Bisphosphonates: A dense issue in equine veterinary care
A look at the use of this bone-modifying drug in horses and the concern for proper bone metabolism.
Bone is a dynamic organ-always changing, constantly being reshaped, old cells removed and replaced with new. Bone responds to stress by removing damaged or injured bone and laying down new bone-an ongoing process. Bone is constantly remodeled to meet the needs of stress and loading. The response of bone to strain is based on Wolff's Law, 1892. According to this law, bone adapts to increased load or weight-bearing, which occurs in regularly worked horses.
“Bone remodeling is the process by which bone changes its shape, structure and strength in response to the strain, or exercise, that is applied to it,” says Patty Hogan, VMD, DACVS, Hogan Equine, Cream Ridge, New Jersey. “To do this, the bone actually develops tiny microfractures in response to training, and the osteoclasts and osteoblasts are called in to remodel and rebuild, resulting in a stronger structure. It is an expected and welcomed effect of gradual and progressive training in the racehorse.”
But the requirements of race training can put too much stress on the process. “The bone cannot keep up with the training requirements and it enters a stage of inappropriate or ‘stress' bone remodeling where we begin to see distinct clinical stress fractures, such as in the tibia and humerus, and the stress remodeling response commonly observed in shins, third carpal bones and the distal cannon bones (condyles) known as sclerosis,” says Dr. Hogan.
Susan Stover, DVM, PhD, a professor at the University of California, Davis, builds upon the importance of bone remodeling. “Remodeling is also critical in growing animals where it's responsible for converting calcified cartilage to bone. It's a finely tuned balance between resorption of damaged bone and replacement by healthy bone as well as for resorption of rapidly deposited, but relatively weak, woven bone and replacement by higher-strength lamellar bone–important for bone's adaptation to increasing levels of exercise. And further, remodeling is key to the culmination of fracture healing. Horses are not born with racehorse skeletons-bone remodeling and adaption in response to training mold the skeleton to become a racehorse skeleton.”
Jeff Blea, DVM, of Von Bluecher, Blea, Hunkin, Inc., and chairman of the Association of American Equine Practitioners (AAEP) Racing Committee, says, “When you have a young horse or a horse who is injured, and you're trying to rehab that injured individual, or as a young horse begins his training, the body responds to load/exercise by remodeling bone. Osteoclasts resorb injured bone, while osteoblasts lay down new woven bone, the process of remodeling. For that bone to become stronger, as that woven bone gets stronger it turns into strong lamellar bone.”
In thoroughbreds, this bone regeneration is needed to develop healthy bones to meet the demands of racing. “When you have a young horse that doesn't experience load or exercise, their bones are not as durable or as strong as they need to be to withstand the rigors of training and racing,” says Dr. Blea. “In the same vein, when you have a horse that is recovering from any type of musculoskeletal injury and that horse is limited in its exercise or load, that bone won't remodel the same way that it would if you had the ability to provide exercise to that individual or load to that bone structure.”
Bone load is critical to bone remodeling. It's known that young horses confined to stalls will develop bone degradation due to lack of movement (lack of load pressure), with bone becoming thinner due to the action of osteoclasts to resorb/remove bone. Thus, it's important that young horses be given outdoor exercise and not be totally confined or else they will begin to show signs of bone degradation due to this lack of load pressure.
“A good example is turning a horse out for a four-month interim into a 14-by-14-ft pen versus turning a horse out for four months into a five-acre paddock,” Dr. Blea explains. “Those are ‘apples and oranges,' even though one is still turning the horse out. That horse in that five-acre paddock, he's going to remodel, strengthen his bone, while the horse in the 14-by-14-foot pen is not going to be able to remodel his bone in the same way.”
Enter the bisphosphonates
Bisphosphonates are a class of bone-modifying drugs that have been used as an adjunctive treatment for specific bone disorders in human medicine for the past 20 years. “The mechanism of action of the bisphosphonates in the bone comes from studies in rodents, rabbits and humans, and I would expect it to be similar in horses,” says Dr. Stover. “There might be some differences among species, but in general they're likely to behave similarly.”
"Basically, bisphosphonates work specifically at the cellular level and act to block a certain type of bone cell called an osteoclast,” says Dr. Hogan. “Osteoclasts are a very important spoke in the wheel of bone remodeling in that they essentially act as ‘garbage collectors' to first clean up any diseased, weakened or damaged bone before any new bone can be brought in and laid down by the osteoblasts, the ‘bone builders.'”
