95% CI, 0.49 to 0.60)77, which would be additive to the effect size of hyaluronic acid found by Rutjes et al.58 and would place it well beyond the MCID relative to no treatment. Likewise, this explains the results from Jevsevar et al. where the treatment effect size of hyaluronic acid on pain in the sham-controlled trials (−0.29 MCID [95% CI, −0.42 to −0.16 MCID]) was similar to that in trials with an active control comparator (−0.49 MCID [95% CI, −0.70 to −0.29 MCID]) and lower than that in trials comparing hyaluronic acid with no treatment (−1.52 MCID [95% CI, −1.87 to −1.17 MCID])65. This phenomenon is termed the “efficacy paradox,” where a treatment with a small or clinically unimportant effect relative to placebo in a trial produces a larger or clinically important effect in a clinical setting78,79. Finally, caution needs to be exercised when making study conclusions based solely on the MCID. Although the MCID provides important information relative to the smallest change that is clinically important, it is meant to be a distributional characteristic and not a single cutoff80. In each of the trials assessed, there would have been a proportion of patients who reached a treatment effect at or above the MCID, even if the mean effect size fell below that point80. A comparison of these proportions across the trials would have been more informative with respect to the overall clinically important benefit offered by intra-articular hyaluronic acid.
Given that the viscosupplementation literature is fraught with a variety of comparators, it becomes difficult to adequately quantify the effect of hyaluronic acid using traditional meta-analytic techniques. Network meta-analyses are an alternative that uses direct and indirect comparisons to quantify the relative effectiveness of more than 2 comparisons when few head-to-head trials exist81. Bannuru et al. recently performed a series of network meta-analyses examining the relative efficacy of different placebos and treatments, including hyaluronic acid82,83. They initially combined 137 trials, consisting of 33,243 patients, to assess the comparative effectiveness of all pharmacological interventions for knee osteoarthritis82, and subsequently assessed 149 trials with 39,814 patients to specifically assess the role of alternate placebos83. When assessing all treatments for knee osteoarthritis, Bannuru et al. found that active intra-articular treatments were superior to oral NSAIDs, with hyaluronic acid being the most efficacious with respect to both pain and function82. Interestingly, the authors were able to show that intra-articular placebos had a greater effect than oral placebos in reducing pain, demonstrating that use of inappropriate placebos for comparisons may lead to inaccurate and misleading effect estimates79,83. This information raises important questions about the extent to which therapeutic effects are attributable to a true placebo response compared with physiologic effects after directly injecting a fluid into the knee joint83.
In a 2015 systematic review, Campbell et al. compiled 14 overlapping meta-analyses39,40,42-44,48,50,52,56,58,59,62,63,67, all of which compared viscosupplementation with oral NSAIDs, intra-articular corticosteroids, intra-articular platelet-rich plasma, or intra-articular placebo for the treatment of knee osteoarthritis84. The studies ranged in Level of Evidence from I to IV, and, after application of the Jadad algorithm85, 2 high-quality, Level-I, independent meta-analyses remained from which to draw conclusions63,67. Campbell et al. found that for patients with knee osteoarthritis, intra-articular hyaluronic acid results in improvements in better pain and function than other treatments for up to 6 months in comparison with other current treatment options84.
Safety and Adverse Events
Adverse events are uncommon; however, a self-limited soft-tissue reaction at the site of injection, which is a minor side effect of viscosupplementation, has been recognized. These reactions are characterized by localized pain and knee effusion and typically resolve without treatment in 1 to 3 days. They may be related to improper injection techniques or an inappropriate mixture of hyaluronic acid with other products9,23. A more severe side effect, although rare, is a pseudoseptic reaction, which can be characterized as inflammation and joint swelling not associated with infection86. Pseudosepsis is thought to be an immune-mediated response usually occurring after sensitization to hyaluronic acid formulations requiring multiple injections.
The U.S. Food and Drug Administration (FDA) defines a serious adverse event as any undesirable experience associated with the use of a medical product in a patient, including death, hospitalization, disability or permanent damage, birth defects, and other important events requiring medical or surgical intervention87. Serious adverse events have been a major recent driver of concern associated with viscosupplementation58. These events include disorders related to the gastrointestinal system, cardiovascular system, and cancer, in addition to musculoskeletal-related events. However, it is difficult to interpret these findings because of limited transparency in serious adverse event reporting in trials and the lack of a direct relationship with viscosupplementation treatment88.
Amidst these concerns, an industry-supported meta-analysis by Miller and Block specifically set out to determine the safety and efficacy of intra-articular hyaluronic acid injections approved for use in the United States59. They outlined predetermined criteria to identify treatment-related serious adverse events and subject withdrawals both for any reason and for reasons directly associated with serious adverse events. A total of 29 randomized, intra-articular placebo-controlled trials were included, with 4,866 subjects. The authors found that intra-articular hyaluronic acid was effective with respect to reductions in knee pain and improved physical function. There were no significant differences compared with saline solution controls for any of the safety outcomes, and all of reported serious adverse events were deemed to be unassociated with the use of intra-articular hyaluronic acid.
