MR allows non-invasive means of evaluating the non-mineralized components of bone, particularly the bone marrow. This thesis focuses on potential changes occurring in bone marrow perfusion and marrow fat in osteoporosis, - changes which may improve our understanding of osteoporosis pathophysiology. We know from histology studies that as osteoporosis develops and bone tissue is lost, it is replaced by fat filling the vacated marrow space. MR allows non-invasive quantification of this fat component. Although fat content may be increasing, it is not known whether any change in fat composition occurs with osteoporosis i.e. does the type of fat within bone change. Epidemiological studies have indicated a link between arterial disease and osteoporosis. It is not known, however, whether any changes occur in bone perfusion in osteoporosis and how these may be related to increasing fat within the marrow. / The hypothesis to be tested is that: Advanced magnetic resonance (MR) techniques can be applied to investigate the non-mineralised components of bone tissue in osteoporosis thereby providing more information on bone physiology both in health and disease / This thesis is based on a series of eight studies designed to study the relationship between bone marrow perfusion, bone marrow fat content, bone marrow fat composition and bone mineral density. These studies showed that as bone mineral density decreased, bone marrow perfusion decreased. A strong reciprocal relationship was found between decreasing bone marrow perfusion and increasing marrow fat. The reduction in perfusion occurred only with bone and did not affect the extra-osseous tissues alongside bone with the same arterial supply. This indicates that the reduction in bone perfusion is not simply a reflection of a more generalized circulatory impairment in subjects with osteoporosis. This same effect is seen in both males and females and in the proximal femora as well as the spine. / In animal-based studies, we found that reduction in bone perfusion was apparent as little as two weeks after orchidectomy or oorphorectomy and closely paralleled features of impaired endothelial function as well as decreased bone mineral density and a hitherto unrecognized reduction in red marrow fraction within the medullary canal. Nitric oxide synthase, produced by the endothelium, is a potent stimulator of angiogenesis and osteoblastic activity. Mesenchymal stem cell differentiation may switch from osteoblastogenesis to adipocytogenesis under hypoxic conditions, while haematopoetic stem cells also supply endothelial stem cells. Potentially endothelial dysfunction, mesenchymal stem cell differentiation and haematopoetic stem cell maturation may be implemented in the development of osteoporosis. / In normal subjects, blood perfusion was markedly reduced in the femoral head compared to the femoral neck. In osteoporotic subjects, a further reduction in blood perfusion occurred in both areas. Overall perfusion indices reduced relatively more in the femoral neck than the femoral head region. These changes in bone perfusion help explain why subjects with osteoporosis have impaired healing of femoral neck fractures though do not seem to be at increased risk of avascular necrosis. At a micro-architectural level, reduced bone perfusion may also help explain the impaired healing of microfractures seen in subjects with osteoporosis, a feature likely to contribute to reduce bone strength, microfracture accumulation and eventually clinical insufficiency fracture. / Marrow fat was increased in subjects with osteoporosis. Our studies showed that percentage marrow fat content increased even allowing for the quantitative effect increased marrow fat has on the bone densitometry measurements. This effect was shown to be of negligible clinical significance. We found a strong reciprocal relationship between increasing fat and decreasing bone perfusion in both the proximal femur and vertebral body. Although fat content increased, very little difference in marrow fat composition was apparent between normal subjects and those with osteoporosis. We found no difference was apparent in either the N3/N6 marrow fat ratio or the spectrum of individual fatty acids in the marrow of subjects with either normal bone mineral density or osteoporosis. This suggests that alternation of marrow fat composition is not likely to be a direct contributory factor in osteoporosis. Also marrow fat increase was shown to be due to an increase in number rather than size of marrow fat cells. This suggests that marrow fat increases as a result of a switch in mesenchymal cell maturation to adipocytes rather than osteoblasts. / Below average perfusion indices in the acetabulum and adductor muscle is predictive of more pronounced bone loss at the femoral neck over the ensuing four years. Perfusion indices can also predict between fast and slow losers with a high sensitivity / To summarise, in the eight studies presented, it was shown that osteoporosis is associated with a significant reduction in bone perfusion and a reciprocal increase in marrow fat content though no change in marrow fat composition. Reduction in bone perfusion is most likely due to an accompanying reduction in functioning marrow fraction. Marrow fat increase is most likely the result of a switch in mesenchymal cell maturation to adipocytes rather than osteoblasts. The studies present in this thesis confirmed the initial hypothesis that “Advanced magnetic resonance techniques can be applied to investigate the non-mineralised components of bone tissue in osteoporosis thereby providing more information on bone physiology both in health and disease. / Griffith, James Frances. / "June 2009." / Thesis (M.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 227-250). / Appendix includes Chinese. / PREFACE AND DECLARATION --- p.1 / DEDICATION --- p.2 / ACKNOWLEDGEMENT --- p.3 / PRECIS --- p.4 / PUBLICATIONS AND PRESENTATIONS OF STUDIES RELATED TO THIS THESIS --- p.8 / INTRODUCTION --- p.16 / Chapter STUDY 1 --- What is the relationship between bone perfusion, marrow fat and bone mineral density? --- p.76 / Chapter STUDY 2 --- Vertebral marrow fat content, molecular diffusion, and perfusion indices in women with varying bone density, including osteoporosis: MR evaluation --- p.94 / Chapter STUDY 3 --- Could the results of Study 1 and Study 2 be spurious due to the effect of increasing marrow fat lowering BMD estimation by DEXA? --- p.111 / Chapter STUDY 4 --- Are the same changes in perfusion and marrow fat seen in the proximal femur as were seen in the lumbar spine (Study 1 & Study 2)? --- p.128 / Chapter STUDY 5 --- What is the reproducibility of MR perfusion studies and 1H spectroscopy of bone marrow? --- p.150 / Chapter STUDY 6 --- Marrow fat content increases but does the composition of marrow fat change in osteoporosis? --- p.159 / Chapter STUDY 7 --- Likely causes of reduced bone perfusion in osteoporosis: novel findings in an ovariectomy rat model --- p.180 / Chapter STUDY 8 --- Do perfusion indices or marrow fat content predict rate of bone loss? --- p.204 / SUMMARY --- p.222 / REFERENCES --- p.227 / ABBREVIATION LIST --- p.251 / APPENDIX --- p.253
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_328804 |
| Date | January 2012 |
| Contributors | Griffith, James Frances., Chinese University of Hong Kong Graduate School. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography |
| Format | electronic resource, electronic resource, remote, 268 leaves : ill. (chiefly col.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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