ARTHRITIS
October 15, 1999

Emerging Treatments: Viscosupplementation for Osteoarthritis

Osteoarthritis should no longer be considered an inevitable accompaniment of aging but rather a dynamic and largely treatable disease. Recently, the FDA approved the use of hyaluronan (hyaluronic acid, hylan), a high molecular weight sugar, for the treatment of osteoarthritis of the knee for patients who have failed treatment with acetaminophen, NSAIDs (nonsteroidal anti-inflammatory agents) and physical therapy. The drug is given as a series of weekly injections directly into the affected joint (viscosupplementation) over three to five weeks. The beneficial results -- relief of pain, improved joint mobility and improved ambulation -- appear to last for several months to one year.

What Does Hyaluronan Do?
The type B lining cells of the joint membrane produce hyaluronan. In the joint, there is a constant turnover of hyaluronan. The half-life of hyaluronan injected into the joint is 24 to 48 hours. The large molecules of hyaluronan overlap with each other to form a continuous mesh. It is this property of hyaluronan that contributes to joint stability. Hyaluronan also dampens the response of the pain fibers in the joint membrane by coating the pain receptors. Hyaluronan is also synthesized by other joint cells (articular chondrocytes), where it forms the backbone of the joint cartilage and gives the cartilage its elasticity and compressibility.

In osteoarthritis, the hyaluronan concentration in the joint fluid is decreased, as is the molecular weight of the hyaluronan molecules. It is believed that these changes contribute to the decrease in joint function, as well as the pain, which are characteristic features of the disease.

Osteoarthritis is also characterized by the degeneration of the joint cartilage leading to its loss, irritation of the joint lining and hardening of the joint bone. The causes of the cartilage degeneration appear to include physical stresses, such as repeated trauma to the joint, and biochemical changes in the joint cartilage.

History of Hyaluronan Treatment
With the advent and availability of total joint replacement surgery, interest in hyaluronan waned for several years. Recently, however, as a result of clinical trials in Europe, there has been renewed interest, primarily because hyaluran consistently helps relieve pain and causes very few negative side effects.

How It Works
It is not at all clear how hyaluronan relieves the symptoms of osteoarthritis for such a long period of time since, within a few days after its injection into the joint, it can no longer be found there. It may be that the hyaluronan promotes long-lasting changes by stimulating the lining cells of the joint to synthesize more hyaluronan.

Many people, however, cannot be treated with NSAIDs. They may have a history of gastric bleeding or kidney disease and will need to be treated with short courses of corticosteroids or intravenous colchicine.

Who Should Be Treated?
People with osteoarthritis of the knee that is symptomatic despite treatment with conservative measures (acetaminophen, physical therapy and NSAIDs) should be given hyaluran injections. Hyaluronan, like most therapies, is more effective in people who have some remaining range of motion and some remaining joint cartilage, as judged by X-ray or MRI imaging. While total joint replacement is probably the treatment of choice for patients with advanced disease, hyaluronan injections may provide symptomatic relief for those who cannot have or refuse surgery.

Preparations and Dosing
There are currently two hyaluronan preparations approved for use in osteoarthritis of the knee. One is Synvisc® (hylan G-F 20, distributed by Wyeth Laboratories), manufactured from rooster combs. Synvisc® is retained in the joint for seven to fourteen days after intra-joint injection. Three weekly injections of 16 mg. of this product into the knee produce the best response. The other preparation, Hyalgan®(sodium hyaluronate, distributed by Sanofi Pharmaceuticals), is also purified from rooster combs but has a lower weight than hylan. Compared to hylan, it has a shorter biological half-life in the joint but may have wider distribution after intra-joint injection. The optimal dosing for Hyalgan® appears to be five weekly injections of 20 mg. each. Both agents appear to have few side effects. If you are allergic to chicken products, you should not receive these agents. The safety of the agents in pregnancy or for nursing mothers has not been established, though animal studies have not shown any effects on the developing fetus. Patients on anticoagulant therapy should be treated with caution, if at all. Repeat courses of hyaluronan have not been studied or approved by the FDA although, theoretically, they should continue to be effective.

Other Therapy for Osteoarthritis
Recently, there have been additional treatments advocated for osteoarthritis. The media has trumpeted the use of oral glucosamine with and without chondroitin sulfate. Why and how these agents might work are not known. The original enthusiasm was based mainly on popular testimonials but there is now at least one controlled trial indicating some mild clinical benefit for the combination form of therapy. Experimentally, the use of autologous cartilage implants -- your own cartilage cells harvested from another site in your body and stimulated to grow in the laboratory -- and orthopedic procedures to stimulate new cartilage growth and change the weight bearing surfaces of joints are attracting increasing interest.
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