Dr. Blea says, “Essentially what bisphosphonates do is ‘chew up' damaged bone, simplistically shutting down the osteoclast process. The body can still lay down bone; it just can't remodel bone in a ‘normal' way. Bisphosphonates are inhibiting part of that normal remodeling osteogenesis process, which is a natural response of the body to heal.”
As discussed by Kenneth Marcella, DVM, in May 2014, the FDA's Center for Veterinary Medicine licensed the bisphosphonates Tildren (tiludronate disodium) and Osphos (clodronate disodium), which are “intended to control the clinical signs of navicular syndrome.” Prior to this time, tiludronate disodium had been used as a treatment for lameness in multiple locations in horses, but in May 2014, its use in the United States was restricted to treat navicular disease. Clodronate disodium was a new drug, so at the time it had no previous history for its use.
In 2014, there was limited evidence as to the benefits of tiludronate disodium and clodronate disodium to treat navicular disease and other lameness issues in horses. Though there were noted concerns, equine practitioners were optimistic about their use for treating lameness issues that were recalcitrant to all other treatments and those of the lower leg and hoof in horses, as it was shown that bisphosphonates modified the action of osteoclasts.
Current concerns about bisphosphonate use
In 2017, the British Racing Authority outlawed the use of bisphosphonates in horses younger than 3.5 years of age and restricted them to products licensed in the U.K. And as of 2018, the Association of Racing Commissioners International (ARCI) has been concerned that the use of bisphosphonates may go too far. How so? There is limited information on the use of bisphosphonates, their efficacy and side effects in young horses the receive the drug before or during initial training. It is also an off-label use in young horses since these products are labeled for older horses.
Dr. Blea also raises the issue that there are no longitudinal studies on bisphosphonates regulating what happens in young growing bone or mature bone over the long term. “We do know that they stay in the bone a long time. And we can identify them for about 26 to 27 days in blood and urine,” he says. “That's why the British Horseracing Authority has a 30-day stand-down time.”
The concern? Dr. Blea says there have been anecdotal reports of yearlings and young horses in training receiving bisphosphonates. “We don't know what that is doing to the bone today, next month, next year or years after administration. Therefore, there is concern for their lingering effects as the horse ages.”
Dr. Stover looks to the genesis of the drug in the first place. “Bisphosphonates were developed for use in humans who have an imbalance in bone resorption and formation, where bone resorption exceeds bone formation and results in diseases like osteoporosis,” she says. “Slowing osteoclastic activity in these individuals makes sense. Bisphosphonates were not developed for healthy horses that have innately balanced bone resorption and formation. Disturbing that balance does not make sense.”
Dr. Stover thinks that bisphosphonates used in immature animals could lead to disturbed growth and joint development as well as the accumulation of microdamage in the bone tissues. “Because some growth plates do not close until 3.5 years of age in racehorses, there is the potential for adverse effects in racehorses that are still growing and fully developing skeletal structures,” she says. “At one extreme, accumulated microdamage could coalesce and promote bone fracture. Fracture healing may be delayed in horses that sustain a fracture.”
And Dr. Blea sees another angle that is even more concerning, especially on the racetrack since bisphosphonates are used quite effectively to mitigate pain in humans. He says if you factor in potential pain mitigation with the use of bisphosphonates on young horses in addition to their ability to improve soundness and improve lameness, yet don't know the effect on bone, “I think that is a dangerous situation."
Since Dr. Blea thinks more research is needed on bisphosphonate use in thoroughbred horses, he only recommends them for administration to older horses being turned out for a specific problem, and he does so infrequently. “I think, within the thoroughbred industry, we've got to be careful with their use,” he says. “Because we don't know their effects, we have to be careful how we're using these off-label in young horses.”
Dr. Blea says there are rumors of bisphosphonate use on the racetrack but he doesn't think this is the case in thoroughbreds. “I polled the AAEP Racing Committee and we don't feel so,” he says. “I think a lot of it is rumor. It may have been used to see if they could be used to treat various diseases or injuries and they didn't see any benefits. I do not think they're being overly used on the thoroughbred racetrack.”
Dr. Stover's take on the issue: “I am concerned about the potential adverse effects of bisphosphonates on bone's internal remodeling process for staying healthy and being able to adapt to increasing intensity of training. Further, there is some evidence that bisphosphonates relieve pain, and so I have concern about racehorses with mild injuries continuing to train and race, which increases the potential for mild injuries to become catastrophic. Further, I am concerned about the potential longevity of bisphosphonates' effect relative to fetal growth and development in racehorses that become broodmares.”
