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Treatment Options for Osteoarthritis

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ABSTRACT

Osteoarthritis is the most common form of arthritis and can be a major source of disability. Many older patients continue to be active in sports-related activities. Therefore, treating an active patient with osteoarthritis is becoming more common. Physical therapy and weight loss continue to play a central role in the treatment of patients with osteoarthritis. Nonsteroidal anti-inflammatory drugs decrease inflammation and swelling, which makes physical therapy more effective. Intra-articular corticosteroids have been used for the treatment of osteoarthritis. However, no guidelines exist for the administration of corticosteroids and they can be associated with increased risk of tendon rupture and infection. Viscosupplementation has gained popularity in the treatment of osteoarthritis of the knee. Intra-articular injections of hyaluronic acid have been shown to decrease pain and improve functional outcomes.

Osteoarthritis is the most common form of arthritis and can be a major source of disability. Patients typically have pain that worsens with weight bearing and activity, and improves with rest. The treatment goals for patients with osteoarthritis are to reduce pain, improve joint mobility, and limit functional impairment. Traditional nonoperative treatment includes activity modification, weight loss, exercise, assistive devices, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroid injections. Specifically, NSAID treatment is associated with significant morbidity to the gastrointestinal system. The economic burden of the gastrointestinal side effects of NSAIDs is estimated to exceed $500 million annually.¹ Surgical treatment of osteoarthritis of the hip and knee is effective but not indicated for early stages of the disease in all patients. Also, potential complications and enormous costs are associated with surgery.

Since the early 1950s, intra-articular corticosteroids have been used to manage arthritic conditions. Hollander et al² showed that intra-articular hydrocortisone decreases the leukocyte count and temperature of the synovial fluid. More recent studies have shown superior anti-inflammatory effects of tertiary-butyl esters of hydrocortisone compared with hydrocortisone.³ Intra-articular corticosteroids are accepted as an important treatment modality, but currently no administration guidelines exist. Even less information is known regarding intra-articular cortico-steroid injections and the treatment of sports-related injuries.

In recent years, intra-articular viscosupplementation with hyaluronate-derived products has gained popularity as a modality for the treatment of osteoarthritis of the knee. Hyaluronic acid provides the elastic and viscous function of synovial fluid, protecting the joint from compressive and shear forces. The content of synovial fluid, in the presence of osteoarthritis, has a decreased concentration and the molecular weight of hyaluronic acid. This process reduces the viscosity and the protective function of the synovial fluid.

The initial rational for the intra-articular injection of hyaluronic acid was to restore the viscoelasticity of synovial fluid. Several studies have shown that injected hyaluronic acid can augment the flow of synovial fluid, normalize the synthesis and inhibit the degradation of endogenous hyaluronic acid, and relieve joint pain.⁴

Nonpharmacologic Modalities

The cornerstone of treatment for patients with osteoarthritis is education. Patients, as well as their families and caregivers, must be educated about the cause of their pain and the treatment options. Informed consent for treatment must include the risks and benefits of each protocol.

Physical therapy for osteoarthritis plays a key role in managing patients with functional limitations. Therapists develop exercise programs to maintain or improve the range of motion of joints and peri-articular muscle strength. Assistive devices such as canes, crutches, and walkers also help patients improve their functional capabilities. A recent study demonstrated the efficacy of an exercise program in improving muscle strength, mobility, and coordination in patients with osteoarthritis of the hip or knee.⁵ Quadriceps weakness is common in patients with osteoarthritis of the knee. It is most likely due to disuse atrophy that develops from unloading the painful extremity.

Patients can also have decreased proprioception of their joints due to osteoarthritis.⁶ Hurley et al⁷ showed that an organized exercise regimen improved joint proprioception, quadriceps strength, and performance of activities of daily living. Van Baar et al⁵ showed that patients randomly assigned to an exercise group had improved pain and observed disability, but also reported taking less acetaminophen and had fewer physician visits after 12 weeks.

