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Why Do Veterinarians Use Bisphosphonates Off Label?

Veterinarians can legally administer tiludronate to young Thoroughbreds, but should we?

Tiludronate disodium (Tildren) is one of two Food and Drug Administration (FDA)-approved bisphosphonate drugs “For the control of clinical signs associated with navicular syndrome in horses.”

As we know, young Thoroughbred racehorses rarely suffer navicular syndrome, yet tiludronate can be found in the trucks of many racetrack veterinarians. This product is not licensed for anything but navicular syndrome and the safety of this product has not been studied in horses under four years of age. So how and why is tiludronate being used in juvenile racehorses?

How veterinarians use off-label drugs

The FDA grants veterinarians the legal ability to use approved human and animal drugs in an extra-label manner. This means that a drug can be administered to a horse in a way that the product's label does not list.

To prescribe drugs off label, veterinarians need to follow the FDA's requirements for extra-label drug use. For example, the FDA would permit off-label use of a specific medication if:

There is no animal drug approved for the intended use; or
There is an animal drug approved for the intended use, but the approved drug does not contain the required active ingredient.

Furosemide (known commercially as Salix or Lasix) provides a good example of off-label drug use in horses. The product information for Salix—which is FDA approved in horses—states, “Salix® is indicated for the treatment of edema, (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema.” This label clearly does not indicate that the product may be used for prevention of exercise-induced pulmonary hemorrhage. Yet, as we know, furosemide is widely used in competitive horses, including Thoroughbreds, for this purpose.

Similarly, tiludronate can be used off label (i.e., for more than just navicular syndrome) should the veterinarian deem it necessary.

Why use Tiludronate off label?

Tiludronate has “anti-resorption” effects on bone. By binding to osteoclasts, the cells that break down bone, tiludronate minimizes bone turnover. For conditions like navicular syndrome characterized by bone degeneration, stopping this degeneration by decreasing turnover is deemed helpful.

Osteoarthritis (OA), another musculoskeletal condition frequently seen in horses, is characterized by degenerative changes leading to inflammation, pain, and loss of function/retirement. A study published in 2010 demonstrated a beneficial effect of intravenous (IV) tiludronate in the treatment of bone spavin (tarsal osteoarthritis). Specifically, a significant improvement in lameness was appreciated at 60 and 120 days following treatment. That research team concluded, “Tiludronate in combination with controlled exercise offers an alternate medical treatment for bone spavin.”

A similar study found a beneficial effect of IV tiludronate in horses with OA of the thoracic vertebral column.

Most recently, IV tiludronate was evaluated in racehorses with naturally occurring OA of the fetlock (ankle).

The latest research on Tiludronate for OA

The September 2021 edition of the Journal of the American Veterinary Association includes a study of 567 Standardbreds diagnosed with initial-stage OA treated with one of the following:

A single joint injection of a combination of the anti-inflammatory corticosteroid triamcinolone acetonide and hyaluronic acid (TA-HA).
Intra-articular (within the joint) administration of a polysulfated glycosaminoglycan (PSGAG) once every week for four weeks.
IRAP therapy (interleukin-1 receptor antagonist protein) once every week for four treatments.
A single intravenous dose of tiludronate.

Clinical responses (i.e., lameness scores, joint flexion tests), radiographic and ultrasonographic findings, and biochemical analyses on blood and synovial fluid samples were compared between the four treatment groups at baseline (Day 0 of the study) and again six months later.

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All four treatments resulted in improved lameness scores and flexion test responses. Tiludronate, however, was the only treatment that appeared to inhibit the radiographic progression of OA.

The study also showed that:

Only TA-HA inhibited inflammatory mediators such as interleukin 1-beta and prostaglandin E;
Only TA-HA effectively inhibited the degeneration of articular cartilage that occurs with OA. This was demonstrated by a decrease in serum and synovial fluid CTX-II (carboxy-terminal telopeptides of collagen type II), a molecule that increases with progressive articular cartilage degeneration.
When treated with tiludronate, horses had increased CTX-II (i.e., articular degeneration).
A decrease in CTX-I (carboxy-terminal telopeptides of collagen type I), a marker of bone degeneration, was observed in horses treated with tiludronate.
IRAP and PSGAG both had a “significant effect on the clinical manifestations of osteoarthritis.” They did not, however, control radiographic progression and an increase in CTX-II was noted a the 6-month mark, indicating cartilage degeneration.

