More than 27 million Americans have osteoarthritis, a number projected to increase rapidly over the next few decades due to the aging of the Baby Boomer population.1 According to the Centers for Disease Control and Prevention, the annual combined direct and indirect costs for arthritis and related rheumatic diseases totals more than $86 billion.2 The pathophysiology of osteoarthritis is commonly characterized by several features, such as progressive erosion of articular cartilage, subsequent joint space narrowing, subchondral cysts, synovial inflammation, and osteophyte formation.3 Individuals with this condition experience a combination of symptoms, including joint pain and stiffness, decreased range of motion, muscle weakness, and functional disability. Osteoarthritis tends to follow a pattern of joint mechanics deterioration, with symptoms such as disabling pain, causing alterations of normal function, leading to muscle atrophy and weakness, initiating a cycle that worsens and aggravates joint degradation (Figure).4,5
Figure. The Deteriorating Cycle of Osteoarthritic Symptoms, Leading to the Degeneration of Joint Mechanics.
There are no U.S. Food and Drug Administration (FDA)-approved osteoarthritis interventions that ultimately modify the actual disease. Organizations such as the American College of Rheumatology, the European League Against Rheumatism, the American Academy of Orthopaedic Surgeons, and the Osteoarthritis Research Society International have developed recommendations in the pursuit of contemporary management of osteoarthritis to control pain and improve function and health-related quality of life, while avoiding toxic effects of therapy.6–8
Although total knee replacement is a proven method to relieve pain and restore function, not all patients agonized by osteoarthritis are candidates for surgery and others would like to postpone this course of action, which requires a rigorous rehabilitation program. Current guidelines include nonpharmacological interventions (ie, patient education, personalized social support, exercise programs) in combination with medicinal treatment. The focus of this article is to provide an update of frequently used treatment options for osteoarthritis, with a specific focus on the latest evidence supporting the use of viscosupplementation.
Muscle Strengthening and Aerobic Exercise
The common initial treatment guidelines for osteoarthritis are some form of therapeutic exercise (commonly, rehabilitation, muscle strengthening, range of motion, and aerobic exercises), as well as weight loss. Quadriceps weakness is one of the commonly targeted culprits in disabling joint pain and progression of osteoarthritis.9 In a meta-analysis of 18 studies, resistance training improved the muscle strength and self-assessed measures of pain and function in 50% to 75% of the participants (age range, 55 to 74 years).10 The financial cost of this approach is minimal; simple exercises completed from the comfort of a patient’s home, without professional equipment, is therapeutically effective.11 Conversely, if the guide of a professional physical therapist is desired, fees can be expensive. The most frequently experienced adverse effect associated with a sound muscle strengthening program is minor muscle soreness. Unfortunately, the benefits of muscle strengthening are not sustained in the long term.12 Strengthening exercises are a solution to the problem of quadriceps weakness and can reduce levels of pain, allowing for an increase in functional ability.
An established correlation exists between obesity and osteoarthritis, which lends to the notion that aerobic exercise with a goal of weight loss can alleviate osteoarthritis symptoms. On a mechanical level, obesity increases the biomechanical loading of the knee, with subsequent gait modification, which has been commonly thought to accelerate osteoarthritis.13 On a microbiological level, elevated adipokine level, due to large amounts of adipose tissue, has been proposed as a contributing factor.14 Leptin, one of these adipokines, is a key regulator of chondrocyte metabolism and is markedly elevated in osteoarthritis cartilage and in osteophytes, promoting the idea that this protein may contribute to the pathophysiology of osteoarthritis.15 Reduction of body fat, decreased joint loading, and resulting modification of the adipokine profile may delay the onset or even reverse the symptoms of osteoarthritis. Like muscle strengthening, aerobic exercise may be free of financial cost and is also associated with minor muscle soreness. Unfortunately, patient compliance with a weight loss or strengthening exercise regimen is frustratingly low, limiting the effectiveness of the recommendation.16
Orthotics, Knee Bracing, and Supporting Devices
Current evidence supports sole inserts in footwear as a useful mechanism to decrease loads and to reduce joint pain and instability in an osteoarthrtitic knee; similar benefits have been reported with knee braces.17–19 Many different types of sole inserts and knee braces are recommended for use, and although a majority of sole inserts and knee braces are primarily aimed to treat other joint conditions, the current literature suggests that only some of them have a useful niche for osteoarthritis.20,21 Although no randomized controlled trials analyzing the use of supporting devices such as canes exists, they remain popular tools owned and appreciated by patients with osteoarthritis.6 There are a few limits to these devices: sole inserts require bigger, perhaps less stylish shoes; braces can be obtrusive; and there is a fear in the general population that overuse of assistive devices will grow into a dependency for ambulation.22 There is a lack of trials comparing the effectiveness of these nonpharmaceutical approaches with standard medicinal treatments. However, the use of an sole insert wedge, brace, or cane is more cost effective than long-term treatment with over-the-counter or prescription medications.
