Osteoarthritis (OA) of the knee, a musculoskeletal disease characterized by degenerations in multiple joint tissues including the articular cartilage and subchondral bone, is a major clinical challenge worldwide that currently has no cure. Traumatic knee injuries such as anterior cruciate ligament (ACL) tear predispose subjects to early onset of post-traumatic OA (PTOA), necessitating the development of effective disease modifying therapies as total knee replacement surgeries have a limited lifetime. Significant knowledge gap remains in the pathogenesis of OA, while recent evidence suggests the important role of subchondral bone microstructure and mechanics in OA development. Subchondral bone is composed of the subchondral bone plate, a thin layer of cortical lamella, and the subchondral trabecular bone, composed of individual plate- like and rod-like trabeculae. These trabecular plates and rods determine the microstructure and mechanics of trabecular bone entirely and can be quantitatively analyzed using individual trabecula segmentation (ITS). Recent application of ITS showed that changes in the plate-and-rod microstructure of subchondral trabecular bone precede cartilage damage and are implicated to play a role in disease pathogenesis. Studies presented in this thesis aim to provide a deeper understanding of subchondral bone in knee OA scientifically and clinically, which may ultimately be used to improve diagnosis, prevention and treatment of this prevalent and disabling disease.

In the first study, we comprehensively quantified microstructural and tissue biomechanical properties of the subchondral bone and articular cartilage in human knee specimens with advanced OA and control knees without OA. We found reduced tissue modulus in trabecular plates and rods in regions with moderate OA, where cartilage is still intact, that persisted in severe OA regions, where cartilage is severely damaged. These observations suggest that tissue biomechanical changes in the subchondral trabecular bone may precede cartilage damage in OA development. Furthermore, we found strong correlations between structural and mechanical parameters of the cartilage and subchondral bone in CT knees, suggesting cross-talk at the tissue level. This coupling persisted in moderate OA regions but disappeared in severe OA regions, suggesting that loss of tissue crosstalk may be an additional indicator of disease progression.

In the second study, we quantified subchondral bone microstructural changes after ACL tear in vivo in human subjects using the second-generation high resolution peripheral quantitative computed tomography (HR-pQCT). We examined short-term longitudinal changes during the acute phase (~18 days to ~141 days) after injury, as well as long-term adaptations (~5 years post injury) in the injured knee relative to the contralateral knee in a cross-sectional cohort. We found subchondral bone loss within 1 month from injury that primarily targeted trabecular rods, especially at the distal femur. We also found increased spatial heterogeneity in subchondral trabecular microstructure within the injured knees compared to the contralateral knees in the long- term after injury. These findings indicate that ACL tear results in both short-term and long-term microstructural adaptations in the subchondral bone. ITS based on HR-pQCT knee scans may be a valuable tool to monitor disease progression in vivo.

Finally, we quantified subchondral bone microstructural changes after ACL-transection in a canine model of PTOA and investigated the effects of bisphosphonate and NSAID treatment on subchondral bone changes and OA progression. Studies were conducted in skeletally-mature and juvenile animals to investigate the effect of injury age. We found that subchondral boneadaptations after surgery and treatment effects depended on skeletal maturity of animals. In mature animals, changes in the microstructure of trabecular plates and rods occurred 1-month post-op and persisted until 8-months post-op. Bisphosphonate treatment attenuated these microstructural changes and cartilage degeneration while NSAID treatment did not. In juvenile animals that have not reached skeletal maturity, transient changes in trabecular plate and rod microstructure occurred at 3-months post-op but disappeared by 9-months post-op. Neither bisphosphonate nor NSAID treatment attenuated bone microstructural changes or cartilage damages. These findings suggest that age and skeletal maturity at time of injury may need to be considered as additional factors in studying PTOA progression and developing preventative treatments.

Taken together, these studies highlight the importance of microstructural and tissue biomechanical changes of subchondral bone in the development of OA. In vivo quantification of subchondral bone using advanced imaging modalities enable longitudinal monitoring of disease progression. Therapeutic agents targeting subchondral bone changes after traumatic injury may be effective preventative strategies for PTOA.