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The paradox of fragile but dense bones in Type 2 diabetes

Eve Donnelly, Cornell University
Tuesday November 19, 12-1pm
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In Person: 550 Sherbrooke, Room 189

Abstract: Epidemiologic evidence from the past decade has demonstrated that increased bone fracture risk is one of the myriad clinical complications of type 2 diabetes mellitus (T2DM). Counterintuitively, the increased fracture risk in T2DM occurs despite greater bone mineral density, and persists after accounting for potential confounders like body mass index, neuropathies, and falls. Therefore, T2DM may alter aspects of bone鈥檚 intrinsic resistance to fracture beyond bone mineral density, such as material properties or microarchitecture, thereby increasing bone fragility independently of bone mass. Although the mechanisms that underlie bone fragility in T2DM are not yet well established, a multiplicity of factors, including hyperglycemia, altered bone remodeling, and non-enzymatic collagen crosslinking in the bone matrix are implicated. In this work we elucidate the factors that influence fragility in T2D by characterizing the biochemical, material, microarchitectural, and mechanical properties of bone from clinical populations of men and women with and without T2D. The cancellous bone from patients with T2DM had greater concentrations of the advanced glycation endproduct pentosidine and sugars bound to the collagen matrix, had greater mineral content, and trended toward a greater bone volume fraction than the non-DM specimens. Across study populations, bone tissue from patients with T2D had greater concentrations of AGEs and mineral content. Our data suggest that high concentrations of AGEs can increase fragility by reducing the ability of bone to absorb energy prior to failure, especially for the subset of T2DM patients with low bone volume fraction. Further, our statistical models show that an increase in bone volume fraction offers a protective effect for T2DM patients, even with the inferior intrinsic quality of the T2DM bone, whereas loss of bone volume fraction substantially increases risk of bone fragility for T2DM patients. The primary clinical implications of these findings are that preservation of bone volume fraction is critical in patients with T2DM.
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Biography: Dr. Donnelly is an Associate Professor of Materials Science and Engineering at Cornell University. Her primary research focus is on the contribution of the organic and inorganic bone tissue constituents to material properties and whole-bone fracture resistance, particularly in pathologic tissues. Her group鈥檚 translational studies bridge basic materials science and clinical research in orthopedics, with the goal of identifying disease-induced alterations in mineral and matrix properties that can be targeted with therapeutics or monitored as diagnostics of response to treatment intervention.

Dr. Donnelly received her BS and MS in Materials Science and Engineering at Stanford University and in 2007 she received her PhD in Mechanical Engineering at Cornell University. As a postdoctoral fellow at the Hospital for Special Surgery Dr. Donnelly received an NIH Ruth L Kirchstein National Research Service Award for her postdoctoral fellowship examining the material properties of bone from individuals with fragility fractures.

The focus of her work is characterization of the contribution of tissue microstructure and composition to the material and structural behavior of healthy and pathologic connective tissues. The long-term goals of the work are to integrate materials science with translational orthopedic research to develop a mechanistic understanding of pathologic fractures in bone to identify the factors that contribute to the integrity of healthy bone tissue (鈥渂one quality鈥�) and improve prediction of structural failure and treatments that may restore function to diseased bone tissue.