Hyaluronic acid pharmaceutical



by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

Click here: Second Opinion Arthritis Treatment Kit




From the FDA, Arthritis Foundation, and the National Institutes of Health

Hyaluronic acid ( sodium hyaluronate, hyaluronan, HA), is a linear polysaccharide composed of repeating disaccharide units of N-acetyl-glucosamine and D-glucuronic acid.

Hyaluronic acid is widely used in cosmetic and pharmaceutical industries.

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 viscoelastic 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) has approved hyaluronic acid viscosupplementation products for the treatment of osteoarthritis in 1997. These include Hyalgan, Synvisc, Supartz, Euflexxa, and Orthovisc.

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-$2,000. Studies suggest the injections may have beneficial effects lasting 12 to 26 weeks or longer.

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.

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 cartilage degrading enzymes, an effect on the nociceptive (pain) 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. Anaphylaxis has not 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.

Some studies have indicated that anabolic effects on cartilage may help to improve or maintain the cartilage matrix. Also, long-term chondroprotective effects, including an improvement in the natural history of osteoarthritis has not yet been shown.

Not everyone has been convinced of the efficacy of these products as this article relates...



Expensive Arthritis Treatment Produces Only Modest Benefit

by Krisha McCoy, MS

More than 20 million Americans have osteoarthritis (OA), the most common form of arthritis. It is currently the most common diagnosis among elderly patients. OA is a joint disease that affects the cartilage”a slippery tissue that allows the bones to glide over one another. When cartilage breaks down and wears away, joints become painful and movements may be limited. The knee joint is commonly affected with OA because it bears the brunt of your body weight. OA can make your knees stiff, swollen, and painful, making it hard to walk, climb, and get in and out of chairs and bathtubs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat OA, but one drawback to NSAIDs is that they have side effects, which may include serious gastrointestinal discomfort and even bleeding.

In 1997, the Food and Drug Administration approved hyaluronic acid, a naturally occurring joint lubricant, to treat OA. The American College of Rheumatology has recommended hyaluronic acid injections as an alternative to NSAIDs for people at increased risk for gastrointestinal problems. But since the injections must be performed as often as 3“5 times weekly, with each injection costing between $100 and $200, some researchers question whether they should be recommended at all.

A study in the December 17, 2003 issue of the Journal of the American Medical Association examined 22 trials investigating the effectiveness of hyaluronic acid in relieving OA-associated knee pain. The trials showed that hyaluronic acid was slightly more beneficial than placebo injections. The increased benefit was roughly equivalent to that of NSAIDs over acetaminophen.

About the Study

The researchers conducted a widespread search for published and unpublished randomized clinical trials that compared the effectiveness of hyaluronic acid injections to placebo injections in the treatment of knee OA. To be included, the trials had to assess pain, have a follow-up time of two months or more, and at least 50% of the subjects had to complete the study.

The researcher analyzed a total of 22 trials, which included over 2,500 osteoarthritic knees. Three of the trials evaluated a high-molecular-weight formulation of hyaluronic acid, which some researchers believe may be more beneficial than lower-molecular-weight formulations.

The researchers looked at the results of each trial to determine the effectiveness of hyaluronic acid in reducing pain 1“4 months after the first injection (the time frame in which the injections are supposed to be most effective). For each study, they determined whether it had a small effect (similar to NSAIDs) or large effect (similar to a total knee replacement).

The Findings

In almost all of the trials analyzed in this study, hyaluronic acid injections had a small effect on OA-associated pain. In fact, in most of the trials, the researchers could not exclude an effect size that did not include zero, which means it is possible the injections had no effect.

The only two trials that showed a large effect both used high-molecular-weight hyaluronic acid. The third trial that evaluated high-molecular-weight hyaluronic acid, on the other hand, showed nearly no effect.

Overall, the researchers found that hyaluronic acid was minimally effective for relieving OA pain, when compared to placebo injections. They did find, however, that a publication bias was present in their analysis. A publication bias occurs when studies that find an effect are more likely to be published than studies that find no effect. Furthermore, most of the studies were industry-sponsored, and research funding by pharmaceutical companies is more likely to have outcomes favoring the sponsoring company product. So the researchers speculate that the favorable effects of hyaluronic acid may have been exaggerated in some of the studies.

