Local factors acting either directly or indirectly on hemopoietic precursors regulating osteoclast formation and activity. Locally generated TGFβ promotes PTHrP production by tumor cells (16). Therapeutic aims could be to reduce PTHrP production or prevent its action. Some other current approaches to reducing osteoclast formation or activity are shown (reviewed in refs. 5 and 21), with a minus sign indicating inhibition: OPG as an inhibitor of RANKL stimulation; RANK-Fc as a competitive inhibitor of RANKL binding to RANK; anti-RANKL; and bisphosphonates acting upon osteoclasts to reduce their activity and enhance apoptosis.(7). Not shown here are several targets for therapeutic intervention within the osteoclast itself (21).