Lebanese Medical Journal 2012 • Volume 60 (4) 237
G G G GE E E ER R R RI I I IA A A AT T T TR R R RI I I IC C C CS S S S / / / / G G G GÉ É É ÉR R R RI I I IA A A AT T T TR R R RI I I IE E E E
MANAGEMENT OF KNEE OSTEOARTHRITIS
An Evidence-Based Review of Treatment Options
Mira MERASHLY, Imad UTHMAN*
Current approaches for the treatment of knee osteoarthritis
(OA) are mainly symptomatic . The target in treating
patients with OAshould be the safest possible intervention,
with the best pain relief and prevention of further func-
tional disability . Better understanding of the patho-
physiology of the disease will lead to emergence of novel
therapies in the future . There are two types of OA: pri-
mary, due to unknown cause, and secondary as occurs with
trauma or other rheumatic, endocrine, metabolic, and con-
genital disorders . Risk factors for knee OAinclude both
non-modifiable risk factors such as, genetic predisposition,
female gender, and age (> 50 years), and modifiable risk
factors like obesity, recurrent trauma, and sedentary life
style . The clinical picture emerges with worsening
pain, morning stiffness of less than half an hour duration,
swelling, and limited range of motion in the affected joint
. Physical exam reveals crepitus (especially over the
knees), joint tenderness, effusion, and joint deformities in
advanced stages. In addition, limited active and passive
range of motion occurs. The diagnosis of knee OAis main-
ly a clinical one. It is also important to assess for depres-
sion, which can result from chronic untreated pain, and
affects patients with OAquite regularly . When present,
depression must be acknowledged and addressed for the
optimal management of OA. Various radiographic modal-
ities are used to evaluate the severity of the joint involved.
Plain radiography is the most practical, affordable, and
available. Magnetic resonance imaging (MRI), however,
is the most useful for demonstrating cartilage and joint
structure damage and detecting early changes . Despite
excellent imaging techniques, radiological findings do not
correlate well with the patients’symptoms .
In this brief review, we will discuss treatment options
for OA and provide supporting evidence behind the rec-
ommendations. One must acknowledge from the onset the
difficulty in designing studies for this purpose. Measuring
*Division of Rheumatology, Department of Internal Medicine
American University of Beirut Medical Center (AUBMC),
Corresponding author: Imad Uthman, MD. American Uni-
versity of Beirut Medical Center. P.O. Box 11-0236, Riad El-
Solah 1107 2020. Beirut. Lebanon.
a subjective entity like pain, which fluctuates with disease,
emotion, expectation, and personal experience, is chal-
lenging and requires large trials in order to mitigate indi-
vidual and temporal variability. While radiographic studies
may be used as a surrogate measure, the poor correlation
with symptoms creates their own set of problems. For
these reasons and others, the strength of the recommenda-
tions have been known to change over time, and are likely
to do so in the future. Much of the recommendations in
this review rely heavily on the most recent consensus state-
ments from the European League Against Rheumatism
(EULAR) , the Osteoarthritis Research Society Inter-
national (OARSI) , the American College of Rheuma-
tology (ACR) , and the trials on which they were
Weight reduction decreases pain, improves physical activ-
ity, and has structure modifying effects on the knee carti-
lage. Early randomized controlled studies (RCT) showed a
small but significant improvement in knee pain, stiffness,
and function with weight loss . In a more recent study
by the Arthritis, Diet, and Activity Promotion Trial group
(ADAPT), 76 obese or overweight inactive adults with
knee OA were followed for 18 months, and their weight
was documented. Subjects who achieved 10% weight loss
had marked decrease in knee joint compressive loads dur-
ing walking as compared to those with low or no weight
loss . Another trial showed that massive weight loss
(20% body weight) induced by surgery in morbidly obese
patients with knee OA not only improved pain and func-
tion, but also decreased inflammatory markers and had a
structural effect on cartilage . However, voluntary and
involuntary weight loss in elderly patients leads to loss of
muscle and bone mass resulting in an increased risk of falls
and fractures. Weight reduction should be prescribed in
the geriatric population with extreme caution and under
expert guidance, and only for those who are obese (Body
mass index [BMI] > 30 kg/m2). Despite these concerns,
based on multiple randomized controlled trials (RCT), the
OARSI gives weight reduction the highest level of recom-
mendation with 100% consensus.