FDA approval of bisphosphonates
So how did the FDA CVM approve these drugs with the scarcity of scientific data available about their use in horses?
“I don't have access to all the evidence that the FDA used to assess Tildren and Osphos,” says Dr. Stover. “However, the published clinical evidence for the use of bisphosphonates in navicular disease is based on only a few small studies. Unfortunately, the marketing of bisphosphonates and ‘star quality' of newer drugs has resulted in significant off-label use that does not have a physiologic basis.”
Dr. Hogan sees the financial burden of trying to get a drug approved for a relatively small market like horses. “In people, there is a tremendous amount of testing and long-term clinical trials,” she says. “For horses, there is a much smaller window of proof required. So they marketed them for use for navicular disease issues, which we know is very rarely a clinical entity in racehorses. Unfortunately, the data used was a very simple study with very little science. It was all about clinical data, looking at lameness, per se, as a standard. Their conclusions were based on whether horses-not racehorses-were lame at the end of trial, or that they improved their AAEP grade of lameness. If one looks at the paper closely, many of the horses were still lame, they just improved their grade of lameness, and some only improved slightly. A horse is either lame or it's not, and therefore it was a poor conclusion to base approval of these drugs solely by their effects on lameness.”
Dr. Hogan says that at the racetrack, bisphosphonates are largely being used to ameliorate the clinical signs of the painful stress remodeling response, or sclerosis. “The working theory is that by blocking the action of the osteoclasts, then stress remodeling will cease and the bone will not progress to develop an actual stress fracture,” she says. But she says this is not the case at all, noting there is recent concern based on research in people and other species that bone placed under high strain rates becomes weaker and more susceptible to a stress fracture with bisphosphonate use.
“The lack of racehorse-specific research in the use of the bisphosphonates should give anyone considering using these drugs great pause, if for no other reason than for the inherent legal liabilities that choice may carry,” cautions Dr. Hogan. “Extrapolating results from human research in elderly and/or sedentary osteoporotic people and applying it to 2- and 3-year-old thoroughbred racehorses traveling at 35 mph is, at the very least, scientifically unsound. Much of the use of bisphosphonates in racehorses today is off-label-most horses that are treated are less than 4 years of age and they do not have navicular disease. To go one step further and explore the possibilities of the potential for a catastrophic bone injury in a racehorse that had been administered a bisphosphonate, resulting in human injury or loss of life, one should consider the dearth of scientific and clinical evidence available for the defense of its use. There simply is none.”
Dr. Hogan has been skeptical since bisphosphonates first entered the equine market. Then she started to observe an unusual trend in horses with relatively simple, routine fractures that she had repaired. “I noticed that some of these horses that were referred from barns that I knew were heavily using bisphosphonates, particularly tiludronate, had incredibly bizarre healing responses-delayed healing, unusual zones of bone lysis associated with the fracture lines. So as a surgeon, the use of the bisphosphonates in the racehorse just seemed to defy everything I had come to know about bone healing for the last 20 years and some of the clinical cases I personally came in contact with seemed to bear out that concern.”
Is there a difference when bisphosphonates are used in standardbreds? Dr. Hogan finds that it is not essentially different. “I've seen the same sort of issues with the use of bisphosphonates in standardbreds. For example, I recently examined a standardbred that was given multiple doses of bisphosphonates last year as a 2-year-old because as a colt, he competed through the seasons with a lot of soreness due to distal cannon bone remodeling,” she says. “Recently, examining him as a 3-year-old, he was having lameness issues very early on in training and imaging revealed he had some permanent degenerative bone changes in his hind cannon bones that would be considered uncommon at this stage of his career. I don't know of course if bisphosphonates are directly responsible, but my index of suspicion is very high.”
Industry position on bisphosphonates
“For clodronate in horses, we want the drug to be used in horses over 4 years of age,” says Torri Maxwell, DVM, a technical services veterinarian with Dechra Veterinary Products, the manufacturer of Osphos (clodronate injection). “The 4-year statement is on the label because we know the drug has an affinity for areas of high metabolic bone turnover.”
