Nitrogen‐containing bisphosphonates, such as alendronate and ibandronate, inhibit bone resorption by preventing protein prenylation in osteoclasts, whereas non‐nitrogen‐containing bisphosphonates, such as clodronate, are metabolized to nonhydrolyzable analogs of ATP, resulting in osteoclast apoptosis. Because these two classes of bisphosphonates have different molecular mechanisms of action, we examined in vitro whether combined treatment with clodronate and alendronate would alter antiresorptive effectiveness. Although, in cultures of rabbit osteoclasts, the antiresorptive effect of 10 μM alendronate was increased by the addition of clodronate, the effect of higher concentrations of alendronate was not altered by addition of clodronate. Furthermore, the inhibition of protein prenylation in osteoclasts caused by higher alendronate concentrations was partially prevented by cotreatment with clodronate. As in osteoclasts, the inhibition of protein prenylation in J774 cells caused by alendronate or ibandronate treatment was dose‐dependently prevented by cotreatment with clodronate. Furthermore, alendronate‐induced J774 apoptosis was significantly inhibited in the presence of clodronate. The presence of clodronate also decreased the short‐term cellular uptake of [¹⁴C]ibandronate. These observations suggest that combined treatment with clodronate could enhance the antiresorptive effect of a low concentration of nitrogen‐containing bisphosphonate, but clodronate can also antagonize some of the molecular actions and effects of higher concentrations of nitrogen‐containing bisphosphonates. The exact molecular basis for the antagonistic effects between bisphosphonates remain to be determined, but could involve competition for cellular uptake by a membrane‐bound transport protein.