Exercise and assistive devices
Patients with OA usually avoid physical activity because
of pain which eventually leads to muscle atrophy thereby
increasing the stress on the knee joints . Despite strong
supporting evidence for the benefits of exercise on knee
Merashly M, Uthman I. Management of knee osteoarthritis :
An evidence-based review of treatment options. J Med Liban
2012 ; 60 (4) : 237-242.
A Ag gi in ng g S Su uc cc ce es ss sf fu ul ll ly y
238 Lebanese Medical Journal 2012 • Volume 60 (4) M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis
OA (level of evidence Ia, table I), physical activity unfor-
tunately continues to be underutilized in clinical practice.
In one survey, adults with OAwere almost 50% more like-
ly to be physically inactive compared to those without OA,
which is not entirely surprising. However, in a meta-analy-
sis of 13 RCTs, moderate but significant improvement in
pain was shown with aerobic and knee strengthening exer-
cises . The choice of specific exercises, whether aero-
bic (isotonic), resistance (isometric), flexibility, range of
motion, or aquatic should be individualized according to
each patient’s needs and condition . An exercise pro-
gram is best guided by a trained physical therapist or adult
sports medicine specialist rather than be self-guided. It is
difficult to entirely tease apart exercise and weight loss,
and most people will experience the benefit of both simul-
taneously. The combination of weight loss with physical
exercises (as aerobic and quadriceps muscle strengthening)
has been shown to decrease symptoms by strengthening
the muscles of the knee . Assistive devices can also
decrease symptoms and improve function. There is wide-
spread belief that a walking cane (in the contralateral hand)
improves mobility and pain, but the strong recommenda-
tion supporting the use of walking aids is based on con-
sensus rather than RCT. The level of evidence (LoE) for
assistive devices at this time is IV and further trials are
needed (Table I). On the other hand, in patients with varus
or vulgus instability, a properly fitted knee brace can
improve mobility, reduce pain, and decrease falls (LoE Ia).
Due to frustration with the limits and shortcomings of
Western medicine in relieving arthritic pain, many patients
have sought complementary and alternative interventions.
Commonly used non-pharmacological treatments that have
gained popularity in the past two decades are acupuncture,
transcutaneous electric nerve stimulation (TENS), and tai
chi . Despite early anecdotal evidence of efficacy, few
studies have investigated the role of alternative interven-
tions in the management of knee OA. A trial that recent-
ly compared traditional Chinese acupuncture with sham
acupuncture revealed that both have the same efficacy and
the behavior of the acupuncturist plays a role in relieving
the pain. Previous meta-analysis or RCT, however, showed
significant improvement of chronic pain with acupuncture,
which has earned it a level Ia evidence rating, but with low
consensus agreement (Table II). The intrinsic difficulty in
sham blinding, and the potential relaxing effect of the envi-
ronment and operator may be the reason for inconsistent
results. The role of transcutaneous electric nerve stimula-
tion in treatment of knee OA is still debatable. A systemic
review comparing TENS with sham versus no specific in-
tervention was inconclusive . TENS may be more
effective for the management of low back pain and hip
OA, but more trials are needed to further clarify its role in
knee OA. tai chi is a traditional Chinese mind-body relax-
ation exercise aimed at decreasing pain, anxiety, and de-
pression, and improving physical activity. It has rapidly
gained popularity in Europe and the US over the past two
decades due to the perceived multiple benefits. In fact, var-
ious clinical trials have shown improvement in psycho-
logical stress, pain, and physical activity . Neither
EULAR nor OARSI included tai chi among the interven-
tions reviewed for recommendation, but there is general
consensus that tai chi is a safe and effective intervention.