Weight loss is recommended for patients with osteoarthritis of the hip or knee. Weight loss can decrease the forces across weight bearing joints and improve symptoms. The proper use of a cane (in the hand contralateral to the affected knee) also reduces loading forces across the joint, decreases pain, and improves function. In addition, patients may benefit from wedged insoles to correct malalignment of the knee and patella stabilization braces for patellofemoral arthritis.

Pharmacologic Therapy

Pharmacologic treatment of osteo-arthritis is most effective when combined with nonpharmacologic treatment such as exercise and weight loss. Many patients experience relief of joint pain from acetaminophen or traditional NSAIDs. Several studies have shown that acetaminophen and ibuprofen are comparably effective in patients with mild to moderate pain, but ibuprofen was statistically superior to acetaminophen for both pain and function. Acetaminophen can cause hepatic toxicity with doses that exceed 4 g per day. NSAIDs are associated with serious upper gastrointestinal and renal toxicity. Therefore, acetaminophen is recommended for osteoarthritis treatment in patients with impaired renal function. In patients >65 years old, 20%-30% of all hospitalizations and deaths due to peptic ulcer disease were attributable to NSAID therapy.⁸ In patients at risk for upper gastrointestinal adverse events, misoprostol and proton pump inhibitors are recommended in combination with NSAID treatment.

Cyclooxygenase-2 (COX-2) inhibitors have been effective in the treatment of osteoarthritis. Endoscopic studies have shown that COX-2 inhibitors are associated with a lower incidence of gastroduodenal ulcers when compared to traditional NSAID treatment.⁹ Cyclooxygenase-2 inhibitors also do not have any significant effect on platelet aggregation or bleeding time. Cyclooxygenase-2 therapy should be used cautiously in patients with hypertension, congestive heart failure, and renal insufficiency. Celecoxib should not be used in patients with a history of an allergic reaction to sulfonamides.

Corticosteroids

Mechanism of Action
Corticosteroids are a well-known anti-inflammatory medication, but their mechanism of action is not completely known. Corticosteroids are highly lipid soluble and bind to receptors in the nuclei of cells. Corticosteroids inhibit the accumulation of inflammatory cells, such as leukocytes and neutrophils. They prevent phagocytosis, lysosomal enzyme release, and the synthesis of several inflammatory mediators.

Recent studies have shown that intra-articular corticosteroid injections decrease neutrophil migration into inflamed joints of patients with osteoarthritis.¹⁰ The investigators speculated that the mechanism of action is blocking the action of macrophage inhibitory factor, which reduces vascular permeability, and cell adhesion and migration. In addition, intra-articular corticosteroids reduce prostaglandin synthesis up to 50% and decrease interleukin-1 secretion by the synovium. Intra-articular corticosteroids also inhibit leukocyte secretion from the synovium. This inhibition increases the concentration of hyaluronic acid in the joint, which increases the viscosity of the synovial fluid.

Indications
Intra-articular corticosteroid injections are frequently used to treat acute and chronic inflammatory conditions. Injections decrease inflammation and swelling, which decreases pain and increases joint mobility. Results vary depending on the type of joint injected. Small non-weight bearing joints have better results than larger weight bearing joints.³

An intra-articular corticosteroid cannot prevent the pain derived from weight bearing forces across the joint. The literature has shown that intra-articular cortico-steroid injections for the treatment of osteoarthritis can be variable. In a double-blind, placebo-controlled study of 59 patients, Doherty¹¹ reported a significant reduction in pain scores 3 weeks after an intra-articular cortico-steroid injection. Another comparison of intra-articular triamcinolone and placebo showed greater pain relief with a steroid injection at 1 week, but similar results at later intervals.¹² Intra-articular cortico-steroid injections are commonly used for rheumatoid arthritis and show excellent long-term pain relief. Therefore, it is thought that the primary effect of the corticosteroid is on the synovium. Other indications for intra-articular corticosteroid injections are adhesive capsulitis of the shoulder. Several studies have shown improved motion up to 6 weeks after injection, but results are short lived and unreliable.³

