Treating early osteoarthritis-Orally administration hyaluronic acid can be a new arrow in practioner's quiver, but few efficacy studies exist

The early signs of osteoarthritis (OA) are synovitis, mild inflammation, pain and lameness associated with it, but there are little or no abnormalities within the joint. As the problem progresses, more and more changes involve everything around the joint, and within the joint, degeneration of the cartilage begins to occur, as well as fibrosis of the joint capsule, stiffening of the joint and continued wear, which eventually results in erosion of the cartilage and exposure of the bone. The conventional treatment for lameness associated with osteoarthritis, in addition to rest and physical therapy, are non-steroidal anti-inflammatory drugs (NSAIDs) such as phenylbutazone (bute) to reduce pain and inflammation; intra-articular corticosteroids, with more aggressive anti-inflammatory effect; as well as and polysulfated glycosaminoglycans (PSGAGs). In recent years, a new therapeutic aid has been added to the veterinary tool-kit, intra-articular (IA) or intravenous (IV) administration of hyaluronic acid (HA).

Treatment options for osteoarthritis depend on the severity of the condition and the degree of lameness, says Dr. Larry D. Galuppo, DVM, associate professor and chief of service for equine surgery at the Department of Surgical & Radiological Sciences, School of Veterinary Medicine at University of California-Davis.

Hyaluronic acid, typically administered intra-articularly, can be used to treat osteoarthritis and lameness depending on the severity of the condition.

"My initial therapy would be to see how the horse responds to NSAIDs alone. However, understanding that clients are looking to do whatever they can, I often will recommend oral glucosamine supplements. It is better if you don't have to perform joint injection immediately, and there is some evidence in people that this therapy gives some response for mild arthritis," he says. "If it's a mild case of secondary joint disease, I will often recommend the use of NSAIDs along with oral supplementation of glucosamine. However, this depends on the horse's performance level. There is also the question if we should be using glucosamine-type supplements as a preventive treatment. Although there is no specific published research studies, there is some anecdotal evidence that it may be beneficial to help maintain a more normal joint environment in people. If you do not get a response from the combined therapy of NSAIDs and other joint supplements, then it is often recommended to use intravenous or intra-articular hyaluronic acid and/or intramuscular PSGAGs.

"Typically for high-motion joints, I'll start with HA injections into the joint, plus or minus the use of IM Adequan(R (PSGAGs) and/or IV Legend(R (HA). As you get a more-severe condition in a high-motion joint, I will combine the HA joint injection with low-dose corticosteroids as the last option," Galuppo says. "For the low-motion joints (i.e. tarsal joints), most of the time I'll use a medium-dose of corticosteroids along with NSAIDs. For those joints I don't use intra-articular HA because they have such small joint spaces. This allows you to maximize the medication to the joint. Arthritis of the low-motion joints can be managed with the addition of IM (PSGAGs) or IV (HA) as well."

Several products recently have evolved that declare the efficacy of orally administered HA for horses. Intra-articular or IV injection of HA has considerable research and clinical history, but what of oral HA? The basis for oral HA products tout the presence of HA as a lubricant naturally found in healthy joints and its benefit as used either IA or IV, but is there a basis for its use orally?

In some cases of chronic proliferative synovitis, the synovial lining throughout the joint thickens. Typically this causes resorption of the palmar aspect of the metacarpus immediately proximal to the condyles, termed supracondylar lysis (arrows).

The presumed origin for oral HA's benefit comes not from its assistance to horses, but from the Japanese village of Yuzuri Hara outside of Tokyo. Dubbed "The Village of Long Life" by the media, its diet is particularly unique. Unlike other regions of Japan that grow rice, Yuzuri Hara's hilly terrain is better suited to harvesting satsumaimo, a type of sweet potato; satoimo, a sticky white potato; konyaku, a gelatinous root-vegetable concoction; and imoji, a potato root.

Dr. Toyosuke Komori, a town doctor, believes these locally grown starches help stimulate the body's natural creation of hyaluronic acid. It is believed that this stimulation of HA in the people of Yuzuri Hara wards off the aging process, helping the cells of the body thrive and retain moisture, keeping joints lubricated, protecting the retina of the eyes and keeping skin smooth and elastic.

From this basis, one of Japan's leading pharmaceutical companies began researching and developing a pill supplement containing hyaluronic acid. Testing the pills on 1,000 people, they claim that roughly half reported smoother skin, less fatigue and better eyesight.

Effusion or swelling within the fetlock joint pouch is a common clinical sign when the joint is afflicted with arthritis.