Acetaminophen, in doses under 4000 mg per day, is a safe
and effective treatment for patients with mild-to-moderate
OA of the knee. All three organizations, (EULAR, ACR,
and OARSI) recommend acetaminophen as first-line treat-
ment for osteoarthritis, and if effective, as the preferred
long-term oral analgesic . Acetaminophen has no sig-
nificant anti-inflammatory activity. Among analgesics, it
is generally viewed as the safest on gastric mucosa, blood
pressure, and renal function. A recent study, however,
showed that acetaminophen has an effect on both COX-1
and COX-2, which raises concern regarding long-term
safety . In fact, in recent years, both the safety and effi-
cacy of long-term acetaminophen have been questioned.
In a 2006 review of nearly 6000 subjects in 15 randomized
controlled trials, acetaminophen showed a statistically sig-
nificant but very small reduction in pain over placebo
, raising the question of clinical efficacy. There was no
significant difference in toxicity between acetaminophen
and placebo in these short-term trials. However, possible
renal and gastrointestinal toxicity occurs with long-term
treatment, as shown in some, but not all, studies. In a case-
control study using the UK General Practice Research
Database , the relative risk for upper gastrointestinal
(GI) bleeding or perforation was RR 3.6 (95% CI 2.60 to
5.10), but these findings were not replicated in a meta-
analysis of three case-controlled trials (RR 1.2, CI 0.8-1.7)
. Similarly conflicting results were found for renal tox-
icity. In any case, acetaminophen is associated with less
toxicity than other analgesic medications and remains the
initial choice for treatment of knee OA. Acetaminophen is
given the highest level of evidence (level Ia) by all agen-
cies, with a strong recommendation and high consensus
LEVEL OF EVIDENCE (LoE)
Type and strength of evidence
Meta-analysis of Randomized Controlled Trials
At least one Randomized Controlled Trial
At least one well-designed controlled study, but without
At least one well-designed quasi-experimental study
At least one non-experimental descriptive study
(e.g., comparative, correlation, or case-controlled study)
Expert committee reports, opinions and/or experience
of respected authorities
M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis Lebanese Medical Journal 2012 • Volume 60 (4) 239
Non-steroidal anti-inflammatory drugs (NSAIDs)
All orally administered NSAIDS, whether selective or
non-selective, should be cautiously prescribed in elderly
people due to their side effects on the kidneys, blood pres-
sure (more so with COX-2 inhibitors), cardiovascular sys-
tem, and GI tract. NSAIDs are more effective than aceta-
minophen in pain control, but in one study the effect size
was minimal; side effects, on the other hand, are consider-
Current guidelines recommend the use of NSAIDs at
the lowest effective dose and caution against long-term
use. In patients with increased GI risk, a selective COX-2
agent should be considered, or a non-selective NSAID
with co-prescription for a proton pump inhibitor (PPI) or
misoprostol for gastrointestinal protection. In fact, in elder-
ly patients, a proton pump inhibitor should be prescribed
with both selective and non-selective NSAIDs. Both non-
selective and COX-2 selective agents should be used with
caution in patients with cardiovascular disease. Naproxen
is the preferred drug among the NSAIDs regarding cardio-
vascular safety . A new drug, naproxcinod (nitrona-
proxen) is a derivative of naproxen with a nitroxybutyl
ester which allows it to act as a nitric oxide donor. Naprox-
cinod is the first in this new class of drugs, the cyclooxy-
genase inhibiting nitric oxide donators (CINODs), and has
the theoretical added benefit over naproxen of gastro-
intestinal and cardiovascular protection due to nitric oxide
release. Over a one-year trial period, this drug showed sim-
ilar analgesic efficacy compared to naproxen, and less gas-
trointestinal and blood pressure effects, but without reach-
ing statistical significance .
