Determinants of Fracture Risk in Type 1 Diabetes
There are no clinical guidelines to diagnose or manage the skeletal complications of type 1 diabetes mellitus (T1D) because we lack fundamental knowledge about how the disease negatively affects the determinants of fracture resistance of bone throughout life. Addressing this knowledge gap requires well-controlled, longitudinal and cross-sectional studies investigating which clinically relevant factors may contribute to the disproportionate increase in fracture risk that exists for individuals with T1D. Thus, the immediate goal of this pilot study is to acquire the preliminary data to power clinical studies that will establish the key predictors of fracture risk in T1D. As such, we propose a comprehensive assessment of diabetic bone disease (DBD) in middle-aged adults who were diagnosed with T1D in adolescence. The overarching hypothesis is that T1D causes, over time, deficits in cortical micro-/macro-structure, matrix-bound water, and resistance to micro-indentation, all of which make the T1D skeleton more prone to fracture compared to those without T1D. Comprehensive in vivo assessments of bone properties and clinical markers of metabolism will be performed for women and men without T1D (age-/sex-matched controls) and with T1D diagnosed before peak bone accrual. For all subjects, the bone assessments will include i) areal bone mineral density (BMD) at the hip and at the lumbar spine, ii) volumetric BMD of trabecular and cortical bone along with architectural and structural properties, respectively, as provided by high resolution, peripheral quantitative computed tomography (HR-pQCT) imaging of the distal radius and tibia mid-shaft (including finite element analysis to predict bone strength), iii) concentrations of bound water and pore water of cortical bone provided by magnetic resonance imaging (MRI) of the tibia mid-shaft, and iv) resistance to impact microindentation provided by OsteoProbe testing of the shin. Serum assays will measure markers of bone formation & resorption, endogenous insulin, osteocalcin, and insulin-like growth factor 1. Identifying which bone characteristics at different hierarchical levels of organization (ultra- to macro-structural) differ between T1D and non-T1D individuals will support large, cohort studies into how best to manage DBD. Moreover, linking clinical markers of metabolism to specific bone properties (micro-structure, volumetric BMD, bound water concentration) will give insight into a potential pathological mechanism that could be targeted to prevent DBD.

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