Conundrum

If hyaluronic acid definitely were beneficial via oral administration, then certainly it would be an excellent treatment for osteoarthritis in people and in horses. But is it? Regardless of the testimonials and anecdotal evidence, solid scientific studies as to its benefit when administered orally are still missing. According to Charles Nissen, MD, University of Connecticut Health Center, "Hyaluronic acid itself is not absorbed when taken orally and therefore, its use at this point is limited to an injectable form."

According to Dr. Bob Schneider, DVM, diplomate ACVS, The Robert D. McEachern Distinguished Professor in Equine Medicine at Washington State University's veterinary school, the treatment options for osteoarthritis depend on the stage and progression of the disease.

"Hyaluronic acid (IV and IA) probably has its greatest benefit early in the course of the disease, as probably do all the treatments. With the PSGAGs, there is some effect of blocking and inhibition of the metalloproteinases that do start to degrade the proteoglycans that are in the cartilage," he says. "If you are early on in the process of the disease, then that's when most people would agree that if we are going to use hyaluronic acid (IV and IA). It likely is used frequently with cortisone, especially when it's administered intra-articularly. As far as oral HA, I don't think there is any data to show that oral HA has much effectiveness, at least not yet."

This radiograph shows advanced secondary joint disease of the fetlock joint. Intra-articular administration of HA has reduced lameness in some studies.

According to Schneider, NSAIDs are effective, too. Especially bute, which is one of the most common and consistent treatments used for horses with arthritis of all kinds. Even for show horses that can't always use it because there is a limit to its use during competition, but the horses can train on it. Certainly, racehorses not only train on it but also race on it. Acetaminophen is not used very much in the horse, while aspirin is a very weak NSAID in the horse compared to bute. Aspirin has been used for other medical conditions. But compared to the effectiveness of bute, aspirin would be pretty ineffective.

"If I had an early-stage osteoarthritis in a horse, my first choice probably would be bute, and then if we were going to medicate the joint, I'd probably be using HA with a small dose of cortisone," Schneider says. "If we were going to try to keep the horse going in performance, I think that would be a very common treatment used by a lot of equine practitioners."

Veterinarians obtain a synovial sample from the fetlock joint; Acute synovitis and capsulitis can cause significant clinical compromise directly due to fluid swelling and pain and equally important, may contribute to the degenerative process in joints by the release of enzymes, inflammatory mediators and cytokines.

What is HA?

Hyaluronic acid is one of the most hydrophilic molecules in nature and has been described as "nature's moisturizer".

Hyaluronic acid, hyaluronan or HA, is a very large molecule, a high-viscosity mucopolysaccharide glycosaminoglycan (GAG), composed of repeating disaccharides of beta-1-4-glucuronate-beta-1-3-N-acetylglucosamine. It appears to be unique amongst glycosaminoglycans as it can be synthesized to a very large molecular weight (1,000 to 5,000 kDa). Isolated from the human vitreous humor about 60 years ago, HA's name is derived from the Greek word for glass, hyalos, which accurately describes its transparent, glassy appearance.

An important lubricant, HA is a natural substance found in all living organisms, in hemolytic streptococci (bacteria), and in all of the horse's body tissue. High concentrations are found in soft connective tissue, such as rooster comb and Wharton's jelly, and in the fluid (vitreous humor) surrounding the eye. Hyaluronic acid also is present in heart-valve tissue, keeping valves pliable as they regulate passage of blood between the heart chambers. The highest body concentrations are located in the extracellular matrix of the skin and the synovial fluid that bathes and lubricates the joints and cartilage.

Hyaluronic acid plays an important role in tissue hydration, maintaining and regulating moisture, tissue lubrication, and it facilitates the transport of nutrients into the cells and the removal of metabolic waste out of the cells. It is able to hold more water than any other natural substance. Hyaluronic acid is what makes young skin supple. In skin tissue, hyaluronic acid is a jelly-like substance that fills the space between collagen and elastin fibers. Its role in skin is similar to it's role throughout the body, to provide a mechanism of transport of essential nutrients from the bloodstream to living skin cells, hydrate the skin by holding in water, and it acts as a cushioning and lubricating agent against mechanical and chemical damage.

It works similarly in horse's joints, providing lubrication and reducing friction. Hyaluronic acid, a major component of normal synovial fluid is synthesized by the synoviocytes. HA as long-chain molecules, entangled and overlapped, providing viscosity and lubrication that forms a barrier to inhibit cells and larger molecules from intruding into the joint. The quantity and quality of HA can be altered by synovial inflammation. Such alteration can lead to a loss of joint fluid viscosity, decreased lubrication and loss of barrier function as part of joint deterioration in synovitis.

