Osteoporosis is a disease characterized by low bone mass leading to an increased risk of fracture. Bisphosphonate therapies are commonly prescribed medications that reduce the risk of osteoporotic fractures through reduced bone turnover. Recently, a rise in atypical femoral fractures (AFF) has occurred in patients taking long-term bisphosphonate treatments. These fractures have features similar to a fatigue failure;​ however, the mechanisms through which these fractures initiate are unknown. Knowledge of material property changes with bisphosphonates has been limited to monotonic tests and measures above the scale of bone structures. The purpose of this thesis was to examine the fatigue and nanoscale properties of bisphosphonatetreated cortical bone tissue.

To examine these properties an osteoporosis model was used in sheep followed by osteoporosis treatment:​ bisphosphonate (alendronate or zoledronate), SERM (raloxifene), PTH (teriparatide) or vehicle. Beams of known geometry were created from the cortical bone tissue and tested in four-point bend fatigue to failure. Differences in fatigue life occurred including a loss of fatigue life with alendronate and a rise in fatigue life with PTH treatment when compared to the grand mean. The lack of fatigue life change with zoledronate treatment indicates that factors such as dosage, method of administration, or chemical structure are affecting material properties, and not solely the class of drug. Increased fatigue life with PTH may indicate effectiveness for AFF treatment.

Fatigue loading induces microdamage in cortical bone tissue that is well characterized using microscale techniques. Bisphosphonate treatments are likely inducing changes to tissue properties at the nanoscale, below levels typically viewed with bone measure techniques. To examine nanoscale tissue damage, methods were developed and implemented using transmission-ray microscopy with synchrotron radiation to gain nanoscale imaging of fatigue damaged bone tissue. Heavy metal staining of microdamage was used, in conjunction with transmission x-ray tomography (TXM), to determine where damage initiates and forms at the nanoscale. Fatigue loaded samples had more staining present within the lacunar-canalicular network as compared to monotonic loaded samples. Damage may, therefore, be occurring within the bone structures themselves and not through surrounding tissue. The lacunar-canalicular network may be altered through bisphosphonate treatments, leading to development of novel imaging networks to examine these questions. Trabeculae were examined with TXM, and tomographies were created to compare nanoscale porosity. Results indicated porosity differences throughout trabeculae with the majority of the lacunar-canalicular network forming near the surface. The TXM methods are among the first studies to view bone at the nanoscale in three dimensions. Overall, results indicated differences in fatigue life of bone tissue given an osteoporosis treatment, with novel methods developed to help examine the origin of this difference