No clear, objective evidence exists on intra-articular corticosteroid injections in the treatment of osteoarthritic or sports-related injuries of knees, ankles, shoulders, acromioclavicular joints, lumbar facet joints, and smaller hand and foot joints. Injections around joints are associated with significant risk. Corticosteroid injections around ligaments and tendons inhibit collagen synthesis. Therefore, injections may cause ligament and tendon rupture, which is the reason many orthopedists do not recommend corticosteroid injections in these locations.

Treatment of bursitis and tedonitis, such as subacromial bursitis, greater trochanteric bursitis, and medial/lateral epicondylitis, is common and results have varied in the literature. Stahl and Kaufman¹³ conducted a prospective, randomized, double-blind study on 60 elbows with medial epicondylitis. They reported significant pain relief at 6 weeks after corticosteroid injection. At 3 months, no difference in symptoms was seen between the group that had the injection and the group that did not. Retrocalcaneal and prepatellar burse injections have less promising efficacy and are associated with tendon rupture. In the presence of inflamed bursae or tendons, the injection of corticosteroids provides some relief, but the duration of relief is usually short lived.

Preparations
Hydrocortisone was the first steroid used for intra-articular injection. Additional research led to the development of longer lasting compounds in the form of esters of prednisolone, triamcinolone, and dexamethasone (Table). The duration of effect of the corticosteroid is inversely proportional to the solubility. Triamcinolone hexacetonide is the least soluble and therefore the longest lasting.

Table

Corticosteroids Commonly Used in the Treatment of Patients with Osteoarthritis Generic Name Proprietary Name Concentration (mg/mL) Average Duration of Effect (days) Triamcinolone hexacetonide Aristospan 2 21 Triamcinolone diacetate Aristocort 25-40 7 Triamcinolone acetonide Kenalog 10-40 14 Methylprednisolone sodium succinate Solu-Medrol 40-125 4 Methylprednisolone acetate Depo-Medrol 40-80 8 Prednisolone tebutate Hydeltra 20 10-14 Betamethasone acetate Soluspan 6 9 Dexamethasone acetate Decadron-LA 8 8 Dexamethasone sodium phosphate Decadron 4 6 Hydrocortisone acetate Hydrocortone 25 8

Contraindications
Suspicion of infection is the main contraindication to intra-articular cortico-steroid injection. Active infection of the skin and overlying tissues increases the risk of inoculating the joint during injection. Other absolute contraindications are hypersensitivity, presence of a joint prosthesis, and uncontrolled bleeding diathesis. Relative contraindications include anticoagulation therapy, joint instability, poorly controlled diabetes, and adjacent skin abrasions. Direct injection into a tendon or ligament should always be avoided due to the risk of rupture.

Complications
Adverse effects of corticosteroid injections include local and systemic effects of the medication. The local effects include tendon and ligament rupture, cutaneous atrophy at the injection site, calcification of the joint capsule, and infection. At low doses, the systemic effects including transient eosinopenia and anti-inflammatory effects on distant joints are beneficial. At higher doses, which occur when treating multiple joints, the corticosteroids can inhibit the hypothalamic-pituitary-adrenal axis. This inhibition can occur 2-7 days after the injection.

Viscosupplementation

Hyaluronic acid is a polysaccharide chain made of repeating disaccharide units of N-acetylglucosamine and glucuronic acid. Type B synoviocytes in the synovium synthesize hyaluronic acid and secrete it into the joint space. Hyaluronic acid is made of approximately 12,500 disaccharide units resulting in a molecular weight of 5 × 106 daltons. The human knee contains 2 mL of synovial fluid with a concentration of hyaluronic acid of 2.5 to 4 mg/mL.

