Skeletal Health in Youth with Type 1 Diabetes and Gender Diversity

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Adolescence is a critical window for building bone and interrupting endocrine function during puberty jeopardizes peak bone mass accrual. In our parent study, we are finding that children with type 1 diabetes (T1D) have altered bone structure at the start of peak bone accrual as compared to matched controls. Our preliminary data show that trabecular area by high resolution peripheral quantitative CT (HRpQCT) is decreased in T1D. This deficit is associated with worse glycemia, including higher time in hyperglycemia by continuous glucose monitoring (CGM) and increased advanced glycation endproduct (AGE) accumulation by skin autofluorescence (SAF). Yet a community that is likely at even greater risk than T1D for disrupted endocrine function during peak bone mass accrual is transgender and nonbinary youth (TNB). Pubertal blockade by a GnRH agonist (GnRHa) in TNB can prevent testosterone from increasing trabecular bone density and size and estrogen from increasing cortical bone density. It is known that bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) is decreased in TNB, especially with GnRHa use. However, there are almost no data about how volumetric, compartment-specific microarchitectural bone accrual, strength and turnover are affected in TNB not on GnRHa, and in TNB with the additional insults of GnRHa or T1D. The objective of this supplement is to expand our ongoing study of T1D and control children to include gender diverse youth both before and during pubertal blockade, with and without T1D, using volumetric, microarchitectural and bone turnover analysis to explore the impact on bone acquisition of the independent and combined endocrine disruptions of gender diversity, pubertal blockade and T1D. Our hypothesis is that expanding our cohort to include TNB enables the study of TNB skeletal health, with and without T1D. We further hypothesize that the preferential trabecular deficit that we observed in T1D with hyperglycemia will be exacerbated in TNB, especially with GnRHa use. To attain the overall objective, we will compare bone geometry, microarchitecture, trabecular morphology, microfinite element analysis (µFE)- derived bone strength and turnover in TNB youth with and without T1D. In 30 TNB (10 T1D, 20 non-T1D) before or during pubertal blockade, prior to cross-sex hormone treatment, we will perform once identical measurements to the parent study: Tanner stage, bone age; bone size, areal BMD and body composition by DXA; volumetric BMD, trabecular and cortical microarchitecture and µFE-derived bone strength by HRpQCT; trabecular morphology by individual trabecula segmentation (ITS); turnover by markers of formation and resorption and sex steroids by biochemistries; glycemia by HbA1c and CGM, and AGE accumulation by skin autofluorescence. We expect these exploratory data to inform the development and implementation of future prospective clinical trials of bone health for T1D with the unique health concern of TNB, as well as for TNB without T1D, from initiation of GnRHa through cross-sex hormone treatment. This will set the stage for mitigating future fracture risk in T1D with the disparity of TNB, as well as in TNB without T1D, and improving lifelong bone health outcomes.