A team from the University of California, Davis, (UC Davis) and the University of Kentucky recently took the first step toward describing bisphosphonates’ residence time in horses’ bones. Heather K. Knych, DVM, PhD, Dipl. ACVCP, professor of Clinical Veterinary Pharmacology at UC Davis’ K.L. Maddy Equine Analytical Pharmacology Lab, presented their findings at the 2020 American Association of Equine Practitioners’ convention, held virtually.
How Do Bisphosphonates Work?
Knych first described what we do know about bisphosphonates and their mechanism of action. Under normal circumstances, the processes of bone formation and bone resorption are in balance. However, she explained, in some circumstances, such as aging, this balance can become disrupted, and resorption can overwhelm formation. The result is weakening of the bone.
Doctors use bisphosphonates to increase bone density and treat disorders of bone resorption (e.g., osteoporosis, Paget’s disease) in humans. In horses, these drugs (tiludronate, clodronate) are labeled to treat the clinical signs associated with navicular disease; however, veterinarians also administer them off-label for other bone disorders.
Bisphosphonates act by binding to sites on bone surfaces that are undergoing active resorption, Knych said.
“When the osteoclasts (cells that break down bone) come in and begin to resorb bone in which the bisphosphonates reside,” she explained, “the osteoclasts internalize the bisphosphonates, and this ultimately leads to apoptosis and cell death, and we see a decrease in the osteoclastic activity.”
Based on studies in humans and lab animals, said Knych, we know that:
- Bisphosphates distribute widely throughout the body to both calcified and noncalcified tissues;
- Drug concentrations in bone increase as concentrations in noncalcified tissues decrease;
- Bone distribution appears to be nonuniform, with higher concentrations in trabecular bone than cortical bone, “presumably due to the higher rate of turnover in the former versus the latter.”
- The only route of elimination is through renal (kidney) excretion; and
- The elimination half-life (the time required for the drug’s concentration to decrease by 50%) in bone is prolonged and can range from months to years, depending on the species.
Knych said bisphosphonates’ long residence time in bone has led many human doctors to recommend a “drug holiday.”
“This holiday is a prolonged period of time whereby bisphosphonate administration is discontinued in an attempt to reduce the potential for adverse effects such as atypical femur fractures,” a reported side effect in humans, she said.
“Another thing to note is even after the drug is released from bone, it can recirculate locally and systemically and reattach to bone surfaces, which would further prolong the antiresorptive effects of the drug,” Knych added.
Why does all this information matter? Because veterinarians are still grappling to understand the drug’s long-term effects in horses. And, while we know bisphosphonates inhibit osteoclastic activity and impact bone turnover, we don’t yet know how this might impact bone growth in young horses, especially those training for high-impact disciplines such as racing. This is one of the reasons bisphosphonates are only FDA-approved for use in horses 4 years or older.
Based on the knowledge that bisphosphonates can reside long-term in human and lab animal bones, Knych and her team hypothesized the drug would have a similar prolonged residence time in the bones of horses.
“Specifically, we sought to describe drug concentrations in bone following clodronate and tiludronate administration,” she said, “and to determine concentrations of clodronate and tiludronate in bone in samples collected at necropsy from horses that had suffered a fatal musculoskeletal breakdown.”
They conducted a two-phase study to find out. Phase 1 involved four adult horses being euthanized for unrelated reasons. Two received the label dose of clodronate, and two received the label dose of tiludronate. One horse from each group was euthanized four days after administration, and the remaining two horses were euthanized 30 days post-administration. The researchers collected bone samples from various locations in each horse to determine drug concentrations. They found that:
- On Day 4, both drugs were well above the limit of quantitation (lowest detection amount) in the sampled bones;
- On Day 30, concentrations of both drugs were highest in the tuber coxae (point of the hip); and
- On Day 30, the team detected both drugs in horses’ right and left molars.
In the study’s second phase, Knych’s team collected post-mortem bone samples from four racehorses as part of the California Horse Racing Board’s necropsy program. Three horses had no history of bisphosphonate administration, and one had received clodronate 18 months prior.
She said they did not detect bisphosphonates in the bones of the first three horses but found detectable concentrations in the radius (the bone above the knee) of the treated horse.
Knych’s team confirmed that, as expected, both clodronate and tiludronate reside in the bone for extended periods, leading to potential long-term pharmacologic effects and increasing the risks of side effects in young and/or athletic horses. She said that additional studies to characterize the pharmacologic and metabolic effects of bisphosphonates on bone in young, exercising horses are necessary and underway.