Insulin‐like growth factor binding protein‐5 (IGFBP‐5) stimulates osteoblast proliferation directly or indirectly through IGF‐I action, but its effects on osteoclast formation and osteoclastic activity are unknown. We tested the effects of IGFBP‐5 on osteoclastic activity and osteoclast formation. IGFBP‐5 significantly stimulated pit formation by pre‐existent osteoclasts in mouse bone cell cultures and its stimulatory effect was completely blocked by IGF‐I antibody (Ab). However, IGFBP‐5 did not affect the bone‐resorbing activity of isolated rabbit osteoclasts. When IGFBP‐5 was added to unfractionated bone cells after degeneration of pre‐existent osteoclasts, IGFBP‐5 (77 pM–7.7 nM) dose‐dependently stimulated osteoclast‐like cell formation, irrespective of the presence of IGF‐I Ab. Moreover, osteoclast‐like cells newly formed by IGFBP‐5 from unfractionated bone cells possessed the ability to form pits on dentine slices. We next examined the direct effect of IGFBP‐5 on osteoclast precursors in the absence of stromal cells, using hemopoietic blast cells derived from spleen cells. IGFBP‐5 dose‐dependently stimulated osteoclast‐like cell formation from osteoclast precursors, irrespective of the presence of IGF‐I Ab. Growth hormone (GH) as well as IGF‐I significantly stimulated bone resorption by pre‐existent osteoclasts in mouse bone cell cultures and these stimulatory effects were completely blocked by IGF‐I Ab. GH as well as IGF‐I stimulated osteoclast‐like cell formation from unfractionated bone cells and this stimulatory effect of GH was significantly but partially blocked by IGF‐I Ab. The direct stimulatory effect of GH on osteoclast‐like cell formation from hemopoietic blast cells was not affected by IGF‐I Ab. The present data indicate that IGFBP‐5 stimulates bone resorption both by stimulation of osteoclast formation in an IGF‐I–independent fashion and by IGF‐I–dependent activation of mature osteoclasts, possibly via osteoblasts, in vitro. (J Bone Miner Res 2000;15:902–910)