off-label bisphosphonate use in racehorses

In 2014 the U.S. Food and Drug Administration approved two bisphosphonate drugs—clodronate and tiludronate—for controlling clinical signs associated with podotrochlosis (more commonly known as navicular syndrome) in horses ages 4 and older. Since then, some veterinarians have started using these products off-label to treat other equine bone issues, such as bucked shins or osteoarthritis. But could this off-label use be detrimental? One equine veterinarian recently gave a rundown on what research says.

“With the increasing awareness of bisphosphonates among racehorse trainers, owners, and veterinarians, it is prudent to examine the existing evidence to determine if this class of drugs has a place in the off-label treatment of orthopedic disorders in racehorses,” said Jonathan McLellan, BVMS, Dipl. ACVSMR, of Florida Equine Veterinary Associates, in Ocala.

He reviewed some of the available information at the 2018 American Association of Equine Practitioners (AAEP) Convention, held Dec. 1-5 in San Francisco, California.

Bisphosphonates and Bone Remodeling

Understanding how bisphosphonates work is key to evaluating their place in racehorse medicine.

In healthy animals, including horses, bone turns over continually—a natural process known as bone remodeling. Cells called osteoclasts break down old bone while osteoblasts create new. This ensures bones remain strong and healthy and allows them to adapt to changes in exercise level or musculoskeletal system stress. In the case of high-performance athletes, including racehorses, this makes them stronger and more resistant to stress-induced injuries.

Bisphosphonates inhibit osteoclasts to block excess bone resorption—a hallmark of podotrochlosis. Studies in humans and animals suggest they’re anti-inflammatory, chondroprotective (protect joints), and pain-relieving, as well. But they’ve also been shown to be anti-angiogenic (preventing new blood vessel growth), and because curbing osteoclasts interrupts the remodeling process, the osteoblasts don’t kick into gear to build new bone.

Ultimately, this inhibition of bone remodeling could place racehorses at risk for more injuries, McLellan said.

Questions That Need Answers

What is the current equine-specific evidence?

McLellan said researchers have conducted studies on tiludronate for treating lower hock osteoarthritis, chronic back soreness, and navicular disease. “These studies all yielded favorable results from blinded analysis, but (resolution of) clinical signs were the main determinant of success,” he said.

He cautioned that in these studies, “all horses were older (>4 years old) and none were racehorses, so extrapolation of these results to that population may be inappropriate.”

McLellan described one paper on five racehorses with bucked shins. These are, essentially, microfractures to the front of the cannon bone, (often due to bone fatigue caused by loading a structure that has not remodeled enough to tolerate the stress.) The horses responded to treatment with a combination of weekly intravenous (IV) regional limb perfusions (that is, delivery of the drug to the lower limb via a vein close to the treatment site, keeping it in the desired area with the assistance of a tourniquet) with 50 mg of tiludronate, shock wave therapy, rest, and controlled exercise.

However, he said “it is impossible to ascertain the influence of tiludronate on healing due to the presence of multiple concurrently used modalities,” which the study authors did note in their manuscript.

In summary, he said, there is a limited number of equine-specific research studies into bisphosphonate use, and even fewer racehorse-specific investigations.

What diseases might be amenable to treatment?

McLellan said veterinarians have anecdotally used bisphosphonates to treat several conditions:

