Treatment of Osteoarthritis

CHAPTER 100 

Treatment of Osteoarthritis David T. Felson

KEY POINTS Treatment approaches for painful osteoarthritis (OA) should take into account causes, frequency, and severity of pain. Nonpharmacologic treatments such as activity modification, education, and exercise should be a part of treatment for everyone with OA. Many different types of exercise can be effective for knee and hip OA. Patient adherence to exercise is the main challenge. Nonsteroidal anti-inflammatory drugs are moderately effective in OA, more than acetaminophen, and should be started either as topical preparations or on an as-needed basis. Intra-articular steroid injections are highly effective, especially within a few weeks after the injection. Evidence does not support the efficacy of glucosamine, chondroitin, or both to treat OA, and the evidence to support hyaluronic acid preparations is not conclusive. There are many unproven remedies used by patients. Knee and hip joint replacements are highly effective surgeries and should be offered to patients with advanced osteoarthritis who have nocturnal joint pain or pain with rest, or patients in whom pain causes work and functional impairment.

Osteoarthritis (OA) is the most common type of arthritis in the United States and throughout the world, and is the cause of more mobility disability than any other disease. At least 27 million people in the United States have symptomatic OA of the knee, hip, or hands. Symptomatic OA is defined as pain in the joint on most days of a recent month and radiographs that show osteoarthritis in the painful joint.1 The number of affected individuals is rising with the aging of the population, higher rates of obesity (a major risk factor for disease), and frequent sports-related joint injuries that predispose to later disease, especially in the knee. More than 50% of those affected by painful knee or hip osteoarthritis will eventually undergo joint arthroplasty, although only after living many years with pain and functional loss.2 The primary symptom of OA is joint pain, and relieving this pain is the main goal of therapy. In OA, pain is primarily related to carrying out activities. For example, going up and down stairs or getting out of a chair often triggers knee pain in those with knee OA. Cooking or other manual activities can precipitate hand pain in people with hand OA.   Video available on the accompanying ExpertConsult website.

The genesis of joint pain in OA is complicated. The joint is protected from damage by multiple overlapping physiologic systems. Among these are limits to excursion established by muscles, ligaments, and the joint capsule; smooth and coordinated muscle contraction instituted by both the muscles and nervous system–mediated spinal reflexes; and reflexes that provide instantaneous input on the position and tension of muscles across the joint. Activities probably induce joint pain because the load transmitted during these activities is beyond the physiologic capabilities of the joint to withstand. This can occur because the joint is already damaged and cannot withstand much loading—as often occurs in the osteoarthritic joint—or can occur with excess loads in a normal joint. In addition to factors affecting loading are those that lower the threshold for pain, including synovitis within the joint, a common feature of OA. Synovitis may itself be triggered by microscopic damage to cartilage and other structures within the joint, with shards of tissue released into the synovial fluid ingested by synovial lining cells, generating a secondary inflammatory response. In addition, the inflammatory milieu of OA can generate peripheral and even central nervous system changes that lead to chronic pain sensitization. Other factors, including psychological and sociocultural factors, contribute to the presence and severity of pain. Thus, many factors (Figure 100-1) including loading with activities, aberrant structure of the joint that increases focal loading (such as occurs with malalignment), synovitis, impaired muscle function and coordination, deficient proprioception, and nervous system sensitivity contribute to pain. Even psychological factors could theoretically be targeted in patients with painful OA. Pain causes a person to have difficulty carrying out functional activities, including work, household activities, shopping, laundry, and recreational pursuits. Patients with painful OA often experience other symptoms that the physician should elicit during the initial examination and patient history. These symptoms, including giving way of the joint, could be the focus of treatment. Giving way or buckling tends to occur in patients who feel that their joints are unstable, and is a common feature of painful knee and, to a lesser extent, hip OA. Factors that increase the risk of giving way include muscle weakness and the co-occurrence of pain in multiple lower extremity joints. The physician should ask patients whether their knees or hips are unstable or give way because these symptoms may increase their risk of falling and, for some patients, may be more disabling than their pain. 1719

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Psychological factors

Injurious load

Joint pathology

Synovitis

Neurobiologic mechanisms

Sociocultural factors

OA-related pain

Function

Participation/ disability

Health-related quality of life Figure 100-1  Pathophysiology of osteoarthritis (OA)-related pain and its consequences. (Modified from Neogi T: The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage 21[9]:1145-1153, 2013.)

Core treatments for all patients - Exercise - Weight loss - Self-management and education

Mild, intermittent pain No function limitation

Frequent pain Limited function

- As-needed analgesics, including acetaminophen, low-dose NSAIDs - Intra-articular corticosteroids - Topical NSAIDs (not for hip)

- Intra-articular corticosteroids - NSAIDs—oral or topical - Bracing, cane - Duloxetine with depressive symptoms or widespread pain

Moderate/severe pain Affecting work and/or with night pain Limited function - NSAIDs—oral or topical - Intra-articular corticosteroids - Bracing, cane - Duloxetine with depressive symptoms or widespread pain - Opioids as needed - Referral to orthopedist

Figure 100-2  Algorithm for management of knee and hip osteoarthritis.

The management of OA can be divided into nonpharmacologic interventions, pharmacologic interventions, and surgical options. Patients with mild or intermittent pain are likely to need only nonpharmacologic treatment, whereas those with more severe symptoms will probably require both nonpharmacologic and pharmacologic treatments (Figure 100-2).

