The use of bone allografts for skeletal reconstructions is commonplace clinically, but they are known to have incomplete healing even years after implantation, fail to develop union, and ultimately fail due to unrepaired fatigue damage. Identifying patients at risk for bone graft failure remains an unmet clinical need. Additionally, developing new ways of enhancing bone healing are being devised, so there is need for quantitative evaluation of their efficacy. The goals of this dissertation were to evaluate the specific structural qualities that contribute to the mechanical properties of grafted bones in a critically-sized defect in the mouse femur, to generate a novel measure of graft-to-host union, and to evaluate parathyroid hormone (PTH), a systemic anabolic bone therapy, for its effect on bone graft healing.

An alternative to bone allograft from a tissue bank is to harvest bone from one site within the patient and implant it into the skeletal defect site. This live bone transplant is known as an autograft. In the first part of this dissertation, the two standard options of bone grafting were evaluated over time to determine what structural and morphological differences yielded the best mechanical performance over time. Through this study a working toolset was created which could be used to for evaluate novel adjuvant treatments for bone graft healing. We compared processed bone allografts from donor mice which lack any intrinsic healing capacity, with live autografts, whose live periosteum and intrinsic healing capacity make them the gold standard of bone graft materials. Surprisingly, autografts did not produce more bone callus, but compared to the allograft the callus was better organized, forming a bridge over the graft entirely. Correlations of the measures of cross sectional geometry and volume of the callus and graft helped to explain up to 44% and 50% of the variation in torsional strength and rigidity, respectively.

We observed that allograft-to-host union was deficient in many samples in this model, which recapitulates the complication found clinically. Therefore, in the second stage of this dissertation we devised an imaging analysis tool to measure the degree of graft-to-host union from the CT images and coined it the Union Ratio. The Union Ratio significantly improved the ability to predict torsional mechanics from CT imaging by 8 to 26%, and was particularly critical in delineating successfully healed allografts at these time points.

In the third section of this dissertation, we then investigated an adjuvant treatment for enhancing the host's healing capacity to allografted bones. PTH has been used to reverse osteoporotic bone loss and has recently been found to significantly enhance fracture healing. Systemic PTH treatment was found to almost double the callus bone volume and the union area on the allograft and nearly doubled the yield torque and rigidity compared to saline treated controls within 6 weeks. Multivariate regression models combining the Union Ratio, the host-to-host bridging and the minimum cross-sectional polar moment of inertia could explain 71 – 84% of the variation in biomechanical rigidity and strength, respectively.

Lastly, progress towards evaluating persistent non unions from clinical case studies, and measuring the effect of PTH to consolidate these fractures was made.

Together, these results indicate that achieving a high level of union, as measured by the Union Ratio, is an important non invasive biometric in allograft functional strength and can be improved with systemic intermittent PTH therapy during healing.