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Viscosupplementation in Knee
Osteoarthritis: Evidence Revisited
Herman Johal, MD, MPH, Abstract
FRCSC The body of evidence surrounding the use of viscosupplementation
in knee osteoarthritis is extensive and fraught with heterogeneous
Tahira Devji, BSc trials with conflicting conclusions.
Emil H. Schemitsch, MD, FRCSC
Attempts to aggregate the evidence through systematic reviews,
Mohit Bhandari, MD, PhD, meta-analyses, and guidelines have also resulted in unclear, discordant
FRCSC recommendations. Closer examination reveals that the evidence
around viscosupplementation favors clinically important reductions in
pain among higher-molecular-weight and cross-linked formulations
Investigation performed at the and is a safe option in patients with knee osteoarthritis.
Division of Orthopaedic Surgery,
McMaster University, Hamilton, Further large trials assessing the use of viscosupplementation across
Ontario, Canada 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

O
steoarthritis is the most disability8, and in the United States, osteo-
common form of articular arthritis is second only to back pain as a
disease in the world and is a cause of lost productivity9. Globally, the
leading cause of pain and burden of osteoarthritis will continue to
disability1. Characterized by progressive rise as life expectancy increases and patients
degeneration of cartilage, osteoarthritis remain active later in life. By 2025, the
clinically manifests as joint pain, stiffness, prevalence of knee osteoarthritis is
and dysfunction1. It is estimated to affect expected to increase to 40%, largely
approximately 27 million adults in the because of an aging population and the
United States2. Symptomatic osteoarthritis obesity epidemic10. This will have
most commonly affects the knee and is substantial implications for both health
prevalent among nearly 17% of American systems and economies11,12. In 2003, total
adults older than 45 years of age2. Nearly osteoarthritis-related annual costs in the
half of all adults will have symptoms of United States, including medical care
osteoarthritis by the age of 85 years3. and lost wages, exceeded $128 billion13.
Chronic, abnormal, and/or excessive joint Direct medical costs accounted for
loading, varus alignment, joint injury, $80.8 billion, and more than $47 billion
and obesity are all harbingers of disease in costs were indirect expenditures13.
development4,5, leading to substantial
disability in activities of daily living and Treatment of Knee Osteoarthritis
declines in health-related quality of life6,7. The treatment of knee osteoarthritis con-
In the United Kingdom, half of adults sists of a combination of treatment options
with osteoarthritis report some level of aimed at alleviating pain and improving

Disclosure: There were no external funding sources in the preparation of this manuscript. On the
COPYRIGHT 2016 BY THE Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the
JOURNAL OF BONE AND JOINT article, one or more of the authors checked yes to indicate that the author had a relevant financial
SURGERY, INCORPORATED relationship in the biomedical arena outside the submitted work.

JBJS REVIEWS 2016;4(4):e1 http://dx.doi.org/10.2106/JBJS.RVW.15.00098 1


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TABLE I Characteristics of Common Viscosupplement Formulations

Product Name Active Ingredient Manufacturer Year of FDA Approval Type

Hyalgan Sodium hyaluronate Fidia Pharma 1997 Avian


Synvisc Hylan G-F 20 (80:20 ratio of hylan A to hylan B) Genzyme, Sanofi-Aventis 1997 Avian
Supartz, Supartz FX Sodium hyaluronate Bioventus 2001, 2015 Avian
Orthovisc Sodium hyaluronate DePuy Synthes 2004 Avian
Nuflexxa, Euflexxa Sodium hyaluronate Ferring Pharmaceuticals 2004, 2011 Non-avian
Synvisc One Hylan G-F 20 (80:20 ratio of hylan A to hylan B) Genzyme, Sanofi-Aventis 2009 Avian
Gel-One Hyaluronan hydrogel Zimmer 2011 Avian
Monovisc Sodium hyaluronate DePuy Synthes 2014 Non-avian

33
*The doses, if .1, were given 1 week apart. The costs are given in 2015 U.S. dollars, based on the mean wholesale price from Micromedex 2.0 . NA 5
not available.

