SAT-782 - Long-Term Skeletal and Body Composition Responses to Androgen-Based Therapies in Male Hypogonadism

Background: The skeletal and metabolic consequences of male hypogonadism and its treatment evolve over extended time horizons.

Objective: To compare long-term changes in DXA-derived bone mineral density (BMD), body composition, and fracture risk among men treated with testosterone (T) gel, intramuscular T undecanoate (TU), or human chorionic gonadotropin (hCG), and to identify modifiers of therapeutic efficacy and fracture vulnerability.

Methods: We studied 394 men aged 22–76 years with primary (n=132), secondary (n=96), or functional (n=166) hypogonadism treated for up to 7 years with T-gel (1–3 actuations/day; n=168), TU 1000 mg intramuscularly every 10–14 weeks (n=142), or hCG 1500 IU subcutaneously twice weekly (n=84). Lumbar spine and total hip BMD, total fat mass, and lean mass were assessed serially by DXA. Longitudinal outcomes were analyzed using generalized additive mixed models with nonlinear time effects. Models included T and E2 levels as time-varying covariates, treatment group, hypogonadism type, age, BMI/obesity class, androgen receptor gene exon 1 CAG repeat length, Klinefelter Syndrome (KS), and interactions (treatment×time×T/E2; CAG×T; obesity×treatment). Comparative effectiveness was estimated using cross-fitted targeted maximum likelihood estimation (TMLE). Fragility fractures included hip fractures (n=5), clinically manifest vertebral fractures (n=12), and radiographically confirmed silent vertebral fractures detected following DXA-based suspicion (n=26). Fracture risk was analyzed using Firth-penalized Cox regression, a parsimonious fracture risk score was derived.

Results: Lumbar spine/total hip BMD increased with achieved T and E2 levels (both p< 0.001). Advancing age (p < 0.001), longer CAG repeat length (p=0.004), and KS (p=0.02) independently attenuated skeletal gains; hCG conferred the greatest adjusted BMD increase (p=0.01), whereas T-based therapies were superior for lean mass gain and fat mass reduction (both p< 0.001), with strong modification by baseline obesity (interaction p< 0.001). Fractures clustered in older men (p=0.003). Independent fracture predictors were CAG repeats (in interaction with T) (p=0.02), KS (p=0.02), low baseline BMD (p < 0.001), low achieved T and/or E2 (p=0.008, p=0.009). The type of hypogonadism did not have an influence on outcomes.

Conclusion: Long-term skeletal and metabolic outcomes of T therapy are governed by achieved sex steroid exposure within constraints imposed by age, genetic androgen sensitivity, chromosomal context, adiposity, and baseline skeletal integrity. hCG confers superior osteoanabolic effects, whereas testosterone therapy more effectively improves body composition. A simple fracture risk score integrating hormonal, genetic, and DXA parameters enables clinically meaningful risk stratification and supports individualized management of male hypogonadism.

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