In osteoarthritis, the concentration and molecular weight of hyaluronic acid is reduced. The interaction between the hyaluronic acid molecules decreases, which results in lowering the viscosity and elastic properties of the synovial fluid. The lower viscosity creates increased stress forces that can permanently damage the delicate articular cartilage. The lower viscosity also creates an environment that reduces the barrier and filter effects of the synovial fluid. This reduces the nutrient availability and waste removal functions that are vital for the survival of articular cartilage.

Hyaluronic acid has both viscous and elastic properties. At high shear forces, hyaluronic acid exhibits increased elastic properties and reduced viscosity. The opposite is true with low shear forces. Therefore, hyaluronic acid acts as a shock absorber during fast movements and a lubricant during slow movement. Hyaluronic acid also has several anti-inflammatory effects by inhibiting phagocytosis and adherence of leukocytes. It reduces the levels of inflammatory mediators such as prostaglandin and cyclic adenosine monophosphate. Hyaluronic acid also reduces the release of arachidonic acid from synovial fibroblasts. Arachidonic acid is usually taken up by synovial leukocytes and converted into inflammatory mediators. The reduction of the release of arachidonic acid by hyaluronic acid depends on the dose and molecular weight.

The intra-articular injection of hyaluronic acid may affect the synthesis of hyaluronic acid by synovial fibroblasts. Osteoarthritic joints produce a lower level of hyaluronic acid compared to normal joints. Smith and Ghosh¹⁴ studied the effect of hyaluronic acid products on their ability to stimulate synovial fibroblasts. The concentration and the molecular weight of hyaluronic acid were shown to be essential for the hyaluronic acid production. A molecular weight of 5 × 105 daltons was most effective, but, at a high concentration, it can have an inhibitory effect on synovial fibroblasts.

Ghosh¹⁵ showed the direct analgesic effect of hyaluronic acid in a rat model. Intra-articular hyaluronic acid was found to be equivalent to indomethacin in reducing pain. The investigator proposed that hyaluronic acid modulates pain by directly inhibiting nociceptors or indirectly binding substance P, which is involved in pain signals.

The chondroprotective effects of hyaluronic acid have not been clinically proven. Several animal studies have supported the chondroprotective effect of hyaluronic acid. In a canine model, osteoarthritis was induced by transection of the anterior cruciate ligament and matrix production increased, which included hyaluronic acid.¹⁶ In a sheep model in which osteoarthritis was induced by medial and lateral meniscectomies, 5 weekly injections of hyaluronic acid improved gait.¹⁷ The injections did not prevent the progression of osteophyte formation and cartilage degeneration.

The use of hyaluronic acid for viscosupplementation began in the late 1960s by Biotrics, Inc (Arlington, Mass). The source material was taken from human umbilical cord and rooster combs. The hyaluronic acid was purified and initially injected into race horses after traumatic injuries. In recent years, developers have targeted several properties that are important for the human application of hyaluronic acid. These properties are a lack of immunogenicity, capability of allowing passive diffusion within the synovial fluid, native rheologic properties, and a prolonged half-life within the synovium.¹

The hyaluronic acid products that are available in the United States are Synvisc (Biomatrix, Ridgeford, NJ), Hyalgan (Sanofi, New York, NY), and Supartz (Seika-gaku, Falmouth, Mass). They are approved for use in patients with osteoarthritis of the knee. The hyaluronic acid is derived from rooster combs and purified, and the noninflammatory hyaluronan product is isolated. The Food and Drug Administration classifies viscosupplements as medical devices. Therefore, the difficult regulations of a drug are not applied to these products. Orthovisc (Anika Therapeutics, Woburn, Mass) and Neovisc (Stellar International London, Ontario, Canada) are viscosupplements available in Canada.

