THE UNKNOWNS
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 90minute 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 flunixin 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 electrolyte balances, such as hyperkalemic 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.”
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