Why hyaluronan is essential to healthy joints
It’s easy to take healthy equine joints for granted. Thousands of times each day, week after week, year after year, the mobile joints in a horse’s legs bend and flex, bearing his weight and enduring punishing shocks–all without attracting undue attention. After a hard workout, the muscles may be tired but not the joints. With a bit of rest, the horse is galloping around the paddock, good as new.
All of which is especially amazing when you consider that trouble-free joint function hinges on two seemingly mundane substances: water–ordinary H2O–and hyaluronan (HA), one of the simplest, but also most essential, molecules in the animal kingdom. Together, HA and water are the primary components of synovial fluid, the slippery lubricant that fills the spaces between the bones at the joints and enables them to flex without friction.
HA also has an anti-inflammatory effect that minimizes the potentially debilitating consequences of everyday wear and tear.
Keeping the synovial HA healthy–even replenishing it when necessary–is at the heart of maintaining equine soundness. For 30 years HA injections have been used to relieve pain and inflammation in equine and human joints.
Today, HA (usually labeled as sodium hyaluronate or hyaluronic acid) is also an ingredient in a number of over-the-counter oral preparations intended to sustain joint health and function. Researchers are still uncovering many of the secrets of how supplemental HA works and how it is best administered, but much already is known about this vital substance and how it keeps our horses on the move.
Simple but Versatile
Chemically, hyaluronan is a rather simple substance. Each molecule consists of only two sugars strung together in a long chain of alternating pairs, as many as 10,000 units long. The oxygen bonds that link these chains are powerful, giving the molecule the solidity it needs to help form the foundation of strong bodily structures, such as bone, cartilage, skin and blood vessel walls.
The versatile nature of the oxygen bonds also allows the chain to be near-infinitely flexible, giving the molecule the elasticity it needs to twist and bend without losing cohesion. With it, skin can stretch, ribs can expand and contract and blood vessels can pulse for a lifetime.
Another property that makes hyaluronan indispensable to life as we know it is that it is extremely hydrophilic–it attracts and holds onto water molecules–and, when the molecule takes on certain configurations, there are regions along the chain that are hydrophobic, repelling water.
As a result, when pure HA is placed in a solution, the hydrophobic patches tend to be attracted only to each other, so the long molecules double back on themselves and stick together to form a three-dimensional mesh. Filling the spaces within the mesh are the water molecules, trapped in place by their attraction to and repulsion from different segments of HA. The result is a thick, viscous fluid where water shifts and slides but cannot flow freely. This interaction between HA and water (and other assorted molecules) is vital to functions throughout the body.
Through Thick and Thin
The horse’s key locomotor joints–including the hocks, knees and ankles–are formed by bones that do not interlock but instead stack on top of each other like building blocks, connected only by flexible, fibrous tissue. Called synovial joints for their ability to flex freely, these mobile structures consist of two bone ends with a protective covering of articular cartilage that meet face-to-face.
They are connected on the sides by collateral ligaments to prevent lateral movements of the joint, and enclosed in a fibrous covering called the joint capsule that stabilizes the structure and retains the fluids that protect the inner surfaces. At the center of all of this is the synovia, the sticky yellow fluid secreted by the synovial membrane lining the interior of the joint capsule.
The synovial fluid is as crucial to a healthy joint as motor oil is to a car’s engine. Its physical value, as a lubricant that protects the bone surfaces from abrasion as they slide over each other, is crucial.
But HA also has anti-inflammatory properties: Even when there are no big injuries, the daily wear and tear an equine athlete imposes on his limbs causes minor inflammation throughout his tissues, including the joint capsule and its lining. Among other effects, that inflammation leads to the production of several enzymes that can damage local tissues. HA binds with those enzymes before damage becomes extensive.
However, if an acute injury does occur, or if a horse repeatedly is asked to work beyond his ability to recover, the inflammatory enzymes produced can overwhelm the amount of HA present.
“HA is a good free-radical scavenger, but it can’t handle too much,” says C. Wayne McIlwraith, BVSc, PhD, director of orthopedic research at Colorado State University. “Excessive inflammation leads to depolymerization of the molecule. That is, it breaks down.”
That can set off a cascade effect: When the HA strands break down, they can’t retain as much water, and the synovial fluid loses its viscosity-it gets thinner. Then the bone surfaces begin to rub each other, producing more inflammation, breaking down the HA even further. The buildup of inflammatory fluids within the joint capsule increases the pressure within the joint, leading to pain and stiffness. Left unresolved, the path of destruction can become grim: Increased weakness of the cartilage leads to more wear, which leads to more inflammation and pain, which leads to more degradation.
Eventually, the cartilage can tear and the bones chip, leaving debris within the joint, and the lesions in the articular cartilage can expose the bone below–this is an advanced case of the painful and debilitating condition called osteoarthritis.
Supplementing the Stores
Little can be done to repair such severely damaged joints. Surgery can remove chips and large debris, and medications, such as bute, help control pain and inflammation. But both of these courses are intended more to reduce discomfort and slow the course of destruction than to actually heal the damage.
A better tactic is to break the cycle of destruction before it causes irreparable harm to the joint. One time-honored approach toward that goal has been to administer supplemental HA to horses to help offset the effects of inflammation. Two modes of administering HA have been approved by the Food and Drug Administration (FDA):
Intra-articular injection. In 1970, European researcher Endre Balazs first injected hyaluronan directly into the arthritic joints of Standardbred and Thoroughbred racehorses. Those who received HA showed significantly more improvement than those who were treated only with a corticosteroid. Balazs was using the horses as a model to research arthritis treatments for people, but within a few years, HA injections became standard in both human and veterinary medicine.
