How these drugs break the bone absorption cycle

In recent years bisphosphonates have emerged as promising treatments for horses with podotrochlosis (aka navicular or caudal heel syndrome). The drug inhibits bone resorption, which enables horses with navicular bone lesions to live more comfortable lives and, in many cases, return to their previous level of performance. Though it might seem like these ­medications have exploded onto the scene, Kent Allen, DVM, owner of Virginia Equine Imaging, in The Plains, says the increasing use of bisphosphonates has been a slow-burning fire gaining intensity over the past decade.

“High-level practitioners have been using these drugs for years in Europe and with compassionate-use permits in the United States,” he says. Allen serves as chairman of the United States Equestrian Federation (USEF) Veterinary Committee, the USEF Drug and Medication Committee, and the Federation Equestre Internationale (FEI) Medication Subcommittee. “(Bisphosphonates) may feel ‘new’ to horse owners because today there are more advertisements about using them.”

Initially, these medications emerged to treat human patients with bone fragility disorders, such as osteoporosis. However, equine practitioners saw promise in using the drugs to treat podotrochlosis, a disease with no cure.

Over the past 10 years veterinarians have observed off-label benefits when using bisphosphonates to treat a variety of musculoskeletal conditions. For example, Allen says, horses receiving the drug to treat overriding dorsal spinous processes (kissing spines) and lower hock arthritis have experienced relief.

Horses, like all other animals, have continuous bone turnover. Bone cells called osteoclasts break down bone, while osteoblasts create new bone. This natural process ensures bones remain strong and healthy with changes in exercise level or musculoskeletal system health. Specific musculoskeletal disorders, such as podotrochlosis, lead to excess bone resorption, which is where bisphosphonates can help.

“It is important to note that these drugs inhibit osteoclasts,” says Heather Knych, DVM, PhD, Dipl. ACVCP, professor in equine pharmacology at the University of California (UC), Davis. “These cells reabsorb bone, so these drugs are meant to prevent this and decrease the loss in bone density. These cells play an important role in normal bone remodeling, and the prolonged residence time (of the drug, more on this in a moment) can impair the remodeling process.”

Two bisphosphonates FDA-approved for use in horses older than 4 are available on the U.S. market: tiludronate disodium (Tildren) and clodronate disodium (Osphos). It is essential to note they’re not approved for use in racehorses, says Allen. He acknowledges that other bisphosphonate products are available, some of which are potent and promising, but drugs other than the two mentioned here are banned from use in almost all competitive disciplines.

Here’s what researchers know about the use of bisphosphonates and future opportunities for further investigation.

Recent Study Findings

To date, the most extensive study looking at the use of bisphosphonates in horses is the 2022 paper “Retrospective Analysis of the Use of Tiludronate in Equine Practice: Safety on 1,804 Horses, Efficacy on 343 Horses,” published in the Journal of Equine Veterinary Science.

Allen and Richard D. Mitchell, DVM, MRCVS, Dipl. ACVSMR, of Fairfield Equine Associates, in Newtown, Connecticut, provided data for the study. Their records included notes about each horse’s lameness grade evolution, ­observed side effects, and subsequent return to performance. All horses received slow intravenous (IV) administration of 1 mg/kg tiludronate between 2006 and 2019.

The results:

• 82% of horses competed at a better or similar level after treatment.
• More than 80% of the horses initially scored 1.5/5 on the lameness scale and were sound 30 days after treatment.
• 0.9% of horses experienced side effects.

In a recent review of clodronate (Markell et al., 2020), the authors concluded that equine studies have consistently demonstrated the drug has both a good therapeutic effect and a good safety profile when used to treat navicular bone disease. “But we need larger studies to better understand how useful it is in various cases,” says Allen.

At UC Davis, Knych, associate professor Carrie Finno, DVM, PhD, and a team of researchers are conducting studies to add to the body of knowledge on clodronate. Their study, “Clodronate detection and effects on markers of bone resorption are prolonged following a single administration to horses,” was published in the Equine Veterinary Journal in July.

The study, funded by the Grayson Jockey Club and the Viola Foundation, included 11 horses—a limitation Knych acknowledged. Seven exercised Thoroughbreds received 1.8 mg/kg of clodronate, and four received an equal dose of saline. Knych says their goal was to better understand how bisphosphonates affect equine athletes’ long-term health and soundness.

“It was also meant to provide information that would help regulate bisphosphonates in horse racing,” she adds.

The researchers found that clodronate was detectable in blood for 14 to 175 days and in urine up to 175 days. In some horses, Knych says, drug concentrations were undetectable at one time point but detectable at a subsequent time point.

