Bone mineral density (BMD) is a macro-scale measurement used to diagnose osteoporosis and assess treatment efficacy, but it cannot capture nanoscale alterations within bone microstructures where fracture initiates. The objectives of this research were to determine variations in tissue properties within the microstructures of cortical and cancellous bone with aging, osteoporosis, and treatment, and examine their effects on microcrack resistance and mechanical function at higher length scales.

First, changes in tissue properties with the natural ageing process were examined in a baboon model for human ageing. Tissue stiffness and hardness followed trends in mineralization and aligned collagen content with animal age, increasing sharply during growth and remaining constant after sexual maturity.

Once this baseline for the natural ageing process was established, osteoporosis and antiresorptive treatment effects on bone tissue properties were examined in an ovine model for human osteoporosis. Zoledronate, from the most widely prescribed class of osteoporosis drugs (bisphosphonates), was compared with a treatment that acts through endogenous estrogen receptor pathways in bone, raloxifene (a selective estrogen receptor modulator, SERM). zoledronate was most effective in cancellous rather than cortical tissue and provided the greatest increases (relative to osteoporotic tissue) in stiffness, hardness, and mineralization at trabecular surfaces. In comparison, increases in these properties with raloxifene were similar throughout cancellous and cortical tissue. Both treatments improved the estimated bending stiffness of individual trabeculae, possibly providing some explanation for the large reductions in fracture risk with these drugs despite minimal changes in BMD. At higher length scales, zoledronate improved bending stiffness and failure moment in whole bone tests.

Finally, microcracking resistance was assessed via a newly-developed experimental technique. The reduced resistance to crack elongation in cortical tissue from the osteoporosis model was largely corrected by raloxifene. These results suggest that bisphosphonate/SERM cotreatment treatment could possibly combine the best aspects of both drugs—the rapid improvement in strength with zoledronate and the improved microcrack resistance with raloxifene. The nanoscale alterations in bone tissue documented in this thesis provide a better understanding of normal and pathological bone function and may enable development of improved therapies for the prevention and treatment of osteoporosis.