A critical gap in scientific knowledge regarding the effects of bisphosphonates in horses under two years of age has been highlighted in a just published review.
Bisphosphonates are involved in the process of bone resorption, causing cell 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 approved bisphosphonates for the treatment of navicular syndrome in horses four years of age or older. Indeed, the drugs can strengthen the bones of adult horses.
However, they are sometimes used off-label in juvenile exercising animals, where osteoclast activity is higher. The use of bisphosphonates in juvenile and/or exercising animals could lead to adverse effects, including poor adaptation to exercise or accumulation of microdamage.
Additionally, 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 study to provide insight into osteoclast function and explore the characteristics of bisphosphonates, including their mechanisms of action and side effects.
By doing so, they hoped to contextualize the potential for adverse/side effects in young animals or those exercising.
The trio, writing in the diary Animals, noted that bisphosphonates, in addition to their effects on bone resorption, would have anti-inflammatory and analgesic effects. This makes it an interesting potential treatment for multiple diseases, including osteoarthritis.
“These pain-relieving effects could be beneficial for some people, but in human or animal athletes, masking pain could also be dangerous and lead to further deterioration of joint conditions,” they said.
Bisphosphonates have both short-term and long-term side effects. Humans treated with the drugs may experience short-term problems, including fever, muscle aches, vomiting, and transient low blood calcium levels.
Long-term exposure in humans can cause serious side effects, including bone necrosis of the jaw and atypical fractures of the femur. Similar bone problems have been noted in other species.
In horses, short-term side effects may include kidney toxicity, particularly when the animal has a history of kidney disease or has been treated with nonsteroidal anti-inflammatory drugs. Transient colic-like symptoms have also been documented following 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 paucity of long-term studies currently available.
“Bisphosphonates can be present in the skeleton of horses for long periods of time, potentially masking pain, and have been documented to cause adverse bone effects in several species,” the review team wrote. “Therefore, further investigation of the relationship between bisphosphonates and bone damage in horses is crucial for equine health.”
The authors noted that several publications have focused on the short-term benefits of bisphosphonate use in horses. However, long-term studies examining potential long-term adverse effects are lacking.
At the 2019 American Association of Equine Practitioners convention, a panel discussion focused on the off-label use of bisphosphonates by equine veterinarians.
Participants reported that bisphosphonates were used for a variety of conditions, with radiographic or nuclear scan abnormalities of the sacroiliac region, pelvis, or limbs.
Participants described frequent administration of bisphosphonates (eg, three full doses in one month), despite the manufacturer’s recommendation of a six-month interval between doses.
Researchers, the review team noted, have raised concerns about off-label use of these drugs, particularly in young horses, where bone turnover is significantly higher in those under 24 months of age.
Regarding drug use in young horses/working horses, the authors stated that there is evidence that improper training and management of young racehorses is more of a factor in skeletal injury than injury. age, as high performance exercise can lead to a gradual accumulation of microdamage, which can lead to stress fractures.
Stress fractures, they noted, have been associated with a high rate of remodeling, leading to bone weakness and accumulation of microdamage over time.
It is thought that bisphosphonates may be useful in the prevention of athletic stress fractures. However, there is no conclusive evidence indicating the healing of stress fractures 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 reduced remodeling.
“Although it is unclear which pathophysiological mechanism prevails in racehorses, any interruption in normal osteoclast resorption could be harmful and lead to accumulation of damage over time.”
Bone turnover can be affected by exercise, they said, and bisphosphonates can influence physiological adaptation to exercise.
Assessing the anti-resorptive effects of bisphosphonates through serum bone markers is probably insufficient if done alone.
“Future studies should consider new, comprehensive approaches to assess the effects of bisphosphonates, including measurement of bone mineral density, fracture healing, and biomechanical testing, while simultaneously determining the concentration of bisphosphonates in bone.” More advanced imaging may be warranted, they said.
“The use of bisphosphonates may have a greater impact on young horses due to their active growth, where osteoclasts play an important role in the process of endochondral ossification. Osteoclasts are abundantly present in the growing epiphyseal plates until at two years old.
“Off-label use of bisphosphonates in young animals may impair physiological bone development in this population.”
This, they noted, was demonstrated in a rabbit model, where administration of bisphosphonates caused a 3% decrease in tibia length.
“Therefore, bisphosphonate use in young animals could pose a significant risk to skeletal growth and/or exercise adaptation, leading to accumulation of microdamage in juvenile horses without degenerative bone disorders.”
Looking ahead, the authors noted that several animal models have already been used to study bisphosphonates, including mice, rabbits, mini-pigs, dogs, and sheep.
“The authors recognize the ethical concerns associated with the use of animals for research purposes. However, certain 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 the use of bisphosphonates in humans.
They noted that although animal models have been used to study the long- and short-term effects of bisphosphonates with an emphasis on human health, few studies are available to guide the use of horses, particularly in juvenile and working populations.
“Future studies could include experimental large animal models of bisphosphonate use, which incorporate exercise to mimic athletic training.”
To date, only one large retrospective study has evaluated the efficacy and safety of tiludronate in 1804 horses; 343 horses were followed for over a year.
The study revealed a low incidence of short-term adverse effects (1.3%), with colic-like symptoms being the most common. Less than 20% of horses were treated for navicular syndrome, confirming the off-label use of bisphosphonates.
Between one and nine doses of tiludronate were administered to the horses included in the study. The horses treated were between 2 and 26 years old.
“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 go beyond serum biomarkers and report on multiple clinical and experimental endpoints. These could include physical and lameness exams coupled with bone biopsies, joint fluid analysis, advanced imaging and biomechanical testing.
“Veterinarians, owners and researchers would benefit from a better understanding of the half-life of bisphosphonates in the skeleton and the physiological factors, such as age and exercise, that can alter the half-life of bisphosphonates. “
The long-term presence of bisphosphonates in bone in a large clinical population is currently not reported. Little information is currently available to guide frequency of administration to ensure clinical efficacy and safety.
“The analgesic effects of bisphosphonates are still being studied. Although pain relief may be a clinical benefit, it could also lead to other injuries, especially in high performance athletes.
Bisphosphonates have been detected in joint fluid after systemic administration. “Further investigation is needed to understand the potential anti-inflammatory effects of bisphosphonates systemically and in the joint environment.”
In conclusion, they stated that further research needs to focus on identifying the short- and long-term effects of bisphosphonates in young animals and those exercising to ensure the effective and judicious use of bisphosphonates. these powerful and long-lasting drugs.
Vergara-Hernandez, FB; Nielsen, BD; Colbath, AC Does bisphosphonate use put horses at risk? An osteoclast perspective. Animals 2022, 12, 1722. https://doi.org/10.3390/ani12131722
The review, published under a Creative Commons Licensecan be read here.