The effects of several diphosphonates on murine bone marrow proliferation

Six diphosphonates were examined for their ability to alter proliferative responses of mouse bone marrow cells to recombinant human M-CSF and recombinant murine GM-CSF. Risedronate ([2-(3-pyridinyl)-ethylidene] hydroxy bisphosphonic acid) added to in vitro cultures at 10 microM, suppressed the response to M-CSF by 58%, but had no significant effect on GM-CSF-induced proliferation. Ethane-1-hydroxy-1,1-bisphosphonic acid (EHDP), dichloromethylene bisphosphonic acid (Cl2MBP), 3-amino-1-hydroxy-propylidene-1,1-bisphosphonic acid (APD), (4-chlorophenyl)-thiomethylene bisphosphonic acid (tiludronate) and (cycloheptylamino)-methylene bisphosphonic acid (YM-175) had no significant effect. Treatment of mice for 5 or 14 days with 200 mg/kg/day p.o., Cl2MBP or 3 mg/kg/day p.o. of risedronate failed to inhibit M-CSF- or GM-CSF-induced proliferation by recovered bone marrow cells. Addition of Cl2MBP or risedronate in vitro to these cells did not reveal any change in sensitivity to CSFs as a result of exposure to diphosphonate in vivo.