Mild to moderate osteoarthritis pain historically has been treated with simple analgesics, such as acetaminophen. More recent evidence has suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may be more efficacious in significantly reducing overall pain.23 This class of drugs inhibits both COX-1 and COX-2 in the cyclooxygenase (COX) family, thus preventing the production of prostaglandins—proteins that lead to pain and inflammation. Overshadowing these promising benefits are several induced gastrointestinal side effects. Symptoms such as nausea, heartburn, dyspepsia, and abdominal pain can occur in up to 40% of patients taking chronic NSAIDs.24 Risk factors for developing these adverse symptoms include age over 65 years, history of peptic ulcers, and use of anticoagulants or corticosteroids.25 Although gastroprotective countermeasures are recommended when using these medications, persistent gastrointestinal side effects associated with NSAIDs may lower the quality of life enough that patients will discontinue their use.
In an attempt to circumvent gastrointestinal complications, NSAIDs that selectively inhibit the isoenzyme COX-2 have been used. Analysis of multiple studies has concluded that these COX-2 inhibitors have a significant decrease in ulcers, gastric bleeding, dyspepsia, and abdominal pain, while maintaining equivalent therapeutic effects compared with the nonselective predecessors.26,27 Unfortunately, for more than a decade, this drug has been tied with a risk of myocardial infarction.28 Recent evidence now connects both nonselective and cyclooxygenase-2-selective NSAIDs to increased cardiovascular risk.29,30 Another detrimental aspect of the COX-2 inhibitor is its capacity to cause renal toxicity. Those who are at high risk for this side effect are elderly patients and patients with congestive heart failure, diabetes mellitus, or concomitant diuretic use.31 Therefore, NSAIDs should be limited to the minimum effective dose for the shortest duration necessary and should not be encouraged for elderly patients.
The use of synthetic opioids and narcotic analgesics is not uncommon for the short-term treatment of severe pain; stronger opioids are reserved for extreme circumstances.6 Although these prescription medications have been reported to reduce pain intensity, their benefits are limited by prevalent side effects, including nausea, constipation, dizziness, somnolence, and vomiting.32 Opioids should not be considered for long-term palliation due to the concerns of dependency, tolerance, and addiction. Nonetheless, the efficacy of these analgesics to reduce acute attacks of pain gives this medication a useful niche in the treatment of osteoarthritis.
Glucosamine and Chondroitin Sulfate
Glucosamine and chondroitin sulfate are both vital components of the extracellular matrix in articular cartilage.33 When taken as an oral medication, these supplements are claimed to relieve pain, restore function, and slow joint space narrowing. Recommendations from the Osteoarthritis Research Society International support the use of these agents based on these suggestions but note continuing controversy to the efficacy of these drugs as symptom modifiers.6 There is one common finding: these supplements seem to have minimal adverse effects.34,35 The proven safety profile of these oral medications and the potential benefit to patients with osteoarthritis makes these medications an attractive option. A unique pharmacokinetic characteristic of these supplements is that they require a large loading dose and therapeutic effects may not be seen for several months, which can be a frustrating time for an ailing person.34,36 A simultaneous, secondary treatment plan should be utilized to ensure symptoms are alleviated quickly.
Intra-Articular Corticosteroid Injection
Intra-articular corticosteroid injection is another applicable tool in the treatment of osteoarthritis symptoms. Corticoids act directly on nuclear steroid receptors down-regulating the synthesis of certain pro-inflammatory and pain-inducing proteins.37 A direct injection of this medication has been associated with significantly reduced pain as soon as 1 week after treatment.38 The reports concerning the duration of palliation vary widely, but the positive effects seem to last for only 3–6 months at most.39 Although fast-acting and effective in treating pain and inflammation, overuse of this medication has been associated with chondrocyte apoptosis in mouse and canine models.40,41 Recommended injection dosages are limited to 3 to 4 injections per year to avoid a potential risk of advancing cartilage degradation.6 In rare instances, some patients may acquire a mild flare of synovitis caused by a reaction to the crystalline steroid suspensions.8 Infection is a possibility after any intra-articular injection, but this risk is exceedingly low, especially when proper aseptic technique is used. Corticosteroid injection is advised for patients with local inflammation, joint effusion, and acute exacerbation of pain; due to risks with overuse, it should be considered as an adjunct to other rehabilitating treatments.38
Another type of intra-articular therapy for osteoarthritis, and the remaining focus of this article, is viscosupplementation. Hyaluronic acid is a high molecular weight gylcosaminoglycan with unique characteristics that contribute to the joint’s normal rheologic and viscoelastic properties. The fluid in an osteoarthritic joint contains lower concentration and molecular weight of hyaluronic acid.42 The aim of viscosupplementation is to replace hyaluronic acid with the hope of improving the disabling mechanics and symptoms inflicted by osteoarthritis. Intra-articular injection of hyaluronic acid was approved under the category of “biologic device” by the FDA in 1997.