Subsequent independent analyses on the safety of viscosupplementation have been consistent with these findings. In their network meta-analysis of comparative efficacy, Bannuru et al. found that oral NSAIDs lead to more treatment-related events and withdrawals than any of the intra-articular therapies, including hyaluronic acid82. Through their systematic review of overlapping meta-analyses, Campbell et al. also found that hyaluronic acid has a more favorable side-effect profile than NSAIDs, making it a good option for those patients unable to tolerate oral NSAIDs84.
Making Sense of Guidelines
Given the array of conflicting trials and meta-analyses that have come forward on the use of viscosupplementation, clinicians look to guidelines to evaluate and summarize current data and to provide evidence-based recommendations for practice. However, consistent with the RCT and meta-analysis literature, current guidelines have discordant recommendations with regard to the role of intra-articular hyaluronic acid in knee osteoarthritis. The American College of Rheumatology (ACR)89, Osteoarthritis Research Society International (OARSI)90, European League Against Rheumatism (EULAR)91, National Institute for Health and Care Excellence (NICE)92, and the American Academy of Orthopaedic Surgeons (AAOS)16 have all put forth evidence-based clinical practice guidelines (CPGs) outlining the optimal approaches to non-surgical treatment of knee osteoarthritis. In the face of conflicting empirical evidence and inconsistent recommendations from guidelines, clinicians require knowledge of methods to critically evaluate study methodology and should be familiar with tools to assess the quality of current evidence. In a recent systematic review of the guidelines for the treatment of knee osteoarthritis, Altman et al. applied the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument to assess the presence of bias and quality of reporting across CPGs, and found inconsistencies in the quality of reporting (Table II)93,94.
Although the guidelines are in agreement with respect to the role of certain therapies in clinical practice, they each take a different stance on the use of viscosupplementation (Table III)93. All 5 organizations above recommend against the use of intra-articular lavage, in keeping with the consistency across the literature with respect to this intervention21. Similarly, all of the guidelines support the administration of both topical and oral NSAIDs95, although the EULAR does outline that oral NSAIDs have a worse toxicity profile than most other treatments, including hyaluronic acid. Beginning in 2007, the OARSI began performing comprehensive systematic reviews across treatment modalities for osteoarthritis and have since provided 2 updates to reflect technological advances and emerging therapies15,90,96,97. In the initial 2 iterations of OARSI recommendations, they identified hyaluronic acid as useful in the treatment of knee osteoarthritis15,97. However, the most recent set of guidelines, from 2014, took a more tempered stance, and offered an uncertain recommendation due to the recent conflicting meta-analyses52,55,58.
In their most recent set of guidelines on the treatment of osteoarthritis of the knee, the AAOS performed a series of network meta-analyses of Level-I trials, rather than using analyses already published in the literature16. They used measures to identify clinically important differences instead of significant changes in patient-reported measures such as knee pain and function. The application of MCIDs for the interpretation of treatment effects resulted in the AAOS making a strong recommendation against the use of viscosupplementation in knee osteoarthritis, which contradicts their position statement from 200816. The reversal from their earlier position was because, despite significant benefits of hyaluronic acid, these effects did not reach the MCID cutoffs. Considerable debate about the approach in the AAOS guidelines has resulted98, despite a thorough and evidence-based approach (Table II). Unfortunately, guidelines, to a major extent, are prone to challenges when the quality of primary evidence used has methodological limitations. Most notably, by failing to adequately account for the additive placebo effect associated with intra-articular knee injections77, guidelines may provide inaccurate and misinformed recommendations78,79.
State of the Evidence
The body of evidence regarding the use of viscosupplementation in knee osteoarthritis is extensive, to a much greater extent than several other treatment modalities in this area, and in orthopaedics in general. Much of the RCT literature is heterogeneous, attributed mostly to small sample sizes and multiple comparators, leaving them underpowered to draw consistent conclusions. By aggregating the evidence into systematic reviews, meta-analyses, network meta-analyses, and guidelines, a message begins to emerge but remains difficult to fully understand because of conflicting results and poor methodological quality of clinical trials. It should be noted that guidelines tend to lag behind the most up-to-date evidence in terms of their recommendations because of the time required by the organizations and experts to compile the literature and prepare documents. A careful examination of the most recently published articles suggests that viscosupplementation is a safe option with a clinically important reduction in pain for younger patients with knee osteoarthritis, in those formulations with higher molecular weights or hyaluronic acid cross-linking. Further, large primary trials with improved methodology investigating these effects are likely needed. Rare adverse events and long-term safety may be best observed through large cohort studies or registry-type databases rather than randomized trials99. Improved knowledge translation of the current literature and guidelines is required to ensure that a clear and consistent message regarding the use of viscosupplementation for knee osteoarthritis is reaching clinicians faced with making evidence-based treatment decisions in the context of their own experience and patients’ values and preferences.
Investigation performed at the Division of Orthopaedic Surgery, McMaster University, Hamilton, Ontario, Canada
Disclosure: There were no external funding sources in the preparation of this manuscript. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work.
- Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated