Bisphosphonates are drugs used to treat degenerative bone diseases in humans. Think osteoporosis, or Paget’s disease. In horses, they’re used to treat a similar array of problems, like navicular syndrome, a painful disease whereby the navicular bone in the heel of the horse loses its bone density.
Like all drugs, bisphosphonates are a proven fillip when administered to treat specific conditions in accordance with official guidelines. But like all drugs, bisphosphonates can be misused and abused.
And it’s the potential consequences from misuse in racehorses — especially in young racehorses — that’s causing mounting concern among a growing number of respected veterinarians and regulators in the industry.
“There’s no checks and balances on this,” said Mary Scollay, equine medical director of the Kentucky Horse Racing Commission, about a group of drugs that are currently unregulated.
“If the risk is as real as we perceive it to be, we can be facing a real problem in terms of racing injuries and racing fractures if we don’t as a community come together to decide how to responsibly manage this,” she added.
There’s still so much unknown about the way bisphosphonates affect the physiology of the racehorse, with the bulk of the drug research done on humans and on animals other than horses. But many experts point to studies suggesting that, if bisphosphonates are used to treat bone problems in young horses — those being prepared for the sales, for example — that, rather than strengthen the bone, bisphosphonates might actually have the opposite effect.
What’s more, bisphosphonates can be challenging to detect and can remain in the bone for months, even years at a time, making the regulation of them an even greater obstacle.
“It’s a big concern industry wide,” said Jeff Blea, a Santa Anita-based veterinarian, one of a number of prominent veterinarians in recent years to have dug into the effects of bisphosphonates in racehorses.
“I don’t think they belong on the racetrack,” he added. “The biggest reason why I take that position is that bisphosphonates potentially have potent pain-modifying abilities, and that bothers me.”
How do they work?
Only as recently as 2014 did the Food and Drug Administration (FDA) approve two bisphosphonates — Tiludronate (Tildren) and Clodronate (Osphos) — for use in horses over the age of four.
Tildren and Osphos are non-nitrogenous, and are a less potent version of nitrogenous bisphosphonates.
To understand how bisphosphonates work, it’s good to understand the biological mechanics of the bone.
Dynamic and adaptive, bones are (or should be) in a constant state of growth — at a rate that obviously slows over time — so that they maintain the right balance between rigidity and flexibility.
As Sue Stover, a professor of veterinary anatomy at the UC Davis School of Veterinary Medicine, explained it in an email to TRC, “Bones are continually renewing themselves throughout life to prevent fatigue failure [bone fracture].”
In order for bones to keep remodeling and generating new bone cells, they need to shed the old dead bone tissue, which is where osteoclasts and osteoblasts come in.
Osteoclasts are cells that essentially help dissolve, break down and absorb damaged or weakened bone tissue. This process is called resorption.
Osteoblasts, on the other hand, are cells integral to the growth of new bone. They help to fill the tiny little holes left when cells have died, and where resorption has occurred.
Bisphosphonates work by inhibiting the work that osteoclasts do, thereby preventing the breakdown of bone tissue (hence why they’re used to treat navicular disease).
The potential for harm occurs when bisphosphonates are administered to treat conditions outside of FDA recommendations. And here’s where the lack of comprehensive research in bisphosphonates — especially in racehorses — leaves a lot of hovering questions marks.
Let’s start with their potential analgesic effects.
Studies have pointed out that in some cases where bisphosphonates have proven effective in treating lameness, it’s difficult to know just how much of the improvement was a result of the drug’s pain-killing effect, and how much was due to its function as an osteoclast inhibitor.
Which leads neatly back to osteoclasts.
As we know, bisphosphonates inhibit the functions that osteoclasts perform. Old dead bone cells aren’t destroyed. Rather, this dead tissue — which has lost all its former elasticity — stays exactly where it is. Crudely put, it’s like a bullet fired into the trunk of a tree that has never been removed.
This has the effect of making the diagnosis of brewing bone conditions hard to do with things like x-ray machines, for the dead bone material can give the impression of everything appearing okay, said Rick Arthur, California Horse Racing Board equine medical director.
“The concern is bisphosphonates make bone look good on radiographs,” he said. “When in fact, the bone is weakened.”
Similar concerns surround the effect that the osteoclast-inhibiting process can possibly have on the formation of bones in young racehorses.
‘Bone has to undergo resorption before it gets stronger’
Broad research has shown that young racehorses need to be exposed to a certain amount of strenuous exercise to adequately prepare their bones to the rigors of training and, later on, racing.
Ideally, the bones of young racehorse are exposed to increasingly faster amounts of work, then given enough time in between these workouts for the bone to adapt.
As Sue Stover put it in this recent TRC story, “A horse’s skeleton responds just like muscles in a muscle builder. So, you expose it in small increments to a higher speed, and then you let the bone respond.”
During this conditioning period, the bones of young horses suffer little micro-fissures, leading to niggly aches and pains.
Given adequate time and patience, new bone material would form to fill these micro-fissures. But, in order for these fissures to repair, the process of resorption (triggered and performed by osteoclasts) must first occur.
Only, as we know, bisphosphonates hinder this process, which can prevent the replacement of damaged bone with new bone at the micro-fissure site, studies have suggested.