Opioids can safely be used in the elderly provided proper
guidelines are followed. Opioids are usually indicated in
moderate-to-severe pain when NSAIDs are ineffective or
contraindicated. Opioid abuse or misuse should be consid-
ered when prescribing it to elderly patients despite the low
risk of this overstated concern. Most opioids are metabo-
lized in the liver by the cytochrome P-450 enzymes and
have an associated risk of drug-drug interactions. Renal
function should be monitored since opioid metabolites,
which may be bioactive themselves, are cleared by the kid-
neys. In addition, other known adverse effects of opioids
as constipation, nausea, and excessive sedation should be
anticipated and addressed . Many physicians and pa-
tients continue to be apprehensive about the use of opioids,
particularly in the elderly, resulting in this class of drug
being underutilized. The efficacy and safety profile of opi-
oids, when used properly, is matched by few other anal-
gesics, and clinicians should have a low threshold for start-
ing opioids in moderate-severe pain. Weak opioids, such as
codeine, are recommended by the World Health Organi-
zation (WHO) for early use in the progression of pain, and
are often combined with acetaminophen for enhanced effi-
cacy . It is noteworthy to mention that in a recent ran-
domized controlled trial, Tramadol was shown to have a
similar efficacy to sustained release diclofenac in patients
with knee or hip OA, and with a more favorable safety
profile . Tramadol is a centrally acting analgesic with
weak opioid activity.
Glucosamine and chondroitin
Glucosamine is an endogenously synthesized hexosamine
involved in the formation of hyaluronic acid, proteogly-
cans, glycolipids, and glycoproteins which are important
constituents of articular cartilage. Chondroitin sulfate is
a structural part of the extracellular matrix which is essen-
tial for pressure resistance through retaining water within
the cartilage. The European League Against Rheumatism
(EULAR) has given both glucosamine sulfate and chon-
droitin sulfate the highest level of evidence and recom-
mendation strength . Many clinical trials have shown
marked symptomatic improvement with glucosamine sul-
fate compared to placebo or NSAIDs, as well as better tol-
erability and sustained effect, while others have shown no
significant difference between placebo and glucosamine
[29-30]. A recent randomized controlled pilot study using
magnetic resonance imaging (MRI) in patients with OAof
the knee showed a significant reduction in cartilage loss
as early as six months in patients taking chondroitin sulfate
. The most recent Cochrane review of 4963 patients
with OAtaking glucosamine included 25 randomized con-
trolled trials and showed a 22% improvement in pain and
an 11% improvement in function using the Lequesne Index
. Glucosamine was shown to be better than placebo
in patients using the Rotta glucosamine crystalline prepa-
ration, but not with other preparations . In most stud-
ies, 1500 mg of glucosamine and 1200 mg of chondroitin
sulfate was used daily. The effects are generally apparent
RECOMMENDATIONS for VARIOUS INTERVENTIONS COMPILED
from ACR, EULAR, OARIS, and OTHER GUIDELINES [10-12].
Injectable hyaluronic acid
Total knee replacement
* Strength of recommandation - A: high B: moderate C: low D: very low
LoE: level of evidence
TENS: transcutaneous electric nerve stimulation
NA: not available NSAIDs: non-steroidal anti-inflammatory drugs
240 Lebanese Medical Journal 2012 • Volume 60 (4) M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis
2-3 weeks after starting treatment, and persist for a pro-
longed period . If no response is noted within six
months, treatment should be discontinued. The Glucosa-
mine/chondroitin Arthritis Intervention Trial (GAIT) was
the largest multicenter, randomized, placebo-controlled
study which showed some efficacy in combining both glu-
cosamine and chondroitin sulfate for people with moderate
to severe knee OA. Despite the clinical benefit and the
structural modifying effects from combining glucosamine
and chondroitin sulfate that the GAIT and other trials have
shown , limited data exist concerning their long-term
safety. Concerns such as hyperglycemia with glucosamine
or bovine spongiform encephalopathy in patients taking
chondroitin sulfate (can be derived from animal sources)
were unfounded. Caution should be taken when prescrib-
ing the combination to patients on warfarin because of the
risk of increased INR and bleeding .
