Using glycosaminoglycans for treating equine joint diseases
Glycosaminoglycans have helped veterinarians target therapies toward the underlying pathology of equine joint disease, says Dr. Gary W. White.
During the past 20 years medical therapy for non-septic equine joint diseases and injuries has been greatly enhanced by the use of drugs classified as glycosaminoglycans (GAGs). These compounds have allowed us to direct our therapies toward the underlying pathology of equine joint disease and in many cases extend the useful careers of athletic horses. There has been an explosion in the numbers and types of these products available. Many are supported by solid scientific research and are manufactured and marketed under approval by the U.S. Food and Drug Administration (FDA). FDA approval assures that a product is safe and effective as demonstrated in controlled studies and is manufactured under strict guidelines to assure purity and potency. Others have weak or no scientific support and their manufacturing is subjected to little or no regulation. It is important that veterinarians and horse owners understand all GAG products are not equal.
What are GAGs?
Glycosaminoglycans are polysaccharides made up of repeating disaccharide units and are an important component of many connective tissues including tissues in the equine joint. The most important GAGs in the equine joint are hyaluronic acid, chondroitin sulfate and keratin sulfate.
Hyaluronic acid (HA) is a non-sulfated GAG (Figure 1) that is produced by cells in the synovial membrane and released into the synovial fluid. Here these long chain molecules function as the barrier lubricant of the synovial membrane and joint capsule and help to form the synovial barrier. This barrier helps keep cells and large molecules out of the synovial fluid. The health of a joint is dependent on normal synovial fluid HA content. HA is also said to be a component of articular cartilage lubrication at low loads. HA is also a critical component of proteoglycan complexes (Figure 2, p. 9). A molecule of HA forms the "backbone" of the large proteoglycan complexes.
Figure 1: Comparative molecular structure of glucosamine, hyaluronic acid, Chondroitin Sulfate and PSGAG
Chondroitin and keratin sulfates are sulfated GAGs and are also important components of the proteoglycan complexes in articular cartilage matrix. Side chains of these GAGs are attached to a protein core to form a large molecular aggregate (Figure 2). The negative charges from carboxyl and sulfate radicals cause these side chains to repel each other. Water is drawn into the spaces between the GAG side chains. This arrangement contributes to the ability of cartilage to distribute forces acting upon it and allows cartilage to change shape and comply with loads then resume its resting shape when loads are removed.
In joint inflammation and injury, these GAG components can undergo degredation due to direct injury and to the action of inflammatory mediators and catabolic enzymes. Reduced concentration and a decrease in the mean molecular weight of synovial fluid HA are early effects of synovial inflammation. The proteoglycan complexes may also be damaged or degraded and diseased cartilage is often characterized by depletion of GAG content.
The restoration of normal synovial fluid hyaluronate and repair or replacement of GAGs and other cartilage matrix components should be one of the goals of therapy for equine joint injuries.
Pharmaceutical GAGs approved for equine joint disease
There are two types of GAGs approved for the therapy of joint disease and injury in the horse. The first is sodium hyaluronate, the sodium salt of HA. There are four FDA products approved for intraarticular use in horses: Legend" Injectable Solution (Bayer), Hylartin-V" (Pfizer), Hyvisc" (Boehringer Ingleheim), and Hyalovet" (Fort Dodge). One product is approved for intravenous use, Legend" Injectable Solution. The efficacy of sodium hyaluronate has been well established. The drug is anti-inflammatory by several mechanisms and may stimulate endogenous HA production. Treatment helps to normalize the synovial environment. HA probably does not have direct effects on diseased cartilage but may help protect cartilage through its anti-inflammatory effects on synovial tissue. Efficacy and safety have been confirmed by the required dose, efficacy and safety studies for FDA approval as well as independent research and more than 20 years of clinical experience. There have been more than 15 published reports of clinical or experimental studies that support the efficacy of intraarticular sodium hyaluronate in the horse. Intravenous sodium hyaluronate is also supported by dose, efficacy and safety studies required for FDA approval as well as independent studies in two equine joint disease model test systems. The HA products are indicated for the treatment of joint dysfunction due to non-infectious synovitis associated with equine osteoarthritis.
Figure 2: Proteoglycan Complex
The second approved GAG is polysulfated glycosaminoglycan or Adequan" (Luitpold). PSGAG is synthetically polysulfated chondroitin sulfate (Figure 1) which means it has a higher sulfur content compared to chondrotin sulfate. The drug is approved for intrarticular and intramuscular use in equine joint disease. The drug is anti-inflammatory, inhibits enzymes which may degrade GAGs and HA in the joint and may have a positive effect on HA and GAG synthesis in diseased joints. For this reason, PSGAG is said to be a disease modifying osteoarthritis drug. Optimal dose, efficacy and safety studies for FDA approval by the intraarticular and intramuscular route was established in six well controlled studies. Efficacy has been confirmed by at least 10 published experimental or clinical studies in the horse and nearly 20 years of clinical experience. Adequan" is indicated for the treatment of non-infectious degenerative and/or traumatic joint dysfunctions and associated lameness in the horse.
GAGs marketed without approval
There are a number of GAGs marketed as treatments for equine DJD without FDA approval. These include a medical device for wound healing containing chondroitin sulfate called Chondroprotec" currently being marketed as an intramuscular treatment for equine joint disease. There is also an HA product labeled as a device for semen cryopreservation called MAP-5. This product is also sold as an injectable treatment for equine joint disease. There are also pharmacy compounded products containing HA in combination with glucosamine and chondroitin and oral paste formulations containing HA. None of these products is supported by efficacy and safety data and they are not manufactured or marketed under an FDA approval for use as a drug. A recent published study examining the efficacy of Chondroprotec" found this product to be significantly less effective than the positive control (intramuscular PSGAG).
Also there are many products sold containing chondroitin sulfate (often in combination with glucosamine) and sold as nutritional supplements or "nutraceuticals". None of these products are manufactured or marketed under FDA approval and quality appears to be highly variable. Efficacy and safety data for these products remain inadequate for an accurate assessment of their value as therapeutics for equine joint disease. Most reports are anecdotal or contain reports of uncontrolled studies. One controlled study using the CFA carpitis model demonstrated no efficacy for a supplement containing chondroitin sulfate, glucosamine and manganese. A more recent controlled study demonstrated efficacy in relief of gait deficits in horses with lower hock joint diseases as measured by force plate gait analysis using a different chondroitin and glucosamine supplement.
Glucosamine is not a GAG; it is an aminomomosaccharide that is a component of the dissacharide unit that makes up HA. As mentioned previously, glucosamine is a component of the so-called "nutraceuticals". Injectable glucosamine solutions are marketed by compounding pharmacists as an intramuscular injection. The efficacy of oral glucosamine in equine joint disease remains to be demonstrated. The efficacy of a compounded solution was evaluated in a recent controlled study and found to be significantly less effective than the positive control (intramuscular PSGAG).
Some of the GAG products described herein are marketed as "generic" substitutes for popular approved products such as Adequan" or Legend" and these products are touted as less expensive alternatives. Generic drugs are exact chemical copies of approved drugs that no longer have patent protection. A generic drug is also an FDA-approved drug. Since none of these products are FDA approved they cannot be generic drugs. FDA-approved generic drugs are subjected to the same manufacturing and quality control standards as are originally approved drugs. At this time there are no approved generic forms of Adequan or Legend available.
Veterinarians and horse owners can only be assured they are using GAG products that are proven effective, proven safe and manufactured under strict quality guidelines when using those products that have been approved by FDA for use in equine joint disease. All GAGs are not equal and the unapproved products described here should not be considered generics of the approved drugs. These unapproved products should also not be considered as the therapeutic equivalent of the approved drugs.
Dr. White, a native of Louisiana, received his DVM degree in 1977 from Louisiana State University. He has been involved in equine practice for 26 years and in animal health research since 1981. He was vice president of Luitpold Pharmaceuticals, Inc from 1988-1993. He has been involved in the development of many equine pharmaceutical products and has published and presented numerous papers on his research.
Dr. White currently owns and operates Sallisaw Equine Clinic, an equine practice in Sallisaw, Okla. and is president of GCT Consulting Services, Inc., an animal health contract research and consulting firm.