Investigating the impact of clodronate disodium on bone metabolism using a Juvenile, exercising sheep model for Juvenile horses
Vergara-Hernandez, Fernando...
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Introduction: Bisphosphonates are used in juvenile, exercising horses;1 their effects on bone metabolism in these animals are unknown. Sheep have been used in bisphosphonate research2 and as a model for exercising horses.3 A clodronate disodium (CLO) dose of 0.6mg/kg IM in sheep has similar pharmacokinetics to horses.2 This study aimed to determine the effects of CLO on serum bone biomarkers (SBB), bone mineral density (BMD), bone microstructure, biomechanical testing (BMT), and bone healing in juvenile sheep under forced exercise.
Materials And Methods: Forty juvenile sheep (253±6d old) were divided into four groups (n=10/group): Control group (saline), T0 (0.6mg/kg CLO, day 0), T84 (0.6mg/kg CLO, day 84), and T0+84 (0.6mg/kg CLO, day 0 and day 84). Sheep were exercised 4 days/week. Outcome measures included physical and lameness examinations (PE) every 14 days; serum was harvested every 28 days for SBB until euthanasia at 165 days. Micro-CT was used to evaluate BMD, bone microstructure, and bone healing of tuber coxae (TC) biopsies (day 84 and day 165). The fused metacarpus and fourth lumbar vertebrae underwent BMT. Data were analyzed using PROC MIXED in SAS.
Results: Sheep PE, SBB, BMD, microstructure, BMT and bone healing results did not differ between groups. SBB showed an increase in bone formation (P0.03) and a decrease in some bone resorption markers over time (P0.03). TC biopsies showed an increase in bone volume fraction, trabecular spacing and thickness, and reduced trabecular number at day 165 compared to day 84 (P0.04).
Discussion/Conclusion: CLO had no measurable skeletal effects. The lack of treatment effects may be due to the lower CLO dose used in large animals versus humans. Previous research has shown clinical improvement in lameness without changes in bone turnover markers.4,5 Therefore, further research could focus on the analgesic effects of CLO in large animals.
References
- Vergara-Hernandez FB, Nielsen BD, Colbath AC. Is the use of bisphosphonates putting horses at risk? An osteoclast perspective. Animals. 2022;12:1722. doi:10.3390/ani12131722.
- Vergara-Hernandez FB, Nielsen BD, Kottwitz JJ, Panek CL, Robison CI, Paris BL, Welsh TH Jr, Bradbery AN, Leatherwood JL, Colbath AC. Pharmacokinetics and plasma protein binding of a single dose of clodronate disodium are similar for juvenile sheep and horses. Am J Vet Res. 2023;84(8):1-7. doi:10.2460/ajvr.23.03.0051.
- Vernon KL, Riggs L, Coverdale J, Bodine AB, Gibbons J. The effects of forced exercise on collagen type II fragments, lysyl oxidase concentrations, and total protein concentrations in sera and synovial fluid of lambs. J Equine Vet Sci. 2010;30:266-74. doi:10.1016/J.JEVS.2010.03.001.
- Richbourg HA, Mitchell CF, Gillett AN, McNulty MA. Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial. BMC Vet Res. 2018;14:1-11. doi:10.1186/s12917-018-1423-2.
- Mitchell A, Wright G, Sampson SN, Martin M, Cummings K, Gaddy D, Watts AE. Clodronate improves lameness in horses without changing bone turnover markers. Equine Vet J. 2019;51:356-63. doi:10.1111/EVJ.13011.
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Affiliation of the authors at the time of publication
1 Michigan State University, College of Agriculture and Natural Resources, Department of Animal Sciences, East Lansing, MI, USA, Chile ; 2 Michigan State University, College of Agriculture and Natural Resources, Department of Animal Sciences, East Lansing, MI, USA, Estados Unidos (EEUU) ; 3Michigan State University, College of Osteopathic Medicine, Center for Neuromusculoskeletal Clinical R, East Lansing, MI, USA, Estados Unidos (EEUU) ; 4 Cornell University, College of Veterinary Medicine, Department of Large Animal Clinical Science, Ithaca, NY, USA, Estados Unidos (EEUU)
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