NONPHARMACOLOGIC TREATMENTS Psychosocial Interventions As in other types of arthritis, patient education is an important first step in OA therapy. The patient should be an integral part of the decision-making team. To do this effectively, the patient should understand the nature of OA, including its natural history and treatment options. It is often reassuring for the patient to realize that OA is a common, slowly progressive ailment and is not typically as

disabling or deforming as the inflammatory arthritides. A significant number of patients have already tried nonprescription medications or nutraceutical remedies before seeing a physician and will want to discuss these options. Physicians should emphasize that treatment includes nonpharmacologic and pharmacologic interventions. Organizations such as the Arthritis Foundation can be valuable sources of information geared toward patients and can provide helpful reading materials. Some patients may develop emotional disturbances related to the pain and changes in normal daily activities that can stem from OA. These may include mood disorders such as depression or sleep disorders.

Avoiding Painful Joint Loading Osteoarthritic pain is activity-related, and for most affected patients, certain activities will reproducibly elicit their joint pain. The painful activities probably cause pain in part by



increasing focal loading across a damaged segment of the joint. Any of the following strategies may be successful in alleviating the pain: • Avoiding activities that cause joint pain • Improving the strength and conditioning of muscles that bridge the joint, to optimize their function • Unloading the joint, either by redistributing load within the joint with a brace or a splint, or by unloading the joint during weight bearing with a cane or a crutch The simplest effective treatment for many patients is to avoid activities that precipitate pain. For example, for the middle-aged patient whose running triggers pain in their knees, a less demanding form of weight-bearing activity may alleviate discomfort. For an older person whose daily constitutionals up and down hills cause knee pain, routing the constitutional away from hills might eliminate symptoms. Each pound of weight increases the overall load across the knee three- to sixfold. Weight loss may have a commensurate multiplier effect, unloading both knees and hips. Obese people undergoing bariatric surgery with subsequent massive weight loss experience a marked reduction in pain.3 Trials of modest weight loss (5 to 10 kg) suggest a moderate reduction in knee pain,4 and the combination of exercise with weight loss appears more effective at relieving pain and reducing knee loading than weight loss alone.5 In hand joints affected by OA, splinting, by limiting motion, often minimizes pain for patients with involvement especially in the base of the thumb. Weight-bearing joints such as knees and hips can be unloaded by using a cane in the hand opposite to the affected joint for partial weight bearing. A physical therapist can teach the patient how to use the cane optimally, including ensuring that its height is optimal for unloading (the optimal height for a cane is with the elbow of the arm holding the cane flexed at an approximately 20-degree angle, or with the top of the cane at approximately the level of the femoral greater trochanter). Crutches or walkers can serve a similar beneficial unloading function.

Exercise Osteoarthritic pain in knees or hips during weight bearing results in lack of activity and poor mobility and, because OA is so common, the inactivity that results increases the risk of obesity and cardiovascular disease, thus representing a public health concern. Aerobic capacity is poor in most elders with symptomatic knee OA, and worse than others of the same age. Weakness in muscles that bridge osteoarthritic joints is multifactorial in etiology. First, there is a decline in strength with age. Second, with limited mobility comes the muscle atrophy of disuse. Third, patients with painful knee or hip OA alter their gait to lessen loading across the affected joint, which further diminishes muscle use. Fourth, “arthrogenous inhibition” may occur, whereby contraction of muscles bridging the joint is inhibited by a nerve afferent feedback loop emanating in a swollen and stretched joint capsule; this prevents maximal attainment of voluntary maximal strength.6 Because adequate muscle strength and conditioning are critical to joint protection, weakness in a muscle that bridges a diseased joint makes the joint more susceptible to further damage and pain. The degree of

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weakness correlates strongly with the severity of joint pain and the degree of physical limitation. One of the cardinal elements of the treatment of OA is to improve the functioning of muscles that surround the joint. For knee and hip OA, trials have shown consistently that exercise lessens pain and improves physical function.7 Most effective exercise regimens consist of aerobic and/or resistance training, the latter of which focuses on strengthening muscles across the joint. Exercises are likely to be effective, especially if they train muscles for the activities a person performs daily. Activities that increase pain in the joint should be avoided, and the exercise regimen needs to be individualized to optimize effectiveness. Range-of-motion exercises, which do not strengthen muscles and isometric exercises that strengthen muscles, but not through range of motion, are unlikely to be effective by themselves. Lowimpact exercises, including water aerobics and water resistance training, are often better tolerated by patients than exercises involving impact loading, such as running or treadmill exercises. A meta-analysis of exercise trials has suggested that, although aerobic, resistance, and performance exercise were all effective for relieving pain in knee OA, single-type exercise programs were substantially more effective than programs including different types of exercise.8 A patient should be referred to an exercise class or to a therapist who can create an individualized regimen, and then an individualized home-based regimen can be crafted. In addition to conventional exercise regimens, tai chi may be effective for knee OA. Despite the clear-cut effectiveness of exercise for knee and hip OA, there is no strong evidence that patients with hand OA benefit from therapeutic exercise. In addition, although exercise reduces pain in knee and hip OA patients, physical therapy referral may have little efficacy in relieving pain, at least in hip OA.9 The reason for the disappointing effect of physical therapy is unclear. Physical therapists may use a combination of treatment modalities for each patient, only some of which are effective, and also patients may not continue to carry out the prescribed exercises after their treatment sessions end. Adherence over the long term is the major challenge to an exercise prescription. In exercise trials involving patients with knee OA, one-third to more than one-half of patients stop exercising by 6 months, and less than 50% continue regular exercise at 1 year. The strongest predictor of a patient’s continued exercise is a previous personal history of successful exercise. Physicians should reinforce the exercise prescription at each clinic visit, help the patient recognize barriers to ongoing exercise, and identify convenient times for exercise to be done routinely (see Table 100-1 for strategies to improve adherence to exercise). The combination of exercise with calorie restriction and weight loss is especially effective in lessening pain.

