Scientists who have examined evidence around bisphosphonate drugs say more research is needed around their use in horses, saying that little is known about their effects.
Bisphosphonates are a family of molecules characterized by two key properties: their ability to bind strongly to bone mineral and their ability to inhibit the effects of mature osteoclasts – the cells that clear away damaged bone and make way for development of new bone.
Bisphosphonates are used to treat older horses with navicular syndrome and some other bone conditions. They are FDA-approved for use only in horses aged four and over. They are not approved for use in pregnant or lactating mares because questions remain over potential effects on foal development.
Chemically, two groups of bisphosphonates are recognized – those that contain nitrogen and those that do not. Each has a different action.
In the equine setting, only non-nitrogen-containing bisphosphonate are FDA-approved.
An article by Alexis Mitchell and her colleagues in a recent issue of BMC Veterinary Research noted that the use of bisphosphonates in horses has been complicated recently by public discussion over their off-label use in the yearling Thoroughbred industry.
“While the public outcry is concerned about ‘cleaning up’ potentially abnormal radiographs in young Thoroughbreds or change in fracture risk as the young thoroughbreds reach training and racing age, this is not supported by laboratory animal research,” they said.
Early preclinical rodent studies of non-nitrogen-containing bisphosphonates convincingly and repeatedly demonstrate effects in young growing rats with significant reductions in long-bone length due to disruptions in bone formation, but no differences in the mechanical properties of bone.
In their article, the authors – Mitchell, Ashlee Watts, Frank Ebetino and Larry Suva – discuss the current understanding of the strengths and weaknesses of bisphosphonate use in horses and highlight the future utility of these potentially highly beneficial drugs.
They caution that there is a lack of information regarding the effect of single and repeated doses of the non-nitrogen bisphosphonates clodronate and tiludronate.
They said well-designed studies by non-biased researchers with relevant bone parameters as outcome measures must be completed.
“Only with this data can horse owners and practitioners alike make informed decisions regarding the efficacy and appropriate clinical use of these potent molecules.”
Certainly, they continued, clients and practitioners alike require ongoing educational efforts regarding their effectiveness and appropriate clinical use.
Once scientists have a better understanding of their effects in the horse, appropriately designed and powered placebo-controlled studies could be undertaken to determine appropriate dosing and to what extent beneficial bisphosphonate effects on lameness are due to the inhibition of bone resorption.
“Such a strategy is required to ensure safer clinical use and produce a sufficient level of evidence to ensure safety.”
The authors note that in the years since the widespread approved use of tiludronate disodium and clodronate in adult horses suffering from navicular syndrome, there have been reports of additional benefits of tiludronate use, including the treatment of chronic back soreness and lower hock osteoarthritis.
“Bisphosphonates are used in the horse in the treatment of chronic lameness due to many different causes, presumably, in part, due to the reported analgesic effects of bisphosphonates.
“Although blinded, these studies had clinical signs as the primary outcome measure and do not report any changes in bone mass.
“Interestingly, bone mass has not been measured as an endpoint in any published equine study of bisphosphonate safety or efficacy.
“One of the oft-stated goals of bisphosphonate treatment in the horse is an increase in bone mass and strength, the result of a reduction in osteoclastic bone resorption, as observed in humans, but this parameter is largely unmeasured or ignored in equine studies.
“Indeed, some of the positive outcomes reported following bisphosphonate treatment may be due to the pain-relieving or anti-inflammatory effects of bisphosphonate therapy and not the efficacy of bisphosphonates to inhibit bone resorption.”
In general, they said, equine-specific investigations of bone turnover and bone mass changes following bisphosphonate treatment are lacking and sorely needed.
“Given the rampant bisphosphonate use in the equine industry, there are only a few reports demonstrating a positive effect of either bisphosphonate approved for use in horses with navicular syndrome and none report bone-related complications.
“However there is a report that documented lack of change in bone resorption following tiludronate (1 mg/kg IV) or clodronate (1.8 mg/kg IM) treatment as well as a lack of any significant change in serum markers of bone turnover following clodronate (1.4 mg/kg IM) treatment.”
In contrast, the majority of human studies report both beneficial and not so beneficial effects of bisphosphonate therapy in the treatment of postmenopausal osteoporosis and bone metastasis.
“The adverse events reported in humans, including an association with osteonecrosis of the jaw and perhaps the more troubling atypical fractures may forewarn of concerns about bisphosphonate use in the veterinary field.”
The authors pointed to growing concerns regarding treatment length and potential side effects, suggesting it was time for the veterinary community to push for more research and controlled trials of the use of bisphosphonates.
Mitchell, Watts and and Suva are with the Texas A&M College of Veterinary Medicine and Biomedical Sciences; Ebetino is with the University of Rochester in New York.
Bisphosphonate use in the horse: what is good and what is not?
Alexis Mitchell, Ashlee E. Watts, Frank H. Ebetino & Larry J. Suva
BMC Veterinary Research, volume 15, Article number: 211 (2019) https://doi.org/10.1186/s12917-019-1966-x