February 1998 Bulletin

Special report/William W. Tomford, MD

Review of hyaluronic acid, glucosamine, chondroitin sulfate therapies for OA pain

No evidence they inhibit breakdown or increase synthesis of articular cartilage

Osteoarthritis (OA) is the most common form of arthritis, affecting up to 30 million Americans. Although joint replacement has been a very successful treatment of advanced disease, no reliable and effective treatment exists for the early stages for osteoarthritis. Current approaches employed for this condition include nonsteroidal anti-inflammatory medicines, exercise, cortisone injections, arthroscopic surgery and osteotomy.

In the absence of reliable conservative treatments, alternative therapies may be reasonably applied. Two such therapies that are gaining popularity are hyaluronate injections and oral glucosamine/chondroitin sulfate. To educate orthopaedic surgeons about these therapies for osteoarthritis, the following review has been developed by the Academyís Committee on Biological Implants.

INJECTABLE THERAPIES

The synovial fluid from osteoarthritic joints has a lower elasticity and viscosity than the synovial fluid from normal joints. This characteristic results in a decrease in the rheological properties of synovial fluid, which has led to the development of viscosupplementation therapy. This therapy consists of injections of hyaluronate into the knee joint in an attempt to improve the elasticity and viscosity of the synovial fluid and thereby reduce pain.

The Food and Drug Administration (FDA)approved two hyaluronic acid viscosupplementation products for the treatment of osteoarthritis in 1997. Hyalgan®, manufactured by Fidia Pharmaceutical Corp., was approved on May 28, 1997, and Synvisc®, manufactured by Biomatrix, Inc., was approved on August 13, 1997. Hyalgan® is marketed to orthopaedic surgeons by Orthologic and Synvisc® is marketed by Wyeth-Ayerst. Other similar products are in various phases of clinical trials and should soon be available to orthopaedic surgeons.

Hyaluronate products are used in a series of three to five weekly injections depending on the product. Average cost of the entire series of injections is approximately $500. Studies suggest the injections may have beneficial effects lasting 12 to 26 weeks.

The major implied benefit of hyaluronic acid (HA) therapy is its replacement of OA synovial fluid to result in improved mechanical action and improved lubrication of the joint. However, studies in the 1970s suggested the lubricating efficacy of joint fluid likely results from a glycoprotein rather than hyaluronic acid, even though the latter contributes to its viscosity. Other benefits that have been proposed have included stimulation of endogenous HA synthesis by synovial cells and proteoglycan synthesis by chondrocytes, inhibition of the release of chondrodegradative enzymes, an effect on the nociceptive receptors in joint tissues, and a scavenging function on oxygen-free radicals.

Adverse effects of the injectable products have been few and mainly related to local inflammation at the site of injection into the knee joint. No fatal cases of anaphylaxis or anaphylactoid reactions have been reported. Although several placebo-controlled clinical trials performed in Europe have demonstrated a beneficial effect of hyaluronate therapy, with effects persisting for a number of weeks following the injections, one large randomized double-blind placebo-controlled trial conducted in the US failed to demonstrate significant beneficial effects. In addition, one animal and one in vitro study have suggested that anabolic effects on the cartilage may help to improve or maintain the cartilage matrix. The mechanism by which these effects are mediated remain to be elucidated. Finally, the existence of long-term chondroprotective effects, including alteration of the natural history of osteoarthritis, by these injectable compounds has not yet been shown.

ORAL THERAPIES

The two compounds, glucosamine and chondroitin sulfate, taken either singly or in combination, have been promoted as substances that will improve the formation of proteoglycans, loss of which is one of the earliest biochemical changes in osteoarthritis. Proteoglycan monomers consist of a core protein (aggrecan) to which glycosaminoglycan (GAG) side chains of chondroitin sulfate and keratan sulfate are covalently bound. These side chains account for the hydration and resistance to compression within and by the cartilage matrix. Glucosamine, as one of the substrate components of glycosaminoglycans, can be rate-limiting for the synthesis of the side chains, and insufficient chondroitin sulfate can be rate-limiting for the synthesis of complete aggrecan molecules. The basis for oral glucosamine and chondroitin sulfate as chondroprotective therapies for cartilage degeneration is that they might shift the chemical equilibrium in articular cartilage to favor synthesis of complete aggrecan molecules, and thereby provide increased levels of substrates or components of proteoglycans.

Glucosamine and chondroitin sulfate have been widely used for many years in veterinary medicine as a means of ameliorating the symptoms of arthritis in animals. Several human trials have been conducted in Europe and Asia which have demonstrated the efficacy of these compounds as judged by improvement in subjective symptoms of osteoarthritis and improved range of motion. Benefits have been moderate with approximately 50 percent to 80 percent of the treatment group of patients showing improvement as opposed to 20 percent to 30 percent in placebo groups. Beneficial effects appear to persist for several months after cessation of therapy.

However, there are relatively few studies of the use of these compounds in osteoarthritis in the United States, and in particular, none have demonstrated alteration of the natural history of osteoarthritis. Most studies have concluded that these compounds have a place in the armamentarium of the physician as a means of treatment which is essentially as effective as anti-inflammatory medication.

One compound that recently has been touted to be more effective than glucosamine and chondroitin sulfate taken singly is known as Cosamin DS®. This compound includes a patented combination of glucosamine, chondroitin sulfate, and manganese ascorbate. Manganese and ascorbate have been added as cofactors for the biosynthesis of proteoglycans. Whether or not this particular combination is effective is yet to be determined in controlled trials.

One of the reasons for the popularity of these new oral therapies is the publication of The Arthritis Cure, authored by Theodosakis et al, and published by St. Martinís Press in paperback in 1997. This book reviews the use of chondroitin sulfate and glucosamine in osteoarthritis. The book also reviews the use of NSAIDs and makes recommendations for healthful diets, maintenance of an ideal body weight, regular exercise and other reasonable approaches to the treatment of osteoarthritis. There is no doubt that some of the attention that is currently being paid to the use of these oral therapies is a result of the advice given in this book. Glucosamine and chondroitin sulfate are available without prescription. A one-month supply costs between $15 and $50.

New therapies that are being used for the treatment of osteoarthritis include intra-articular injections of hyaluronic acid and oral intake of glucosamine and chondroitin sulfate. FDA approval was sought and achieved by the manufacturers of the injectable therapies, but FDA approval was not necessary for the use of the oral therapies. Orthopaedic surgeons may use either of these therapies. The injectable therapies obviously require intra-articular injections; oral therapies do not require prescriptions, but can be obtained over-the-counter and are frequently sold through Internet outlets.

The role of these therapies appears to be additional or supplemental to traditional therapies such as the use of NSAIDs or mild analgesics. The literature on the injectable therapies as well as the oral therapies suggests that these treatments will ameliorate the pain of osteoarthritis over the short-term. These therapies may delay the need for operative intervention for pain relief, but there is no evidence to suggest that they are chondroprotective in inhibiting the breakdown or increasing the synthesis of articular cartilage in osteoarthritis. They seem to have few adverse effects, and, therefore, appear to be reasonably safe. Nonetheless, further studies should be performed to document clear efficacy. Until that time, widespread application is not warranted. As with any new compounds, physicians recommending these products should review package inserts to become familiar with their use and adverse effects.

William W. Tomford, MD, is chairman of the Academyís Committee on Biological Implants


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