How Does This Affect You?

These findings suggest that hyaluronic acid injections have just a modest”at best”benefit in the treatment of OA-associated pain in the knee. In fact, the benefit is similar to that of NSAIDs, which are a more convenient and affordable treatment for OA.

But what about the two trials that showed a larger effect for high-molecular-weight hyaluronic acid injections? Would these injections be more beneficial? Perhaps, but consider the fact that these two trials were sponsored by manufacturers of high-molecular-weight hyaluronic acid injections, and another study funded by the manufacturer of a competing formulation found that high-molecular-weight hyaluronic acid showed almost no effect.

If hyaluronic acid injections are no more effective than NSAIDs in treating knee OA, is the cost and inconvenience of getting the injections worth it?

Its important to bear in mind, however, that the results of this study do not mean that hyaluronic acid is ineffective for everybody. It makes physiologic sense, and for those patients who have run out of options, it may still be worth a try in an effort to delay surgery. What the study does suggest is that hyaluronic acid shouldn't be counted on as a mainstay of treatment for osteoarthritis.

On the other hand, other researchers and authors have come to a different conclusion...

Commentary & Perspective on
"Therapeutic Effects of Hyaluronic Acid on Osteoarthritis of the Knee: A Meta-Analysis of Randomized Controlled Trials"
by Chen-Ti Wang, MD, et al.
Commentary & Perspective by
Michael D. Ries, MD*,
Department of Orthopaedic Surgery, University of California-San Francisco, San Francisco, California


Hyaluronic acid is an effective lubricant that is present in normal synovial fluid. Since the concentration of hyaluronic acid is decreased in osteoarthritis, intra-articular injections of synthetic forms of hyaluronic acid may be beneficial. Many clinical studies have been conducted in an effort to determine the relative safety and efficacy of the use of hyaluronic acid injections for the management of osteoarthritis, and these studies have yielded varying results. Wang et al. have addressed this controversial issue by performing a meta-analysis of randomized controlled studies of hyaluronic acid treatment for osteoarthritis of the knee. Of 665 studies on this topic, only twenty met the rigid criteria for inclusion in the meta-analysis (single or double-blind randomized controlled trials that compared hyaluronic acid injection with placebo injection and had adequate outcome measures for pain or function and quantitative data on therapeutic effects), for a total of 818 knees treated with hyaluronic acid and 829 treated with placebo.

The authors found that pain and function were improved with hyaluronic acid treatment and that there were few side effects. These findings support the use of hyaluronic acid injections as an alternative to or in addition to other conservative measures, such as activity restrictions, non-steroidal anti-inflammatory or analgesic medications, glucocorticoid injections, exercise, and bracing for the treatment of osteoarthritis of the knee. Importantly, the treatment was less effective in patients who were more than sixty-five years of age and for the most advanced radiographic stage of osteoarthritis. Younger patients, particularly those in the early to moderate stages of osteoarthritis, seem to be the best candidates for this treatment that is used in an effort to delay the need for total knee replacement.

The lack of adverse side effects would indicate that hyaluronic acid injections are a decent treatment, eespecially in older patients or those with more advanced disease. For patients with medical disorders that would possible make surgery dangerous, hyaluronic acid injections would appear to be appropriate in an effort to avoid surgical complications.

The authors also found that the results were quite variable between studies. Many of the studies were industry funded. Industry-funded studies have been associated with a more positive outcome than non-industry-funded studies and report a lower rate of adverse effects2-4. However, in this meta-analysis the authors used very strict inclusion criteria and a quantitative pain and function scoring system that should have overcome any potential bias. The authors have conducted a well-designed analysis of the available literature on hyaluronic acid treatment for osteoarthritis of the knee and found a beneficial effect with a low complication rate. Patients should also be aware of the variable response to treatment and the risk of adverse side effects.





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