As animals age, the body produces lesser amounts of HA, and it becomes more difficult to replenish it. Over time, either through the natural aging process or due to the action of free oxy radicals (produced mostly via exposure to pollutants and sunlight), the body's natural store of HA is degraded and destroyed. The joints can become stiff and movement painful. With osteoarthritis, the cartilage and other structures of the joint begin to break down.

Therapeutic use of HA

The efficacy and clinical usefulness of exogenous HA (IA and IV) in the medical management of equine synovitis and joint injury has been well established over the last several years (as it has for people). The definitive mechanisms of action of HA are not well understood, though it is theorized to replace reduced or altered HA, restoring barrier and lubricant functions, triggering endogenous HA production, and inhibiting the damaging influence of the chemicals that cause joint inflammation.

Though endogenous HA injected into the joint disappears relatively quickly, its benefit seems to outlast its presence. How that is accomplished, as well as the benefit of larger or smaller molecular weight of HA, is a mystery. The amount required and the usefulness of the source of the HA, either natural (rooster comb or umbilical) or synthetic (bacterial) is also controversial.

In human medicine during the last 30 years, synthetic forms of hyaluronic acid have been developed and used to correct disorders in the fields of rheumatology (treatment of joint disease), ophthalmology, wound repair, and use in fertility clinics. More recently, synthetic forms of hyaluronic acid are being manufactured for use in facial augmentation. Popular brands of manufactured hyaluronic gels for this purpose include Hylaform®, Restylane® and Perlane®. In the past few years, biotechnology has been used to develop hyaluronic acid derivatives with tailor-made molecular sizes, which further increases its potential application.

According to several scientific studies in horses, results reported on the clinical use of exogenous HA indicate that there is 80-percent to 99-percent improvement following intra-articular injection. Comparisons between clinical responses to conventional treatment (NSAIDS, rest, physical therapy and IA corticosteroids) and intra-articular HA, show that satisfactory results can be achieved in 80 percent of hyalurate-treated horses but only 6 percent of conventionally treated horses.

A veterinary group at Colorado State University showed that IV administration of HA extracted from the bacteria Strep equi, is effective at improving clinical signs associated with joint disease caused by osteochondral fragmentation. A study by Gary White, DVM, and colleagues (Sallisaw, Okla.) also demonstrated the efficacy of intravenous and intra-articular HA. They found that various preparations of HA, both low- and high-molecular weight forms were effective to relieve lameness.

"Significant improvements in lameness scores in the treated groups as compared to the control group (without HA) confirm the efficacy of HA products in the treatment of synovitis," White says.

Though all HA products have shown effectiveness administered IA or IV, they vary in concentration, molecular weight and dose.

"Clinical and scientific studies to date are inconclusive as to the role of molecular weight in HA efficacy," White says.

Comparing IV HA, IA low-molecular weight HA and IA high-molecular weight HA, they concluded: "The controversy regarding the relationship between molecular weight of exogenous HA and efficacy and duration of efficacy remains without a definitive answer."

"Opposing viewpoints argue that the high molecular weight formulations are superior or that efficacy is unrelated to molecular weight. There are scientific and clinical data to support both viewpoints," White says. "Although these results tend to support the efficacy and duration of efficacy of intra-articular high-weight HA as compared to other formulations of the drug, the question of the relevance of molecular weight to efficacy of HA remains without definitive answer. Large scale controlled clinical trials will probably be necessary to provide the final answer."

Oral hyaluronic acid

Though IA and IV administration of hyaluronic acid are proven treatments for joint disease in horses, there is little definitive data regarding oral HA.

"Oral HA is a novel idea," says Scott Pierce, DVM, Rood & Riddle Equine Hospital in Lexington, Ky., (originator of Conquer(TM) oral HA). "It started off strictly as a marketing tool since everyone knows what hyaluronic acid is in the horse business, anyway. So it started off that way. Everybody started using it.

"They were seeing marked improvement in joint effusion in weanling foals, something they had not seen before," Pierce explains. "Though in the literature there is nothing about oral efficacy (of HA), if you look at the other glyco-saminoglycans (dermatin sulfate, chondroitin sulfate, heparin sulfate), those have been proven to be absorbed orally. I said to myself, okay I would like clinical proof at least. Those three glyco-saminoglycans all have very similar chemical compositions. This a brother or sister, so it's got to be absorbed orally."