Strategies to Realign the Joint For knee OA especially, misalignment across the joint increases focal load and, when the joint is loaded, such as with walking or other weight bearing, this excess load can translate into pain. Most commonly, knee OA shows varus deformities in which the medial joint is much narrower than the lateral. In normal nondiseased knees, the medial

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TABLE 100-1  Strategies to Facilitate Long-Term Adherence to Exercise and Physical Activity in People with Osteoarthritis Educate patients about the disease and the benefits of exercise. Develop the exercise or physical activity plan with the patient and vary activities to maintain interest and enthusiasm. Use a graded progressive exercise or physical activity program, and ensure that pain and discomfort are not excessive during or after exercise. Initiate exercise under expert instruction, and supervise exercise sessions if possible. Supplement face-to-face instruction with other materials, such as written handouts, videos or DVDs, and online demonstrations. Increase patient self-efficacy by incorporating behavioral techniques such as goal setting, positive reinforcement, use of an exercise contract, and self-monitoring by use of a diary or pedometer. Include the patient’s partners and family in the exercise program and garner support from family and friends. Monitor the patients during the long term, with periodic reassessment by a health professional. Supplement exercise instruction with an activity monitor (e.g., a wristband that tracks activity) coupled with goal setting. Modified from Bennell KL, Hunter DJ, Hinman RS: Management of osteoarthritis of the knee. BMJ 345:e4934, 2012.

compartment bears approximately 60% of the load during walking, but when medial knee OA and varus deformities are present, that load increases to 80% to 100% of weightbearing load. Joint damage occurs increasingly as a consequence of that load; damage to bone occurs, as evidenced by bone marrow lesions in the medial compartment, and synovitis develops with release of shards of cartilage. Both synovitis and bone marrow lesions are sources of pain. Unloading the medial compartment in these patients by reducing the misalignment might alleviate pain and slow disease progression. The knee is the fulcrum of a large lever arm, extending when walking from the trunk to where the foot meets the floor. When the knee has a varus (bowlegged) malalignment in the frontal or coronal plane, the knees are farther apart than the feet, and the disease in the knee is more often present in the medial than lateral compartment. A small percentage of patients (approximately 10% to 20%) with knee OA have the opposite—a valgus deformity in which the knees are close together and the feet farther apart. Generally, they have disease in the lateral compartment, which is narrower than the medial compartment. When the knee is malaligned, excessive load during weight bearing is transmitted across the narrowed compartment, often causing damage in that area. Realigning the joint and lessening that malalignment might provide therapeutic benefit. One could focus on changing the position of the foot below the knee at the bottom end of the lever arm or on the position of the trunk, above the knee at the top end of the lever arm. Examples of the former strategy include the use of various shoe orthotics, especially lateral wedge insoles, which can be used to treat medial disease. Lateral wedge insoles that are thicker on the outside than on the inside are placed into the shoe. During walking, these wedges move the knee closer to a vertical line through the center of the body, and in doing so lower the varus moment across the knee, a

Figure 100-3  A valgus knee brace used to realign the knee.

measure of medial load. However, despite their effect on reducing medial load during walking, trials of wedge inserts have shown10 that they do not alleviate knee pain compared with neutral inserts, which have no effect on medial loading of the knee. The failure of this promising unloading treatment raises questions about whether unloading of the varus malaligned knee will be effective at all. Reasons for the failure of wedge inserts include the fact that they do not reduce the varus knee moment in all treated patients, the fact that their effect on medial load is small and may be insufficient to produce pain relief, and the fact that patients may not consistently place them in their shoes. Another strategy that rectifies malalignment and unloads the knee is the use of bracing. With metal struts on the side and straps that force the knee into a more neutral alignment, valgus braces can straighten a knee that has varus malalignment (Figure 100-3). Three randomized trials of valgus bracing in patients with knee OA have been carried out, and two of these have reported that, compared either with neutral braces or with sleeves, the braces had moderate efficacy in alleviating knee pain.11,12 Unfortunately, adherence to the use of these large bulky braces is poor, and most patients are unwilling to wear them for long periods of time. Thus, even though they are effective, valgus braces have not been a terribly popular treatment for OA. Given their availability and effectiveness, patients with obviously malaligned varus or valgus knees should be presented with the option of obtaining a knee brace. They should be shown pictures of braces so that they can anticipate what wearing them will be like. For a minority of patients, this may be an acceptable effective long-term treatment. The patellofemoral compartment of the knee is frequently diseased in patients with OA and is a major source



