Aseptic loosening of total joint replacements is associated with bone resorption. A heavy infiltrate of foreign body macrophages in response to biomaterial wear particles is commonly found in the fibrous membrane surrounding loose components. It has recently been shown that foreign body macrophages can differentiate into osteoclastic cells. To determine whether pharmacological inhibitors of bone resorption have a role to play in controlling the osteolysis of aseptic loosening, we analyzed the effect of a bisphosphonate, disodium ethane-1, 1-diphosphonate (EHDP) on this process. Murine monocytes and foreign body macrophages (derived from granulomas formed by subcutaneous implantation of particles of prosthetic biomaterials) were co-cultured with UMR106 osteoblast-like cells in the presence of 1,25 dihydroxyvitamin D3 for 14 days on glass coverslips and bone slices. EHDP significantly inhibited bone resorption in these co-cultures. There was little or no expression of the osteoclast-associated enzyme, tartrate-resistant acid phosphatase (TRAP) in EHDP-treated co-cultures. Addition of EHDP to monocyte-UMR106 co-cultures after the appearance of TRAP-positive cells did not abolish bone resorption, indicating that EHDP, in addition to its known inhibitory effect on osteoclast function, suppresses differentiation of osteoclast precursors. EHDP inhibition of the osteolysis induced by particulate biomaterial-associated macrophages shows that pharmacological inhibition of bone resorption might be used to control the osteolysis of aseptic loosening.