In the market today, several viscosupplements are available: Hyalgan (Sanofi-Aventis, Bridgewater, NJ), Synvisc (Genzyme Corp, Cambridge, Mass), Supartz (Seikagaku Corp, Tokyo, Japan), Orthovisc (Anika Therapeutics Inc, Bedford, Mass), and Euflexxa (Ferring Pharmaceuticals Inc, Parsippany, NJ) (Table 1).43–45 Synvisc is a product in that it is cross-linked—a property connected to longer duration and improved viscoelastic mechanics, but associated with a risk of pseudosepsis.46 All products are derived from rooster combs, except for Euflexxa and Orthovisc, which are bioengineered by fermentation. Euflexxa has been associated with a reduced occurrence of postinjection effusion, giving it a slight safety advantage.47
Table 1: Characteristics of Available Hyaluronic Acid Formulations43–45
Hyaluronic acid is an integral component of healthy synovial fluid and is essential for normal joint function. The hydrophilic molecule is a long polysaccharide chain composed of repeating disaccharide units, N-acetyl-glucosamine, and glucuronic acid. Endogenous hyaluronic acid is produced by type B synoviocytes and fibroblasts in the synovium. It serves as a backbone for the attachment of proteoglycans and is intertwined among superficial and deep collagen fibrils of cartilage. This fundamental molecule has both viscous and elastic properties, giving the synovial joint a unique ability to adjust function under distinct loading conditions.48 Consequently, synovial fluid acts as a lubricant during slow movements and as a shock absorber during rapid movements.
In the osteoarthritic knee, degradation and dilution leads to a 2- to 3-fold reduction in hyaluronic acid concentration. Moreover, the hyaluronic acid present in the osteoarthritis plagued joint has a much lower molecular weight.43 Both alterations lead to dramatic changes in joint properties and mechanics. Theoretically, increasing the amount of hyaluronic acid in the diseased joint will improve function.
Mechanism of Action
The exact mechanism by which hyaluronic acid alleviates symptoms is not clear presently. Several in vitro studies and experimental models have unveiled clues with respect to the anti-inflammatory, analgesic, and potentially even chondroprotective effects induced by hyaluronic acid.
In experimental osteoarthritis, nociceptors of articular nerves become hyperalgesic, discharge spontaneously, and are sensitive to non-noxious movements.49 Injection of hyaluronic acid into this osteoarthritis model decreased ongoing and motion-induced nociceptor activity. This finding is a likely explanation for the prolonged symptomatic relief that hyaluronic acid has been shown to provide.50
An array of studies51–53 using several different osteoarthritis models have provided evidence that hyaluronic acid has proliferative effects on the extracellular matrix in synovial joints. In these studies, hyaluronic acid injections enhanced hyaluronic acid synthesis, boosted proteoglycans synthesis in the presence of interluekin-1α (IL-1α)—a proinflammatory mediator and stimulator of catabolic pathways—and prevented proteoglycans breakdown from cartilage.51–53 In combination, the augmented production of these molecules is thought to contribute to the restoration of healthy synovial fluid and perhaps lead to improvement of the distorted joint mechanics.
Hyaluronic acid also has positive effects on inflammatory mediators. This aspect of hyaluronic acid action has been studied extensively, with multiple results showing decreased levels of prostaglandin E2, reduced expression of IL-1α and stromelysin, suppressed production of tumor necrosis factor and nitric oxide, and reduced arachidonic acid release.54–58 Hyaluronic acid also regulates the actions of immune cells; it reduces the motility, proliferation, and stimulation of lymphocytes in synovial fluids.59–61 Similar influences were discovered with polymorphonuclear leukocytes.62 The scientific evidence serves as a foundation for the anti-inflammatory therapeutic benefits of hyaluronic acid viscosupplementation.