Initially, Pierce studied the effects of oral HA on weanling foals. Typically, a lot of babies get big joints in their forelegs, especially after weaning. He studied eight foals that were radiographically normal. The foals had no other treatment, i.e. no bandaging, no stall rest, no steroids, nothing except oral sodium hyaluronate gel. Within a week, three to four were normal; within two weeks another was normal, and within another week the other foal was normal. His clients, knowledgeable horseman, said: "Hey doc, you're on to something here." Pierce also has done work comparing orally administered and IV administered HA, and looked at the changes in the serum levels. Of 10 horses, the only group that had an elevated serum level by day 7 was the oral group.

Pierce then went to the racetrack and had some trainers and veterinarians do a study (soon to be published) for him. Of 26 racehorses, 2-6 years old, half got a placebo and the others oral HA. The trainers and the veterinarians did not know which horse was getting what. If racehorses are feeling OK, then they are taken to the track and trained. If they're not, then they're going to be in the shedrow in a stall.

"The first thing I wanted to measure was something simple, the number of days on the track versus the number of days walked," Pierce says.

During a 60-day period, the treated horses went to the track five more days than the non-treated ones. The data were not statistically significant, but it showed a trend. If the group size were larger, then there would have enough difference, about 70 percent to 80 percent, to show clinical significance. The other factor that was measured was whether a horse became lame during a 60-day period. The number of horses that were examined for lameness in the control (placebo) group was 11 of 13. The number examined in the treated group was four. That data was statistically significant.

"Based on that finding, we could conclude that oral HA prevented lameness in the racing Thoroughbred," Pierce says.

They also measured pre-existing conditions, i.e. chronic osselets, etc. They all improved during the study, but it was not statistically significant.

HyalmotionTM, another oral HA product, discusses its research basis.

"We have a clinical study going on at the present time," notes Darren Landis, Hyalogic LLC Co. (Hyalun™). "To date there have been no clinical studies that have either proved or disproved that oral consumption of HA is therapeutic," Landis says. "As far as the oral (HA) horse product, we do not have any clinical evidence, nor have we seen any clinical evidence on the effectiveness of oral HA. Much of our concern was to know that if you give it orally to horses: Does it get broken down in the stomach? Is it getting absorbed into the bloodstream? Is it effective? Nobody knows that right now. We don't claim to know that. We do not say that it is or it isn't. All that we know is that we are getting results.

"I think the answers out there are still unclear," Landis says. Clinical evidence shows that intra-articular injected HA dissipates out of the joint within 14 to 18 hours. It diffuses out into the surrounding tissue via the bloodstream, circulating throughout the body, looking for receptors to stimulate the production of additional HA. It has other therapeutic effects in addition to stimulating the production of HA. "We feel, as long as we can get HA into the bloodstream, we're going to get therapeutic benefits."

Prudence for use of oral hyaluronic acid

John Caron, DVM at the Michigan State University Veterinary School's Large Animal Clinic, has done research on hyaluronic acid in horses focused on the neutraceutical angle, how it's regulating gene expression (Effects of anti-arthritis preparations on gene expression and enzyme activity of cyclooxygenase-2 in cultured equine chondrocytes). He says he has not seen any data in the literature regarding orally administered HA, post-ingestion serum or plasma HA levels, its bioavailability, absorption or metabolism.

Equine orthopedic specialist Alicia Bertone, DVM, PhD, Trueman Family Endowed Chair and Professor, Veterinary Clinical Sciences at The Ohio State University, says she has never read anything scientifically regarding the oral efficacy of HA. She agrees that there is no information in the veterinary literature regarding its absorption, metabolism or transport to the joint tissues. If it is fed, because of the large size of the molecule, whether it is absorbed intact, or broken down, how it is absorbed and/or transported to the tissues, there is no information or data. If it is broken down as it is absorbed, it might not be able to function as it might if it is injected IV or IA. It might have little or no benefit.

"None of that work has been done to my knowledge," Bertone states.

Some companies have anecdotal responses, but there is no good independent science out there as yet. With the oral glycosaminoglycans (chondrotin sulfate, glucosamine) there is research done in people demonstrating some clinical benefit. There is a large study being completed by the National Institutes of Health. Similar unbiased controlled studies should be conducted on oral HA in horses before promoting that it has a benefit.

A recent article in the Horse Journal, May 2003, suggested that oral HA was totally effective. As a result of a field trial, they noted the success of oral HA to quell the effects of lameness and arthritis in horses, though the data they presented was anecdotal and subjective. "All oral HA products consistently performed well. The gels and the liquids gave faster results than the powders, and in some cases, the results were stronger." Their conclusion: "There's definitely something up with oral HA. It consistently resulted in solid improvements and gave quite a boost when we added it to joint-product combinations."