Since then, multiple studies have shown that HA injections do have a beneficial effect on painful, inflamed joints: Treated horses are judged to be significantly less lame, and the biochemical markers of inflammation are dramatically reduced for months.
Yet it was not entirely clear exactly how the treatments worked. At first it was assumed that the exogenous HA, that is, the HA produced outside the body and introduced via injection, was simply replacing the endogenous (naturally occurring) HA within the synovial fluid. “But the half-life of the intra-articular HA injections is short, only a few hours,” says McIlwraith. In other words, the exogenous HA molecules don’t stay in the body long enough to account for the length of time the injections seem to work.
Now, says McIlwraith, “we believe that the most likely reason why we get an effect is that the exogenous HA acts on the receptors of the synovial membrane to increase the production of endogenous HA.” Many of the clues that led researchers to that conclusion arose from research surrounding the development of the other injectable form of HA.
Intravenous injection. In the mid-1980s, the Bayer Corporation developed a solution of HA (Hyonate, marketed under the name Legend) that was pure enough to be injected into the bloodstream. After extensive testing in laboratory conditions as well as in several field trials with hundreds of horses, the intravenous use of Legend was found to work just as well as, and sometimes better than, intra-articular HA injection.
It was becoming apparent that, if it was just as effective approaching the joint capsule by way of the bloodstream, the injected HA must be doing something other than just supplementing the lubrication within the capsule.
The Oral Option
In the last few years a number of oral preparations have come on the market that contain HA, both on its own and in combination with other common ingredients of oral joint supplements, such as glucosamine and chondroitin sulfate.
“When we found that it worked intravenously, that was when we started thinking about receptor-mediating activity,” says McIlwraith. It seems that, in addition to stimulating the production of endogenous HA, the exogenous form also encourages the production of other compounds that combat the inflammatory process. “The half-life of injected HA is four minutes, but the anti-inflammatory effects can still be seen 45 days later,” he adds.
The advantage of the oral products is that they can be administered without veterinary assistance, and there is no risk of problems associated with injections. The disadvantage–and it’s a big one–is that no one is certain that the oral forms work as well as the injected versions of HA. Because they are marketed as nutraceuticals, rather than as drugs, the oral products need only be proven safe to receive FDA approval.
Obtaining the data to prove the efficacy of a new drug in horses is no small task. Earning FDA approval “costs millions of dollars and years of bureaucracy,” says Scott Pierce, DVM, a veterinarian with Kinetic Technologies, LLC, who developed the oral HA preparation called Conquer.
Companies can have many reasons for electing to bring a product like this to market without full FDA approval as a drug. In this case, says Pierce, it was decided that the ultimate sales of the oral preparation most likely would not be extensive enough to cover the costs of the research that would be required for approval.
But Pierce says he has conducted a few small studies that have yielded promising results. In one, 26 Thoroughbreds in race training were given daily oral doses of either a placebo gel or a gel containing 100 milligrams of sodium hyaluronate for 59 days. During that time, the horses’ trainers were asked to note the number of days the horses were worked, the number of days they were just walked, and whether they were referred to veterinarians for lameness exams or radiographs.
On average, the horses in the treated group were galloped on the track for five extra days compared to the horses given the placebo. “Also, 11 of the 13 horses in the placebo group were referred for a lameness exam, and only four in the treated group were examined for lameness,” Pierce says. “The numbers may be small, but that’s statistically significant.”
In another study with 10 horses divided into three groups, Pierce showed that oral administration can increase the levels of HA in the blood. In other words, it appears to be absorbed through the horse’s intestinal walls, but no one has proven that HA has any therapeutic value when administered that way.
When HA is Right for Horses
HA can be invaluable for treating the earliest stages of joint inflammation. Numerous studies conducted since the 1970s have shown that HA injections are most effective when they are used to treat mild to moderate cases of synovitis–inflammation of the synovial membrane–and capsulitis, inflammation of the joint capsule. Both can be caused by either a single trauma or by repeated stress, and the signs include lameness and painful swelling in the affected joint.
But HA is not a cure-all for every joint ill. The injections do little to help a joint with a tearing injury, which can produce signs similar to those caused by inflammation alone, nor is HA effective against advancing osteoarthritis.
“If significant chipping or degradation of the joint has already occurred, HA is not a very good treatment,” McIlwraith says. That’s one reason why FDA regulations require that both forms of HA injection be administered only by veterinarians–an accurate diagnosis is necessary to be sure that the drug is being used effectively.
The easy availability of oral HA means that horsekeepers now have the option of administering it on their own, and many people choose to use it prophylactically in horses who work hard enough to be at risk for joint troubles but who have never shown signs of lameness, as well as in older horses with generalized stiffness but no specific signs of arthritis. While the effectiveness of oral supplements may be uncertain, horse owners can be assured that they will do no harm.
“As far as we know, it has no side effects,” says McIlwraith. Nevertheless, he emphasizes that if a horse is showing any signs of lameness, it is important for him to see a veterinarian for a thorough examination before a preparation of any kind is administered.
This article originally appeared in the June 2004 issue of EQUUS magazine.