The management of significant bone defects, delayed and non-union of fractures can be extremely challenging. Development of specific treatment is hindered by an absence of information regarding the molecular events which regulate these processes. In this thesis, a bilateral cancellous bone defect model of the femur and tibia was developed in a rodent and the spatiotemporal profile of TGF-β, BMP 2 and 7, Smads 1, 4 and 5 characterised. Next, the capability of acid solution to augment healing was tested in both a bone defect and in a closed femoral fracture model. Finally, a long term oestrogen deficiency (OVX) rat model of postmenopausal osteoporosis was characterised and the spatiotemporal profiles of IGF-1, IGFR-1, MMP-1, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, BMP-2, BMP-4, BMP-7, TGF-β, Smad4, Smad7, VEGF, Flt-1, Ihh and FGF-2 were compared in femoral osteotomies between OVX and Sham groups. The bilateral cancellous defect model was successfully created with a number of advantages with which to recommend its use in future studies. TGF-β, BMP 2 and 7, Smads 1, 4 and 5 had characteristic spatiotemporal profiles during cancellous bone defect healing suggesting that they have a regulatory role. The results of the acid study were inconclusive and problems with substance delivery and maintenance at the desired site need to be addressed in the future to fully test this hypothesis. No significant differences were detected on histology or three-point mechanical testing between the fracture calluses of acid and control groups. In the final study, OVX rats after six months had significantly increased weight and decreased bone mineral density compared to their sham counterparts. A histological delay in osteotomy healing was observed in the OVX group but no significant differences on tensile testing were seen between OVX and Sham groups up to six weeks. Immunohistochemistry revealed that delayed healing may be due to the down-regulation of IGF-1, BMP-2, 4, and 7 and the up-regulation of MMP-3 in OVX compared to Sham groups. In conclusion, the results of this thesis give some insight into the molecular biology of bone defects and osteoporotic fractures. This information may also be useful in the development of specific treatments aimed at augmenting healing in bone defects and osteoporotic fractures.

[Truncated abstract] The cost of managing osteoporotic fractures places a significant financial burden on the health-care system. To reduce the fracture burden, early identification of fracture risk is essential to allow early intervention. The limitations associated with dual-energy X-ray absorptiometry (DXA), such as limited sensitivity and specificity, cost, ionising radiation and accessibility, have resulted in the emergence of other technologies for assessing bone fragility. An example is the portable and non-ionising quantitative ultrasound (QUS) technology. The discriminatory power of quantitative ultrasonometry in fracture risk identification, either independently or in combination with other established risk factors, currently remains contentious. It is recommended that fracture risk assessment should not only focus on bone status, but also on the risk of falls. Additionally, it has been noted that disability arising from osteoporotic fractures, even when these fractures are not identified clinically, can translate into psychosocial symptoms and a poorer perception of health-related quality of life (HRQoL). The primary aim of the present study was to investigate if a composite model comprising: calcaneal QUS, falls risk and HRQoL assessments, can identify a group of elderly women at high risk of osteoporotic fracture from those at lower risk. One hundred and four community-dwelling women (mean age 71.3 ±5.8 years) were recruited for this study. These women underwent a series of tests that included: DXA bone mineral density (BMD) evaluation of the proximal femur and lumbar spine (L1 L4); calcaneal QUS measurement; spinal radiography; rasterstereographic back surface curvature (BSC) examination; and performance-based assessment of strength, mobility and balance. The women were classified into a `High Risk’group or a `Low Risk’ group using three separate classification criteria: i) low BMD, based on the World Health Organisation (WHO) recommended T-score of < -2.5, and⁄or a history of fragility fracture (Osteoporotic [OP] group versus Non-Osteoporotic [NOP] group); ii) presence of at least one radiographically identified prevalent vertebral fracture (Vertebral Fracture [VF] group versus Non-Vertebral Fracture [NVF] group); or iii) a history of either forearm or wrist fracture (Forearm/Wrist Fracture [WF] group versus Non-Forearm/Wrist Fracture [NWF] group)

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 6, 2008). Includes bibliographical references (p. 36-42).

Thesis PlanB (M.S.)--University of Wisconsin--Stout, 2007. / Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2006. / Härtill 4 uppsatser.