Just a few short years ago, owners of horses diagnosed with navicular syndrome had very few options. An infuriatingly vague diagnosis, the term “navicular” was often applied to cases of otherwise unexplained heel pain. Therapeutic trimming and shoeing could help preserve soundness for a few years, as could non-steroidal anti-inflammatory drugs (NSAIDs), but there was no way to head off the inevitable: early retirement for the horse and heartache for the owner.
Then the navicular landscape shifted dramatically. Advances in MRI technology led to more precise identification of injuries and abnormalities in the heel area. A case that may have been chalked up to “navicular” even five years ago might now be revealed as an impar ligament strain that is manageable by specific, focused treatments. The ability to see all structures in the back of the hoof transformed the veterinary profession’s understanding of what navicular was and wasn’t. With better diagnostics, options for treatments to manage heel pain, especially when caused by soft-tissue changes, suddenly multiplied.
But mysteries and frustrations remain. Horses who exhibit heel pain with no obvious soft tissue or cartilage damage are still tough cases. Lesions on the navicular bone, as well as bone edema (bruising), are often found in lame horses, but they are also seen in plenty of horses who are perfectly sound. The relevance of “abnormal” looking navicular bones is still unclear. And treatments to address navicular lameness related to bone changes were still limited to corrective shoeing and anti-inflammatory medications. That is, until very recently.
In the summer of 2014, the navicular landscape made a sudden shift again. That’s when the Food and Drug Administration (FDA) approved two new medications for the treatment of navicular syndrome, specifically targeting bony changes seen in many cases. Both drugs, sold under the names Tildren and Osphos, belong to a medication class known as bisphosphonates. Both have similar action, and both are prescribed with the same intentions. But they aren’t identical. This means that horse owners coping with bone-based navicular problems have, for the first time in a long time, options.
Tildren and Osphos are available only by prescription, and a veterinarian will need to determine if one or the other may help treat a particular bone problem. But if you’re caring for a horse with navicular syndrome, you’ll want to have a conversation with your veterinarian about the role bisphosphonates might play in your long-term management plan. Here’s what you need to know to start that discussion.
A balancing act
Bisphosphonates were first synthesized in 1897 by chemists in Germany for industrial applications. Named for the two phosphate groups they contain, bisphosphonates were used to prevent calcium carbonate scaling on machinery and plumbing. It wasn’t until nearly a century later that the chemicals were considered for clinical applications in human medicine based on their effects on bone remodeling.
The continuous breakdown and repair of bone tissue, remodeling helps bone adapt to stresses, becoming stronger and/or repairing damage. “Bone remodeling is why you can break your arm and it heals,” says Kyle Creech, DVM, equine veterinary services manager for Ceva Animal Health, the makers of Tildren. The remodeling processes is a marvel of biology, but it can be explained fairly simply:
Cells called osteoclasts continually roam bone surface, resorbing old or damaged bone. In their wake, different cells known as osteoblasts arrive to lay down new bone. At times of bone stress, such as during extreme physical activity or after a traumatic injury, this process is accelerated, with osteoclasts working faster to tear down the damaged bone. Generally, osteoblasts can keep up the increased pace, laying down new, stronger bone quickly, but the process isn’t instantaneous.
“There can be a lag,” says Jill Stohs, DVM, technical services veterinarian with Dechra Veterinary Products, the makers of Osphos. “In normal bone remodeling, generally it takes about three weeks for osteoclasts to finish their job of removing the damaged and stressed bone. Once the osteoclasts have completed their job, they signal and recruit osteoblasts to the area of removed bone. Osteoblasts may take up to three months to complete their process of adding new bone. By that time, though, the underlying stress has been relieved, so osteoclasts have slowed down their efforts and the osteoblasts can catch up to them.” In cases of navicular syndrome, however, the stress on the navicular bone is continual, meaning osteoclasts are continually working to remove stressed bone tissue and osteoblasts do not have a chance to catch up, and degradation of the bone occurs. This, say Creech and Stohs, is where bisphosphonates can help.
Bisphosphonates restore balance to the bone remodeling process by inhibiting the resorption of bone. Bisphos-phonates become attached to calcium in the bone. Then they are ingested by osteoclasts and disrupt the metabolic process of the bone-eating cells, which causes them to die. With fewer osteoclasts at work tearing down bone, the osteoblasts can then keep up with the job of laying down new bone, leading to fewer lesions. “It’s all about re-establishing that balance between the osteoclasts and the osteoblasts,” says Stohs.
With the discovery of this mechanism in the late 1960s, bisphosphonates were put to use treating human bone disorders, such as osteoporosis (the rapid breakdown of bone throughout the body) and Paget’s disease (disorganized bone remodeling in specific locations such as the femur). Fosamax, Boniva, Reclast and other bisphosphonates quickly became the most prescribed treatment for osteoporosis.
As often happens when a new human drug comes onto market, equine health researchers began looking for potential applications of bisphosphonates in horses. Horses, however, don’t get osteoporosis. Or Paget’s disease, for that matter. So researchers began considering which equine conditions might have similar physiological processes.