“It was not necessarily a surprise but interesting to observe that the drug can stay in the body for so long following a single administration,” she says, noting that in a 2021 study, her team found one horse retained a bisphosphonate in bone for 18 months.

“Similar to what we see in humans (the half-life of bisphosphonates in human bone is several years), the drug resides in the horse’s body for an extended period, which can prolong the drug’s effect,” she says. “In humans, clinicians often recommend a ‘drug holiday’ after prolonged use because of the long residence time and the potential for accumulation of the drug. This prolonged effect has been associated with an increased incidence of fractures and impaired healing.”

Administration varies by medication. As noted, veterinarians administer tiludronate intravenously.

Allen says it’s critical to monitor the horse following treatment. For example, excessive drinking or urinating could indicate an underlying kidney problem not previously observed. For this reason, some veterinarians run bloodwork to assess renal function before administration. Although side effects are low (0.9%), they could include a mild coliclike episode.

“We would support the horse with more fluids in this case,” he says. “However, in my experience and in our study, this is extraordinarily rare.”

Conversely, clodronate is given via intramuscular injection and also carries minimal risks, but the side effects are slightly different. For example, the horse might experience pain at the injection site. Researchers on studies in humans have described using lidocaine with an injection to reduce the pain, but this is uncommon in equine medicine, says Allen.

“More commonly in veterinary medicine, we sedate the horse before administration and then let the horse wake up and observe the horse for 30 minutes after injection to make sure he is doing fine,” he says.

Clodronate can also aggravate underlying kidney issues, so watch a horse for excessive drinking or urination for two to three days after treatment.

“These are reasonable things on both those drugs,” Allen adds.

Veterinarians also advise against administering bisphosphonates and non-steroidal anti-inflammatory drugs such as flunixin meglumine concurrently in horses because of potential kidney ­damage.

Lessons Learned

While bisphosphonates were first brought to equine medicine to treat navicular pain, their use can be game-changing in other situations. For example, Allen says studies indicate tiludronate has significantly reduced osteoarthritis development in horses.

“Say you put a cast on a horse,” he says. “You know (the injured limb) will lose bone density because it is not being used. It happens in humans and horses. One study that treated a horse with Tildren found it was effective at reducing the amount of osteoarthritis and the accepted associated pain.”

Bisphosphonates are valuable tools in equine practice, he says, especially for horses that might have once been sidelined from their careers or living in discomfort. However, as their use has expanded and additional studies have been published, veterinarians have learned several key lessons about these drugs.

First, they should not be used on horses under 4 years of age, says Allen. Juvenile horses have active growth plates. Because bisphosphonates are designed to inhibit bone absorption, using these medications on young horses interferes with the development of bony structures. It is also inadvisable to give bisphosphonates to pregnant mares. As with all mammals, changes in bone and cartilage occur in utero, and those natural processes should not be altered, Allen says.

“After age 4, and in older horses, bisphosphonates can be effectively used in cases where there is active inflammation and bone pain,” he says.

Also, the risks related to using this drug are dramatically different in ridden sport horses than juvenile racehorses, Allen says. Therefore, when evaluating effectiveness, those two groups of horses must not be compared because the risk factors of using the drugs differ wildly.

One piece of information that has emerged is when to delay bisphosphonate use. For example, Allen says an acute ­fracture of the coffin bone in a sport horse is an instance he would recommend waiting 30 to 90 days before using the treatment.

“You want to let the osteoclasts get in and clean up a fracture line and do their job,” he explains. “Then if bony inflammation is still going on, you can go ahead and intervene with bisphosphonates.”

What Work Still Needs To Be Done?

Veterinarians have learned a lot about the benefits of bisphosphonates administered to horses with musculoskeletal conditions. Based on FDA approval and the results from the study Allen participated in, he believes science has proven the safety and effectiveness of this class of drugs. However, there is always more to be understood. Specifically, he sees a need for larger, more comprehensive studies of clodronate, similar in scope to the study he participated in with tiludronate.

“The more information and retrospective studies we can make available outside of all that is available in veterinary medical databases, the better,” he says. “It takes time to pull out the information. It is a challenge and hard to do, but it is really worthwhile for practitioners in the field and the clinics treating horses.”

As with any treatment, veterinarians are also looking for opportunities to find benefits outside those the drug was initially developed to address. Knych sees this as an area that needs future research.

“There are anecdotal reports of analgesic (pain-relieving) effects, but we still don’t completely understand how this works, duration of effect, etc.,” she says. “Overall, a better understanding of the long-term effects on the musculoskeletal system would be prudent.”