of pain. Because the disease in the patella often affects one compartment preferentially, there is often malalignment of the patella in the trochlear groove; a patellar brace may push the malaligned patella back into the trochlear groove in the femur, increasing the contact area and decreasing the focal load on the diseased patellar compartment. A recent trial6 suggests that patellar bracing may alleviate knee pain at least over the short term in patients with patellofemoral OA. Patellar braces are easier to wear than the larger bulkier tibiofemoral valgus braces and often fit easily underneath trousers. A less obtrusive option that may have similar mechanism of action is patellar taping, which has been shown13,14 to relieve knee pain. Another way to realign the knee is to change the position of the trunk, the top of the lever arm, during walking. In this case, the patient needs to be taught how to position his or her trunk during ambulation so as to lessen malalignment across the knee, a strategy known as “gait retraining.” Although promising, this approach has not been comprehensively evaluated, and long-term patient adherence to gait retraining strategies is unclear.

PHARMACOLOGIC TREATMENTS Acetaminophen (Paracetamol) Many guidelines recommend acetaminophen either on an as-needed or continuous basis as the initial analgesic treatment for OA. Doses as high as 1 g three times daily can be used. Unfortunately acetaminophen, even in high doses, is rarely effective by itself in the treatment of OA. Metaanalyses suggest an effect size of acetaminophen versus placebo of only 0.2 standard deviations, a very small treatment effect.15 In addition, acetaminophen is a weak cyclooxygenase (COX) inhibitor, with a greater COX-2 than COX-1 effect. There is strong evidence that the use of acetaminophen regularly causes gastrointestinal blood loss and that its overall side effect profile is therefore not necessarily benign.16 Although its occasional use for treatment of mild OA with occasional pain is recommended, its lack of substantial efficacy suggests that it should not be a primary treatment for moderate to severe OA.17

NSAIDs Including Oral and Topical Agents and COX-2 Inhibitors NSAIDs are among the most popular treatment for OA. They have both analgesic and anti-inflammatory effects. Meta-analyses suggest that when regularly taken, oral NSAIDs are more effective than high-dose acetamin­ ophen (effect size difference between NSAID and acetaminophen for pain is approximately 0.30, a modest but significant difference).17 Occasionally, patients treated with NSAIDs experience dramatic and complete relief of pain, but this is not universal. NSAIDs, especially when taken orally, have many adverse effects (see Chapter 59). To lessen the risk of side effects, treatment should be started initially on an as-needed basis or by using topical agents, especially for superficial joints such as the hands and knees. If topical or occasional oral medication is insufficient to control symptoms, then daily regular treatment may be indicated.

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NSAIDs cause upper gastrointestinal adverse effects in 30% to 40% of patients, including stomach discomfort, dyspepsia, nausea, and vomiting, and can cause upper gastrointestinal bleeding. These symptoms are partly the result of prostaglandin inhibition in the upper gastrointestinal tract. Prostaglandins are necessary for mucosal protection of the stomach, and inhibiting them makes the stomach mucosa vulnerable. In addition, inhibition of prostaglandins may compromise the perfusion of the superficial lining of the upper gastrointestinal tract, making it more susceptible to injury. Among the risk factors for NSAID-induced gastrointestinal symptoms and complications are higher doses of nonsteroidal drugs; also, particular nonsteroidals increase the risk of gastrointestinal symptoms and bleeding. Based on meta-analyses and a large number of observational studies,18,19 the most dangerous NSAIDs from the perspective of upper gastrointestinal toxicity are indomethacin, ketorolac, piroxicam, and ketoprofen. The safest nonsteroidals from this perspective are nonacetylated salicylates and nabumetone. The former group of drugs, which are inexpensive and underutilized, do not inhibit gastric prosta­ glandins and therefore have fewer gastrointestinal side effects than conventional NSAIDs. Nabumetone is a prodrug and has no local prostaglandin-inhibiting effect when administered. In addition to drug-related factors, there are other known risk factors for NSAID-associated gastrointestinal complications (Table 100-2). Those who need oral nonsteroidals yet who are at high risk should take gastroprotective drugs to lessen their risk. Drugs that protect against gastric and duodenal ulcers based on endoscopic studies include misoprostol, a prostaglandin analog, and proton pump inhibitors. Histamine 2 blockers are not as effective in preventing gastroduodenal complications as are these other two classes of drugs. In addition to upper gastrointestinal side effects, oral NSAIDs also increase the risk of lower gastrointestinal tract bleeding and perforations. Lower gastrointestinal tract symptoms include diarrhea or constipation, and malabsorption or gut inflammation sometimes accompanies the diarrhea.20 The rate of mortality from lower gastrointestinal bleeding caused by nonsteroidals may approach that of upper gastrointestinal bleeding related mortality.21 COX-2 inhibitors were developed in part to minimize the gastrointestinal side effects of nonsteroidals, but they work by inhibiting prostacyclin which, when inhibited, enhances platelet activation. In addition, COX-2 inhibition causes vasoconstriction. The net effect of COX-2 inhibition is to increase the risk of thrombosis, especially TABLE 100-2  Risk Factors for the Development of NSAIDAssociated Gastroduodenal Ulcers Established Risk Factors

Advanced age (linear increase in risk) History of ulcer Concomitant use of corticosteroids Higher doses of NSAIDs and use of more than one NSAID Concomitant administration of anti-coagulants Concomitant infection with Helicobacter pylori

