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Title: Vascular pleiotrophic effects of bisphosphonates in postmenopausal women : cellular mechanisms and functional consequences
Author: Millar, Auleen
ISNI:       0000 0004 5371 6520
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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Although traditionally vjewed as separate disease entities that increase in prevalence with aging, accumulating evidence indicates that similar pathophysiological mechanisms underlie cardiovascular disease and osteoporosis. This evidence has both clinical and biochemical foundations, however the complex interaction of common risk factors and genetic or molecular determinants; requires further research to clearly define these mechanisms. Nitrogen containing bisphosphonates inhibit the isoprenoid biosynthetic enzyme, farnesyl diphosphate (FFP) synthase, in the same cholesterol biosynthesis pathway as statins. Inhibition of FFP synthase leads to loss of farnesylation and geranylation of small GTPase proteins. Statins have been shown to exert cholesterol-independent vaso-protective effects mediated, through inhibition of these small GTPase proteins, Rho and Rac. By inhibIting both Rho and Rac GTPase activity via inhibition of geranylgeranylation, endothelial nitric oxide synthase (a vasodilator) is up-regulated and superoxide (a vasoconstrictor) production is decreased. Although it has been previously been considered that current dosing regimens and low absorption have resulted in a low body "burden" of N-BPs, an expanding body of evidence would suggest that considerable work is still required to fully elucidate the effect of these drugs beyond the bone matrix. Endothelial dysfunction is the initial step in the atherosclerotic process. This thesis aims to determine if women with post-menopausal osteoporosis have impaired endothelial function and if treatment with Risedronate over a 24 week period has an influence on non-invasive vascular measures of endothelial function. We examine both peripheral and central arterial beds, using well established non-invasive methods to obtain a global measure of endothelial function. We employ novel methods of flow velocity waveform analysis to extract potentially meaningful differences in arterial flow waveforms that would indicate subclinical vascular disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available