The molecular weight of human hyal-uronic acid is approximately 5 × 106 daltons. It has been proposed that there is an improved mechanism of action with a higher molecular weight of the hyaluronic acid. The theory is that the higher molecular weight will improve the viscoelastic properties and residence time within the joint space. The hyaluronic acid molecules can be cross-linked to increase their molecular weight. Synvisc is the only cross-linked viscosupplement that is available in the United States.

Clinical Safety
Hyaluronic acid has approximately a 1% incidence of side effects per injection. The most common side effects are local reactions of the knee such as swelling, pain, and increased warmth. This type of reaction typically lasts for 1-2 days. More recently, several reports of granulomatous inflammation of the knee after injections of hyaluronic acid have been reported.^18,19 Puttick et al¹⁹ observed clinically significant local inflammatory reactions in 11% of injections (27% of patients). Other studies have reported a 2%-4% incidence of local inflammatory reactions.²⁰

Chen et al¹⁸ reported on 6 cases of granulomatous inflammation of the knee following hyaluronic acid injections. All patients had pain, swelling, and warmth within 48 hours after the injection. The swelling gradually resolved in 1-2 weeks. This severe reaction is most likely due to the inability of the synovium to digest or degrade the foreign hyaluronic acid. The investigators finally stated that this pathologic response to an intra-articular injection of hyaluronic acid should raise the clinical awareness of the potential complications of viscosupplementation.

Injection Technique
Several studies have been performed to analyze the technique of injecting cortico-steroids or hyaluronic acid into the knee. Jackson et al²¹ compared 3 techniques of intra-articular injections into the knee. The lateral midpatellar injection was found to be 93% accurate. This lateral midpatellar injection is performed with the patient in a supine position, the knee in extension, and the patella gently medially tilted to open the lateral aspect of the patellofemoral joint. This was significantly better than the more traditional anteromedial and anterolateral injection sites that are the classic arthroscopy portal placement areas. Glattes et al²² described a simple method to confirm the placement of an intra-articular injection in the knee. By injecting a small volume of air into the knee, an audible “squishing” sound occurs with passive range of motion of the knee. This sound occurs only when the air, with the injection fluid, is injected into the closed space of the knee joint. Therefore, injecting a small amount of air with the injection of corticosteroids or hyaluronic acid into the lateral midpatellar region can ensure an accurate intra-articular knee injection.

Post-Injection Protocol
Immediately after an injection of hyaluronic acid, patients should place ice on their knee. Cold treatment can prevent the synovial reaction occasionally seen with hyaluronic acid injections. Patients should also be instructed to avoid vigorous physical therapy or exercise 2-3 days after an injection to prevent a synovial reaction.

If a patient develops a significant synovial reaction with an effusion, the patient should rest his or her knee and stop all exercise. A careful history and physical examination should be performed to rule out infection. If a strong suspicion of infection exists, the knee should be aspirated and cultures with gram stain performed. If an infection is ruled out, an NSAID should be prescribed to decrease inflammation within the synovium. The patient should also be instructed to apply ice to the knee for 20 minutes, 2-3 times a day, for at least 1 week after the injection. Patients should be monitored weekly to ensure that the effusion is resolving. If the effusion does not resolve, a methylprednisolone dose pack can be prescribed to aggressively decrease the inflammation within the knee.

Clinical Results
Numerous studies have evaluated the efficacy of hyaluronic acid for the treatment of osteoarthritis. Most of the studies have compared hyaluronic acid to placebo or corticosteroid injections and the results have been variable. Dixon et al²³ found that injections of hyaluronic acid over a 23-week period showed statistically significant improvement in knee pain at rest. No improvement in pain with movement or activities of daily living was demonstrated. Dougados et al²⁴ found that hyaluronic acid is significantly better than placebo for pain relief and improvement of the Lequesne functional index. The group receiving the hyaluronic acid also had a significantly reduced need for treatment at 1 year.