Possible Risk Factors

Cigarette smoking Alcohol

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myocardial infarction. When studies confirmed that rofecoxib increased this risk, it was removed from the market, but some NSAIDs still on the market have preferential COX-2 inhibiting effects. Large-scale observational studies and clinical trials have suggested that oral diclofenac,22 for example, confers a substantial increased risk of myocardial infarction. Other widely used nonsteroidals such as ibuprofen modestly increase myocardial infarction risk (relative risk, ~1.2). The main exception among NSAIDs is naproxen, which does not confer an increased risk of thrombotic events. The risk of celecoxib, the most prominent remaining COX-2 inhibitor on the market, is increased only if high doses of the drug are taken, such as 400 mg per day. In addition to effects on thrombosis, NSAIDs can also induce congestive heart failure in predisposed patients because they cause retention of fluids and they can increase blood pressure because of renal effects, although the effect on blood pressure is usually small, on the order of an increase of 1 to 2 mm Hg. Sodium retention is common among patients taking NSAIDs and, when pronounced, can even lead to rises in serum creatinine. Other renal complications of NSAIDs are uncommon, including frank renal insufficiency, papillary necrosis, and interstitial nephritis. Oral nonsteroidals should not be used in patients with stage 4 or 5 renal disease, and should be used cautiously in those with stage 3 disease. NSAIDs can cause confusion or dizziness, especially in elderly users. In addition, a syndrome known as “anaphylaxis” occurs among some NSAID users. This is a phenomenon mediated not by immunoglobulin (Ig)E but, rather, is a result of prostaglandin inhibition. It occurs especially in aspirin-sensitive patients who often have the syndrome of asthma and nasal or sinus polyposis. Patients in whom anaphylaxis to NSAIDs develops are sensitive to all drugs in the class, except for nonacetylated salicylates, which cause minimal cyclooxygenase inhibition. When placed into a topical solution with a chemical moiety that enhances penetration of the skin barrier, nonsteroidals can be administered topically. Plasma concentrations of topical NSAIDs are far lower than the same amount of drug administered orally. However, if the drug is administered topically over a superficial joint such as the knees or hands, it can be detected at low concentrations in joint tissues. Randomized trials examining the efficacy of topical nonsteroidals suggest that they are more efficacious than placebo and slightly less efficacious than oral agents.23 They are much safer than oral nonsteroidals, however, and the only major side effect associated with topical nonsteroidals is redness, burning, or itching on the skin where the medication is applied. This side effect occurs in a large percentage of patients. Strategies for the use of nonsteroidals in OA patients could include an initial trial of topical NSAIDs if the patient has painful knee or hand OA. Another option would be a trial of low-dose, oral, intermittent NSAIDs in patients who are not at high risk for the side effects. If tolerated, the drug dose can be increased.

be effective in relieving that pain. In fact, intra-articular corticosteroids decrease synovitis,24 and may work in part by diminishing angiogenesis within the synovium, which secondarily decreases synovial inflammation. In randomized trials testing intra-articular steroids versus placebo injections in knee OA, steroids are more effective than placebo in relieving pain for 1 or 2 weeks. However, the longer-term trial data in knee OA is limited, and for some patients the effects may last much longer. In hip OA, intra-articular steroids have are more effective than placebo for at least 8 weeks.25,26 Evidence suggests that withdrawal of synovial fluid may enhance the efficacy of the steroid injection, and that higher doses of steroid tend to have longer-acting effects. The effect size of intra-articular steroids as a treatment for OA in both knee and hip is large, and intra-articular corticosteroids are probably the most efficacious nonsurgical treatment, at least for pain reduction. They are especially efficacious for treating flares of disease and for cases in which disease is caused in part by the presence of intra-articular crystals, such as calcium pyrophosphate dihydrate crystals. No evidence exists that repeated corticosteroid injections into the joint are dangerous, although some case reports show that high doses of intra-articular corticosteroids may increase the risk of avascular necrosis in the treated joint. The use of systemic steroids to treat OA, either orally or as intramuscular therapy, is unproven and is currently not recommended, although studies examining the benefits of local and systemic steroids in OA are in progress.

Corticosteroids as a Treatment for Osteoarthritis

Duloxetine

Because synovial inflammation plays a major role in pain in OA, potent anti-inflammatories such as corticosteroids can

Opioids Because joint pain is the predominant symptom in OA, analgesic medications such as opioids could play a role in treatment. Opioids generally act in the central and peripheral nervous system by binding to opioid receptors. They have many side effects, including sedation, constipation, psychological effects, and dependence, which consists of unpleasant withdrawal symptoms if opioid use is discontinued. Meta-analyses27 have suggested that opioids and tramadol, an opioid-like drug, both have efficacy in treating the pain of OA, but that compared with placebo, that the efficacy is modest at best (effect size vs. placebo of approximately 0.2 to 0.3). For example, a meta-analysis of tramadol has suggested that compared with placebo, its efficacy is somewhat less than the efficacy of oral nonsteroidals for OA. On the other hand, these same meta-analyses suggested that the adverse effect profiles of opioids in OA patients are formidable and that side effects, including major ones, are far more common among patients who take prescribed opioids than among those given placebo in trials. Because of this poor benefit to risk ratio, it is recommended that opioid use in OA be limited. Although concerns have been raised about tolerance to opioids as part of their use in other diseases, there is no evidence that the efficacy of opioids wanes with long-term use.

Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) relieve pain in patients with chronic pain syndromes, including fibromyalgia. Duloxetine, an SNRI, is



approved to treat fibromyalgia, chronic musculoskeletal pain, and OA. In trials in patients with OA in which an escalating dose of as high as 120 mg a day was used, duloxetine was superior to placebo in pain reduction, with differences emerging at 2 weeks of treatment.28,29 However, discontinuation because of side effects was considerably more common among the duloxetine-treated patients. Although these trials may demonstrate the efficacy of duloxetine (and suggest that other SNRIs may also be efficacious for the treatment of pain in OA), chronic widespread pain commonly accompanies painful knee OA. Further, nervous system adaptations occur as part of the chronic pain of OA, leading to allodynia and central sensitization. It may therefore be possible to identify patients who are more likely to respond to duloxetine, people with pain sensitization or chronic widespread pain. This has not been well studied, however.

CONTROVERSIAL THERAPIES Glucosamine and Chondroitin The signature pathology of OA is loss of hyaline articular cartilage. Both glucosamine and chondroitin are glycosaminoglycans constituents of a large macromolecule in cartilage known as aggrecan. These glycosaminoglycans have high negative charges, and during cartilage compression, the negatively charged molecules are forced into close proximity, increasing the electrostatic repulsion force among them. With the end of compression from weight bearing, the electrostatic force predominates and they move away from each other, allowing cartilage to reassume its usual thickness. Thus the chondroitin and glucosamine contribute to the compressive stiffness of cartilage. It is appealing to imagine that one can ingest a molecule that would then be incorporated into cartilage to improve its function. However, glycosaminoglycans are not synthesized from intact chondroitin or glucosamine molecules, and it is unlikely that ingested glucosamine or chondroitin would be incorporated intact into cartilage. While ingested as glucosamine salts (HCl, sulfate), glucosamine at least dissociates completely to glucosamine and its salt in the stomach. Thus the anion accompanying glucosamine is not relevant to the thera­ peutic effect of glucosamine.30 Animal studies of glucosamine and chondroitin suggest that they may have anti-inflammatory effects.30 Other postulated effects include an incorporation of the compounds into cartilage, effects on bone, and indirect effects on the joint via its direct effects on the liver. Controversy exists regarding the interpretation of clinical trials testing the efficacy of glucosamine and chondroitin in humans. Although large, well-done studies have been performed that support the efficacy of each of these compounds, all nonindustry funded studies have been negative, including one large National Institute of Health (NIH)funded multicenter study.31,32 Other publicly funded studies from the United States, Europe, and Canada have all had null findings. One large meta-analysis has suggested that for each of glucosamine and chondroitin, the 95% confidence interval bound around their estimate of efficacy, although excluding a null effect of 0, is not large enough to signify a clinically important effect.33 All positive trials of glucos-

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amine have emanated from one company that produces a glucosamine sulfate compound, as opposed to the usual preparation sold in the United States: glucosamine HCl. As noted in preceding text, the glucosamine salt dissolves in the stomach so that both HCl and sulfate preparation ultimately produce the same molecule, glucosamine. Based on the results of publicly funded studies and meta-analyses summarizing all trial data on the efficacy of glucosamine and chondroitin major organizations such as the Osteoarthritis Research Society International and the American College of Rheumatology have removed glucosamine and chondroitin from lists of recommended OA treatment.34,35 Some glucosamine and chondroitin trials have also suggested that these nutraceuticals delay joint space loss, but the NIHfunded gait study found no evidence of this.36

Hyaluronic Acid Injections When joints such as the knee move back and forth, the motion of one cartilage surface across another is almost frictionless. The lubrication provided by synovial fluid is to the result of several different molecules, among them hyaluronic acid (HA). Concentrations of hyaluronic acid in synovial fluid are diminished in individuals with OA, and that may decrease the viscosity of this fluid during disease. HA may also have direct effects on synovial fluid function. To increase synovial fluid viscosity, a number of compounds of hyaluronic acid have been developed, which are injected into the joint for therapeutic benefit. HA has previously been used in veterinary medicine; in that context it is given either intravenously or as an intra-articular injection. Preparations of HA, when injected into the joint, are cleared usually after only a few hours, perhaps a day. Purified or synthesized HA products with large molecular weights remain a bit longer, with half-lives within the joint ranging from 17 hours to 1.5 days.37,38 There are two fundamental types of HA molecules. The first is HA itself, which is a long nonsulfated chain of variable length with repeating disaccharide units. The second is a cross-linked hyaluronan chain that can be water insoluble as a gel. In OA, not only the concentration of HA in the synovial fluid but also the size of individual HA molecules diminishes.39 Because HA leaves the joint quickly, yet supposedly produces long-lasting clinical effects, other explanations for efficacy have been suggested, including the idea that synovial sites producing HA are stimulated by injections, although the evidence supporting this explanation is meager.38 HA has also been thought to have anti-inflammatory and anti-nociceptive effects,40 but it is difficult to imagine how HA injections would exert prolonged effects, given their transient presence in the joint. HA injections have been approved by regulatory agencies for the treatment of OA and, depending on the preparation, the course of injections ranges from one to five, usually at weekly intervals. A large number of meta-analyses have assessed the efficacy of HA versus placebo intra-articular injection in trials. It is noteworthy that a large number of unpublished trials have been uncovered, and these have generally shown null results.41 Among 18 large trials with blinded outcome assessment, the effect size of HA in reducing pain versus placebo was 0.11; statistically significant but clinically irrelevant. HA injections were found to increase

