Bone Quality in Patients with Long-Standing Type 1 Diabetes

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ABSTRACT Subjects with type 1 diabetes (T1D) have three- to six-fold higher fracture risk compared with subjects without diabetes, and although bone mineral density (BMD) – the clinical standard to assess osteoporosis and fracture risk – is lower in subjects with T1D compared to controls, BMD alone cannot explain the disproportionate increase in fracture risk associated with T1D. The risk of fracture in middle-age and older subjects with long- standing T1D might be compounded by young-onset T1D, the accumulation of advanced glycation end products (AGEs) due to chronic hyperglycemia, or by a potential superimposition of aging and long-term T1D effects on bone. The “Bone Health in Adults with Type 1 Diabetes” study (R01DK122554) aims to explore BMD and bone strength at the hip using quantitative computed tomography (QCT) in subjects with long-standing T1D and age-, sex- and body mass index-matched controls, as well as to investigate the effects of chronic hyperglycemia and hypoglycemia on bone health. However, bone strength – the main determinant of bone fracture – is determined by BMD, bone quality, and its microenvironment including bone marrow adipose tissue. Therefore, we propose an ancillary study to the “Bone Health in Adults with Type 1 Diabetes” parent study and leverage its well-characterized cohort of subjects, clinical, laboratory, and imaging data to assess phenotypes of bone marrow adiposity (BMA) and bone microstructure in middle-age and older subjects with long-standing T1D using advanced imaging and image analysis techniques. Using chemical shift-based water- fat separation magnetic resonance imaging and high-resolution peripheral quantitative computed tomography (HR-pQCT) we aim to assess differences in 24-month changes in BMA at the proximal femur and in bone microstructure at the distal radius and distal tibia between middle-age and older subjects with long-standing T1D and controls without diabetes. Furthermore, differences in the spatial distribution of 24-month changes in BMA between the two groups will be investigated using voxel-based morphometry; and the associations of chronic hyperglycemia and hypoglycemia with 24-month changes in BMA and bone microstructure will also be explored. Due to the increase incidence of T1D and improved medical care, the life expectancy of subjects with T1D is expected to increase, and although subjects with T1D have an increased risk of fracture during the entire life, most fractures occur at older age when the total fracture burden is greatest in the general population. Therefore, there is a critical need to better understand the etiology of T1D-related bone disorders to develop clinical strategies to prevent clinically and economically costly fractures in this large vulnerable population.