These data suggest that tiludronate can effectively decrease the progression of OA, potentially by inhibiting subchondral bone remodeling. However, this treatment protocol did not diminish the inflammatory component of OA and may in fact worsen cartilage degeneration in horses with OA.

So, what's the problem?

While research supports using bisphosphonates for navicular syndrome as well as OA, neither condition is terribly common in young racehorses.

“The goal of using bisphosphonates in young horses is to enhance bone formation and to manipulate bone development to hide skeletal pathologies,” said Dr. Jessica Leatherwood, an associate professor of equine science at Texas A&M University. “This attempt to promote early bone maturation and mask potential radiographic flaws may lead to an accumulation of microdamage. This damage could eventually lead to bone failure due to lack of appropriate remodeling.

“Bisphosphonate use in juvenile, exercising horses could result in greater risk of death for horses and humans, and to the eventual elimination of racing and the jobs surrounding the industry.”

According to Leatherwood, the controversy surrounding the off-label use of bisphosphonates is becoming more widespread in the equine industry, especially following the spike in breakdowns and fatalities on the racetrack. She said that while concerns have been raised, there is currently no scientific knowledge of the effects of bisphosphonate utilization in young exercising horses, leaving a critical gap in the knowledge.

To help learn more about the effects of bisphosphonates in young horses, Leatherwood recently received a $500,000 grant from the U.S. Department of Agriculture's National Institute of Food and Agriculture. Leatherwood's team includes researchers from Texas A&M University, Michigan State University, and Montana State University with expertise in large animal veterinary medicine, pharmacological analysis, bone and cartilage physiology, mechanical testing, and equine endocrinology.

Leatherwood hopes this work “will create new knowledge to improve equine health and welfare and provide meaningful, scientifically-driven recommendations (or warnings) for bisphosphonate use” in juvenile horses.

Dr. Stacey Oke is a seasoned freelance writer, veterinarian, and life-long horse lover. When not researching ways for horses to live longer, healthier lives as athletes and human companions, she practices small animal medicine in New York. A busy mom of three, Stacey also finds time for running, hiking, tap dancing, and dog agility training.

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CHRB Dismisses Bisphosphonate Complaint Against Jeff Metz

California Horse Racing Board commissioners (Board) voted during closed session Sept. 15 to dismiss a complaint against trainer Jeff Metz pertaining to a positive test last year for a bisphosphonate in one of the horses in his care, Camino de Estrella.

The Board believed it would be unfair to punish Metz when both testing and investigation revealed that the bisphosphonate administration occurred in 2018, well before Metz ever trained the horse.

The complaint (posted on the CHRB website since December) stated that the Maddy Laboratory at UC Davis detected Tiludronic Acid (Tildren, a bisphosphonate) in the urine sample taken from Camino de Estrella after he finished sixth in the third race at Santa Anita on Sept. 27, 2020. The presence of the Class 1 drug prompted the stewards at Del Mar to later disqualify Camino de Estrella and order the redistribution of the purse. The disqualification remains in force and is not affected by the dismissal of the complaint against Metz.

The Board dismissed the complaint pursuant to Business & Professions Code 19577 (d): “Any recommendation to the board by the executive director to dismiss the matter shall be by mutual agreement with the equine medical director. The authority for the disposition of the matter shall be the responsibility of the board.”

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Research Confirms Bisphosphonates Can Linger In Horses’ Bones For Years

Bisphosphonates continue to be a topic of concern in the racing world, most notably raised by a report of a positive test from John Salder trainee Flagstaff, but researchers are still learning about how to find and regulate the drugs in horses. Although two drugs, sold under the trade names Osphos and Tildren, were approved by the Food and Drug Administration for use in horses several years ago, research into the drugs' action in young horses and the length of its life inside the equine body is still catching up. (FDA-mandated testing is focused on safety and efficacy of a new drug, not necessarily the ability of a state racing commission to detect it in a post-race sample from a young racehorse.)

Read more about bisphosphonates in our archives here and here.

Dr. Heather Knych, renowned equine pharmacologist at the University of California-Davis, gave an overview of current research on bisphosphonates at the most recent, virtual convention of the American Association of Equine Practitioners (AAEP).