function14. Evidence-based manage- symptomatic meniscal abnormalities; high shear and as a lubricant during slow
ment begins with conservative measures, however, arthroscopic lavage and de- movement25,26. It is also thought to have
including weight loss, strengthening, bridement have been clearly shown protective effects on the cartilage matrix,
and aerobic exercise, and then progresses to have no benefit in isolated knee as well as anti-inflammatory and anti-
to analgesic medications such as topical osteoarthritis21. nociceptive properties25,26. Hyaluronic
or oral nonsteroidal anti-inflammatory Few orthopaedic interventions have acid acts as an anti-inflammatory by
drugs (NSAIDs)15,16. As knee osteoar- gained as much research attention re- inhibiting the fibroblast release of ara-
thritis progresses beyond the effective- cently as viscosupplementation; however, chidonic acid, impairing leukocyte ac-
ness of these treatments, options become considerable controversy still persists re- tivity, and reducing synovial levels of
limited. Total knee arthroplasty has garding its clinical effectiveness and safety. prostaglandin, fibronectin, and cyclic
been shown to achieve excellent pain In this review, we will examine the body of adenosine monophosphate25. It works
relief and long-term functional out- evidence surrounding viscosupplementa- as an analgesic by inhibiting nocicep-
comes in older patients with severe os- tion, which has been largely synthesized tors, bradykinin synthesis, and sub-
teoarthritis17. However, outcomes in into discordant meta-analyses and clinical stance P signaling27.
younger patients are often suboptimal, practice guidelines. We consider the rea- In contrast, knees affected by os-
as rates of aseptic loosening requiring sons for disparate findings in the literature teoarthritis are found to be deficient in
a revision surgical procedure are in- and translate the vast body of evidence to hyaluronic acid, secondary to degrada-
creased18. Revision total knee arthro- determine the role of viscosupplementa- tion, reduced production, and increased
plasty carries inherent surgical risks for tion in current clinical practice. clearance attributed to elevated levels
infection, fracture, implant failure, ex- of free radicals, inflammatory cytokines,
tended hospitalization, functional Intra-Articular Hyaluronic Acid and cleavage enzymes25,28. This leads
disability, and perioperative mortality19. Injections (Viscosupplementation) to elevated serum markers for hyaluronic
Bridging the gap between systemic Normally, healthy adult knees contain acid, reduced viscoelasticity of synovial
analgesics and arthroplasty for these approximately 2 mL of synovial fluid fluid, cartilage damage, and osteoar-
patients is a challenge and has been an that acts as a lubricant for articular thritis progression4,24. Peyron and
area of intense research. Glucosamine, cartilage and medium for nutrient Balazs first proposed supplementation
chondroitin sulfate, bracing, and or- transport to chondrocytes22. Hyaluronic of exogenous intra-articular hyaluronic
thoses have all been explored as possible acid is a naturally occurring polysaccha- acid for osteoarthritis in 197429. This
options; however, the evidence to ride within synovial fluid produced by was meant to replace the abnormal
support their efficacy has been limited, type-B synoviocytes, fibroblasts, and synovial fluid with a product that held
and their use remains controversial16. chondrocytes23. It is made up of repeating properties similar to those found in a
Periarticular osteotomies and uni- N-acetyl-glucosamine and glucuronic normal knee. Intra-articular hyaluronic
condylar knee arthroplasty may be rea- acid units and has a mean molecular acid was developed to restore the visco-
sonable options for certain candidates, weight of approximately 5 3 106 Da22,24. elastic properties of synovial fluid,
but they pose surgical risks to the pa- In healthy joints, hyaluronic acid has a con- hence the term viscosupplementa-
tient20. Arthroscopy has demonstrated centration of 2.5 to 4 mg/mL and acts as tion.9 Unfortunately, this term focuses
modest benefits in patients with a viscoelastic shock absorber during most of the attention on the lubricating

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TABLE I (continued)

Molecular Weight (kDa) Cross-Linked Hyaluronic Acid Amount/Syringe Volume No. of Injections* Cost Per Syringe ($)

