Tuesday, May. 28, 2024

Do Biological Therapies Offer A Cure For Osteoarthritis?

A wealth of new scientific evidence and good clinical results are making biological therapies the treatment du jour for horses suffering from osteoarthritis.

Watching your equine companion suffer from the pain associated with osteoarthritis can be difficult to witness and, until recently, nearly impossible to fully alleviate. But across the country, veterinarians are working to make that conundrum a bit simpler through research into the most cutting edge biological therapies, including cultured stem cells and interleukin-1 receptor antagonist protein, or IRAP.

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A wealth of new scientific evidence and good clinical results are making biological therapies the treatment du jour for horses suffering from osteoarthritis.

Watching your equine companion suffer from the pain associated with osteoarthritis can be difficult to witness and, until recently, nearly impossible to fully alleviate. But across the country, veterinarians are working to make that conundrum a bit simpler through research into the most cutting edge biological therapies, including cultured stem cells and interleukin-1 receptor antagonist protein, or IRAP.

Osteoarthritis results from a variety of influences—age, conformation, use, conditioning, footing and other physiological factors. Horses with osteoarthritis can suffer from a group of disorders manifested by progressive deterioration of the articular cartilage (the smooth, glass-like cartilage that covers the surfaces of bones connected at a joint) along with changes in the bone and soft tissues of the joint.

When osteoarthritis begins to develop in specific joints, some, or all, of the characteristic signs of pain, inflammation, swelling of joints, stiffness in motion, and alterations in the horse’s ability to perform normally may become evident.

The new biological approaches represent a fundamental step in reversing osteoarthritis for long-term rather than short-term effects. Until recently, typical therapies involved intra-articular medications such as hyaluronic acid and/or steroids, systemic medications like NSAIDS (bute or banamine), shockwave therapy, polysulfated glycosaminoglycan such as Adequan, intravenous hyaluronic acid (Legend), stall rest, and oral supplements that contain glucosamine and/or chondroitin sulfate.

While some of these therapies aid in repairing defects in joint surfaces, others simply decrease inflammation, occasionally impeding the healing process by blanketing the pain rather than targeting a way to repair the injured tissues and/or ligaments.

IRAP To The Rescue

IRAP involves a naturally occurring protein that needs to be in balance with the general inflammatory cytokine Interleukin-1 (IL-1). In a healthy joint, these are in balanced concentrations. However, in cases of osteoarthritis, there is insufficient protein produced to block the accelerated tissue destruction, which results when there is an increase of IL-1. The by-product of this imbalance is inflammation, joint pain and ultimately, cartilage destruction.  

“I believe IRAP to be at the top of the cascade when it comes to inflammation,” said David Frisbie, DVM, PhD, an assistant professor at Colorado State University.

He has tested more than 18 different medications to treat osteoarthritis. “IRAP has been the most effective way of combating osteoarthritis while preventing further deterioration,” he said.

Autologous conditioned serum, marketed in the United States as IRAP, works to protect joints by occupying receptor sites on the membrane of cartilage cells. Like the code to a security system, when certain proteins fit in and attach to the articular cartilage cell membrane, they are capable of preventing harmful proteins (like IL-1) from occupying those sites. The more IRAP present in a horse, the more receptors that can be blocked, therefore lessening articular degeneration.

The procedure is fairly non-invasive, beginning with drawing blood into a syringe from the horse that is to be treated. In addition to the blood, the syringe contains glass beads that stimulate production of the antagonist protein. The blood is harvested, incubated for 24 hours to increase the anti-inflammatory and regenerative protein concentration levels and finally centrifuged to separate the serum from the blood. The blood may then be used immediately or frozen for later treatment.

Normally, IRAP treatments are once-a-week, intra-articular injections for three weeks, however some horses may be treated for as many as eight weeks, depending on the severity of the problem.

Colorado State University’s Equine Orthopedic Research Center is conducting a mass spectroscopy to explore which proteins are differentially regulated.

“We are working on stimulating white blood cells to produce a higher concentration of IRAP, and we’ve found that when we do this, the good proteins in the cells go up more than the harmful proteins. The blood serum contains more than 150 proteins, and we’re testing those other proteins now to try and pinpoint which ones play crucial roles in reducing inflammation,” said Frisbie.

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Since the main benefit of IRAP is its anti-inflammatory powers, it’s best to use right away. However, not all horses with arthritis are good candidates for this therapy.

“If IRAP were utilized in early, more mild cases of osteoarthritis, I’m sure that it would be effective, and long-term it may be the best,” said Wes Sutter, DVM, M.S., a board-certified surgeon at the Ocala Equine Hospital (Fla.). He uses a variety of biological therapies, including IRAP. “But the therapy may not be cost effective in these situations that still respond to sodium hyaluronate and corticosteroids.”

A Florida-based company, Arthrex Vet Systems, developed a second generation IRAP that claims to be more potent than the original IRAP treatments. Another benefit of the new system, which was released this year, is that it’s in a format that fits any centrifuge, making it more user friendly than the original model.

“So far we’ve had a very good distribution of the IRAP II syringe,” said Anthony Orozco, the project manager for Arthrex Vet Systems. “The majority of our clientele converted over to the new system. It’s convenient because it works with the same equipment as the original IRAP syringe.”

Stem Cell Solutions

Stem cells also play a major role in the biological war on osteoarthritis.

“Cultured stem cells are on everyone’s mind right now,” declared Alan Nixon, BVSc, MS, a professor of large animal surgery at Cornell University (N.Y.). “For the last 10 years, a lot of work has been done with stem cells derived from bone marrow. More recently, stem cells have been isolated from fat, muscle, blood and even damaged tendons.”

