HARNESSING DIGITAL TWINS TO UNRAVEL BONE FRAGILITY, REMODELLING, AND MECHANOREGULATION IN DIABETES

Diabetes mellitus (T1DM) is associated with increased fracture risk that cannot be fully explained by traditional bone mineral density (BMD) measurements. Emerging evidence suggests that diabetes-induced alterations in bone microarchitecture, remodeling, and mechanoregulation contribute to skeletal fragility. However, the specific structural and functional changes in bone differ between T1DM and T2DM, and the mechanisms underlying these differences remain incompletely understood. Innovation in medical imaging and increasingly accessible computational power have made it possible to monitor changes in bone microarchitecture and measure the mechanical properties of bone via image-based finite element analysis. Moreover, longitudinal clinical studies have also shown that the combined use of high-resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis can be used to measure load-driven bone remodelling in vivo . This talk will present findings from a meta-analysis of high-resolution peripheral quantitative computed tomography (HR-pQCT) studies assessing diabetes-related differences in bone structure and a longitudinal cohort study, conducted with partners from the FIDELIO – Bone Health in Diabetes Innovative Training Network, examining bone remodeling and mechanoregulation in individuals with type 1 diabetes mellitus (T1DM). The meta-analysis synthesized data from 16 studies, encompassing 743 individuals with diabetes and 3,472 controls, to characterize the impact of T1DM and type 2 diabetes mellitus (T2DM) on bone microarchitecture. Results revealed that T1DM is predominantly associated with adverse trabecular characteristics, whereas T2DM is linked to cortical deficits, with more pronounced deterioration at the radius than at the weight-bearing tibia. These findings suggest that mechanical loading may mitigate some diabetes-associated skeletal changes, emphasizing the role of mechanoregulation in bone fragility. Complementing these insights, a four-year longitudinal cohort study investigated bone remodeling dynamics and responsiveness to mechanical stimuli in individuals with T1DM and diabetic neuropathy. By integrating HR-pQCT imaging with micro-finite element analysis, the study found that T1DM is characterized by lower trabecular bone formation (47% reduction) and resorption (59% reduction) compared to controls. Furthermore, impaired mechanoregulation was evidenced by a reduced likelihood of bone formation and resorption in response to mechanical strain, with these deficits correlating with nerve conduction amplitude and glycated hemoglobin levels. Together, these studies provide a mechanistic understanding of diabetes-associated skeletal fragility, highlighting distinct microarchitectural vulnerabilities in T1DM and T2DM and the role of neuropathy and metabolic control in bone remodeling.