500 to 720 No 20 mg/2 mL 3 to 5 228.00


5,000 to 6,000 Yes 16 mg/2 mL 3 473.88
620 to 1,200 No 25 mg/2.5 mL 3 to 5 276.36
1,000 to 2,900 No 30 mg/2 mL 3 to 4 626.40
2,400 to 3,600 Yes 20 mg/2 mL 3 388.48
5,000 to 6,000 Yes 48 mg/6 mL 1 1,421.65
NA Yes 30 mg/3 mL 3 1,170.00
1,000 to 2,900 Yes 88 mg/4 mL 1 1,252.80

actions and less so on other critically clinical expertise, and patient prefer- among these reviews have led to opposing
important properties. For example, intra- ences and values is the foundation of views on its efficacy and safety.
articular hyaluronic acid has been theo- evidence-based medicine34. To ade-
rized to reduce inflammation and to quately interpret the litany of evidence Efficacy: Do Intra-Articular
promote the synthesis of normal hyal- surrounding viscosupplementation, Hyaluronic Acid Injections Work?
uronic acid, all with the overall aim of de- surgeons must familiarize themselves In 2006, Bellamy et al. conducted an
creasing knee pain and restoring mobility9. with evidence-based medicine con- industry-sponsored Cochrane Review
Intra-articular hyaluronic acid was cepts and judiciously evaluate the that compared 19 different hyaluronic
approved as a biologic device for use in effectiveness and integration of new acid formulations across 76 RCTs46.
humans in Canada in 1992 and in the technologies34,35. The ability to criti- The sample sizes of the trials ranged
United States in 199723,30. Current cally appraise empirical studies will allow from 12 to 495, and the median meth-
commercial hyaluronic acid prepara- surgeons to discern between novel drugs odological quality was rated as 3 of 5 on
tions are either harvested from rooster or devices that may either markedly the Jadad scale66. Despite considerable
combs (synthetic avian-based) or syn- improve patient lives or lead to patient heterogeneity among trials with
thesized by means of in vitro bacterial morbidity and wasted resources35. respect to inadequate sample sizes and
fermentation (biofermented, non- Given the mounting evidence the use of different hyaluronic acid
avian)31. Although the former is easier from clinical trials evaluating the efficacy products, comparisons, and trial de-
to manipulate through cross-linking to of hyaluronic acid in knee osteoarthritis, signs, the authors still found hyaluronic
increase molecular weight and provides a researchers have turned to meta-analysis, acid to be an effective treatment with
theoretical advantage associated with a statistical method to systematically com- beneficial effects on pain, physical
higher-molecular-weight prepara- bine and synthesize results from multiple function, and patient global assessment
tions32, non-avian formulations have trials. Meta-analyses are usually performed scores that were most pronounced at 5
emerged more recently in an attempt to as part of an in-depth systematic review and 13 weeks after the injection. They
avoid the potential risks from poultry of the literature and serve to improve the also found the effect of hyaluronic acid
and egg protein allergies31. Several power and precision of effect-size estimates to be comparable with that of oral
preparations of commercial hyaluronic by pooling data from smaller, individual NSAIDs. However, there were few
acid are currently available in North studies36. If performed using high-quality head-to-head trials available, and firm
America. They each vary by molecular trials and robust methodology, meta- conclusions with regard to the relative
weight, method of production, half-life, analyses are the pinnacle of medical effect of each formulation could not
dosing regimen, and cost (Table I)9,30,33. evidence. However, the inclusion of be made. Furthermore, a variety of
Several formulations have evolved and low-quality trials, inappropriate com- comparators were present among the in-
have emerged over the past 2 decades, bination of heterogeneous studies, and cluded studies, including placebo, intra-
which has resulted in a plethora of failure to perform a comprehensive as- articular corticosteroids, NSAIDs,
randomized controlled clinical trials sessment of methodological quality physiotherapy, and arthroscopy, result-
(RCTs) to assess the efficacy and safety may result in misleading findings from ing in most of the comparisons being
of these products. meta-analyses37,38. Viscosupplementa- based on only a few small trials67.
tion in knee osteoarthritis has been the Campbell et al.68 conducted a re-
Many Conflicting Meta-Analyses subject of no fewer than 26 systematic view comparing the results of 6 meta-
Decision-making that is informed by the reviews and meta-analyses from 2003 analyses, all with conflicting results with
integration of best available research, to 2015 (Fig. 1)39-65. Disparate results respect to the efficacy of hyaluronic

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Fig. 1
Number of Level-I articles included in systematic reviews and meta-analyses published on the use of intra-articular hyaluronic acid for the treatment of knee
osteoarthritis39-65.