Eventually European researchers hit upon the idea of using the drugs to treat bone0 spavin, navicular disease, kissing0 spines, pedal0 osteitis and other conditions affecting bone. Scientific papers began to emerge as early as 2001, and soon after that the bisphosphonate tiludronate disodium (Tildren) was marketed in Europe for use in horses.
Ceva worked with the FDA to create a path through which veterinarians could import Tildren into the United States, a process that required several steps. However, once a veterinarian had the drug, things weren’t always simple, especially if he hadn’t used it before. “The directions weren’t in English,” says Creech. “So veterinarians had to rely on protocols they had heard of from others or at conferences.” For more than a decade, this was the only bisphosphonate available for equine therapy in the United States.
The two companies, however, began working toward Food and Drug Administration (FDA) approval of bisphosphonate medications specifically for the U.S. equine market. The FDA approved Tildren in February 2014 and Osphos two months later.
Compare and contrast
Given their shared drug class and history, it’s no surprise that Osphos and Tildren have many similarities. For starters, despite their many applications in Europe, both are approved by the FDA only for the control of clinical signs associated with navicular syndrome in horses. Any other use by individual veterinarians in this country is considered “off-label.” While that practice is not illegal, those uses have not been studied by either the manufacturers or the FDA.
Both drugs are also labeled specifically for use in horses over the age of 4, when the bone remodeling process naturally slows down a bit. “Young horses are turning over bone at an incredibly high rate,” says Creech. “That’s necessary for their bones to become adapted to the type of work they are going to be doing. It’s a critical process that we don’t want to interfere with at all.” Similarly, neither drug is approved for use in pregnant or lactating mares or those intended for breeding. Bisphosphonates have been shown to cause abnormal fetal development in other species and may be excreted in milk to be ingested by nursing animals.
The route of administration is a primary difference between Osphos and Tildren. Osphos is administered via an intramuscular injection; 1.8 milligrams per kilogram of body weight divided equally among three separate injection sites. Tildren is given as an intravenous infusion, with one milligram per kilogram of body weight being delivered slowly over 90 minutes.
The difference in administration routes, says Stohs, is partially due to the chemical makeup and specific formulation of each drug. “If you go back to organic chemistry, you can remember enough to realize that while tiludronate disodium and clodronate disodium are in the same family and subclass of chemicals, their actual molecular structure is different, which affects the way each molecule acts and can influence how each product can be administered. They are in the same fruit basket, so to speak, but you aren’t comparing oranges to oranges and, more specifi-cally, identical drugs when you talk about the two.”
Another influence is simply how the drug was developed. “In Europe, Tildren was always given intravenously,” says Creech. “That’s what veterinarians had the most experience with, so that’s the path we continued on through development and the approval process.”
As part of the FDA approval process, both Dechra and Ceva had to demonstrate efficacy and safety of their drugs for the specific labeled use. While the end goal was the same, the companies took slightly different approaches.
The Dechra efficacy study was based on 146 horses between the ages of 4 and 22. All had forelimb lameness that was scored at least a grade 2 (out of 5) on the American Association of Equine Practitioners’ lameness scale. The horses moved sound when their heels were numbed and had radiographic evidence of degenerative changes of the navicular bone. Investigators treated the horses with an intramuscular injection of either Osphos or the control saline and then evaluated them for treatment success at days 28, 56 and 180 post-administration. “Success” was defined by an improvement of at least one lameness grade. When the horses were evaluated 28 days after initial injection, 67.4 percent of Osphos-treated horses were considered successes, compared to 20.7 percent in the saline-treated group.
An evaluation at day 56 showed that 74.7 percent of the treated horses had improved; only 3.3 percent of the control horses showed improvement. Seventy-eight successfully treated horses were available for a 180-day follow-up and, of those, 65.4 percent were still considered treatment successes.
The Tildren efficacy study used 208 horses, ages ranging from 4 to 20, that had been diagnosed with navicular syndrome based on clinical exams, nerve blocks and evidence of bone edema on MRI with no soft tissue involvement. The horses had a grade 2 lameness or greater when trotting on a 10-meter circle, with the lamest limb on the inside of the circle. The horses were treated with either a single infusion of Tildren or an inert sucrose solution that served as a control. The veterinarians reexamined the horses two weeks, one month and again two months after treatment. The treatment was considered a success if the horses improved one lameness grade at the two-month evaluation while trotting on the same size circle with no increase in lameness in the opposite limb. Sixty-four percent of the treated horses were deemed successfully treated, while 48 percent of control horses were considered improved.
Both Creech and Stohs stress that regular corrective shoeing is critical to the success of the treatment. “No drug is going to offset the damage done by a foot that’s out of balance and not maintained properly,” says Stohs.
