Skeletal Fragility in Type 1 Diabetes: Glycemic Control and Bone Strength

Patients with type 1 diabetes (T1D) display a high risk of fragility fractures, yet the skeletal pathophysiology of T1D is incompletely understood. Decreases in areal BMD (aBMD) are well-established, but the magnitude of the aBMD deficit explains only 20% of the observed increase in T1D fracture risk. Rather, deficits in bone microarchitecture, turnover and material composition likely predispose to the high fracture risk. In type 2 diabetes (T2D), we have shown reduced bone material strength index (BMSi) using a novel impact microindentation device, which, we found, also correlated with long-term glycemia as reflected by a skin autofluorescence measure of tissue advanced glycation endproduct (AGE) levels. Despite reduced BMSi in T2D, skeletal microarchitecture was found to be intact, as assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). In contrast, in T1D, primary deficits reside in altered microarchitecture and we find reduced trabecular thickness. However, we have little information on effects of T1D on trabecular morphology, biomechanical properties and bone material strength. Importantly, the onset of T1D is generally before attainment of peak bone mass, yet there is little natural history data to demonstrate how bone accrual is impacted. It is also unknown whether glycemic control and variability predict bone deficits. In order to understand the pathogenesis of T1D bone disease, it is thus imperative that we understand the time course of skeletal deficits in T1D, and specifically, how they might progress as a function of glycemic control. Together, these observations underscore our central hypothesis: T1D, in contrast to T2D, is primarily associated with decrements in bone strength due to disrupted microarchitecture occurring during peak bone mass accrual, and that this disruption arises from hyperglycemia and glycemic variability. Thus, the overall goals of this application are: 1) to understand the relationship between glycemic control and bone strength in long-standing T1D adults versus controls using HR-pQCT-based estimates of bone strength (including trabecular and cortical components and trabecular morphology); 2) to elucidate the effects of T1D (including glycemic control and variability by continuous glucose monitoring) on the peak accrual of bone mass by following HR-pQCT-based estimates of bone strength over 2 years in T1D children versus controls; and 3) to examine the relationship between bone material strength by microindentation and AGE accumulation by skin autofluorescence in long- standing T1D adults versus controls. The research will provide comprehensive data about the effects of T1D on the elements of bone that contribute to strength and fracture resistance. The effects of glycemic control on cross-sectional measures and prospective bone acquisition will determine whether skeletal fragility, like other complications of T1D, is associated with poor glycemic control. The results should help unravel the pathogenesis of diabetic skeletal fragility and become a foundation for follow-up studies to develop strategies to mitigate and ideally prevent fractures in this vulnerable population.