Clodronate detection and effects on markers of bone resorption are prolonged following a single administration to horses

Abstract

Background: Clodronate is a potent antiresorptive agent labelled for use in horses over 4 years of age, for the treatment of navicular syndrome. Concerns regarding the extra-label use of clodronate in equine athletes, such as racehorses, have been raised as inhibition of osteoclast activity by clodronate has been postulated to interfere with normal bone healing, which is imperative to the repair of microfractures. The paucity of data describing the long-term pharmacokinetics of clodronate and effects on biomarkers of bone resorption necessitates further study. Objectives:(1) To determine clodronate concentrations in blood and urine over a 6-month period in horses undergoing treadmill exercise and (2) to assess the effects of clodronate on protein biomarkers of bone remodelling in this same group of horses.Study design: Randomised controlled experimental study.Methods: Seven exercised Thoroughbred horses received a single im administration of 1.8 mg/kg clodronate and four horses received an equivalent volume of saline. Blood and urine samples were collected prior to, during and for 182 days post drug administration for drug concentration determination using liquid chromatography-tandem mass spectrometry, and determination of protein biomarker (CTX-1 and TRAcP5B) concentrations.Results: Clodronate was detectable in blood for 14-175 days and for up to 175 days in urine. For some horses, concentrations were nondetectable at one time point but detectable at a subsequent time point. The terminal serum half-life ranged from 1.80 to 283.9 days. CTX-1 concentrations were significantly higher, relative to baseline, in both treated and control groups while concentrations of TRAcP5B were significantly lower in the treated group.Main limitations: Relatively small number of horses studied.Conclusions: Based on assessment of protein biomarkers, clodronate appears to influence osteoclasts at label doses. Furthermore, results of this study support racing regulations that preclude horses administered bisphosphonates for medical reasons, from racing for a prolonged period of time.

Ketoprofen in horses: Metabolism, pharmacokinetics, and effects on inflammatory biomarkers

“…Horses were exercised through a combination of work on a high‐speed treadmill (Mustang 2200, Graber AG, Switzerland) and exercise on an Equineciser (Centaur Horse Walkers Inc, Mira Loma, CA) prior to and throughout the course of the study (apart from the day of drug administration). Horses were exercised 5 days per week according to standard laboratory protocols 14 . As part of the laboratory protocol, all horses are subject to regular fitness testing, including weekly heart rate measurements and calculation of V 200 (running velocity that elicits a heart rate of 200 bpm) and monthly measurements of end‐run plasma lactate concentrations, as a means by which to assess the fitness level of the horses.…”

“…Horses were exercised 5 days per week according to standard laboratory protocols. 14 As part of the laboratory protocol, all horses are subject to regular fitness testing, including weekly heart rate measurements and calculation of V 200 (running velocity that elicits a heart rate of 200 bpm) and monthly measurements of endrun plasma lactate concentrations, as a means by which to assess the fitness level of the horses. Horses received grass hay in the morning and alfalfa hay at night and were supplemented with grain and stable mix in the evening.…”

Effect of clodronate on gene expression in the peripheral blood of horses

“…This study follows a recently published pharmacological project on clodronate (Knych, Finno, et al, 2022). Eleven healthy who was blinded to the treatments being administered, using the American Association of Equine Practitioners scoring system (Adams, 2002;Anon, 1999).…”

“…However, efforts to enforce this ban have been difficult because there is no reliable test to determine long‐term use of bisphosphonates due to its relatively short detection window in the blood compared with its extended residence and effective time in bone (Krueger et al., 2020). A recent comprehensive study on clodronate showed that the drug is detectable up to 175 days in blood and urine by sensitive liquid chromatography–tandem mass spectrometry (LC/MS–MS), but detection in some horses was variable and inconsistent (Knych, Finno, et al., 2022). Clodronate has even been detected in bone from a horse 18 months post‐dose, suggesting that its period of effect can be extensive (Knych, Janes, et al., 2022).…”

Concentrations of dexmedetomidine and effect on biomarkers of cartilage toxicity following intra-articular administration in horses

“…All horses were part of the research herd at the University of California-Davis and were exercised 5 days a week, following standard protocols established by our laboratory. 9 Horses did not receive any medications for a minimum of 4 weeks before the start of the study. Before beginning the study, a complete blood count (CBC), serum biochemistry panel, and physical exam were performed, and all horses were deemed healthy.…”