Slyfield, Craig2012-06-282017-06-012012-01-31bibid: 7745098https://hdl.handle.net/1813/29266Osteoporosis is a disease characterized by low bone mass and increased fracture risk. In adults, bone mass is primarily modified through bone remodeling. Bone remodeling is the coordinated activity of osteoclasts resorbing bone and osteoblasts forming new bone. Bone remodeling occurs at discrete locations on bone surfaces. The number and size of individual remodeling events influence the total amount of bone turnover in the body. Bone turnover is associated with increased fracture risk independent of bone mass. It is therefore believed that the number and size of individual remodeling events are important factors related to bone fragility and fracture risk. Precisely how metabolic bone disease alters individual remodeling events is not known. As a result, the mechanisms behind how metabolic bone disease alters bone biomechanics to increase bone fragility and fracture risk have not been determined. In the current dissertation, a sub-micron resolution three-dimensional imaging technique was developed to visualize individual remodeling events. The ability to measure individual remodeling events provides a means to understand how alterations in bone biology result in changes in bone turnover and fracture risk. This capability also allows for interpretation of individual remodeling events in terms of basic cell functions (proliferation, differentiation, motility, etc.). Using an animal model of postmenopausal osteoporosis, the serial milling approach was then applied to study how estrogen depletion alters bone remodeling at the level of individual remodeling events. Finally, the serial milling approach was used to determine how bone remodeling is related to bone biomechanics. The techniques developed in the current dissertation provide a means of understanding how metabolic bone disease increases fracture risk by altering individual remodeling event number and size. The current dissertation suggests that estrogen depletion primarily influences osteoclast proliferation and differentiation. Therefore, the increase in bone turnover in postmenopausal osteoporosis is attributed to an increase the number of resorption cavities and, potentially, in the number of stress concentrations. Furthermore, the current dissertation also shows that resorption cavities are preferential sites of microscopic tissue damage formation in cancellous bone. Together, these results suggest a potential mechanism behind increased fracture risk associated with increased bone turnover.en-USBoneMedial ImagingBiomechanicsdissertation or thesis