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:

  1. A single joint injection of a combination of the anti-inflammatory corticosteroid triamcinolone acetonide and hyaluronic acid (TA-HA).
  2. Intra-articular (within the joint) administration of a polysulfated glycosaminoglycan (PSGAG) once every week for four weeks.
  3. IRAP therapy (interleukin-1 receptor antagonist protein) once every week for four treatments.
  4. 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. 

The post Why Do Veterinarians Use Bisphosphonates Off Label? appeared first on Horse Racing News | Paulick Report.

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