Study results support the safety of clodronate in the long run for use in horses, without the risk of atypical femoral fractures observed in human medicine.

Post-injection pain/colic

Overall, the panelists felt that the risk of colic following clodronate administration is a non-issue. The consensus was that, based on their clinical observations, there is typically some immediate, localized pain at the injection site which may be misinterpreted by some practitioners as colic. As the drug is acidic (pH 4.4), it is expected that there will be some pain immediately following the administration.

Any post-injection signs observed in horses by the panelists were mild and transient; these included typical signs of pain or discomfort such as pawing, posturing, or raising lips. The panelists recommended observing the horse for a short period of time following clodronate administration, and hand-walking the horse if it exhibits signs of discomfort.

Steve Colburn

"I think that most of the reactions we get from giving [clodronate] are just from the acidity of that drug. I can see them just pulling away from you as you're giving it. […] I make them walk the horse for about 15 minutes after I administer it. […] I've given thousands of doses of this stuff, and I have not really had one [that was truly colicky]."

Steve Colburn, DVM

Bloodwork and monitoring renal function

In general, most panelists do not routinely monitor bloodwork or renal function before or after clodronate administration in otherwise healthy horses. There were a few exceptions:

Per the label recommendations, the panelists recommend vigilance in checking with clients if the horse is on an NSAID prior to clodronate administration. From their own anecdotal experience, they have found that cases where a kidney spike was observed were often linked to an NSAID that was not known to be in use by the practitioner until after clodronate administration.

Risk of atypical fractures

This topic was addressed with the panelists because long-term use of bisphosphonates for the treatment of osteoporosis in human medicine have been linked with incidents of atypical fractures of the femur. With the prevalence of clodronate use, there is concern among equine practitioners that they may be putting horses at risk of atypical fractures in the future.

It should be mentioned that for treatment of osteoporosis in human medicine, a more potent class of bisphosphonates (nitrogenous bisphosphonates) are used over a long period of time of many years. Clodronate and tiludronate, the two bisphosphonate drugs that are FDA approved for use in horses, are both non-nitrogenous bisphosphonates that have less potency and a shorter duration of action. While the panelists have colleagues or know of other equine practitioners who use nitrogenous bisphosphonates to treat horses, they caution against using them due to potential long-term ramifications.

Richard Markell

"And that safety factor, I think, is important in bringing up the conversation about nitrogenous bisphosphonates, […] and the nitrogenous have a very different pathway of pharmacology. They are around for a long, long, long time, years and years. They can create issues that we're not aware of and the safety data has not been done on those nitrogenous ones […].The caution with the nitrogenous ones is real and imminent and should be discussed."

Richard Markell, DVM, MRCVS, MBA

In addressing this concern, the panelists referred to two main studies with regards to the risk of atypical fractures in horses with clodronate use. Dr. Chris Kawcak addressed a safety study he was involved with when clodronate was being approved for equine use, in which no bone density change was observed when horses were given up to 3 times the recommended dose at a monthly frequency over 6 months.

"So we looked at two time points on density just to see if there was a change due to the influence of [clodronate] treatment during that time. And there was not at any of the treatment doses. When you look at the data [from the clodronate safety study] […] what I look at is that it was not only proven safe at [the recommended] dose, but it has a very wide safety margin."

Chris Kawcak, PhD, DVM, DACVS, DACVSMR

Dr. Ashlee Watts spoke to a more recent study in which she monitored levels of CTX-1, a biomarker of bone turnover, in horses before and following a single dose of clodronate to determine the risk of atypical fractures. The premise of the study was that in women who experience atypical femoral fractures following chronic bisphosphonate treatment, there is a lasting 50% reduction in their systemic CTX-1 levels.

Dr. Watts assessed the lameness and CTX-1 levels of horses with navicular syndrome before and after clodronate administration at the recommended dose. It was found that while lameness improved, there was no significant change in systemic CTX-1 levels in these horses.

"I was actually pretty happy with the findings. It means that we can use [clodronate], that we know is very effective in keeping horses with navicular syndrome in work and able to perform with and for their owners, without the risk that we see in people of atypical fractures."

Ashlee Watts, PhD, DVM, DACVS