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Management of knee osteoarthritis: An evidence-based review of treatment

Article  in  Le Journal médical libanais. The Lebanese medical journal · November 2011
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Mira Merashli Imad W Uthman
American University of Beirut American University of Beirut


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An Evidence-Based Review of Treatment Options

Mira MERASHLY, Imad UTHMAN* Aging Successfully

Merashly M, Uthman I. Management of knee osteoarthritis : a subjective entity like pain, which fluctuates with disease,
An evidence-based review of treatment options. J Med Liban emotion, expectation, and personal experience, is chal-
2012 ; 60 (4) : 237-242. 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
INTRODUCTION with symptoms creates their own set of problems. For
these reasons and others, the strength of the recommenda-
Current approaches for the treatment of knee osteoarthritis tions have been known to change over time, and are likely
(OA) are mainly symptomatic [1]. The target in treating to do so in the future. Much of the recommendations in
patients with OA should be the safest possible intervention, this review rely heavily on the most recent consensus state-
with the best pain relief and prevention of further func- ments from the European League Against Rheumatism
tional disability [2]. Better understanding of the patho- (EULAR) [10], the Osteoarthritis Research Society Inter-
physiology of the disease will lead to emergence of novel national (OARSI) [11], the American College of Rheuma-
therapies in the future [3]. There are two types of OA: pri- tology (ACR) [12], and the trials on which they were
mary, due to unknown cause, and secondary as occurs with based.
trauma or other rheumatic, endocrine, metabolic, and con-
genital disorders [4]. Risk factors for knee OA include both NON-PHARMACOLOGIC THERAPY
non-modifiable risk factors such as, genetic predisposition,
female gender, and age (> 50 years), and modifiable risk Weight reduction
factors like obesity, recurrent trauma, and sedentary life Weight reduction decreases pain, improves physical activ-
style [5]. The clinical picture emerges with worsening ity, and has structure modifying effects on the knee carti-
pain, morning stiffness of less than half an hour duration, lage. Early randomized controlled studies (RCT) showed a
swelling, and limited range of motion in the affected joint small but significant improvement in knee pain, stiffness,
[6]. Physical exam reveals crepitus (especially over the and function with weight loss [11]. In a more recent study
knees), joint tenderness, effusion, and joint deformities in by the Arthritis, Diet, and Activity Promotion Trial group
advanced stages. In addition, limited active and passive (ADAPT), 76 obese or overweight inactive adults with
range of motion occurs. The diagnosis of knee OA is main- knee OA were followed for 18 months, and their weight
ly a clinical one. It is also important to assess for depres- was documented. Subjects who achieved 10% weight loss
sion, which can result from chronic untreated pain, and had marked decrease in knee joint compressive loads dur-
affects patients with OA quite regularly [7]. When present, ing walking as compared to those with low or no weight
depression must be acknowledged and addressed for the loss [13]. Another trial showed that massive weight loss
optimal management of OA. Various radiographic modal- (20% body weight) induced by surgery in morbidly obese
ities are used to evaluate the severity of the joint involved. patients with knee OA not only improved pain and func-
Plain radiography is the most practical, affordable, and tion, but also decreased inflammatory markers and had a
available. Magnetic resonance imaging (MRI), however, structural effect on cartilage [14]. However, voluntary and
is the most useful for demonstrating cartilage and joint involuntary weight loss in elderly patients leads to loss of
structure damage and detecting early changes [8]. Despite muscle and bone mass resulting in an increased risk of falls
excellent imaging techniques, radiological findings do not and fractures. Weight reduction should be prescribed in
correlate well with the patients’ symptoms [9]. the geriatric population with extreme caution and under
In this brief review, we will discuss treatment options expert guidance, and only for those who are obese (Body
for OA and provide supporting evidence behind the rec- mass index [BMI] > 30 kg/m2). Despite these concerns,
ommendations. One must acknowledge from the onset the based on multiple randomized controlled trials (RCT), the
difficulty in designing studies for this purpose. Measuring OARSI gives weight reduction the highest level of recom-
mendation with 100% consensus.
*Division of Rheumatology, Department of Internal Medicine
American University of Beirut Medical Center (AUBMC), Exercise and assistive devices
Beirut, Lebanon. Patients with OA usually avoid physical activity because
Corresponding author: Imad Uthman, MD. American Uni-
versity of Beirut Medical Center. P.O. Box 11-0236, Riad El- of pain which eventually leads to muscle atrophy thereby
Solah 1107 2020. Beirut. Lebanon. increasing the stress on the knee joints [15]. Despite strong
e-mail: supporting evidence for the benefits of exercise on knee

