A critical gap in scientific knowledge surrounding the effects of bisphosphonates in exercising horses under two years of age has been highlighted in a just-published review.
Bisphosphonates intervene in the bone resorption process, producing cellular death of osteoclasts, which are vital bone cells involved in bone turnover.
These drugs are used for skeletal conditions, such as osteoporosis in humans, and are available for veterinary use.
Clodronate and tiludronate are bisphosphonates approved for treating navicular syndrome in horses aged four or older. In effect, the drugs can strengthen the bones of mature horses.
However, they are sometimes used off-label in juvenile animals under exercise, where osteoclast activity is higher. Bisphosphonate use in juvenile and/or exercising animals could have harmful effects, including poor adaptation to exercise or accumulation of microdamage.
Furthermore, bisphosphonates can be bound to the skeleton for several years, resulting in a prolonged effect with no pharmaceutical reversal available.
Michigan State University researchers Fernando Vergara-Hernandez, Brian Nielsen and Aimee Colbath conducted a review to provide an overview of osteoclast function and explore bisphosphonate characteristics, including their mechanisms of action and side effects.
In doing so, they hoped to contextualize the potential for adverse/side effects in young or exercising animals.
The trio, writing in the journal Animals, noted that bisphosphonates, in addition to their effects on bone resorption, are believed to have anti-inflammatory and painkilling effects. This makes them an attractive potential treatment for multiple diseases, including osteoarthritis.
“These pain-relieving effects could be beneficial for some individuals, but in human or animal athletes, masking pain could also be dangerous and lead to further deterioration of joint conditions,” they said.
Bisphosphonates have short- and long-term side effects. Humans treated with the drugs can experience short-term problems, including fever, muscle aches, vomiting, and transient low blood calcium levels.
Long-term exposure in humans can result in serious side effects, including bone necrosis of the jaw and atypical femur fractures. Similar bone-related problems have been noted in other species.
In horses, short-term side effects may include kidney toxicity, especially when the animal has a history of renal disease or has been treated with nonsteroidal anti-inflammatory drugs. Transient colic-like symptoms have also been documented after intravenous infusion.
“Other adverse side effects have not been well documented in horses,” they said, “but a lack of documentation may be related to the scarcity of long-term studies currently available.
“Bisphosphonates can be present in the skeleton of horses for long periods of time, potentially masking pain, and are documented to cause adverse bone effects in multiple species,” the review team wrote. “Consequently, further investigation into the relationship between bisphosphonates and bone injuries in horses is crucial for equine health.”
The authors noted that multiple publications have focused on short-term benefits from bisphosphonate use in horses. However, long-term studies investigating the potential long-term adverse effects are lacking.
During the 2019 American Association of Equine Practitioners convention, a roundtable discussion covered the extra-label use of bisphosphonate by equine veterinarians.
Participants indicated bisphosphonates were being used for various conditions, with radiographic or nuclear scintigraphic abnormalities of the sacroiliac area, pelvis, or limb.
Participants described frequent bisphosphonate administration (for example, three full doses in a month), despite the manufacturer’s recommendation of a six-month separation between doses.
Researchers, the review team noted, have raised concern about the extra-label use of these drugs, especially in younger horses, where bone turnover is significantly higher in those aged under 24 months.
Turning to the use of the drugs in young/exercising horses, the authors said there is evidence that improper training and management of young racehorses is more of a factor in skeletal injury than age, as high-performance exercise may result in progressive microdamage accumulation, potentially leading to stress fractures.
Stress fractures, they noted, have been associated with a high remodeling rate, leading to bone weakness and accumulation of microdamage over time.
It is believed bisphosphonates may be useful in preventing athletic stress fractures. However, there is no conclusive evidence indicating stress fracture healing by bisphosphonates, and their use in this condition is not recommended, the authors wrote.
“In truth, bone modeling and remodeling are complex processes, especially when growth and exercise intersect. Stress fractures have been associated with normal remodeling and high strains, or normal strains with decreased remodeling.
