A fresh study hopes to identify the potentially risky effects of bisphosphonate use in growing horses, focusing on animals undergoing sales preparation and early exercise training.
Bisphosphonates are used in veterinary medicine to strengthen the bones of mature horses.
Researchers at Texas A&M University, Montana State University and Michigan State University are joining forces for the study, amid widespread concerns that the off-label use of bisphosphonates in younger horses could lead to bone breakdown.
Manufacturers of the drug are equally concerned about the off-label use of bisphosphonates to mask vulnerability in the developing skeleton of juvenile horses.
Jessica Leatherwood, assistant professor of equine science at Texas A&M University, who will lead the study, noted that despite an overall decrease in racing fatalities over the past 10 years, California, Kentucky and New York documented an increase in racing fatalities in 2018.
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, Leatherwood said.
Despite the recognition of off-label bisphosphonate use by racing commissions, testing capabilities to reliably regulate off-label bisphosphonate use are limited due to the drug’s affinity for bone, rapid clearance from circulation, and long-term effects on bone resorption, the researchers stated.
“Controversy surrounding the off-label use of bisphosphonates is becoming more widespread in the equine industry, especially following the recent spike in breakdowns and fatalities on the racetrack,” Leatherwood told AgriLife Today.
“In addition, bisphosphonates have been heavily marketed in other disciplines that focus on the young performance horse. While concerns have been raised, there is currently no scientific knowledge of the effects of bisphosphonate utilization in young exercising horses, which leaves a critical gap in the knowledge.”
One type of bisphosphonates, clodronate disodium, has been chosen as the bisphosphonate for this study because of its popularity and ease of administration. It, along with others, are not approved for use in young horses. Other bisphosphonates are labeled for use in horses over four years of age to treat degenerative bone disorders, Leatherwood said.
“Bisphosphonates are used to treat osteoporosis and similar diseases that cause the loss of bone density in humans as well as animals,” Leatherwood said.
“However, these drugs are used extensively ‘off-label’ in all ages of horses, and our particular concern is for the off-label use in the juvenile horse.”
Leatherwood said the use of the drug in young horses is to potentially enhance bone formation and manipulate bone development to hide any skeletal problems.
“Young horses who will enter into early performance careers or race training are often placed in intensive management programs and sold early in life, and buyers often request radiographs prior to purchase to confirm skeletal health,” she said.
“However, attempts to promote early bone maturation and mask potential radiographic flaws may lead to an accumulation of microdamage, which may eventually lead to bone failure due to lack of appropriate remodeling.”
Concern over the use of bisphosphonates across Europe and the US in horse racing led to some regional regulations being enacted. However, the concern goes beyond racing, into other performance disciplines where the use of bisphosphonates is heavily marketed.
The FEI has banned the use of nitrogen-containing bisphosphonates – alendronate, ibandronate, neridronate, olpadronate, pamidronate, residronate and zoledronate – and has placed restrictions on the use of non-nitrogenous bisphosphonates – clodronate and tilduronate.
Following a recent rule change, the US Equestrian Federation now allows the use of bisphosphonates, but only in horses aged four and older. This rule still leaves a large number of disciplines unregulated.
“Banned substances should not be used in competition horses at any time, and controlled substances may be used to enhance performance, so they are regulated,” Leatherwood said.
Additionally, she said, testing for bisphosphonates is challenging and not yet well-defined, because bisphosphonates rapidly clear from the blood and urine and have a strong affinity to bind to bone.
The Texas A&M study is designed to determine the wide-ranging effects of bisphosphonate administration in healthy, skeletally immature horses with specific regard to horses undergoing sales preparation and early exercise training.
The researchers say there is known off-label use in skeletally immature horses in an effort to prioritize bone formation and early maturation, and for potential painkilling effects, regardless of long-term implications. Osteoclastic activity is necessary for normal bone development and remodeling; therefore, osteoclast inhibition in healthy, skeletally immature horses will have harmful effects.
This study outlines a rigorous and comprehensive assessment of the effects of clodronate on skeletally immature animals subjected to exercise by investigating the effects on bone turnover, bone strength, bone healing, bone architecture, articular cartilage metabolism and joint analgesia.
“The effects of these drugs have not been tested in horses of this age, as there are no studies that have provided a detailed evaluation of the administration effects on bone mass or bone turnover,” Leatherwood said. “We are concerned this practice may lead to an alteration in bone remodeling, healing or growth that may result in a significant risk of maladaptation, lameness or ultimately may contribute to the early breakdown of young horses, which, beyond being a major concern for animal welfare, may also put the health and safety of jockeys in danger.”
Leatherwood said they will use a horse and sheep model to determine the drug’s effects on bone and joint health in young horses undergoing exercise. The use of sheep as a model allows for further understanding of the physiological and biomechanical effects of bisphosphonates in young animals.
“The sheep study allows for greater insight into changes in bone morphology and biomechanical properties,” she said. “Sheep are typically processed under the age of two, so this allows for a deeper mechanistic understanding, which is not a feasible option in the horse.”
Specifically, Leatherwood said, her doctoral student Brittany Silvers will be gathering data on how quickly the bisphosphonate is cleared from the bloodstream. This will allow them to determine the duration of influence on bone development and the influence the drug has on inflamed cartilage metabolism.
“We expect that younger animals will clear bisphosphonates from their system faster than adult horses, that bone development will be altered in the young, exercising horse, and that bisphosphonates will have anti-inflammatory effects in the joint,” she said.
Leatherwood said the knowledge gained could be used as a basis for any new regulatory policies on the use of bisphosphonates in young horses.
Their study, titled Bisphosphonate Pharmacokinetics and Comprehensive Effects on Juvenile Cartilage, Bone Growth and Healing: Implications for Animal Welfare, has received a $US500,000 grant from the US Department of Agriculture’s National Institute of Food and Agriculture.
Professor Cliff Lamb, head of Texas A&M University’s Department of Animal Science, said the department was proud of Leatherwood and her team in their efforts to learn more about the impacts of bisphosphonate risk in young horses. “This work,” he said, “will inform our knowledge in the areas of administration effects on bone mass or bone turnover.”
Others involved in the project include Tom Welsh, professor of physiology and reproduction and Texas A&M AgriLife Research Faculty Fellow with a dual appointment in the College of Veterinary Medicine and Biomedical Sciences; Kati Glass and Carolyn Arnold, both in Texas A&M’s College of Veterinary Medicine’s Large Animal Clinical Services; Amanda Bradbery, of Montana State University; and faculty at Michigan State University.
Reporting: Kay Ledbetter