Frisbie added that one of the most difficult distinctions in discussing stem cells is defining what it means to be a “stem cell.”

“Current treatment protocols in equine medicine utilize adult versus embryonic stem cells. Adult stem cells are those that arise or are obtained from any post-natal source. Because many of the early reports used bone marrow as a source of stem cells, this source remains the gold standard,” Frisbie stated in a 2007 research article titled “Novel Therapy of Acute Joint Injuries.”

There are currently several labs in this country that work with stem cells, which must be cultured for several weeks.

“I believe that stem cells are over-estimated in their capabilities, but they are potentially still extremely useful,” Nixon inferred.

“The premise of adult stem cell therapy was that these cultured cells were capable of local transformation to whatever musculoskeletal cell was needed, in essence, using stem cells to add the ‘building blocks’ for dedicated repair,” he added. “However, there have been substantial hurdles in successfully turning a cell into a healing cell. What many [researchers] are working on now is driving cells down a specific lineage before they get injected in order to give the cell direction before it’s injected into a patient.”

Stem cells are commonly cited for their ability to differentiate between different tissues. However, they also have other abilities that can be beneficial for healing, such as a knack for recruiting other local and systemic cells to focus on repairing damaged tissue, as well as playing an active role in immune modulation to promote or suppress T-cell function.

Signals from the tissue, based on chemical, neural and mechanical changes trigger stem cells to move into a damaged area. Hypoxia (lack of oxygen) and inflammation are the strongest triggers for stem cells to target an injury. Once the stem cells arrive, they recruit other cells, which the initial cells manage during the healing process. Tiny injections of stem cells are used because injecting large numbers of stem cells into an injured area can actually interfere with healing since some of the injected cells die and thus must be removed during the healing process.

Unfortunately, factors like a horse’s age, its fitness and the levels of free radicals can all inhibit the abilities of stem cells to respond to injuries.

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But despite all of the obstacles that a small number of injected stem cells must overcome in order to successfully target an injury, the therapy is still, in many veterinarian’s minds, a viable option.

Nixon isn’t crazy about calling the process “stem cell therapy,” however. “Simple bone marrow injections started the idea of transfer of stem cells. However, it was an oversimplification,” he said. “It’s just a misnomer to put a ‘stem cell’ title on it since there are only one in 100,000 true stem cells in bone marrow. To really have impact cultured stem cell therapy, to enrich cell members, is required.”

But that doesn’t mean he isn’t a fan of the procedure. “It is an expensive therapy but absolutely worth the money,” said Nixon. “Stem cells give you a much better chance of success. With stem cell we are able to turn back some major joint problems and prevent osteoarthritis. It’s a great application for grafting in acute cartilage disease and also a way to avoid arthritis after an injury.”

The Importance Of Timing

While bone marrow derived stem cells are the target of the majority of the stem cell hype, there are three other types of cells that deserve mention. The first is fat-derived or “adipose” stem cells.

“We know that if we take stem cells from bone marrow, they have the ability to become tendon tissue more easily than cells derived from fat,” explained Frisbie. “There is little work out there being done to compare adipose derived and bone marrow derived cells. So far, the indications are that bone marrow derived are working best, but it is difficult to be sure since not a lot of case numbers on adipose derived cells have been published.”

Regardless of whether you choose bone marrow or adipose cells, it is important to treat injuries early, rather than wait for the ailment to reach “chronic” status.

“We did a study in which we broke horses into groups and treated them at different post-injury periods. We found the most success in the groups treated between one and three months after their initial injury,” revealed Frisbie. “You don’t want to treat immediately after injury because it is a time of maximum inflammation. It is best to let the tissue settle down, thus providing a more stable environment for the cells to live in.

“It’s like if you cut yourself—the wound will get all red and angry, then it settles down. Remodel that idea with the stem cell. You want to wait in order to allow the stuff out that wants out, and within four to six weeks the reparative phase starts. Stem cells aim to bolster the repair phase,” he continued.

While bone marrow and adipose derived stem cells may be harvested at any point, harvesting cells from the umbilical cord requires a bit more pre-planning.

“Cord derived cells are harvested at birth and then stored for later in life when the horse may need therapy,” Nixon described. “It is a very provocative line of research.”

Umbilical cord stem cell research may soon be vying with embryonic stem cell research opponents for the top spot in the moral debate. Now that Americans have begun to lose interest in the battle against embryonic stem cell research, scientists are investing more time researching the possibilities in treating muscular skeletal disease.

“Right now there is a study being done on using embryonic stem cells to treat bowed tendons. These embryonic cells have an enormous potential to differentiate and target cells. I believe that five years from now embryonic stem cells will be the therapy of choice for most muscular skeletal diseases in the horse,” said Nixon.

“It will herald a new phase in cell therapy, using cultured equine embryonic and early fetal cells that enjoy extraordinary immune tolerance,” he added. “These types of cells can be shipped out overnight, providing little delay in getting therapy. It is a substantial leap forward in the ability to treat horses and may even prove useful given by vessel injection for founder, generalized and multifocal ligament diseases, and perhaps even for gastro-intestinal problems, and maybe even cardiac disease!”

If you enjoyed this article and would like to read more like it, consider subscribing. “Do Biological Therapies Offer A Cure For Osteoarthritis?ran in the January 22, 2010  issue. Check out the table of contents to see what great stories are in the magazine this week.

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