Bone regeneration is required for fracture‐healing, and different procedures have been used to promote osteogenesis. Recently, BMP‐2 has been shown to induce bone formation in vivo and has been tested in clinical trials. A recent in vitro study evaluated the osteogenic activity of 14 BMPs on osteoblastic progenitor cells with an osteogenic hierarchical model in which BMP‐2 and BMP‐6 may play an important role in inducing osteoblast differentiation. Although the relative osteoinductive activity of each BMP is important, bone regeneration is a process consisting of bone formation and bone resorption. Therefore, it remains unclear which effects BMP‐5 and ‐6 have on the generation of osteoclasts and by which mechanism osteoclastogenesis is stimulated. To compare osteoclastic potency of each BMP, primary murine bone marrow cells were treated with human recombinant BMP‐2, BMP‐5, or BMP‐6 and 1,25‐(OH)₂ vitamin D₃ and stained for the TRAP enzyme. Osteogenic activity of BMP‐5 was determined by measuring induction of ALP‐activity and proliferation after incubation with primary murine osteoblasts. For elucidating the molecular mechanism, primary bone marrow cells with various concentrations of OPG were added to the TRAP assay and mRNA levels of RANKL and OPG were measured after stimulation with BMP‐5. The presented data show that BMP‐5 and BMP‐6, unlike BMP‐2, enhanced the formation of murine TRAP⁺/MNCs in a biphasic curve. BMP‐5 and ‐6 were less potent in stimulating osteoclastogenesis compared to BMP‐2. Concerning the effects of BMP‐5 on osteoblasts, there was a dose‐dependent increase of ALP activity and proliferation up to a maximum dose of 300 ng/mL. At the mRNA level, BMP‐5 increased the RANKL/OPG ratio. In conclusion, this study demonstrates that in contrast to BMP‐2, BMP‐5 and ‐6 influences the generation of osteoclasts in a biphasic mode. Both proteins might be very important regulators of bone homeostasis, and therefore, potent candidates for future treatment strategies of bone regeneration. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2006