Lebanese Medical Journal 2012 • Volume 60 (4) 237
significant improvement of chronic pain with acupuncture,
TABLE I which has earned it a level Ia evidence rating, but with low
LEVEL OF EVIDENCE (LoE) 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
LoE Type and strength of evidence

results. The role of transcutaneous electric nerve stimula-
Ia Meta-analysis of Randomized Controlled Trials
Ib At least one Randomized Controlled Trial tion in treatment of knee OA is still debatable. A systemic
IIa At least one well-designed controlled study, but without review comparing TENS with sham versus no specific in-
randomization tervention was inconclusive [18]. TENS may be more
IIb At least one well-designed quasi-experimental study effective for the management of low back pain and hip
III At least one non-experimental descriptive study OA, but more trials are needed to further clarify its role in
(e.g., comparative, correlation, or case-controlled study) knee OA. tai chi is a traditional Chinese mind-body relax-
IV Expert committee reports, opinions and/or experience 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
of respected authorities

OA (level of evidence Ia, table I), physical activity unfor- decades due to the perceived multiple benefits. In fact, var-
tunately continues to be underutilized in clinical practice. ious clinical trials have shown improvement in psycho-
In one survey, adults with OA were almost 50% more like- logical stress, pain, and physical activity [17]. Neither
ly to be physically inactive compared to those without OA, EULAR nor OARSI included tai chi among the interven-
which is not entirely surprising. However, in a meta-analy- tions reviewed for recommendation, but there is general
sis of 13 RCTs, moderate but significant improvement in consensus that tai chi is a safe and effective intervention.
pain was shown with aerobic and knee strengthening exer-
cises [16]. The choice of specific exercises, whether aero- PHARMACOLOGIC THERAPY
bic (isotonic), resistance (isometric), flexibility, range of
motion, or aquatic should be individualized according to Acetaminophen
each patient’s needs and condition [16]. An exercise pro- Acetaminophen, in doses under 4000 mg per day, is a safe
gram is best guided by a trained physical therapist or adult and effective treatment for patients with mild-to-moderate
sports medicine specialist rather than be self-guided. It is OA of the knee. All three organizations, (EULAR, ACR,
difficult to entirely tease apart exercise and weight loss, and OARSI) recommend acetaminophen as first-line treat-
and most people will experience the benefit of both simul- ment for osteoarthritis, and if effective, as the preferred
taneously. The combination of weight loss with physical long-term oral analgesic [19]. Acetaminophen has no sig-
exercises (as aerobic and quadriceps muscle strengthening) nificant anti-inflammatory activity. Among analgesics, it
has been shown to decrease symptoms by strengthening is generally viewed as the safest on gastric mucosa, blood
the muscles of the knee [15]. Assistive devices can also pressure, and renal function. A recent study, however,
decrease symptoms and improve function. There is wide- showed that acetaminophen has an effect on both COX-1
spread belief that a walking cane (in the contralateral hand) and COX-2, which raises concern regarding long-term
improves mobility and pain, but the strong recommenda- safety [20]. In fact, in recent years, both the safety and effi-
tion supporting the use of walking aids is based on con- cacy of long-term acetaminophen have been questioned.
sensus rather than RCT. The level of evidence (LoE) for In a 2006 review of nearly 6000 subjects in 15 randomized
assistive devices at this time is IV and further trials are controlled trials, acetaminophen showed a statistically sig-
needed (Table I). On the other hand, in patients with varus nificant but very small reduction in pain over placebo
or vulgus instability, a properly fitted knee brace can [21], raising the question of clinical efficacy. There was no
improve mobility, reduce pain, and decrease falls (LoE Ia). significant difference in toxicity between acetaminophen
and placebo in these short-term trials. However, possible
Other interventions renal and gastrointestinal toxicity occurs with long-term
Due to frustration with the limits and shortcomings of treatment, as shown in some, but not all, studies. In a case-
Western medicine in relieving arthritic pain, many patients control study using the UK General Practice Research
have sought complementary and alternative interventions. Database [22], the relative risk for upper gastrointestinal
Commonly used non-pharmacological treatments that have (GI) bleeding or perforation was RR 3.6 (95% CI 2.60 to
gained popularity in the past two decades are acupuncture, 5.10), but these findings were not replicated in a meta-
transcutaneous electric nerve stimulation (TENS), and tai analysis of three case-controlled trials (RR 1.2, CI 0.8-1.7)
chi [17]. Despite early anecdotal evidence of efficacy, few [23]. Similarly conflicting results were found for renal tox-
studies have investigated the role of alternative interven- icity. In any case, acetaminophen is associated with less
tions in the management of knee OA. A trial that recent- toxicity than other analgesic medications and remains the
ly compared traditional Chinese acupuncture with sham initial choice for treatment of knee OA. Acetaminophen is
acupuncture revealed that both have the same efficacy and given the highest level of evidence (level Ia) by all agen-
the behavior of the acupuncturist plays a role in relieving cies, with a strong recommendation and high consensus
the pain. Previous meta-analysis or RCT, however, showed agreement [10-12].

