The present invention relates to methods and compositions for modulating activity of a TRANCE receptor, including the modulation of TRANCE signaling activity. In particular, the invention provides screening methods by which novel modulators of TRANCE signaling may be identified, including TRANCE inhibitors, agonists and antagonists. The invention also relates to the identification of one or more specific pathways for osteoclast surivival, and the manipulation of this pathway (e.g., using a TRANCE modulator of the invention). Such manipulation may provide strategies for treating osteoclast-related diseases such as osteoporosis and osteopetrosis.