NEWS & VIEWS
OSTEOARTHRITIS
Is viscosupplementation really so unsafe
for knee OA?
Timothy E. McAlindon and Raveendhara R. Bannuru
The latest in a series of meta-analyses of trials assessing viscosupplementation for knee osteoarthritis is the
first to raise concerns about its safety. Questions remain, however, regarding the methodological rigour with
which the serious adverse events were analyzed, and the biological plausibility of the events reported.
McAlindon, T. E. & Bannuru, R. R. Nat. Rev. Rheumatol. 8, 635–636 (2012); published online 11 September 2012; doi:10.1038/nrrheum.2012.152
Osteoarthritis (OA) of the knee is a com­
mon, disabling disorder that poses a con­
siderable challenge to patients and their
physicians because treatment options are
extremely limited and none are curative.
Many of the pharmaceutical agents indi­
cated for OA are especially likely to cause
adverse effects among people with charac­
teristics that predispose them to such
events. Adverse effects of NSAIDs, for
example, include serious and potentially
fatal toxic events ranging from gastro­
intestinal haemor­r hage to myocardial
infarction. Paracetamol (aceta­minophen),
often viewed as the safest analgaesic, is
notorious for causing fatal liver damage in
overdosage,1 and commonly causes gastro­
intestinal abnormalities. 2 Given these
outcomes, locally directed therapy makes
sense because of its potential to limit sys­
temic toxic effects. Indeed, intra-articular
injection of corticosteroids has been used
for decades in the treatment of OA, and
seems to be relatively safe; however, its
usefulness is limited by a duration of effect
that is consider­ably less than the recom­
mended interval between doses. 3 It is
perhaps because of these complexities that
intra-­a rticular hyaluronic acid (IAHA)
preparations have been used consistently
since their introduction in the 1990s,
despite controversy about their efficacy.4–6
For a common problem such as knee OA,
with the limited range of available treat­
ments often further constrained by comor­
bidities or low levels of efficacy, the good
safety profile of an intervention can be the
primary predicate of its use. In the case
of IAHA, viewed by the FDA as a ‘device’,
occasional post-injection flare has been the
only prominent toxic effect.
NATURE REVIEWS | RHEUMATOLOGY VOLUME 8  |  NOVEMBER 2012  |  635
© 2012 Macmillan Publishers Limited. All rights reserved
For these reasons, the assertion arising
from a recent meta-analysis4 of the toxic­
ity of IAHA is surprising and requires
responsible interpretation: if correct, we
could be exposing our patients to unantici­
pated risks; if incorrect, patients might
opt for more toxic alternatives. The with­
drawal (appropri­ately) of rofecoxib from
the market, for example, was followed by
a resurgence in the use of non­s elective
NSAIDs and an upsurge in gastro­intestinal
adverse events.7 In the case of IAHA, its
possible toxicity has already propagated
in somewhat sensa­tionalized terms to the
lay literature, 8 and could lead to patients
ch­oosing unsafe alternatives.
‘‘
...locally directed therapy
makes sense because of its
potential to limit systemic
toxic effects
’’
The meta-analysis of IAHA by Rutjes
et al. 4 is methodologically exemplary in
many aspects, especially in the use of clini­
cal trial quality indicators in the analysis of
pooled efficacy data. The investigators also
obtained unpublished results from three
trials, although the inability to disclose the
con­tributory data clouds the transparency
of the analysis. The result that will attract
greatest attention, how­ever, relates to their
assess­ment of the safety of IAHA. On the
basis of pooled adverse events from a subset
of 14 trials (a total of 3,667 patients), they
reported that, in patients with knee OA,
visco­supplementation is associated with
an increased risk of serious adverse events
(SAEs; relative risk 1.41, CI 1.02–1.97).
The most frequent disorders related to the
gastro­intestinal system (two events among
patients who received visco­s upplemen­
tation versus eight among controls),
cardio­v ascular system (five versus two
events), cancer (six versus zero events), and
musculo­skeletal system (four versus two
events). Rutjes et al.4 concluded, “Because
of increased risks for serious adverse events
and local adverse events, the administra­
tion of IAHA preparations should be dis­
couraged.” Although it is possible that their
interpretation might eventually prove to be
correct, several considerations prompt con­
straint in making a definitive assertion that
IAHA products have unacceptable toxic­ity.
The first problem is that no previous meta-
analyses or guideline panels, or any of the
primary clinical trial reports, identified
safety as a prominent concern of IAHA use.