The FDA approval process also requires proof of safety. Studies toward this end showed that Tildren and Osphos share a potential adverse reaction: Both can cause mild colic-like gastrointestinal pain. Early in the Tildren study, when the infusions were given over a 30-minute period, 41 percent of treated horses showed colic pain during treatment, compared to 10 percent of placebo-treated horses. The infusion time was expanded to 60 minutes, and the adverse reaction rate dropped to 28 percent. (Eventually, the approved Tildren label would specify a 90-minute infusion period.) In the Osphos research, 9 percent of horses showed signs of transient colic. Almost all of the cases of colic were mild and subsided with hand-walking—less than 1 percent required treatment with a dose of flunixin0 meglumine. “What’s interesting is these are similar to the side effects seen in humans,” says Creech. “People also report a mild discomfort. Is it visceral pain? Is it kidney pain? We aren’t quite sure. What we do know is that it’s not serious colic, like an obstruction or other surgical case. The majority of horses in our study responded quickly without additional signs or need for additional treatment.”
The cause of this side effect isn’t fully understood, Stohs says: “Bisphosphonates work by binding calcium, and we do see some transient changes in electrolyte and mineral levels after administration. Are we seeing signs of discomfort because of that calcium binding? We don’t know, but it’s potentially what’s going on. It’s something we will continue to research because if we can identify the problem, we can possibly take steps to prevent it.”
Beyond colic, there are a few other potential adverse effects veterinarians using bisphosphonates will be mindful of: These drugs are excreted by the horse’s kidneys, so caution should be used when administering it to horses with renal problems. The labels of both Tildren and Osphos carry warnings about concurrent administration of other renal-toxic drugs, such as NSAIDs. Both labels also carry a warning about use in horses who have conditions that may affect mineral or electrolyte0 balances, such as hyperkalemic0 periodic paralysis (HYPP). Bone fragility is an observed side effect in long-term bisphosphonate use in humans, so both of the equine product labels warn of the potential to inhibit repair of microfractures in horses.
Both Ceva and Dechra stay in close contact with every prescribing veterinarian to collect their impressions on efficacy and reports of any adverse reactions. “As with any new drug that enters a market, we will learn more from the field veterinarians now,” says Stohs. “They are using it every day, and their observations will be incredibly useful to everyone, including the manufacturers.”
The unknowns
Even while studies produce statistics and facts and veterinarians report their impressions, one big question about the bisphosphonates will remain unanswered for the foreseeable future: How exactly are these drugs relieving the discomfort of navicular syndrome?
Not by repairing damage to the bone that has already been done. “This is important to remember,” says Stohs. “These drugs aren’t reversing old, existing lesions. Those lesions are there for good, which is why it’s very important to start giving bisphosphonates soon after a diagnosis. You can’t make up for lost ground; you can only rebalance the remodeling process from the time of treatment on.”
Creech concurs: “These drugs aren’t a last-ditch effort. You can’t wait until things are very bad and expect them to turn around. You start the drugs in an effort to maintain where you’re at.”
So why, then, do some horses return to soundness after being lame from presumed navicular pain? Nobody really knows. “It’s possible that an overactive remodeling process itself is painful,” says Stohs, “or it’s possible that the overactive remodeling causes bone edema, which leads to soreness. I say ‘possible’ because we didn’t prove any of this at a cellular level; all our studies were designed to do was prove the horses were less lame after being given the drug, which they are. We don’t know why yet, but there’s a lot about navicular that we still don’t know.”
Also unknown is exactly how long the relief lasts. Horses who respond to Osphos, says Stohs, can be given another treatment three to six months later if they begin to show signs of soreness again. “This is not licensed as a preventative drug,” she says, “so we recommend giving it only when necessary and with the reoccurrence of clinical signs of navicular syndrome.”
Creech gives similar guidelines for Tildren repeat treatments: “The frequency of treatment will depend on communication between the veterinarian and a rider who knows the horse well. Oftentimes, they are the first to be able to tell that the horse is off again. We recommend twice a year if necessary, possibly three times at a maximum. We know the drug stays in the bone up to six months, but the concentration then will be much less than it was at, say, three months. What’s the tipping point to keeping the horse comfortable? We don’t know that yet.”
A final unknown is an even more fundamental question: Which horses will respond to either, if any, bisphosphonate drug? “We know that not every drug in a particular class will work the same on every horse,” says Stohs. “So it shouldn’t be surprising to find out horses may have very individualized responses to this new class of drug as well.” For instance, says Creech, a horse who doesn’t improve after a dose of Tildren is a candidate for one more infusion, “but if that also produces no response, it’s not the right drug for that particular horse and continued treatments aren’t likely to be effective.”
If your veterinarian decides your horse might benefit from a bisphosphonate, the specific one he chooses will be a matter of personal preference and professional comfort level. “Veterinarians are constantly making treatment decisions based on many factors,” says Stohs. “From their own experiences to each horse’s and owner’s particular situation, there are a lot of variables to consider in every case. In the situation like we have now, with two options in a new class of drugs, veterinarians have choices they’ve never had before. In the end, though, they are basing their decisions on what is best for that particular horse, and that’s the most important consideration.”
This article first appeared in EQUUS issue #453, June 2015.