“Even though it is not clear what pathophysiological mechanism prevails in racehorses, any interruption in normal osteoclast resorption could be harmful and lead to damage accumulation over time.”
Bone turnover can be affected by exercise, they said, and bisphosphonates can influence physiological adaptation to exercise.
Assessment of the antiresorptive effects of bisphosphonates through serum bone markers is likely insufficient if performed alone.
“Future studies should consider new, comprehensive approaches to evaluate bisphosphonate effects, including measuring bone mineral density, fracture healing, and biomechanical testing, while simultaneously determining bisphosphonate concentration within the bone.” More advanced imaging may be warranted, they said.
“The use of bisphosphonate may have a greater impact on young horses due to their active growth, where osteoclasts play a significant role in the endochondral ossification process. Osteoclasts are abundantly present in growing epiphyseal plates up to two years old.
“The extra-label use of bisphosphonates in young animals could impair physiological bone development in this population.”
This, they noted, has been demonstrated in a rabbit model, where bisphosphonate administration caused a 3% decrease in the length of the tibia.
“Hence, bisphosphonate use in young animals could pose a significant risk to skeletal growth and/or adaptation to exercise, resulting in microdamage accumulation in juvenile horses without degenerative bone disorders.”
Looking ahead, the authors noted that multiple animal models have already been used to investigate bisphosphonates, including mice, rabbits, mini-pigs, dogs, and sheep.
“The authors recognize the ethical concerns around using animals for research purposes. However, some animal models may be particularly useful depending on the research goals and prior studies available. In particular, the sheep model has proven to be a reliable orthopedic model for human bisphosphonate use.”
They noted that although animal models have been used to investigate long- and short-term bisphosphonate effects with a focus on human health, few studies are available to guide equine use, especially in juvenile and exercising populations.
“Future studies may include experimental large animal models of bisphosphonates use, which incorporate exercise to mimic athletic training.”
To date, a single, large, retrospective study has evaluated the efficacy and safety of tiludronate in 1804 horses; 343 horses were followed for over one year.
The study revealed a low incidence of short-term adverse effects (1.3%), with colic-like symptoms being the most frequent. Less than 20% of horses were treated for navicular syndrome, confirming the extra-label use of bisphosphonates.
Between one and nine doses of tiludronate were administered to horses included in the study. Treated horses ranged in age from 2 to 26.
“Future retrospective studies would ideally report diagnosis, age at administration, number and frequency of doses, long-term follow-up, concurrent treatments, and evidence of disease progression.”
The review team said future prospective studies should look beyond serum biomarkers and report multiple clinical and experimental parameters. These could include physical and lameness examinations coupled with bone biopsies, joint fluid analysis, advanced imaging, and biomechanical testing.
“Veterinarians, owners, and researchers alike would benefit from a better understanding of the half-life of bisphosphonates within the skeleton and the physiologic factors, such as age and exercise, which may change the half-life of bisphosphonates.”
The long-term presence of bisphosphonates in bone in a large clinical population is currently unreported. Little information is currently available to guide the frequency of dosing to ensure clinical efficacy and safety.
“The pain-relieving effects of bisphosphonates are still being investigated. Although pain relief may be a clinical benefit, it could also result in further injury, especially in high-performance athletes.”
Bisphosphonates have been detected in joint fluid after systemic administration. “Further investigation is necessary to understand the potential anti-inflammatory effects of bisphosphonates systemically and within the joint environment.”
In conclusion, they said additional research must focus on identifying the short-term and long-term effects of bisphosphonates in young and exercising animals to ensure the efficacious and judicious use of these powerful, long-lasting drugs.
Vergara-Hernandez, F.B.; Nielsen, B.D.; Colbath, A.C. Is the Use of Bisphosphonates Putting Horses at Risk? An Osteoclast Perspective. Animals 2022, 12, 1722. https://doi.org/10.3390/ani12131722