10 of the 14 trials used in this meta-analysis
to calculate relative risk ratios for SAEs
reported that these events were unrelated
to the treatment. Only one study reported
IAHA ­treatment-related SAEs—one case
of cutaneous vasculitis and one severe skin
reaction.9 The remaining SAEs occurred
in three unpublished studies, the results of
which are neither public­ly available (two of
which were funded by Anika Therapeutics
[2000 and 2001] and one by Genzyme
[2005]) nor reported in this meta-­analysis,4
and so are difficult to evaluate. The second
problem is that, with the exception of
local cutaneous or synovitic reactions, it
is hard to discern a biologically plausible
basis for the link between IAHA and the
SAEs reported, which include myo­cardial
infarction, transient ischaemic attack,
cancers (ductal carcinoma of breast, basal
cell carcinoma of the face, malignant mela­
noma, squamous cell carcinoma, prostate
NEWS & VIEWS
and gastrointestinal cancers), pneumonia,
macular hole, fracture, intestinal obstruc­
tion, urinary incontinence, upper gastro­
intestinal bleed and joint sprain. In the
trial by Strand et al.10 (Rutjes et al.4 cited
the abstract but the full results have since
been published), the five cancers reported
in four patients were diagnosed so soon
after treatment administration that a causal
re­lationship seems biologically unlikely.
With regard to the efficacy of IAHA,
Rutjes et al.4 concluded that this was not of
clinically relevant magnitude. This result
comes soon after our own 2011 meta-­
analysis that was able to detect a benefit
that exceeded minimally important clinical
improvement at 8 weeks post-injection.5 It
is pertinent, therefore, to scrutinize why
conclusions of meta-analyses, considered
the highest level of evidence, can be dis­
cordant. In our study, we detected the effect
of IAHA by evaluating its therapeutic tra­
jectory, rather than assuming a time-stable
effect.5 Rutjes et al.4 used a time point for
their primary outcome that would prob­
ably co­incide with a waning of effect. They
tested the trajectory in a secondary analy­
sis, but the set of trials that they pooled
was different from that used in the other
meta-­analyses, and the estimated effect
did not reach their predefined threshold
of minimally important clinical improve­
ment. Similarly, most of the differences in
results among meta-analyses are attribut­
able to differences in the trials pooled and
the data extracted. In most cases, these
choices are made with the intent of improv­
ing the quality of the included data, but
sometimes can be ­counter-productive. For
example, the Rutjes et al.4 analysis pooled
data from studies with placebo and active
comparator arms, which might have biased
their results to the null. Also, the inclusion
of studies that incorporated other types of
interventions (arthro­s copy, ultra­s ono­
graphy, cyclo-­oxygenase 2 inhibitors, and
so on) or con­trols (such as appropriate care,
treatment of the contra­lateral knee) will
introduce hetero­geneity that can obfuscate
interpretation. The inclusion of unpublished
data, whilst considered to be important in
reducing publication bias, also introduces
complexities since these data are not peer-
reviewed, and can vary between meta-
analyses. All of these factors could have
accounted for the inability of the Rutjes
et al.4 analysis to discern a clinically relevant
effect of IAHA.
Finally, although reporting of clinical
trial methodology and efficacy data has
636  |  NOVEMBER 2012  |  VOLUME 8  www.nature.com/nrrheum
improved in recent years, adverse event
ascertainment and description remains
highly inconsistent. To the extent that the
reliability of meta-analytic results is con­
tingent on the quality of the pooled data,
less weight can be placed on results relat­
ing to safety and toxicity than efficacy. In
other words, it is not clear that Rutjes et al.4
applied the same methodological rigour to
their interpretation of safety data as they
did for efficacy data. Nevertheless, there
is likely to be agreement among clinicians
and policy makers that the effectiveness of
IAHA pro­ducts in general appears some­
what modest. In this situation, risk and cost
become pivotal characteristics, and, clearly,
both need to be further determined.
Center for Arthritis and Rheumatic Diseases,
Tufts Medical Center, Boston, MA 02111, USA
(T. E. McAlindon, R. R. Bannuru).
Correspondence to: T. E. McAlindon
tmcalindon@tuftsmedicalcenter.org
Acknowledgements
T. E. McAlindon is supported by funds from the NIH.
R. R. Bannuru is supported by the Agency for
Healthcare Research and Quality (grant number
F32HS021396). The content of this commentary
is solely the responsibility of the authors and
does not necessarily represent the official views
of the NIH or the Agency for Healthcare Research
and Quality.
Competing interests
T. E. McAlindon declares associations with the
following companies: Bioiberica, Flexion
Therapeutics and Sanofi-Aventis. See the article
online for full details of the relationships.
R. R. Bannuru declares no competing interests.
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IMMUNOLOGY
Zoster vaccine and biologic agents:
time to question a paradigm?
Tim Bongartz and Robert Orenstein
Vaccination for the prevention of herpes zoster with the attenuated
live vaccine is currently not recommended for patients with rheumatic
diseases while they are receiving biologic agents, but new evidence calls
the validity of this guidance into question. Is it time to rethink the use
of the herpes zoster vaccine in these patients?
Bongartz, T. & Orenstein, R. Nat. Rev. Rheumatol. 8, 636–638 (2012); published online 2 October 2012;
doi:10.1038/nrrheum.2012.168
For patients with rheumatic diseases,
treat­ment with biologic agents is a contra­
indication for vaccination with the live
© 2012 Macmillan Publishers Limited. All rights reserved
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