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acid for knee osteoarthritis40,42-44,47,67. consider a change in management70,71. including active controls into these
All 6 meta-analyses were found to have Using a prespecified validated MCID set groups may have contaminated the
asked similar clinical questions; however, at an effect size of 20.37, the authors analyses and resulted in an overall un-
variations in search strategies and study concluded that viscosupplementation derestimation of the true effect size.
eligibility criteria resulted in the inclusion demonstrated significant but clinically Comparators included oral NSAIDs72,
of different primary trials in each of the irrelevant pain relief (effect size, 20.37; cyclooxygenase-2 inhibitors73, and
reviews. Additionally, differences in as- 95% confidence interval [95% CI], physiotherapy74, in addition to intra-
sessment of study quality, selection of 20.46 to 20.28). Using the same articular placebos and conventional
pooled outcome measures and outcome thresholds, those studies evaluating either treatment75,76. Further, there has been
time points, and statistical model selec- high-molecular-weight or cross-linked growing recognition that the effects
tion contributed to discordant findings. formulations achieved both significant of intra-articular saline solution in
Overall, using the Grading of Recom- and clinically important pain reductions. placebo-controlled trials may not be
mendations, Assessment, Development Although subgroups are often explora- benign. In a 2008 meta-analysis, Zhang
and Evaluation (GRADE) approach69, tory, these findings appeared to support et al. quantified the extent of
Campbell et al. concluded that visco- further exploration of the specific hyal- the placebo effect in RCTs of knee
supplementation provides a probable uronic acid formulation and relying osteoarthritis. The authors concluded
therapeutic benefit for physical function less on the overall class of viscosupple- that placebo therapy is effective in the
improvement and pain reduction, with a mentation effect. treatment of osteoarthritis, especially
low risk for harm. They also suggested The most recent meta-analysis on for pain, stiffness, and physical func-
that further research would be unlikely viscosupplementation for knee osteo- tion. However, an important determi-
to alter their confidence in the effect arthritis was performed in 2015 by nant of the magnitude of the placebo
estimates68. Jevsevar et al., who similarly used the effect is the expected treatment effect of
It was not long before the pendu- MCID approach to assess the effect of the active agent itself 77. The placebo
lum of consensus would swing back. intra-articular hyaluronic acid injec- effect for pain in the knee was found to
In 2012, Rutjes et al. produced a large tions on patient-reported pain and be 0.54 (95% CI, 0.49 to 0.60)77,
meta-analysis on viscosupplementa- function65. The authors assessed a total which would be additive to the effect
tion, where they assessed pain intensity, of 19 RCTs, consisting of 4,485 patients; size of hyaluronic acid found by Rutjes
frequency of osteoarthritis flareups, 14 of the studies were double-blind, et al.58 and would place it well beyond
and physical function across 89 trials placebo-controlled trials. Jevsevar et al. the MCID relative to no treatment.
involving 12,667 patients58. Trial size, concluded that when considering only Likewise, this explains the results from
use of blinded outcome assessment, those trials that were adequately Jevsevar et al. where the treatment ef-
industry support, and publication blinded, the use of hyaluronic acid fect size of hyaluronic acid on pain in
status were all factors found to be as- did not provide a clinically important the sham-controlled trials (20.29
sociated with treatment effect size. difference over placebo. The lack of MCID [95% CI, 20.42 to 20.16
Rutjes et al. commented on the pres- double-blind placebo-controlled design, MCID]) was similar to that in trials
ence of publication bias, as an asym- the use of hyaluronic acid cross-linking, and with an active control comparator
metric funnel plot indicated that the longer follow-up were all associated with (20.49 MCID [95% CI, 20.70 to
majority of the included studies dem- increased treatment effects, which overlap 20.29 MCID]) and lower than that in
onstrated an effect in favor of the inter- or surpass the MCID in most cases65. trials comparing hyaluronic acid with
vention. Unique to their meta-analysis Upon closer inspection, inferences no treatment (21.52 MCID [95% CI,
was the focus on clinically important re- from the overall pooled analysis across 21.87 to 21.17 MCID])65. This
ductions in knee pain over the standard 71 trials by Rutjes et al. that specifically phenomenon is termed the efficacy
statistically significant reductions in assessed knee pain and 19 trials by paradox, where a treatment with a
pain commonly reported in prior reviews. Jevsevar et al. may be limited for several small or clinically unimportant effect
The most common reference point for important reasons. First, heterogeneity relative to placebo in a trial produces a
the interpretation of patient-reported was a serious issue in each meta-analysis, larger or clinically important effect in a
outcomes, such as pain and physical with individual trials varying with re- clinical setting78,79. Finally, caution
function, is the minimal clinically im- spect to concealment of allocation, needs to be exercised when making
portant difference (MCID), which blinding of patients, follow-up duration, study conclusions based solely on the
describes the smallest change in the number of injections, and structure and MCID. Although the MCID provides
outcome of interest that informed molecular weight of the formulation important information relative to the
patients would perceive as important, used. Second, viscosupplementation smallest change that is clinically im-
either beneficial or harmful, and that was compared with either sham treat- portant, it is meant to be a distribu-
would lead the patient or clinician to ment or non-sham treatment, but tional characteristic and not a single