  • Stress remodeling—McLellan said some practitioners believe that “if bone resorption is halted, the bone will not become weakened and, therefore, stress fractures will not occur. In some cases they are even using it in an attempt to prevent injury” But, he said, microdamage in bone is a natural part of bone remodeling. “The only way a bone can heal these microcracks is to initiate resorption as the first step in the healing process,” he said. “So, bisphosphonate administration to inhibit bone resorption could, in fact, reduce the entire healing process, leading to weaker bones and increasing the risk of stress fractures.”
  • Sesamoiditis—In these cases horses become painful due to inflammation between the sesamoid bones and the suspensory ligament branch. McLellan said this inflammatory cycle can lead to sesamoid bone lysis (bone loss) and pain. Proponents of this use say bisphosphonates could decrease lysis in affected horses, he said, which could be plausible. “The risk in the racehorse is that it is not known whether the anecdotally reported abatement of clinical signs is due to analgesic effects of the bisphosphonates or a true resolution of the disease process,” McLellan said. “It’s possible that treatment is effective at reducing clinical signs without resolving the condition, potentially predisposing the racehorse to a future failure of the suspensory apparatus.”
  • Osteoarthritis (OA)—Studies conducted in nonracehorses have shown that intra-articular (IA, in the joint) bisphosphonate administration may help relieve clinical signs related to OA of the lower hock joints, McLellan said. And, in humans, researchers have found that IA clodronate is an effective pain reliever for patients with knee OA. Currently, IA bisphosphonate use in the horse should be considered experimental, McLellan said. “IA use of tiludronate may lead to concentrations that are potentially damaging to cartilage, although very low doses may be protective,” he said. More research in this area is needed.
  • Subchondral bone cysts—Theoretically, bisphosphonates could benefit horses with cystlike lesions (fluid- and scar-tissue-filled cavities) in the layer of bone directly beneath the articular cartilage, said McLellan, thanks to their anti-inflammatory and antiresorptive properties. However, there’s currently no supportive evidence to condone such use, he said.
  • Palmar/plantar osteochondral disease (POD)—A degenerative condition affecting the lower ends of the cannon bones (lower condyles), researchers believe POD develops due to subchondral bone injury associated with a bone’s failure to adapt to training loads. “There is limited evidence to support the use of bisphosphonates in POD, and a recent Havemeyer meeting report (the Dorothy Russell Havemeyer Foundation is a private foundation that conducts scientific research to improve the general health and welfare of horses) recommended that bisphosphonates have no place in the treatment of this disease based on current evidence,” he said.

 Treatment Risks

Next, McLellan shared some of the potential risks associated with off-label bisphosphonate use.

Analgesic effects Pain relief can, indeed, be beneficial in appropriate situations. But, as he mentioned before, in the racehorse it can also be detrimental, and inappropriate analgesia is one of the major sources of concern regarding bisphosphonates within the racing industry. “It’s hard to differentiate from clinical signs alone how much improvement is caused by actual healing and how much is due to pain relief,” he said. “Practitioners must use extreme caution when evaluating improvement in bisphosphonate-treated racehorses, as it might just be an analgesic response.”

The juvenile skeleton McLellan said, again, that bone remodeling is a prerequisite for a healthy skeleton, and juvenile athletes’ bones are constantly remodeling to adapt to training. Anything that inhibits remodeling could ultimately weaken the skeleton.

“Licensed bisphosphonates are only labeled for use in horses over 4 years old, and the AAEP has warned against use in horses younger than 4 years,” he said. “Similarly, in the United Kingdom, no racehorse is permitted to receive bisphosphonates prior to reaching 42 months of age.”

The penalty for inappropriate administration in the U.K.? A lifetime racing ban for the horse, McLellan said.

“They’re not messing around,” he said. “We have no such rules yet in the USA.”

Drug Testing Testing for bisphosphonates presents another ethical dilemma, said McLellan. These drugs have a short detection window in urine and serum and, while they remain in bone significantly longer, it’s difficult to extract bone for analysis in a living horse, he said. And, there’s limited research on withdrawal times in horses.

“Horses may be trained, raced, or sold while bisphosphonates are still active, and the only way to identify them is by accessing the medical records,” which itself can be a challenge in an industry where horses change hands frequently, McLellan said. “For this reason, and the effect on bone remodeling, it is of great importance to establish industry guidelines for withdrawal times for this class of drug.”

What It All Means

All in all, McLellan said, based on our current knowledge, bisphosphonate use in racehorses is “probably more akin to Russian roulette (than a magic bullet), but it’s not that simple.”

Any use in horses younger than 4 and not suffering from navicular pain is off-label, he said, And, while bisphosphonates might be useful for treating some diseases, they could have detrimental effects when used inappropriately. They have a long duration of action, are difficult to test for, and have several potential untoward side effects.

“Based on the existing knowledge,” he said, “off-label bisphosphonate use in racehorses could be putting both the patient and the practitioner at risk.”