238 Lebanese Medical Journal 2012 • Volume 60 (4) M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis
Non-steroidal anti-inflammatory drugs (NSAIDs) Opioids
All orally administered NSAIDS, whether selective or Opioids can safely be used in the elderly provided proper
non-selective, should be cautiously prescribed in elderly guidelines are followed. Opioids are usually indicated in
people due to their side effects on the kidneys, blood pres- moderate-to-severe pain when NSAIDs are ineffective or
sure (more so with COX-2 inhibitors), cardiovascular sys- contraindicated. Opioid abuse or misuse should be consid-
tem, and GI tract. NSAIDs are more effective than aceta- ered when prescribing it to elderly patients despite the low
minophen in pain control, but in one study the effect size risk of this overstated concern. Most opioids are metabo-
was minimal; side effects, on the other hand, are consider- lized in the liver by the cytochrome P-450 enzymes and
ably higher. have an associated risk of drug-drug interactions. Renal
Current guidelines recommend the use of NSAIDs at function should be monitored since opioid metabolites,
the lowest effective dose and caution against long-term which may be bioactive themselves, are cleared by the kid-
use. In patients with increased GI risk, a selective COX-2 neys. In addition, other known adverse effects of opioids
agent should be considered, or a non-selective NSAID as constipation, nausea, and excessive sedation should be
with co-prescription for a proton pump inhibitor (PPI) or anticipated and addressed [26]. Many physicians and pa-
misoprostol for gastrointestinal protection. In fact, in elder- tients continue to be apprehensive about the use of opioids,
ly patients, a proton pump inhibitor should be prescribed particularly in the elderly, resulting in this class of drug
with both selective and non-selective NSAIDs. Both non- being underutilized. The efficacy and safety profile of opi-
selective and COX-2 selective agents should be used with oids, when used properly, is matched by few other anal-
caution in patients with cardiovascular disease. Naproxen gesics, and clinicians should have a low threshold for start-
is the preferred drug among the NSAIDs regarding cardio- ing opioids in moderate-severe pain. Weak opioids, such as
vascular safety [24]. A new drug, naproxcinod (nitrona- codeine, are recommended by the World Health Organi-
proxen) is a derivative of naproxen with a nitroxybutyl zation (WHO) for early use in the progression of pain, and
ester which allows it to act as a nitric oxide donor. Naprox- are often combined with acetaminophen for enhanced effi-
cinod is the first in this new class of drugs, the cyclooxy- cacy [27]. It is noteworthy to mention that in a recent ran-
genase inhibiting nitric oxide donators (CINODs), and has domized controlled trial, Tramadol was shown to have a
the theoretical added benefit over naproxen of gastro- similar efficacy to sustained release diclofenac in patients
intestinal and cardiovascular protection due to nitric oxide with knee or hip OA, and with a more favorable safety
release. Over a one-year trial period, this drug showed sim- profile [28]. Tramadol is a centrally acting analgesic with
ilar analgesic efficacy compared to naproxen, and less gas- weak opioid activity.
trointestinal and blood pressure effects, but without reach-
ing statistical significance [25]. Glucosamine and chondroitin
Glucosamine is an endogenously synthesized hexosamine
TABLE II involved in the formation of hyaluronic acid, proteogly-
RECOMMENDATIONS for VARIOUS INTERVENTIONS COMPILED cans, glycolipids, and glycoproteins which are important
from ACR, EULAR, OARIS, and OTHER GUIDELINES [10-12]. 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
Intervention LoE STRENGTH OF
the cartilage. The European League Against Rheumatism
Weight reduction Ia small A
(EULAR) has given both glucosamine sulfate and chon-
Aerobic exercise Ia small B droitin sulfate the highest level of evidence and recom-
Quadriceps strengthening Ia moderate A mendation strength [10]. Many clinical trials have shown
TENS Ia NA C marked symptomatic improvement with glucosamine sul-
Acupuncture Ib small B fate compared to placebo or NSAIDs, as well as better tol-
Walking aids IV NA A erability and sustained effect, while others have shown no
significant difference between placebo and glucosamine
[29-30]. A recent randomized controlled pilot study using
Acetaminophen Ia small A