“Bone has to undergo resorption before it gets stronger,” said Arthur. “It’s a normal process, and, if you inhibit that process, you’re inhibiting the ability of the bone to strengthen and to become strong enough to withstand the rigors of racing and training.”
‘I’ve shifted my position’
One study from 2012 also suggests that Tildren, when used in combination with shockwave therapy, can successfully treat bucked shins in horses in training.
California-based veterinarian Ryan Carpenter was the lead author on that study, and while he has modified since then the way in which he uses bisphosphonates — lessening the amount and frequency of dose, for example — he believes that, if used judiciously, they can be a useful tool to tackle common ailments like sore shins in racehorses.
“I can tell you I am very comfortable using Tildren in a racehorse, and I’ve never seen a fracture associated with it,” he said, adding that he uses it in ‘skeletally mature’ racehorses.
Carpenter won’t use Tildren near to a race. Rather, if he uses it to treat a problem (primarily sore shins), he will do so when the horse is in modified, light training.
From his own experiences, Carpenter isn’t sure that the osteoclast-inhibiting function of bisphosphonates works the way it’s feared to do – that it stays in a specific location in the bone for a long period of time, stopping bone from regenerating naturally.
“Do I think every osteoclast in that area is shut down for life? Absolutely not,” he said. “You still have healing. In that study of mine, the fracture lines disappeared, and the high recurrence rate [of sore shins] didn’t happen.”
Ultimately, he said, more research needs to be done. “There hasn’t been a lot of studies to see what they truly do in horses, and I’d love to see that work come.”
Until the science is more concrete, however, other experts are even more circumspect in their approach to using bisphosphonates.
Jeff Blea also participated in Carpenter’s study. And, while he was initially impressed with the results, his thoughts on the use of bisphosphonates have evolved, he said, to the extent that he will only use them on older horses about to embark on a period of convalescence.
“I’ve shifted my position. We just don’t know what the long-term effects are,” he said. “As more information became available, it’s increased my awareness.”
So, how prevalently are bisphosphonates used in racing?
‘It’s a vicious circle’
This is a tough question to answer accurately. Anecdotal evidence suggests that they are being used “much more extensively in the racing population than I would have thought”, said Mary Scollay.
In his everyday practice, Jonathan McLellan, with Florida Equine Veterinary Associates, works with a large population of young racehorses – from yearlings being prepared for the sales to 2-year-olds in early training.
And it was a perception among his clients that “horses maybe not as robust as they used to be” that prompted him to start researching the scientific literature on bisphosphonates, he said.
He admits the body of research is pretty limited, especially when it comes to studies done solely on racehorses. But most of what has been published, he said, strongly suggests that bisphosphonates shouldn’t be used to treat many of the conditions they’re currently being used for - like sesamoiditis, for example, in young horses.
“If there’s enough evidence to suggest you that you shouldn’t be doing something, then you shouldn’t be doing it,” said McLellan.
With so many hovering question marks, therefore, just why are bisphosphonates used in young horses?
“It’s a vicious circle,” said Archie St. George, founder of St. George Sales, about some of the wider factors at play. For industry pressures, he said, can make bisphosphonates an attractive proposition, especially when their effects can be so marked.
“The problem is, we’ve got to present the perfect horse,” said St. George. “And, at the end of the day, we’re put under the microscope. There’s so much money on the line.”
‘It is an irreversible condition’
There is currently no regulatory framework for bisphosphonates in racing in the U.S., and it’s not illegal for veterinarians to use them in ways not approved by the FDA. Some jurisdictions, however, have taken steps to rein in their use.
Just this August, the British Horseracing Authority implemented a policy prohibiting the use of bisphosphonates in horses younger than three and a half. Nor can horses race within a 30-day period after they’ve been administered bisphosphonates.
The problem is, testing for bisphosphonates is something of a minefield.
“It’s very difficult to test for - there’s a limited detection time,” said Dionne Benson, executive director and chief operating officer at America’s Racing Medication and Testing Consortium. “But the drug is designed to stick around for a long time.”
We’re still figuring out just how long individual bisphosphonates remain at detectable amounts in the blood and urine. What studies have been done show that we’re talking days, and in some cases, weeks.
But we also know that bisphosphonates can remain in the bone — where they’re released incrementally over time — for months, even years at a time.
This means that any future Out of Competition Testing regulations, for example, would have to factor in how horses, especially young horses, can pass through multiple hands during that timeframe.
More than simply a regulatory concern, therefore, bisphosphonates raise philosophical questions about the long-term implications from using a drug with potentially only short-term gains.
“If somebody elects to give a 2-year-old prior to training bisphosphonates so that its sesamoids look better on a radiograph at the sales, how does anybody else who’s in contact with that horse after that time have the ability to remedy that?” asked Mary Scollay. “To the extent that it increases the risk of fracture, it is an irreversible condition.”
In the interim, while testing protocols are being thrashed out, educational programs geared towards trainers and veterinarians might be the most effective way to rein in bisphosphonate use in the industry, said Dionne Benson.
“There are people who are using, or horses who are getting, these drugs. And the owners, the breeders, even the vets, may not realize or think about the long-term effect of that,” she said. “So, I think there needs to be a significant education piece to go along with any regulation.”