Glucosamine and chondroitin sulfate are classified as
dietary supplements in the US and therefore not regulated
by the Food and Drug Administration (FDA). Consequent-
ly, they cannot be marketed for the treatment of any specif-
ic disease, and safety and consistency of formulation are the
sole responsibility of the manufacturer. In most of Europe,
both compounds are sold as medical drugs, and are under
strict regulation. European formulations, hence, eliminate
the uncertainty that hangs over unregulated drugs.
Omega-3 polyunsaturated fatty acids
Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are
known for their anti-inflammatory actions and effect on
increasing collagen synthesis. The main dietary source of
ω-3 PUFA is fish, walnut, and flaxseed. The cardiovascu-
lar benefit of PUFA is well known, but only recently has
the effect on OAbeen investigated. In a recent randomized
study of 177 patients suffering from moderate to severe
knee osteoarthritis, ω-3 PUFA was found to have a syner-
gistic effect with glucosamine on pain relief when com-
pared to glucosamine alone . Other studies have shown
the benefits of ω-3 PUFA on OA. In 2011, a study per-
formed on an experimental model of OA to assess the net
effect of ω-3 PUFA showed clear benefits in decreasing
signs of OA. Consensus recommendations at this time
are to increase dietary intake of ω-3 PUFA from natural
sources, or as supplements if necessary.
Hyaluronic acid (HA) is a glycosaminoglycan distributed
widely throughout the body. It is a natural component of
cartilage extracellular matrix and may contribute to cell
proliferation. Hyaluronic acid is given as an intra-articular
injection, and increases synovial fluid viscosity and elastic-
ity. It is safe and well tolerated but relatively expensive.
High molecular weight HA has a delayed onset but pro-
longed effect (up to 3-6 months), and is given once every
3-5 weeks. Many studies, but not all, show that HAcan de-
crease pain and improves physical activity . HAis rec-
ommended for use by ACR and EULAR when other mea-
sures of pharmacologic therapy fail. Because the efficacy
of HAhas been shown in randomized controlled trials, it is
given a LoE rating of Ia. However, because of cost effec-
tiveness, inconsistent benefit, and risk/benefit analysis, it is
recommended as a last alternative before surgery.
Both ACR and EULAR have recommended intra-articular
steroid injection in the treatment of local active joint in-
flammation and swelling. Intra-articular steroids have a
rapid onset of action (few days) and an effect that last for
a relatively short duration (3-4 weeks), in contrast to HA
which has a more delayed onset of action and more pro-
longed effect. Intra-articular steroid injections showed bet-
ter pain relief with no functional improvement according
to most studies in literature . For obvious reasons, this
treatment option should not be used for the primary man-
agement of OA, but can be a useful adjuvant treatment
when additional relief is urgently needed. Due to the clini-
cal evidence of efficacy but short duration of pain relief
and inconvenience, intra-articular steroid injections are
given a high LoE but weak recommendation.
Other applications and new therapies
Duloxetine (Cymbalta), a serotonin-norepinephrin reup-
take inhibitor (SNRI) has shown efficacy in treating pain
in knee OAaccording to a randomized controlled study of
256 subjects . At 13 weeks follow-up, treatment with
duloxetine was associated with significant pain reduction
and functional improvement, but also with significant side
effects and dropout rate . Furthermore, it is not entire-
ly clear how much of the benefit was due to inadvertent
treatment of concomitant depression. Topical NSAIDs and
capsaicin (a chili pepper extract) have been shown to be
effective adjuvant or alternative treatments for knee OAin
RCTs and meta-analysis of these trials , though the size
of the effect has been debated. Topical NSAIDs do not dis-
play the serious side effects of their oral counterpart, and
have been used in Europe for decades. Diclofenac 1% gel
(Voltaren) delivers effective concentrations in the affected
joint but with limited systemic exposure. However, local
reactions such as burning, itching, and rash are not uncom-
mon, especially with capsaicin. A newly developed thera-
py for OAis tanezumab, the first monoclonal antibody that
inhibits nerve growth factor. Tanezumab showed great im-
provement in pain and physical activity, but unfortunately
was withheld by the FDAbecause of increased number of
joint replacements in patients receiving this medication
SURGICALAND OTHER RECOMMENDATIONS
When nonsurgical measures fail to achieve adequate pain
relief, or when there is marked limitation of daily activi-
ties, surgical options must be considered.