A few takeaways:

Bisphosphonates may be new to the horse world, where they are FDA-approved for the management of navicular syndrome in older horses, but the drug class has actually been in use in different settings for a couple of centuries. Knych explained that the substance was first used in the detergent industry in the 1800s as a water softener, anti-corrosive or anti-scaling agent. Their action on calcium carbonate made them effective in these settings. They were adapted as therapeutic drugs for human bone conditions in the 1970s.
While we've most often heard of bisphosphoantes in humans as part of osteoporosis treatment, they've also been used in metastatic bone disorders, and multiple myeloma.
We know that after an administration, bisphosphonates disappear from blood fairly quickly – their half life is one to two hours in plasma, but they can linger on bone surfaces for months or years.
Bisphosphonates seem to prefer settling in trabecular bone – bones like skulls and ribs that take less mechanical stress – over cortical bone, like the long bones in limbs. It withdraws from bones based on the amount of turnover in that bone, which can vary depending on age, exercise, and trauma.
Concentrations of bisphosphonates continues to increase as concentrations of it elsewhere decreases. It can also release from bone back into blood in small amounts and move into other bone surfaces, though we don't know a lot about why and when it does that.
Knych presented the results of a two-part study led by researchers across multiple universities to learn more about how long bisphosphonates linger in the skeleton. The first part of the project required administration of the two FDA-approved bisphosphonates – Osphos and Tildren – to a total of four horses in university research programs who were already slated for euthanasia for unrelated reasons. Bone samples were taken after euthanasia, which came four days or 30 days after administration in each drug group. Samples from the radial bones showed detectable amounts of both drugs four days after administration, with levels of Tildren being higher in both samples. Thirty days after administration, both drugs could be found in all bones sampled, even right and left molars. Concentrations of both drugs were highest in the tuber coxae (hips).
In the second phase of the study, researchers tested blood and fluid samples from four horses euthanized due to on-track injuries in California – three whose connections said they'd never had bisphosphonates, and one who had a treatment 18 months prior. The team could find no evidence of bisphosphonates in the three horses with no treatment history. The horse who had been treated 18 months before had no detectable amounts of the drug in serum, urine, or synovial fluid, but did have a detectable level in a sample from the radial bone.
These results suggest, in line with what veterinarians had expected based on human data, that the drug does linger on the surfaces of bone for considerable periods of time, and lives on different bones in different ways.
Knych acknowledged that both parts of the study came from extremely small sample sizes, as is often true in academic research with horses, and that further study is needed to better understand how bisphosphonates work in the equine body.

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New Test Can Detect Bisphosphonate Three Years After Administration

A new study may give regulators the key to better regulate bisphosphonate use in racing. Controversy has surrounded bisphosphonate use since the drug became approved by the Food and Drug Administration (FDA) for use in horses. Bisphosphonates are labeled for adult horses battling navicular syndrome and similar chronic conditions that don't respond to other types of treatment.

The FDA has licensed two bisphosphonates, which are sold under the trade names Tildren and Osphos. The Horse reports that there are other, non-licensed versions of bisphosphonates marketed for horses which are not FDA-approved. Those non-approved products are advertised as being more powerful than the two approved versions.

The FDA prohibits the use of bisphosphonates in horses younger than four years old, but some owners and trainers continue to use the product off-label on young horses. Bisphosphonates impact the build-up/breakdown cycle in bone, which veterinarians say could have negative effects on growing animals.

Dr. Christopher Riggs, chief advisor in veterinary science at The Hong Kong Jockey Club, studied 24 Thoroughbreds who had received a single therapeutic dose of tiludronate disodium between one month to three years earlier. The research team then tested blood plasma and urine samples using ultra‐high‐performance liquid chromatography high‐resolution mass spectrometry, a new testing technology. The tests found traces of tiludronate disodium in every sample.

Previously, testing was only able to detect bisphosphonates in equine blood or urine if it had been administered in the last 40 days. Hair testing could detect an administration from months prior, but is limited in its ability to pinpoint the time of administration.

Researchers believe the drug lingers on the surface of bone, occasionally releasing back into the horse's body for months or years, but little is known about how long that effect could go on. The drug may be more detectable in horses that are going through training and rest periods that affect bone remodeling.