magnetic resonance imaging (MRI) in patients with OA of
NSAIDs Ia moderate B

the knee showed a significant reduction in cartilage loss
Opioids Ia NA B
Glucosamine/ Ia small-moderate B
as early as six months in patients taking chondroitin sulfate
Chondroitin sulfate [31]. The most recent Cochrane review of 4963 patients
Injectable hyaluronic acid Ia small C with OA taking glucosamine included 25 randomized con-
Injectable steroids Ia strong C trolled trials and showed a 22% improvement in pain and
Capsaicin Ia moderate B an 11% improvement in function using the Lequesne Index
Total knee replacement III NA A [32]. Glucosamine was shown to be better than placebo
in patients using the Rotta glucosamine crystalline prepa-
* Strength of recommandation - A: high B: moderate C: low D: very low ration, but not with other preparations [32]. In most stud-
ies, 1500 mg of glucosamine and 1200 mg of chondroitin
LoE: level of evidence TENS: transcutaneous electric nerve stimulation

sulfate was used daily. The effects are generally apparent
NA: not available NSAIDs: non-steroidal anti-inflammatory drugs

M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis Lebanese Medical Journal 2012 • Volume 60 (4) 239
2-3 weeks after starting treatment, and persist for a pro- of HA has been shown in randomized controlled trials, it is
longed period [33]. If no response is noted within six given a LoE rating of Ia. However, because of cost effec-
months, treatment should be discontinued. The Glucosa- tiveness, inconsistent benefit, and risk/benefit analysis, it is
mine/chondroitin Arthritis Intervention Trial (GAIT) was recommended as a last alternative before surgery.
the largest multicenter, randomized, placebo-controlled
study which showed some efficacy in combining both glu- Intra-articular steroids
cosamine and chondroitin sulfate for people with moderate Both ACR and EULAR have recommended intra-articular
to severe knee OA [34]. Despite the clinical benefit and the steroid injection in the treatment of local active joint in-
structural modifying effects from combining glucosamine flammation and swelling. Intra-articular steroids have a
and chondroitin sulfate that the GAIT and other trials have rapid onset of action (few days) and an effect that last for
shown [35], limited data exist concerning their long-term a relatively short duration (3-4 weeks), in contrast to HA
safety. Concerns such as hyperglycemia with glucosamine which has a more delayed onset of action and more pro-
or bovine spongiform encephalopathy in patients taking longed effect. Intra-articular steroid injections showed bet-
chondroitin sulfate (can be derived from animal sources) ter pain relief with no functional improvement according
were unfounded. Caution should be taken when prescrib- to most studies in literature [40]. For obvious reasons, this
ing the combination to patients on warfarin because of the treatment option should not be used for the primary man-
risk of increased INR and bleeding [36]. agement of OA, but can be a useful adjuvant treatment
Glucosamine and chondroitin sulfate are classified as when additional relief is urgently needed. Due to the clini-
dietary supplements in the US and therefore not regulated cal evidence of efficacy but short duration of pain relief
by the Food and Drug Administration (FDA). Consequent- and inconvenience, intra-articular steroid injections are
ly, they cannot be marketed for the treatment of any specif- given a high LoE but weak recommendation.
ic disease, and safety and consistency of formulation are the
sole responsibility of the manufacturer. In most of Europe, Other applications and new therapies
both compounds are sold as medical drugs, and are under Duloxetine (Cymbalta), a serotonin-norepinephrin reup-
strict regulation. European formulations, hence, eliminate take inhibitor (SNRI) has shown efficacy in treating pain
the uncertainty that hangs over unregulated drugs. in knee OA according to a randomized controlled study of
256 subjects [41]. At 13 weeks follow-up, treatment with
Omega-3 polyunsaturated fatty acids duloxetine was associated with significant pain reduction
Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are and functional improvement, but also with significant side
known for their anti-inflammatory actions and effect on effects and dropout rate [41]. Furthermore, it is not entire-