Hyaluronic acid is postulated to have disease-modifying activity, including chondroprotective actions. The cellular mechanism of these effects is not clearly understood, but new evidence is reinforcing this theory. In various experimental models, studies have depicted the role of hyaluronic acid in reducing cartilage degeneration and promoting tissue repair.63 In 2 separate trials on canine and rabbit models, hyaluronic acid injections were shown to suppress chondrocyte apoptosis in the setting of experimentally induced osteoarthritis.64,65 One clinical study observed that the hyaluronic acid concentration remained above baseline value 6 months after viscosupplementation, long after all injected hyaluronic acid is understood to have been naturally metabolized or excreted.66 These results indicate that hyaluronic acid injections might have stimulated production of endogenous hyaluronic acid, which would theoretically alter the progress of osteoarthritis.
The safety of hyaluronic acid viscosupplementation has been well established over 2 decades of clinical trials and practice. There are no known hyaluronate interactions with other medications, making this injection a favorable option for patients already taking medication. The incidence of adverse effects has been reported to be near 1% to 4% per injection.67 The most common of these events is mild pain and slight swelling at the site of injection, lasting 1 to 2 days, which responds well to local modalities and NSAIDs if needed. In extremely rare cases, a severe acute inflammatory reaction, also known as pseudosepsis or severe acute inflammatory reaction, may occur. This effect has been reported in 2% to 8% of patients who were treated with the cross-linked Synvisc preparation.68 It presents 1 to 3 days after the second or third injection as severe inflammation, effusion, and pain at the treated joint. The fact that the reaction does not follow the first hyaluronic acid injection and the finding of increased eosinophils in the affected synovium point to immunologic sensitization as the culprit mechanism, but the true pathogenesis has yet to be proven.69
Sepsis and pseudogout should be excluded from the differential diagnosis by testing for infectious agents and calcium pyrophosphate crystals, respectively. Pseudosepsis is not a self-limited phenomenon and requires symptomatic treatment with analgesics, NSAIDs, or intra-articular steroids.69 In February 2010, the FDA approved the use of Synvisc-One (Genzyme Corp), a single injection option of Synvisc that theoretically may reduce the risk of developing pseudosepsis; however, it is too early to have substantial evidence regarding its clinical efficacy. Hyaluronic acid preparations, except Euflexxa, are contraindicated in patients with avian-related protein allergies. None of the preparations are recommended for pregnant or nursing women or for patients under the age of 18 because the safety and effectiveness in these sub-populations has not been established.70
Current Hyaluronic Acid Evidence
Although the extent and level of the announced benefits vary, there is a plethora of clinical trials and studies supporting the use of intra-articular hyaluronic acid. In a meta-analysis of 76 randomized placebo-controlled trials, Bellamy et al71 concluded that viscosupplementation is an effective treatment for osteoarthritis of the knee, with positive outcomes on pain, function, and patient global assessment. These effects peaked during the 5- to 13-week period after the hyaluronic acid injection. Results of a study comparing hyaluronic acid with NSAID treatment suggest that hyaluronic acid injection provided superior pain relief and functional improvement over NSAID use.72
Another study comparing hyaluronic acid with corticosteroid injections demonstrated that hyaluronic acid injection has a significantly better outcome in pain reduction and functional improvement during the 3- to 6-month follow-up period, providing evidence that hyaluronic acid has more benefits in the long term.73 In a more recent meta-analysis also comparing the longevity of symptom relief, Bannuru et al74 presented data that showed hyaluronic acid is more efficacious than corticosteroids in maintaining the suppression of symptoms more than 2 weeks after injection.
The American Academy of Orthopaedic Surgeons recommendations currently do not support or oppose the use of hyaluronic acid in treatment of osteoarthritis.75 Although variable trial quality and unclear clinical significance hinders a definitive decision, the report acknowledges that results from 42 trials in 6 meta-analysis generally show positive effects on pain level and functional outcome compared with placebo.76 In forming their recommendation, the European League Against Rheumatism acknowledged 2 random controlled trials that suggest the role of hyaluronic acid in structure modification.7 Patients treated with hyaluronic acid for the course of 1 year arthoscopically displayed less deterioration compared with baseline at the end of the year.77 These same patients also scored higher for quality of life and reduced NSAID use during the study period. The other study78 demonstrated that patients treated with hyaluronic acid had a reduction of flares and subsequent decreased need for additional intra-articular corticosteroid injections.
Future Directions of Hyaluronic Acid Application
With increasing evidence suggesting a disease-altering process, future research may explore the potential of viscosupplementation as a disease-modifying osteoarthritis agent. The combination of this potential and the current published literature exhibiting the symptomatic benefits of hyaluronic acid injections in knee osteoarthritis has led to the increase in its off-label use. Recent reviews on viscosupplementation for ankle and hip osteoarthritis claim that hyaluronic acid treatment may be a safe and effective method of treatment for the respective conditions.70,79 To reach a more definitive conclusion, further clinical studies with a larger number of enrolled patients are needed.
