“I wish we'd never seen these drugs,” said renowned orthopedic surgeon Dr. Larry Bramlage at the conclusion of a recent presentation about bisphosphonates.
Four years after the Food and Drug Administration approved the use of Tildren and Osphos (both trade names for bisphosphonates) for use in adult horses suffering from navicular syndrome, Bramlage said he's seeing unintended side effects from people using the drug off label.
As Bramlage explained at a recent client education seminar held by Rood and Riddle Equine Hospital, there are three main types of cells associated with bone repair and growth: osteoblasts, which make new bone; osteoclasts, which break down damaged or inferior bone, and osteocytes, which direct the repair.
When a horse has a fracture, the crack is initially filled by the osteoblasts with a temporary boney substance called woven bone, which can be made very quickly but is not very strong. Over time, osteoclasts clear away woven bone, which is poorly organized and weak, allowing osteoblasts to lay down the better organized and stronger lamellar bone. The lamellar bone fills in the crack and makes the bone whole again, both practically and on radiograph.
Bones are constantly breaking down and building back up in response to normal wear and tear and training.
Bisphosphonates work by poisoning osteoclasts and for this reason are used to slow osteoporosis in people. They also have an analgesic effect, which is why they are used in human bone tumor patients. This is also why they are presented as an option for horses dealing with painful and hard-to-pinpoint inflammation due to navicular syndrome.
Bramlage is finding bisphosphonates' mechanism of action also disrupts the natural healing process in young horses during training.
“I thought initially it might create a lot of acute fractures,” he said. “I don't think it increases their incidence very much. Where it causes a problem is whenever you're trying to heal something that's happened as a result of training and needs to repair. Part of the horse's natural coping mechanism is disabled.”
Bramlage is seeing stunted healing on radiographs of horses who have had surgery or rest to repair fractures which normally would have improved in a couple of months. Sometimes as much as 14 months after injury, the x-rays still show the injuries that have been “patched up” with woven bone still persist with original fractures visible.
“I've spent 40 years looking at horses' bones trying to understand the process of damage and repair that we consistently deal with in the racehorse. In the last two years we've had horses' injuries that don't behave anything like they did in my first 40 years,” he said. “We can no longer depend on the repair process that we have come to expect as normal for the horse. Bisphosphonates also 'mute' the normal bone turnover we depend on in bone scans.”
Bisphosphonates don't stop horses from making new bone, which Bramlage says is the reason the drugs don't seem to be causing fractures. They do stop osteoclasts from clearing the weak woven bone out of the way of osteoblasts putting in the strong stuff. The radiographs show new layers of bone being added over cracks but not remodeling of the fractures themselves. As a result, a horse's bone gets denser on the radiographs because of the added woven bone but it doesn't get stronger or repair. Bramlage said the drug does nothing to prompt osteoblasts to work harder as some have theorized, so it doesn't speed this layering process, either.
This mechanism doesn't raise the same problems in pleasure horses because their bones aren't subjected to the volume of stress and rapid need for repair.
Bisphosphonates can cause problems healing bones in humans, too. Bramlage recently spoke to several human surgeons about patients who are unlucky enough to break a bone after they've been on bisphosphonates to prevent osteoporosis.
“If you break your femur, which is a common injury of patients on bisphosphonates, in a normal case they make you non-weight bearing for six weeks. They'd give you crutches and a walker for six weeks. At about three months, you can be weight bearing again,” he said. “If you've had bisphosphonates they'll make you non-weight bearing for up to eight months because that's how much it slows healing in people.”
All of this seems to Bramlage like a poor trade-off for a pain-relieving effect that probably wears off in about 30 days. (Bisphosphonates are shown to attach to the bone's surface after administration and persist for years even after just one dose. Repeated doses cause cumulative levels on the interior surfaces of the bones.) Bramlage said it's important to note that because of the drug's long life on bone surfaces, a trainer currently in possession of a horse may not be the one who originally gave the horse bisphosphonates and may not even know the horse has been exposed to the drug.
“Unfortunately a lot of people who are giving it and are having it given, don't understand the price. They see a temporary improvement in the horse's lameness and they don't understand that what happens months later may be related,” he said. “The people who are in charge when the horse gets the drug don't have to be in charge when you're trying to rehab the horse and get it back to racing. So the lay-up facilities, the owners, and the horses pay the price for the remodeling debt precipitated by the use of the bisphosphonates. I am convinced some horses that we would have rehabilitated effectively in the past never make it back to form because of their history of bisphosphonate use.”
The issues Bramlage is seeing are in horses that have been given bisphosphonates outside manufacturer guidelines. The guidelines state the drugs should not be administered to horses under the age of five. A quick look at the drug literature will make the intended use clear.
“If you're interested in using them, you should go to the manufacturer's website because more than 50 percent of the package insert is telling you why you shouldn't use them in young horses,” he said. “However, they're perfectly willing to sell them to you for use in young horses. All of those disclaimers are meant to put the blame for anything bad that happens to your young training horse on you and not the company.”
Bisphosphonates became a concern for racing regulators in 2015 when the Kentucky Equine Drug Research Council announced its intent to study the drugs after receiving information some managers and trainers could be using it for its analgesic effect.
In England, the British Horseracing Authority issued a mandatory 30-day stand-down period for horses receiving bisphosphonates and prohibits their use in horses less than 3 1/2 years of age. Unfortunately, the drug is difficult to test for and Bramlage worries the temptation of general analgesia can prove too much for some horsemen.
“Routine use of it I think is accelerating on the racetrack based on the number of horses we see that don't follow the normal healing pattern,” he said. “That's a temporary fix, and there's a price to pay.”
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