increasing collagen synthesis. The main dietary source of ly clear how much of the benefit was due to inadvertent
ω-3 PUFA is fish, walnut, and flaxseed. The cardiovascu- treatment of concomitant depression. Topical NSAIDs and
lar benefit of PUFA is well known, but only recently has capsaicin (a chili pepper extract) have been shown to be
the effect on OA been investigated. In a recent randomized effective adjuvant or alternative treatments for knee OA in
study of 177 patients suffering from moderate to severe RCTs and meta-analysis of these trials [11], though the size
knee osteoarthritis, ω-3 PUFA was found to have a syner- of the effect has been debated. Topical NSAIDs do not dis-
gistic effect with glucosamine on pain relief when com- play the serious side effects of their oral counterpart, and
pared to glucosamine alone [37]. Other studies have shown have been used in Europe for decades. Diclofenac 1% gel
the benefits of ω-3 PUFA on OA. In 2011, a study per- (Voltaren) delivers effective concentrations in the affected
formed on an experimental model of OA to assess the net joint but with limited systemic exposure. However, local
effect of ω-3 PUFA showed clear benefits in decreasing reactions such as burning, itching, and rash are not uncom-
signs of OA [38]. Consensus recommendations at this time mon, especially with capsaicin. A newly developed thera-
are to increase dietary intake of ω-3 PUFA from natural py for OA is tanezumab, the first monoclonal antibody that
sources, or as supplements if necessary. inhibits nerve growth factor. Tanezumab showed great im-
provement in pain and physical activity, but unfortunately
Hyaluronic acid was withheld by the FDA because of increased number of
Hyaluronic acid (HA) is a glycosaminoglycan distributed joint replacements in patients receiving this medication
widely throughout the body. It is a natural component of [42].
cartilage extracellular matrix and may contribute to cell
proliferation. Hyaluronic acid is given as an intra-articular SURGICAL AND OTHER RECOMMENDATIONS
injection, and increases synovial fluid viscosity and elastic-
ity. It is safe and well tolerated but relatively expensive. When nonsurgical measures fail to achieve adequate pain
High molecular weight HA has a delayed onset but pro- relief, or when there is marked limitation of daily activi-
longed effect (up to 3-6 months), and is given once every ties, surgical options must be considered.
3-5 weeks. Many studies, but not all, show that HA can de- Based on individual criteria, several surgical proce-
crease pain and improves physical activity [39]. HA is rec- dures can be performed, including arthroscopic debride-
ommended for use by ACR and EULAR when other mea- ment, osteotomy, unicompartmental knee replacement,
sures of pharmacologic therapy fail. Because the efficacy patellofemoral replacement, total knee replacement, and

240 Lebanese Medical Journal 2012 • Volume 60 (4) M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis
joint fusion. With total knee arthroplasty, pain scores im- [44]. They recommend aerobic and aquatic exercises and
proved more rapidly and completely than does physical decreasing body weight as a part of non-pharmacologic
function. For optimal results, patients with OA should be management of knee OA. Acetaminophen, oral or topical
referred for surgical care prior to the onset of joint con- NSAIDs, Tamadol and intra-articular corticosteroid injec-
tracture, severe muscle atrophy, or advanced joint defor- tions are recommended as needed. On the other hand, they
mity. Total knee replacement generally is less effective in recommend against the use of chondroitin sulfate, gluco-
restoring patients to normal function when compared to samine, and topical capsaicin, and made no mention of
hip replacement surgery. More severe pain, functional lim- duloxetine, hyaloronic acid, or opiod analgesics. The full
itation, frailty, mental distress, and co-morbid conditions report can be accessed online [44].
are associated with poor surgical outcome. Ten to twenty
percent of patients who undergo total knee replacement are REFERENCES
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242 Lebanese Medical Journal 2012 • Volume 60 (4) M. MERASHLY, I. UTHMAN – Management of knee osteoarthritis

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