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the risk of adverse effects, including flares of pain. Different meta-analyses have concluded that trials of HA either provide no evidence of efficacy or that the evidence suggests minimal efficacy. These meta-analyses have focused on knee OA, for which the preponderance of studies has been carried out. Two randomized trials of hip OA comparing the intraarticular HA injection with articular placebo have shown no efficacy of treatment. The recent Osteoarthritis Research Society International guidelines for OA rated hyaluronic acid as uncertain in its efficacy for knee OA and inappropriate for other types of joint OA. The American College of Rheumatology guidelines for the treatment of OA did not make recommendations regarding the use of hyaluronic acid injections for either knee or hip. The National Institute for Health and Care Excellence (NICE) guidelines recommends against offering intra-articular hyaluronate injections. Based on findings from a meta-analysis of pharmacologic treatments in OA,42 intra-articular injections (including intra-articular placebo) are more efficacious in general than orally administered drugs, and a favorable patient response to HA may be explained, in part, by its delivery method.

Tetracyclines Although tetracyclines inhibit enzymes that break down cartilage, doxycycline, tested in a large trial for OA, was not found to consistently protect joints from progressive OA, or to alleviate pain.43

Hydroxychloroquine Given the potential influence of articular inflammation of joint pain and joint destruction, it is appealing to assume that a drug that abrogates inflammatory processes would be efficacious not only for rheumatoid arthritis but also for OA, especially hand OA, where inflammation is so clinically evident. However, there is an absence of evidence on the efficacy of hydroxychloroquine for OA, and it is not recommended in treatment guidelines.

UNPROVEN REMEDIES IN OSTEOARTHRITIS OA is a painful chronic condition that affects many millions of people throughout the world. Furthermore, approved and effective medical therapies, most of them described in this chapter, are often not very effective in alleviating all the pain and discomfort of disease. That has left a major opening for companies and entrepreneurs to market unproven remedies as effective treatments for OA. From copper bracelets to ginger to health food supplements, a multitude of treatments, many with little scientific rationale, are advertised as effective for OA pain. The market for these unproven remedies is large. Any health food store, many pharmacies, and websites with a focus on arthritis, contain ads and opportunities to purchase many of these supposedly effective treatments. Patients will ask whether there is evidence that they work, and many will be convinced that they or a close friend or relative have been helped by use of one or more of these treatments. The threshold that distinguishes an unproven treatment from a treatment that fits within the accepted armamen-

tarium is a fine and blurred line. To be a proven therapy, a treatment needs to have a convincing biologic rationale or mechanism of action that can be proven. Also, randomized clinical trials must demonstrate the efficacy of the treatment. Glucosamine constitutes an excellent example of this blurred line as noted above. For many unproven remedies, there is not as much evidence as there is for glucosamine. In some cases, there is one industry-sponsored trial that reports efficacy, perhaps from a developing country, where trials are often reported as positive. There may be a history of use of this treatment for OA or cultural support among particular communities for its use. There may be some suggestive evidence that a health food or vitamin contains a compound that might be therapeutic, and an industrysponsored trial that purportedly demonstrates efficacy. Such is the case for ginger, which has some mild anti-inflammatory effects. For many unproven remedies, the biologic rationale or mechanism of action is unclear, and there may not be a placebo-controlled randomized trial that suggests efficacy. Because the market is so large and potentially lucrative for those marketing potential treatments for OA, it is not surprising that manufacturers and producers will present rationales for treatment that may not be credible, and that randomized trials are carried out the results of which may not be trustworthy. In evaluating whether patients should be given unproven remedies, several different considerations emerge. First, placebo treatments in OA44 often work moderately well to relieve pain, and their effect on pain compared with no treatment at all is sometimes greater than that of effective treatments compared with placebo. Intra-articular injections are especially likely to be effective.42 Some authors have recommended that if the unproven remedy is benign, then clinicians should provide it to patients even if it is no better than placebo. Given these considerations, when faced with a patient who insists that a specific unproven remedy has been of value for them or those close to them, the clinician should strongly consider not disabusing patients of this notion and should try to take advantage of whatever effect this treatment has, whether it is real or placebo based.

SURGERY FOR OSTEOARTHRITIS Arthroscopy and Meniscal Surgery Many knees affected by OA also have coexistent meniscal tears. These knees often are painful and sometimes have mechanical symptoms, such as catching or locking, which may be referable to their tears. Several randomized trials comparing surgery to no surgery have shown consistently that arthroscopy with meniscal surgery is not effective for these patients. In addition arthroscopy with lavage and débridement is no more effective than no surgery at all.45,46 Even mechanical symptoms presumably related to the meniscal tears often do not respond to arthroscopic surgery. Short of knee replacement, what surgical options are available for patients with OA? If knees have isolated compartment involvement, such as medial tibiofemoral disease, orthopedists may choose to do osteotomies, which break the



CHAPTER 100    Treatment of Osteoarthritis

tibia and can realign the knee to correct malalignment. Alternatively, they can carry out unicondylar replacement with realignment. Both of these surgeries may delay the knee for a knee replacement or even obviate it. Of the two approaches, osteotomies are becoming less popular as there are fewer surgeons familiar with carrying them out.

