The ACL, a ligament connected to the distal femur, has little regenerative capacity. In consequence, surgical intervention is required if a patient hopes to remain active following ACL injury. In addition to the long recovery time and associated morbidities (e.g., osteoarthritis) following surgery, up to 12% of the primary reconstructed ACL grafts will fail within 15 years. Revision reconstructions are inferior to primary ACL reconstructions, thus, understanding the mechanism of failure is critical to mitigating worst-case outcomes. Reasons for revision risk have largely focused on technical errors despite that biological factors may also be a cause. Bone, a biological factor, decreases in mass following ACL injury. However, how bone microstructure changes following injury has remained largely unexplored.

It was determined in this study that bone microstructure differs on a patient-by-patient basis undergoing ACL reconstructive surgery. Differences in microarchitecture could not be explained by time from injury to operation (i.e. time of disuse) or activity the patient was participating in at the moment of injury. Thus, differences in bone quality are due to variability present at baseline, in response to injury, and/or activity level following injury. Clinically, these findings are important because we are the first to show that bone quality varies across patient groups, pointing out that microstructure may be an important factor to consider in assessing ACL injury risk and surgical outcomes.

The second half of this thesis compared age-related and sex-specific differences in bone microstructure to whole bone strength in the proximal femur with the long term goal of improving diagnostic methods to assess osteoporotic hip fracture risk. Hip fragility fractures are costly, associated with a severe decrease in the quality of life, and nearly half of patients (>65 years) who suffer a hip fracture never regain normal function. Unfortunately, approximately fifty percent of patients that experience a hip fracture receive no prophylactic treatment prior to fragility fracture because they are not diagnosed as osteoporotic using current clinical diagnostic methods. Both bone mass and microstructure change with age and the progression of osteoporosis. However, technical limitations have made it difficult to measure fracture risk from a biomechanical perspective - relating proximal femur bone strength and microstructure in synergy.

The second study determined that the magnitude of sex-specific differences in bone strength was greater than age-related strength loss endured throughout life. Further, there was no sexspecific difference in the rate of loss observed herein. Clinically, these findings demonstrate that if females could maximize bone quality early in life, they may be able to maintain the structural strength later on, even with bone loss, to mitigate fragility fractures altogether. Further, mechanical variables (i.e., stiffness and post-yield-displacement) and demographic data (i.e., age and sex) could not adequately explain variability in whole bone strength. Microstructural analysis in the femoral neck improved our ability to predict whole bone strength but demonstrated that sub-regional microstructural detail only modestly improved strength predictability in comparison to average measures across the femoral neck. Despite this, we found that increased levels of micro-architectural detail are needed to identify sex-specific differences in whole bone strength. Clinically, these findings demonstrate that regional analysis may be useful for identifying those at greatest risk of fracture earlier in life and in a sexspecific manner.