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TABLE II AGREE II Checklist Scores for Knee Osteoarthritis Guidelines*


AGREE II Domains

Scope and Stakeholder Rigor and Clarity of Editorial


Guideline Year Country Purpose Involvement Development Presentation Applicability Independence

American 2013 U.S.A. 94% 86% 94% 100% 23% 100%


Academy of
Orthopaedic
Surgeons (AAOS)
American 2012 U.S.A. 78% 75% 72% 72% 19% 50%
College of
Rheumatology
(ACR)
European 2003 France 92% 67% 73% 83% 44% 21%
League Against
Rheumatism
(EULAR)
National Institute 2014 U.K. 100% 100% 92% 89% 71% 96%
for Health and
Care Excellence
(NICE)
Osteoarthritis 2014 U.K. 86% 81% 86% 100% 23% 100%
Research Society
International
(OARSI)

*Reprinted, with modification, from Altman RD, Schemitsch E, Bedi A. Assessment of clinical practice guideline methodology for the treatment of knee osteoarthritis with intra-articular hyaluronic acid.
Semin Arthritis Rheum. 2015 Oct;45(2):132-9. Epub 2015 May 7.

cutoff 80. In each of the trials assessed, with 39,814 patients to specifically as- Jadad algorithm85, 2 high-quality, Level-I,
there would have been a proportion sess the role of alternate placebos83. independent meta-analyses remained
of patients who reached a treatment When assessing all treatments for knee from which to draw conclusions63,67.
effect at or above the MCID, even if the osteoarthritis, Bannuru et al. found that Campbell et al. found that for patients
mean effect size fell below that point80. active intra-articular treatments were with knee osteoarthritis, intra-articular
A comparison of these proportions superior to oral NSAIDs, with hyal- hyaluronic acid results in improvements
across the trials would have been more uronic acid being the most efficacious in better pain and function than other
informative with respect to the with respect to both pain and function82. treatments for up to 6 months in com-
overall clinically important benefit of- Interestingly, the authors were able to parison with other current treatment
fered by intra-articular hyaluronic acid. show that intra-articular placebos had a options84.
Given that the viscosupplementa- greater effect than oral placebos in reduc-
tion literature is fraught with a variety of ing pain, demonstrating that use of inap- Safety and Adverse Events
comparators, it becomes difficult to ad- propriate placebos for comparisons may Adverse events are uncommon; how-
equately quantify the effect of hyal- lead to inaccurate and misleading effect ever, a self-limited soft-tissue reaction at
uronic acid using traditional meta-analytic estimates79,83. This information raises the site of injection, which is a minor
techniques. Network meta-analyses are important questions about the extent to side effect of viscosupplementation, has
an alternative that uses direct and indi- which therapeutic effects are attributable been recognized. These reactions are
rect comparisons to quantify the relative to a true placebo response compared characterized by localized pain and knee
effectiveness of more than 2 compari- with physiologic effects after directly effusion and typically resolve without
sons when few head-to-head trials injecting a fluid into the knee joint83. treatment in 1 to 3 days. They may be
exist81. Bannuru et al. recently per- Ina 2015 systematic review,Campbell related to improper injection techniques
formed a series of network meta-analyses et al. compiled 14 overlapping meta- or an inappropriate mixture of hyal-
examining the relative efficacy of differ- analyses39,40,42-44,48,50,52,56,58,59,62,63,67, uronic acid with other products9,23.
ent placebos and treatments, including all of which compared viscosupplementa- A more severe side effect, although rare,
hyaluronic acid82,83. They initially tion with oral NSAIDs, intra-articular is a pseudoseptic reaction, which can be
combined 137 trials, consisting of corticosteroids, intra-articular platelet- characterized as inflammation and joint
33,243 patients, to assess the compara- rich plasma, or intra-articular placebo for swelling not associated with infection86.
tive effectiveness of all pharmacological the treatment of knee osteoarthritis84. Pseudosepsis is thought to be an
interventions for knee osteoarthritis82, The studies ranged in Level of Evidence immune-mediated response usually oc-
and subsequently assessed 149 trials from I to IV, and, after application of the curring after sensitization to hyaluronic