In a large double-blind trial of patients treated with Hyalgan, Altman and Moskowitz²⁵ found a significant benefit compared to placebo for the primary outcome in an efficacy analysis. The efficacy analysis was performed on only the patients who completed the study. The investigators also measured the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and found a significant improvement of pain and disability based on the WOMAC scores. Wobig et al²⁶ performed a study on patients receiving hyaluronic acid who discontinued their NSAIDs for the study. The investigators found that hyaluronic acid was significantly more effective than placebo. In a 12-week study by Scale et al,²⁷ the authors compared a 2-injection regimen to a 3-injection regimen of hyaluronic acid. The authors demonstrated a significant improvement in pain, activity, and patient-physician global assessment. They also found a significant improvement with a 3-injection regimen compared to a 2-injection regimen.

Jones et al²⁸ reported on 63 patients who were prospectively randomized to receive hyaluronic acid or a corticosteroid injection for inflammatory knee arthritis. The patients receiving hyaluronic acid reported less pain at 6 months than the steroid group. In the study, 68.3% of all patients withdrew from the study due to worsening symptoms. A more recent study by Leopold et al,²⁹ also compared hyaluronic acid to corticosteroid injections in a prospective, randomized trial. The results showed no significant difference between the 2 treatment groups in terms of WOMAC scores, the Knee Society Scoring System, or visual analog scale results. The average follow-up was 6 months for this study, so long-term analysis has not been performed.

Dahlberg et al³⁰ performed the only study to date on the use of intra-articular hyaluronic acid in patients with early arthritis. The study was a 52-week trial of hyaluronic acid in patients with normal knee radiographs. The patients had clinically significant knee pain and arthroscopically had evidence of early arthritis. There was no clinical benefit of injecting hyaluronic acid compared to placebo. This study did not support the use of hyaluronic acid in young patients, but supports further research on the use of viscosupplementation in patients with purely arthroscopic cartilage injuries.

Wang et al³¹ performed an extensive meta-analysis of randomized, controlled trials on the effect of hyaluronic acid on osteoarthritis of the knee. The investigators found that single-blind and single-center study designs resulted in higher estimates in the efficacy of hyaluronic acid. They also found that when acetaminophen was introduced as an escape analgesic, there were lower estimates in the efficacy of hyaluronic acid. Lastly, they concluded that patients aged &>60 years with advanced radiographic stage osteoarthritis (loss of joint space) were less likely to benefit from intra-articular hyaluronic acid injections. Therefore, the investigators concluded that hyaluronic acid can significantly improve pain and functional outcomes with few adverse effects, but well-designed randomized controlled trials must be continued.

Many stages of osteoarthritis exist in various locations and in different patient populations. The treatment of osteoarthritis should be designed for each patient to reduce pain, preserve joint mobility, and limit functional impairment. Conservative management should include exercise, weight loss, and patient education. Patients can also achieve pain relief with the use of pharmacologic agents such as acetaminophen and NSAIDs.

Corticosteroids have been used for many years in the treatment of osteoarthritis. They are relatively inexpensive and safe but do not have clear, long-term benefits and can damage collagen structures surrounding joints. Orthopedic surgeons must continue to use corticosteroids cautiously and conservatively. As older patients increase their activity and demand on their joints, investigators must perform further research into the value and efficacy of hyaluronic acid for osteoarthritis of the knee.

Future projects should also incorporate the subset of patients with arthroscopic evidence of cartilage injury without radiographic changes. These patients have a larger amount of native articular cartilage in their joints compared to late-stage osteoarthritis, which may enhance the effects of intra-articular hyaluronic acid. The research must also be expanded to include the use of hyaluronic acid in other joints such as the hip, shoulder, elbow, and ankle that are affected by osteoarthritis. Hyaluronic acid injections should be limited until more convincing data on their efficacy are available from well-designed clinical trials.

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Authors

From the Beverly Hills Orthopedic Group, Beverly Hills, Calif, and the Kerlan-Jobe Orthopaedic Clinic, Los Angeles, Calif.