T cells are required for continuous parathyroid hormone (cPTH) treatment to induce bone loss as they sensitize stromal cells to PTH through CD40 ligand (CD40L), a surface molecule of activated T cells. Since CD40L expression is a feature of activated T cells, we investigated whether antigen (Ag)-mediated T cell activation is required for PTH to exert its catabolic activity. We report that inhibition of Ag presentation through silencing of either class I or class II MHC-T cell receptor (TCR) interaction prevents the cortical bone loss induced by in vivo cPTH treatment. We also show that the bone loss and the stimulation of bone resorption induced by cPTH treatment are prevented by CTLA4-Ig, an inhibitor of T cell costimulation approved for the treatment of rheumatoid arthritis. Since inhibition of antigen-driven T cell activation by blockade of either TCR signaling or T cell costimulation is sufficient to silence the catabolic activity of cPTH, antigen-presenting cells and T lymphocyte interactions therefore play a critical role in the mechanism of action of PTH.