Hyaluronic acid is frequently used outside of the United States to treat shoulder pain.80 The most convincing evidence for the use of viscosupplementation in shoulder osteoarthritis comes from a study conducted within the United States reporting that patients who had received hyaluronic acid injections experienced significant pain reduction compared with a control group.81
The use of viscosupplementation is also being experimented with conditions beyond osteoarthritis. A recent study using a rabbit model reported that hyaluronic acid injection following ligament-reconstruction had positive effects on tendon-to-bone healing.82 These results make patients undergoing an anterior cruciate ligament reconstruction another potential group that could experience the benefits.
Currently, the recommended dosage of hyaluronic acid is 3 to 5 weekly injections of varying amounts, depending on the products characteristics. A recent pilot study reported that a single 6-mL injection of cross-linked hyaluronic acid may be as efficacious and well tolerated as the current multiple injection recommendations.83 A single-dose injection would have many benefits, including lowering the risk of adverse events related to injections and decreasing medical costs associated with multiple office visits.
Much debate exists over the idea that higher molecular weight hyaluronic acid preparations are more clinically efficacious than lower molecular weight hyaluronic acid. Evidence has been produced supporting both sides of the argument, leaving this matter a continued mystery.84,85 Due to the lack of substantive evidence to the contrary, the general consensus holds that hyaluronic acid preparations of varying molecular weight provide the same clinical efficacy.44
In the clinical recommendations of the Osteoarthritis Research Society International, there are more than 50 modalities of pharmacological and nonpharmacological treatments for knee osteoarthritis.6 Seemingly overwhelming, the recommendations of this organization and others concur that the decision on a particular option is the result of a delicate balance between the severity of the disease and symptoms, the therapeutic results on the patient, and the adverse effects. The negative effects are summarized in Table 2.
Table 2: Risks and Disadvantages of Current Osteoarthritis Treatment Options6,22,24,28,35,67
Viscosupplementation with hyaluronic acid is an adequate, safe addition to the treatment of osteoarthritis. The effects of hyaluronic acid on inflammatory mediators, immune cells, and the cell matrix allow the medication to serve as a source of palliation. In addition, the potential chondroprotective effects of the molecule could make hyaluronic acid more than just a symptom relief injection. It has become a useful therapeutic option that health care professionals utilize to treat symptoms associated with degenerative joint disease.
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Characteristics of Available Hyaluronic Acid Formulations43–45
|NAME||YEAR APPROVED||ORIGIN||CONCENTRATION (mg/mL)||DOSING REGIMEN||MOLECULAR WEIGHT (kDa)||COST (TOTAL FOR 1 COURSE)|
|Euflexxa®||2004||Bacterial fermentation||10||3 weekly injections||2400–3600||$437.44|
|Orthovisc®||2004||Bacterial fermentation||15||3 weekly injections||1000–2900||$543.00|
|Supartz®||2001||Rooster combs||10||3 weekly injections||620–1200||$533.50|
|Hyalgan®||1997||Rooster combs||10||3–5 weekly injections||500–720||$524.50|
|Synvisc®||1997||Rooster combs||8||3 weekly injections||5000–6000||$589.00|
|Synvisc-One®||2010||Rooster combs||8||1 injection||5000–6000||$939.99|
Risks and Disadvantages of Current Osteoarthritis Treatment Options6,22,24,28,35,67
|Sole insert, brace, cane||Limited shoe selection to fit inserts|
|Braces can be obtrusive|
|Dependency for ambulation|
|Muscle strengthening||Minor transient muscle soreness|
|Aerobic exercise||Minor transient muscle soreness|
|Acetaminophen||Side effects are exceedingly rare; mild lightheadedness may occur|
|Nonselective NSAIDs||Gastrointestinal symptoms: dyspepsia, abdominal pain, gastric bleeding|
|Increase risk of myocardial infarction|
|COX-2 selective NSAIDs||Increase risk of myocardial infarction|
|Opioids||Nausea, constipation, dizziness, somnolence, vomiting|
|Glucosamine and chondroitin sulfate||Rare cases of mild gastrointestinal irritation have been reported|
|Corticosteroid injection||Synovitis, mild pain, and minor inflammation at the injection site|
|Articular cartilage degradation if overused|
|Hyaluronic acid viscosupplementation||Mild pain and minor inflammation at the injection site|
|Allergic reaction in patients with avian allergies (except when taking Euflexxa®)|
|Pseudosepsis has been documented in rare cases|