Total Joint Arthroplasty Knee and hip replacements are efficacious and cost-effective for patients with advanced osteoarthritis who have severe pain. There is little agreement among surgeons, practitioners, or even patients as to exactly which patients ought to get knee or hip replacement.47 Indications not only vary among surgeons, but they also vary across countries. However, a number of investigators in different countries have suggested that particular patients are good candidates for knee or hip replacements. Recommended indications are shown in Table 100-3 based on a recent survey of patients and orthopedists. Although these guidelines focus on pain and disability, surgery should be reserved for those whose symptoms have not responded to nonsurgical treatments, such as exercise and anti-inflammatory drugs. The major determinant of the need for surgery is pain, and not necessarily radiographic severity or the amount of joint destruction. Many patients with severe joint destruction have surprisingly little pain; whereas others whose radiographs do not show advanced disease are disabled by pain. Among these two contrasting groups, those with disabling pain are likely to be better candidates for knee replacement, although recent data48 suggest that those in whom a knee replacement is most likely to fail are often those whose radiographic disease at the time of surgery is extremely mild. This may be because the knee pain experienced by these patients is not actually the result of knee OA but, rather, more diffuse pain syndromes such as fibromyalgia. The indications for knee and hip arthroplasty are not necessarily the same. Hip arthroplasty is, on average, a more successful operation, with faster rehabilitation times than knee replacement. That suggests that the threshold for seeking a hip replacement might be lower than that for knee

Table 100-3  Indications that Patients May Be Good Candidates for Hip or Knee Replacement Patients report that arthritis symptoms are negatively impacting their overall quality of life. The patient has evidence of arthritis on examination (clinical and radiographic/imaging) of the joint being considered for surgery. The patient has had an adequate trial of nonsurgical arthritis treatment. The patient’s expectations for joint replacement surgery are achievable. The patient is physically and mentally ready to have surgery. The patient and surgeon agree that the potential benefits to the patient of joint replacement surgery outweigh the potential surgical risks. From Hawker G, Bohm ER, Conner-Spady B, et al: Perspectives of Canadian stakeholders on criteria for appropriateness for total joint arthroplasty in patients with hip and knee osteoarthritis. Arthritis Rheumatol 67(7):1806– 1815, 2015.

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replacement. For patients undergoing knee replacements, 20% to 30% have persistent pain and disability, even 2 or more years after the operation, and the rehabilitation after knee replacement often takes several months, in part to regain full range of motion. Risk factors for a poor outcome after knee replacement include the presence of pain in the contralateral knee or other joints,49 and the presence of a higher comorbidity burden. Although those with worse pain and disability have greater absolute improvements in their pain and function scores after joint replacement, they still are left with more functional limitations than those who went into joint replacement with milder functional limitations. Although obese individuals also experience the benefits of knee and hip replacement, the failure rates of these prostheses is higher. Younger patients (those younger than 60 years) are increasingly presenting with a need for knee and hip replacement. In the United States, especially, there is a marked increase in the rates of knee and hip replacement among these people, and although prostheses last many years, it is unclear whether the durability of prostheses will be the same in patients who undergo the surgery at a younger age, in large part because they are far more active than older patients. Patients who meet clinical criteria for knee or hip replacement and are age 60 years and older are old enough to benefit from the surgery without being at high risk of loosening or other joint failure. Increasingly it is thought that patients 55 years and older have a similar benefit to risk ratio, but it is unclear whether those younger than 55 years will similarly benefit without an increased risk. Although patients with OA that affects the thumb base (the first carpometacarpal [CMC] joint) often experience a reduction in pain and improvement in hand function after surgery, the surgical approaches are varied, and it is unclear which has better outcomes.50 Options include trapeziectomy and the same surgery with tendon interposition and/or ligament reconstruction, CMC fusion, and even total joint replacement. Other joints affected by OA may benefit from joint replacement. Although glenohumeral joint OA is uncommon, evidence51 suggests that patients with this disorder who undergo shoulder joint arthroplasty experience a marked reduction in pain. Ankle joint OA, usually a consequence of trauma to the ankle, can be treated with either ankle joint replacement or ankle fusion.

Joint Distraction A novel and still experimental approach to treating OA is joint distraction arthroplasty, in which an external fixation frame bridging the joint is fixed with two bone pins on each side of the joint, and the frame gradually elongates, increasingly distracting the joint and separating one side of the joint from the other. The tubes with distraction are applied for approximately 2 months, after which they are removed. One effect of this distraction is to unload the osteoarthritic joint. This approach has been used most often for ankle OA, for which surgical and other treatments are limited. The joint space or bone-to-bone distance in the ankle increases in many patients after distraction arthroplasty, especially of the ankles, and more comprehensive studies have suggested that cartilage redevelops within the joint, although it is

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not clear whether this is hyaline articular cartilage. Bone marrow lesions also appear to shrink or even resolve. Recent reports suggest that distraction arthroplasty might additionally be successful for knee OA,52 at least at a follow-up of 24 months. Although promised as a treatment, distraction arthroplasty requires the patient to wear the fixation device around the affected joint for a couple of months with limited activity during that time, and the long-term effects beyond 2 years are not well documented. The references for this chapter can also be found on ExpertConsult.com.

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