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Mechanics of bone is widely studied and researched, mainly for the study of fracture. This has been done mostly on a macro scale. In this work hierarchical nature of bone has been explored to investigate bone mechanics in more detail. Flexural test were done to classify the bones according to their strength and deflection. Raman spectroscopy analysis was done to map the mineralization, collagen crosslinking changes across the thickness of the bone. Nanoindentation was done to map indentation hardness and indentation modulus across femoral cortex of the bone. The results indicate that the composition of the bone changes across the thickness of the femoral cortex. The hypothesis is confirmed as increase in mineralization, carbonate to phosphate ratio and collagen crosslinking shows the effect as increased indentation hardness and modulus and decreased deflection.

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) results in an increased fracture risk, partially due to elevations in parathyroid hormone (PTH) that lead to substantial bone loss. On its own, bone loss does not explain bone fragility in CKD, suggesting that changes in skeletal tissue (bone quality) may also be present. Understanding the factors that lead to fracture in these patients will have a substantial impact on patient care and could lead to a better understanding of how to reduce their fracture risk. Due to their suppression of PTH, calcitriol and its analogues are the current standard of care for bone disease in CKD. Yet, surprisingly little is known of their effects on bone. Agents effective in treating osteoporosis are not recommended in advanced CKD due to the lack of data regarding their efficacy and safety in these patients. The goals of the current study were to determine (1) the impact of CKD on bone quality, (2) the ability of calcitriol to improve skeletal parameters, and (3) the efficacy of various pharmacological interventions (calcium, bisphosphonates, anti-sclerostin antibody, and raloxifene) on bone mass, quality, and mechanical properties in CKD bone disease. Using a slowly progressive rat model of CKD, renal and mineral metabolism, bone morphology, bone quality, and bone mechanics (at several length scales) were assessed. Primarily due to elevated PTH, mechanical testing and tissue-level assessments revealed compromised bone quantity (high cortical porosity and low trabecular volume) and quality (high collagen cross-linking and low matrix bound water). Despite clinically relevant reductions in PTH, calcitriol treatment had no positive impact on skeletal properties. Most agents were only effective when PTH levels were normal. Raloxifene, however, led to greater whole bone and material toughness (the ability of bone to tolerate existing damage) despite modest PTH suppression. While the examination of bone quality in CKD is still in its infancy, these results indicate that enhancing bone quality with raloxifene may be an effective means to compensate for bone loss in CKD.

Current treatment for spinal metastasis involves a multimodal approach, including bisphosphonates and radiation therapy. Yet, tumour response varies considerably, thus novel treatments or combination therapies are needed to treat these metastases while preserving stability and integrity of the spinal column. Photodynamic therapy (PDT) has been shown to be successful in destroying vertebral osteolytic tumours and enhancing vertebral structure, particularly in combination with bisphosphonates. This thesis aims to evaluate the longer-term effects of PDT alone and in combination with bisphosphonate or radiation therapy on healthy vertebrae, and the short-term effects of PDT combined with radiation therapy on healthy and metastatically-involved vertebrae. The benefits of PDT on vertebral structure, both at short-term and longer-term time-points, were greatest in combination with previous bisphosphonate therapy. Similar effects, to a lesser magnitude, were seen with PDT in combination with radiation therapy. This work supports future translation of PDT for the treatment of spinal metastases.

Current treatment for spinal metastasis involves a multimodal approach, including bisphosphonates and radiation therapy. Yet, tumour response varies considerably, thus novel treatments or combination therapies are needed to treat these metastases while preserving stability and integrity of the spinal column. Photodynamic therapy (PDT) has been shown to be successful in destroying vertebral osteolytic tumours and enhancing vertebral structure, particularly in combination with bisphosphonates. This thesis aims to evaluate the longer-term effects of PDT alone and in combination with bisphosphonate or radiation therapy on healthy vertebrae, and the short-term effects of PDT combined with radiation therapy on healthy and metastatically-involved vertebrae. The benefits of PDT on vertebral structure, both at short-term and longer-term time-points, were greatest in combination with previous bisphosphonate therapy. Similar effects, to a lesser magnitude, were seen with PDT in combination with radiation therapy. This work supports future translation of PDT for the treatment of spinal metastases.

Osteoarthritis (OA) is a chronic, painful, and currently incurable disease characterized by structural deterioration and loss of function of synovial joints. OA is known to involve profound changes in bone density and microstructure near to, and even distal to, the joint. The prevailing view is that these changes in density and microstructure serve to stiffen the subchondral region thereby altering the mechanical environment (stresses and strains) within the epiphyseal and metaphyseal bone, and that these alterations trigger the aberrant cellular signaling and tissue damage characteristic of the progression of OA. Critically, however, these alterations in mechanical environment have never been well documented in a quantitative fashion in hip OA. Separately, although OA is generally thought to be inversely associated with fragility fracture, recent data challenge this idea and suggest that OA may actually modulate which regions of the proximal femur are at risk of fracture. Therefore, the goal of this work was to provide a spatial assessment of bone density and microstructure in hip OA and then examine the mechanical consequences of these OA-related abnormalities throughout the proximal femur. First, micro-computed tomography and data-driven computational anatomy were used to examine 3-D maps of the distribution of bone density and microstructure in human femoral neck samples with increasing severity of radiographic OA, providing evidence of the heterogeneous and multi-faceted changes in hip OA and discussion of the implications for OA progression and fracture risk. Second, the feasibility of proton density-weighted MRI in image-based finite element (FE) modeling, to examine stress, strain, and risk of failure in the proximal femur under sideways fall, was assessed by comparison to the current standard of CT-based FE modeling. Third, phantom-less calibration for CT-based FE modeling was used with clinically available pre-operative patient scans to assess bone strength and failure risk of the proximal femur in hip OA. Overall, the results of this work provide a rich, quantitative definition of the ways in which the bone mechanical environment under traumatic loading differ in association with hip OA, and then highlight the potential for clinical image-based FE methods to be used opportunistically to assess bone strength and failure risk at the hip. This work is significant because it directly tests the long-standing premise that OA is associated with changes in the mechanical environment of the bone tissue in ways that are impactful for OA progression; further, this work examines how these changes may influence risk of hip fracture. The results can be used to identify mechanistic predictors of OA progression, to inform development of bone-targeting treatments for OA, and to more broadly understand bone damage and fracture in this population.

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Current interventions used to reduce skeletal fragility are insufficient at enhancing bone across multiple hierarchical levels. Bisphosphonates, such as Zoledronate (ZOL), treat a variety of bone disorders by increasing bone mass and bone mineral density to decrease fracture risk. Despite the mass-based improvements, bisphosphonate use has been shown to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties by binding to collagen and increasing tissue hydration in a cell-independent manner. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality of bone. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or RAL and ZOL from 8 weeks to 16 weeks of age. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, direct measures of the tissue’s ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, bone volume fraction was significantly higher with combination treatment in both genotypes. Similar results were seen in trabecular number. Combination treatment resulted in higher ultimate stress in both genotypes, with RAL additionally increasing ultimate stress in OIM+/-. RAL and combination treatment in OIM+/- also produced a higher resilience compared to the control. Given no significant changes in cortical geometry, these mechanical alterations were likely driven by the quality-based effects of RAL. In conclusion, this study demonstrates the beneficial effects of using combination therapy to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a future mechanism to improve bone health and combat skeletal fragility on multiple hierarchical levels.