Testosterone Delays Bone Microstructural Destruction via Osteoblast‐Androgen Receptor‐Mediated Upregulation of Tenascin‐C

) are associated with higher risk of bone loss. In vivo, tail-suspended mice lacking osteoblastic androgen receptor (AR) displayed similar femoral deterioration, with decreased trabecular bone and increased cortical porosity. Mechanistically, Tes enhances osteoblastic differentiation via AR-mediated upregulation of tenascin-C (TNC). Molecular docking suggests the fibrinogen C-terminal domain of TNC inhibits osteoclastogenesis by binding integrin αV, blocking adhesion of RGD-containing proteins. A synthetic peptide (pep2) mimicking this domain preserved bone architecture in osteoblast-specific Ar-knockout, tail-suspended mice. Moreover, elevated serum extracellular vesicle amyloid precursor protein, secondary to Tes-AR-TNC decline and osteoclast overactivation, emerged as a biomarker of bone loss when combined with low Tes. This study identifies the Tes-AR-TNC axis as a key regulator of male bone remodeling, offering insights into fracture risk assessment and targeted interventions in bone destruction.