Based on individual criteria, several surgical proce-
dures can be performed, including arthroscopic debride-
ment, osteotomy, unicompartmental knee replacement,
patellofemoral replacement, total knee replacement, and
M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis Lebanese Medical Journal 2012 • Volume 60 (4) 241
joint fusion. With total knee arthroplasty, pain scores im-
proved more rapidly and completely than does physical
function. For optimal results, patients with OA should be
referred for surgical care prior to the onset of joint con-
tracture, severe muscle atrophy, or advanced joint defor-
mity. Total knee replacement generally is less effective in
restoring patients to normal function when compared to
hip replacement surgery. More severe pain, functional lim-
itation, frailty, mental distress, and co-morbid conditions
are associated with poor surgical outcome. Ten to twenty
percent of patients who undergo total knee replacement are
dissatisfied with the result .
Osteoarthritis is the most common form of arthritis, and
its incidence increases rapidly with age. Osteoarthritis is a
progressive degenerative disease, and treatment must
evolve with disease progression. Several classes of med-
ications and treatment modalities have been used to relieve
pain and preserve function. Most have been studied exten-
sively but results of even well-designed trials can diverge.
Furthermore, effect of a drug (beneficial or adverse) in an
individual patient is not always predictable and may differ
from the class effect. Ashort treatment trial may be neces-
sary to determine efficacy. This potential discrepancy be-
tween statistical outcome and individual result is captured
in the guidelines, to whatever extent possible. A summa-
ry of recommendations for select interventions compiled
from multiple guidelines is presented in table II.
In closing, interpretation of guideline recommenda-
tions, and how they were derived, must be clarified, since
they have been a source of confusion and misinterpreta-
tion. Level of evidence (LoE) refers to the source from
which the evidence was derived. It describes the quality of
evidence and academic vigor, with meta-analysis of RCT
being of strongest quality and expert opinion the lowest.
The strength of effect describes how much of a clinical
effect (usually benefit) is expected from the intervention.
The strength of recommendation incorporates LoE and
strength of effect, as well as cost, safety, and feasibility.
An intervention with a high LoE does not necessarily trig-
ger a strong recommendation. For example, NSAIDs have
a greater effect on pain reduction than acetaminophen in
most studies, but carries a lower recommendation due to
concerns with long-term safety. Total knee arthroplasty has
a LoE of III since no blinded RCT have studied the pro-
cedure, yet it carries a strong recommendation in advanc-
ed OA. In the five years between the publication of the
EULAR and the OARIS guidelines (2003-2008), new
studies were published explaining, in part, the difference in
recommendations among the agencies. Future guidelines
will undoubtedly evolve further.
As this issue of the LMJ went to print, the 2012 guidelines
of the American College of Rheumatology were published
. They recommend aerobic and aquatic exercises and
decreasing body weight as a part of non-pharmacologic
management of knee OA. Acetaminophen, oral or topical
NSAIDs, Tamadol and intra-articular corticosteroid injec-
tions are recommended as needed. On the other hand, they
recommend against the use of chondroitin sulfate, gluco-
samine, and topical capsaicin, and made no mention of
duloxetine, hyaloronic acid, or opiod analgesics. The full
report can be accessed online .
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