Age and disease-related remodeling changes with a negative bone balance involve both trabecular and cortical bone. The micro and ultrastructural changes that affect cortical bone, however, are less well understood than those involving trabecular bone and are far more difficult to quantify. Although age-related thinning of the cortex is partially offset by periosteal expansion, this process is accompanied by increased porosity. It is well known that increased porosity, a hallmark of enhanced bone turnover, significantly contributes to the decline of cortical bone strength and thus increased fracture susceptibility in postmenopausal osteoporosis and, particularly, in renal osteodystrophy. While increased porosity results in decreased volumetric bone mineral density, the pores are below the resolution limits achievable in vivo with any imaging modality. However, the spaces of the haversian and lacuno-canalicular system making up total pore volume are fluid-filled, while a minor fraction of exchangeable water is bound to collagen of the osteoid. We have, in preliminary work in support of this competing renewal application, developed a MRI-based technique for quantification of bone water (BW) and thus, by inference, porosity, in humans and shown the differences in this parameter between subject groups to far exceed those of volumetric bone density. In this project we advance the hypothesis that BW, measured noninvasively by solid-state proton imaging of cortical bone, provides a new metric of cortical bone quality that is more sensitive than either areal or volumetric bone density and, further, that the technique is able to detect changes in response to intervention. In four specific aims we propose the further development of the methodology, its technical and clinical validation, and to apply the method in pilot studies of two groups of human subjects. The first group comprises healthy men and women covering the age range from 30 to 80 years. The second group involves 30 patients with end-stage renal disease who are part of an independently NIH- funded project. These subjects will be evaluated with the new technology at transplantation, compared with age and gender-matched controls, and re-evaluated one year later. The expected outcome of the proposed research is the emergence of a robust clinically practical procedure that provides a parameter of bone quality not previously amenable in vivo. PUBLIC HEALTH REVELANCE: Cortical bone porosity is a hallmark of rapid bone turnover and thus is a ubiquitous manifestation of most metabolic bone disorders including gonadal steroid deficiency and parathyroidism. Porosity, however, cannot be quantified with current imaging modalities. The proposed approach, based on quantification of bone water with a new magnetic resonance imaging technique provides noninvasive surrogate measurement of cortical bone porosity as a new metric of bone quality.
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