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TABLE III Current Knee Osteoarthritis Clinical Practice Guideline Recommendations

Guideline
91 89
Intervention EULAR ACR AAOS16 NICE92 OARSI90

Acetaminophen Beneficial in Beneficial in Uncertain Recommend Recommend


some instances some instances
Oral NSAIDs Beneficial in Beneficial in Recommend Recommend Recommend
some instances some instances
Topical NSAIDs Beneficial in Beneficial in Recommend Recommend Recommend
some instances some instances
Opioids Beneficial in Uncertain Uncertain Uncertain Uncertain
some instances
Intra-articular Beneficial in Beneficial in Uncertain Recommend Recommend
corticosteroids some instances some instances
Intra-articular Beneficial in Uncertain Not Not recommended Uncertain
hyaluronic acid some instances recommended
Acupuncture Beneficial in Beneficial in Not Not recommended Uncertain
some instances some instances recommended
Glucosamine Beneficial in Not recommended Not Not recommended Uncertain
or chondroitin some instances recommended
Arthroscopic Not recommended Not recommended Not Not recommended Not
lavage recommended recommended

acid formulations requiring multiple treatment-related serious adverse events those patients unable to tolerate oral
injections. and subject withdrawals both for any NSAIDs84.
The U.S. Food and Drug Admin- reason and for reasons directly associated
istration (FDA) defines a serious adverse with serious adverse events. A total of Making Sense of Guidelines
event as any undesirable experience as- 29 randomized, intra-articular placebo- Given the array of conflicting trials and
sociated with the use of a medical prod- controlled trials were included, with meta-analyses that have come forward
uct in a patient, including death, 4,866 subjects. The authors found that on the use of viscosupplementation,
hospitalization, disability or permanent intra-articular hyaluronic acid was effec- clinicians look to guidelines to evaluate
damage, birth defects, and other im- tive with respect to reductions in knee and summarize current data and to
portant events requiring medical or pain and improved physical function. provide evidence-based recommenda-
surgical intervention87. Serious adverse There were no significant differences tions for practice. However, consistent
events have been a major recent driver of compared with saline solution controls with the RCT and meta-analysis litera-
concern associated with viscosupple- for any of the safety outcomes, and all ture, current guidelines have discordant
mentation58. These events include dis- of reported serious adverse events were recommendations with regard to the
orders related to the gastrointestinal deemed to be unassociated with the use role of intra-articular hyaluronic acid
system, cardiovascular system, and can- of intra-articular hyaluronic acid. in knee osteoarthritis. The American
cer, in addition to musculoskeletal- Subsequent independent analyses College of Rheumatology (ACR)89,
related events. However, it is difficult to on the safety of viscosupplementation Osteoarthritis Research Society Inter-
interpret these findings because of lim- have been consistent with these findings. national (OARSI)90, European League
ited transparency in serious adverse In their network meta-analysis of Against Rheumatism (EULAR)91,
event reporting in trials and the lack of a comparative efficacy, Bannuru et al. National Institute for Health and Care
direct relationship with viscosupple- found that oral NSAIDs lead to more Excellence (NICE)92, and the American
mentation treatment88. treatment-related events and with- Academy of Orthopaedic Surgeons
Amidst these concerns, an industry- drawals than any of the intra-articular (AAOS)16 have all put forth evidence-
supported meta-analysis by Miller therapies, including hyaluronic acid82. based clinical practice guidelines
and Block specifically set out to determine Through their systematic review of (CPGs) outlining the optimal approaches
the safety and efficacy of intra-articular overlapping meta-analyses, Campbell to non-surgical treatment of knee os-
hyaluronic acid injections approved for et al. also found that hyaluronic acid has teoarthritis. In the face of conflicting
use in the United States59. They outlined a more favorable side-effect profile than empirical evidence and inconsistent
predetermined criteria to identify NSAIDs, making it a good option for recommendations from guidelines,

