PROJECT SUMMARY/ABSTRACT Transgender and gender diverse (TGD) youth initiate gender-affirming medical therapy as early as Tanner Stage 2 with gonadotropin-releasing hormone agonists (GnRHa) for puberty suppression, with variable timing of gender-affirming sex hormones (GAH). Peak bone mass, achieved during puberty and young adulthood, largely determines age-related fractures in later life. There is compelling evidence that pre-treatment bone mineral density (BMD) is low in TGD youth, and that peak bone mass attainment may be attenuated in transfeminine youth. TGD youth who initiate GnRHa in early puberty develop bone geometry distinct from those who start in late puberty. All published longitudinal studies on bone measures in TGD youth have initiated GAH around 16 years (Dutch Model), and no studies have described skeletal trajectories of TGD youth who initiate GnRHa in early puberty and follow a peer-concordant puberty-timing model with GAH by 14 years. The objective of this proposal is to evaluate the trajectory of bone mass, architecture, and strength in TGD youth who follow the peer-concordant puberty-timing model, and to assess the determinants of skeletal health in this population. Dr. Lee will enroll 30 participants from her existing cohort of early pubertal TGD youth who have had detailed bone measures prior to and during the first year of GnRHa. She will determine the skeletal measures during 3 years of GAH by utilizing dual-energy X-ray absorptiometry (DXA) to quantify BMD accrual and BMD Z-score changes (Aim 1). Dr. Lee will correlate DXA measures to high-resolution peripheral quantitative computed tomography (HR-pQCT) for bone architecture and strength estimate changes at weight-bearing and non-weight-bearing sites, and at diaphyseal sites to examine muscle mass and density (Aim 2). She found that low pre-treatment BMD in early pubertal TGD youth was associated with low physical activity and that grip strength was a positive predictor of failure load. Dr. Lee will utilize thigh- mounted tri-axial accelerometers to measure intensity/duration of physical activity/sedentary time and hand- grip and knee extension dynamometry to measure isometric strength to develop threshold targets for future intervention studies (Aim 3). Dr. Lee has assembled a cross-disciplinary mentor team with the necessary expertise to achieve these aims and receive training in the endocrinology of bone and transgender medicine, adolescent DXA and HR-pQCT interpretation, biomechanical load evaluation and muscle strength testing, cohort study implementation, and complex longitudinal data analysis. The proposed research will generate data for Dr. Lee to develop a larger R01 prospective study to follow skeletal trajectories until peak bone mass attainment in order to optimize treatment protocols to mitigate potential impairment in peak bone mass accrual, which could impact future fracture risk. Dr. Lee is committed to rigorous investigation of skeletal development in TGD youth receiving gender-affirming medical therapies and is confident that this K23 proposal will prepare her for her long-term goal of being an independent physician-scientist focused on bone health in TGD youth.

PROJECT NARRATIVE Gender-affirming medical therapy for transgender and gender diverse youth can be initiated in early puberty with gonadotropin-releasing hormone agonists for puberty suppression, but there are sparse data on skeletal outcomes of early pubertal suppression and subsequent peer-concordant puberty-timing of gender-affirming sex hormones. Because puberty is a critical time period for skeletal growth and mineralization, gender- affirming medical therapy is introduced during a particularly vulnerable window. Understanding how bone mass develops as gender-affirming sex steroids are introduced following puberty suppression, in the context of important determinants of bone development such as physical activity, body composition, and muscle strength, will fill a critical knowledge gap and potentially improve current treatment protocols, as future studies further characterize these skeletal trajectories into young adulthood.