Aminobisphosphonates inhibit bone resorption but have been shown to elicit acute-phase-like elevations in interleukin-6 (IL-6) in bone in vitro. The current studies were carried out to determine the relationship between the antiresorptive effects of the aminobisphosphonate alendronate and its effects on IL-6. Resorption was elicited in cultured 19-day fetal rat limb bones by 72 h treatment with interleukin-1β (IL-1β). Bone mass was quantitated at the end of the culture period to assess resorption. IL-6 was determined by bioassay (7TD1 cell proliferation). IL-1β (18 and 180 pM) stimulated bone resorption and increased IL-6. Alendronate (70 μM) inhibited the IL-1β–stimulated resorption. Alendronate alone did not affect IL-6 production by the bones. The IL-6 production from bones stimulated with 18 pM IL-1β was not significantly affected by alendronate, but the IL-6 production from bones stimulated with 180 pM IL-1β plus alendronate (21 and 70 μM) was higher than with IL-1β alone. Indomethacin (1 mM) inhibited the IL-6 increase elicited by 180 pM IL-1β and the enhanced IL-6 production elicited by cotreatment with IL-1β and alendronate. Since bone cultures contain multiple cell types, further experiments were carried out to determine whether alendronate could increase IL-1β–stimulated IL-6 production in an osteoblast cell line, UMR-106. Alendronate alone did not affect IL6 in UMR-106 cells. Alendronate (70 μM) in combination with IL-1β (180, 1.8, or 8 nM), or 7 μM alendronate, in combination with 8 nM IL-1β, significantly increased IL-6 in 48 h cell cultures. The results from the bone organ cultures show that alendronate can enhance IL-6 production elicited by higher concentrations of the cytokine IL-1β in bone, but that this effect on IL-6 does not prevent the inhibitory actions of alendronate on bone resorption. The results with the UMR106 cells indicate that one cellular site at which this enhancement of IL-6 production can occur is the osteoblast.