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clinicians require knowledge of knee pain and function. The application osteoarthritis, in those formulations with
methods to critically evaluate study of MCIDs for the interpretation of higher molecular weights or hyaluronic
methodology and should be familiar treatment effects resulted in the AAOS acid cross-linking. Further, large primary
with tools to assess the quality of cur- making a strong recommendation trials with improved methodology in-
rent evidence. In a recent systematic against the use of viscosupplementation vestigating these effects are likely needed.
review of the guidelines for the treat- in knee osteoarthritis, which contradicts Rare adverse events and long-term safety
ment of knee osteoarthritis, Altman their position statement from 200816. may be best observed through large co-
et al. applied the Appraisal of Guide- The reversal from their earlier position hort studies or registry-type databases
lines for Research and Evaluation was because, despite significant benefits rather than randomized trials99. Im-
(AGREE II) instrument to assess the of hyaluronic acid, these effects did proved knowledge translation of the
presence of bias and quality of report- not reach the MCID cutoffs. Consider- current literature and guidelines is
ing across CPGs, and found inconsis- able debate about the approach in the required to ensure that a clear and con-
tencies in the quality of reporting AAOS guidelines has resulted98, despite sistent message regarding the use of vis-
(Table II)93,94. a thorough and evidence-based ap- cosupplementation for knee osteoarthritis
Although the guidelines are in proach (Table II). Unfortunately, is reaching clinicians faced with making
agreement with respect to the role of guidelines, to a major extent, are prone evidence-based treatment decisions in
certain therapies in clinical practice, they to challenges when the quality of pri- the context of their own experience and
each take a different stance on the use mary evidence used has methodological patients values and preferences.
of viscosupplementation (Table III)93. limitations. Most notably, by failing
All 5 organizations above recommend to adequately account for the additive Herman Johal, MD, MPH, FRCSC1,
against the use of intra-articular lavage, placebo effect associated with intra- Tahira Devji, BSc1,
in keeping with the consistency across articular knee injections77, guidelines Emil H. Schemitsch, MD, FRCSC2,
Mohit Bhandari, MD, PhD, FRCSC1
the literature with respect to this inter- may provide inaccurate and mis-
vention21. Similarly, all of the guidelines informed recommendations78,79. 1Center for Evidence-Based Orthopaedics,

support the administration of both Division of Orthopaedic Surgery (H.J.


topical and oral NSAIDs95, although the State of the Evidence and M.B.) and Department of Clinical
EULAR does outline that oral NSAIDs The body of evidence regarding the use Epidemiology and Biostatistics (T.D.),
McMaster University, Hamilton,
have a worse toxicity profile than most of viscosupplementation in knee osteo-
Ontario, Canada
other treatments, including hyaluronic arthritis is extensive, to a much greater
acid. Beginning in 2007, the OARSI extent than several other treatment 2Division of Orthopaedics, Department of

began performing comprehensive sys- modalities in this area, and in ortho- Surgery, St. Michaels Hospital, University
tematic reviews across treatment mo- paedics in general. Much of the RCT of Toronto, Toronto, Ontario, Canada
dalities for osteoarthritis and have since literature is heterogeneous, attributed
E-mail address for H. Johal:
provided 2 updates to reflect techno- mostly to small sample sizes and multi- herman.johal@medportal.ca
logical advances and emerging ple comparators, leaving them under- E-mail address for T. Devji:
therapies15,90,96,97. In the initial 2 powered to draw consistent conclusions. devjits@mcmaster.ca
iterations of OARSI recommendations, By aggregating the evidence into sys- E-mail address for E.H. Schemitsch:
schemitschE@smh.ca
they identified hyaluronic acid as tematic reviews, meta-analyses, network
E-mail address for M. Bhandari:
useful in the treatment of knee meta-analyses, and guidelines, a bhandam@mcmaster.ca
osteoarthritis15,97. However, the most message begins to emerge but remains
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