Dr. Maxwell says Dechra does not advocate for off-label use. “We certainly agree that the off-label uses of these bisphosphonates are inappropriate in young racehorses 2 to 3 years of age, in 2-year-olds in training and at sales of young horses,” she says. “We understand that there is a temptation to use it in young horses, but we believe those people are not gaining any benefit or advantage by using the drug where it has zero benefit to young stock. I want to be very clear that we support the ethical and judicious use of this drug.”
“I'm not sure that bisphosphonates are ever going to find a home in that younger age group, and with the racing restrictions that are certainly on them,” she continues. “And I don't see us (Dechra Veterinary Products) going into and ever seeking to put the younger horse on the label. So as much as we want to find out the metabolic uses of bisphosphonates, we just don't look into this age group because we don't think that it's appropriate.”
As for how much usage she has noted among racetrack veterinarians, she does not see an overwhelming use. “I've spoken to a number of racetrack practitioners who said that they do not use this drug, and that it does not fit into their portfolio.”
Dr. Maxwell's overall take: “I want to get things right regarding bisphosphonates. I think it has great value for the proper patient. I want to make sure we're getting it into the proper patient and they're benefiting from it. I do want to educate the veterinarian that the improper choice has a multitude of things associated with it. I want to make sure veterinarians are using this drug properly, and we're marketing it to those to use it in an ethical and judicious manner.”
AAEP bisphosphonate research
“The bisphosphonate research ‘wheels have been set in motion,'' Dr. Blea confirms. Although there is some pharmacological testing ongoing now at UC-Davis, the main research thrust will be an AAEP think tank chaired by Jeffrey Berk, VMD, current AAEP president-elect. Their objective will be to begin to understand the uses of bisphosphonates and to examine their effects in young horses on bone long-term. Hopefully in due time they will generate significant scientific data and answer a lot of questions of unknowns now on bisphosphonates.
Completion of the work will take some time. “We're going to look at developing research to examine the effect of administration of bisphosphonates to young horses on bone, as they are exposed to training and racing,” says Dr. Blea. “That hopefully will give us an understanding of what is occurring with their use long-term.”
The end goal is to educate equine practitioners regarding ethical and moral uses of bisphosphonates in the Thoroughbred racing environment. “We are going to try to provide a resource to the industry that is nonpolitical,” Dr. Blea says. “We're going to find out the things we know and don't know about bisphosphonates.”
Everybody is talking about bisphosphonates-owners, farm managers, regulators and veterinarians. “There is a use for these drugs, but I think we all need to step back and better understand the effects of their use,” cautions Dr. Blea. “We need to be smart how we use these drugs.”
Dr. Hogan says, “The concept for their use in racehorses doesn't make any scientific sense with my knowledge of bone healing and bone remodeling. Basically, what it's being used for is a manmade phenomenon that is accelerated stress remodeling of bone that is a reaction to training methods. We've created that issue, and we're trying to use a pharmaceutical fix to absolve the horse of the clinical signs of the deleterious aspects of the training issues. When you're talking about racehorses it's a very complicated issue with many far-reaching effects of trying to shortcut the bone remodeling phenomenon that the body is naturally doing.”
Dr. Stover concurs: “What in many cases we don't talk about is that we're creating these problems in racehorses by the way we manage them. And we need to manage them a little more carefully, and then we wouldn't have to worry about treating with anything. We're always looking for the pill, shot, injection, or something to cure or prevent an issue, where really we shouldn't even have to be dealing with these problems; we just need to be more careful about how we manage our horses.”
Regardless of the statement on the labels of clodronate and tiludronate, equine practitioners need to understand that these bisphosphonates should be used solely for horses 4 years of age and older and not off-label for younger horses or racing horses. As in the U.K., bisphosphonates should be banned for horses younger than 3.5 years until further information is garnered by the AAEP as to their total effects on immature bone and mature bone as well. The veterinary oath to do no harm should be followed to ensure the judicious use of these drugs until scientific data is available as to their total function in equine bone metabolism.
- Marcella K. Bisphosphonates and navicular disease in horses. dvm360 magazine, May 2015.
- Angst F. ARCI Convention: Panel raises bisphosphonate concerns. Blood Horse, April 2018.
- Zhu ED, Louis L, Brooks DJ, et al. Effect of bisphosphonates on the rapidly growing male murine skeleton. Endocrinology 155(4):1188-1196.
Ed Kane, PhD, is a researcher and consultant in animal nutrition. He is an author and editor on nutrition, physiology and veterinary medicine with a background in horses, pets and livestock. Kane is based in Seattle.