Metabolomics of low-trauma fracture among older women with diabetes

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DESCRIPTION (provided by applicant): Among its associated medical complications, diabetes is associated with low-trauma bone fracture: Compared to older women without diabetes, older women with diabetes have 2-times the fracture risk. Paradoxically, this increased risk occurs despite diabetic women having a higher average bone mineral density. The long-term goal is to understand how diabetes among older adults contributes to osteoporosis and low-trauma bone fractures. The objective of this application is to identify, among older, diabetic women, candidate fracture-related metabolic profiles. The central hypothesis is that compared to older, diabetic women without a fracture history, the metabolic profiles of those women with a low-trauma fracture will be significantly different. As prior studie have shown, there are significant differences in metabolic profiles, related to fatty acid and amino acid metabolism, associated with diabetes. Additionally, in an animal-based model of osteoporosis, significant differences were observed in the levels of fatty acids and branched chain amino acids, using targeted metabolomics. The rationale for the proposed study is that the contribution to incident fracture risk among older women with diabetes can be determined in prospective studies, once candidate metabolic profiles are known in this population. In this proposed, cross-sectional study of diabetic women, age �65 years, recruited from general endocrine and primary care clinics, the following aims will be addressed: 1) Assess the levels of amino acids, organic acids, and acylcarnitines in older women with diabetes, both with and without a history of low-trauma fracture; 2) Compare the metabolic profiles of older, diabetic women without a history of low-trauma fracture to those with a history of fracture. Under the first aim, after controlling for both measures of bone metabolism and functional status, the association between a history of low-trauma fracture and the levels of branched-chain amino acids and acylcarnitines, will be measured using targeted metabolomics. Under the second aim, the association between a history of low-trauma fracture and other metabolite classes will be measured using non-targeted metabolomics. The approach is innovative in identifying candidate, fracture-associated metabolic profiles, by utilizing metabolomics. Given the increasing prevalence of diabetes and substantial fracture-related morbidity among older adults, the proposal is significant because it is critically important to understand the key factors in thi population that contribute to low-trauma fractures. The results from the proposed study will inform the design of future studies to develop clinically applicable prospective screening tools to identify at-risk individuals.