Early zoledronate treatment inhibits subchondral bone microstructural changes in skeletally-mature, ACL-transected canine knees

Xu, Lei; Hu, Yizhong Jenny; Peng, Ying; Wang, Zexi; Wang, Jingyi; Lu, W. William; Tang, Bin; Guo, X. Edward

Affiliations

¹Department of Biomedical Engineering, the Southern University of Science and Technology, Shenzhen, PR China

²Department of Orthopeadics and Traumatology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong

³Department of Orthopeadics and Traumatology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, PR China

⁴Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA

Abstract and keywords

Anterior cruciate ligament (ACL) tear leads to post-traumatic osteoarthritis (PTOA), a significant clinical burden worldwide that currently has no cure. Recent studies suggest a role of subchondral bone adaptations in the development of PTOA. Particularly, microstructural changes in the rod-and-plate microstructure of subchondral bone may precede and contribute to OA progression. In this study, we quantified microstructural changes in subchondral trabecular rods and plates after ACL-transection for the first time in the well-established preclinical canine model of PTOA and investigated the therapeutic potentials of a bisphosphonate (zoledronate) and NSAID treatment (meloxicam). Unilateral hindlimb ACL transection was performed on skeletally-mature (2-year-old, N = 20) and juvenile (10-month-old, N = 20) male beagles. Animals were assigned to 4 groups (N = 5): ACLT, un-operated control, ACLT with zoledronate, and ACLT with meloxicam treatment. Subchondral bone microstructure was evaluated by micro-computed tomography and cartilage integrity was evaluated histologically. We found that ACL-induced subchondral bone changes depended on skeletal maturity of animals. In mature animals, significant loss of trabecular plates that resulted in reduced PR ratio occurred at Month 1 and persisted until Month 8. Zoledronate treatment prevented trabecular plate loss while meloxicam treatment did not. Whether cartilage degeneration is also attenuated warrants further investigation. In juvenile animals that have not reached skeletal maturity, transient changes in trabecular plate and rod microstructure occurred at Month 3 but not Month 9. Neither zoledronate nor meloxicam treatment attenuated bone microstructural changes or cartilage damages. Findings from this study suggest that early inhibition of bone resorption by bisphosphonate after injury may be a promising therapeutic approach to prevent alterations in subchondral bone microstructure associated with PTOA. Our results further demonstrate that pathogenesis of PTOA may differ between adolescent and adult patients and therefore require distinct management strategies.

Keywords: Post-traumatic osteoarthritis; Subchondral bone; Bone microstructure; ACL-transection; Bisphosphonate; NSAID; OA; osteoarthritis; PTOA; post-traumatic osteoarthritis; ACL; anterior cruciate ligament; RANKL; nuclear factor-κB ligand; OPG; osteoprotegerin; NSAIDS; Nonsteroidal anti-inflammatory drugs; ITS; individual trabecula segmentation

Links

DOI: 10.1016/j.bone.2022.116638

PubMed: 36464243

WoS: 000899593700009

History

Received: 2022-09-4

Revised: 2022-11-27

Accepted: 2022-11-28

Online: 2022-12-1

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