Rheumatoid arthritis (RA) is characterized by progressive joint destruction resulting from chronic inflammation. Recent studies suggest that bone-resorbing osteoclasts formed in the synovium play an important role in bone destruction in RA. We studied the effect of anti-resorptive treatment with osteoprotegerin and/or pamidronate compared to TNF blockade with infliximab on the development of erosions in TNF overexpressing mice. Systemic treatment with osteoprotegerin (OPG), pamidronate, both osteoprotegerin and pamidronate, infliximab or phosphate buffered saline (PBS) was carried out by intravenous injection . Treatment was initiated at the time of onset of arthritis and continued over 35d. Clinical, serological, radiological and histological outcomes were assessed after treatment. Clinical improvement, as assessed by reduction in paw swelling was only seen in the infliximab treated group. X-Rays of the hind paws were performed to quantify erosive changes. Erosions were detectable in each joint compartment Grading of erosions was performed analogous to the Larsen score. There was a marked and significant (P < 0.05) reduction in the Larsen scores of mice treated with OPG (-54%), OPG and pamidronate (-64%) and infliximab (-66%). Microscopic examination of decalcified joint tissue sections using a semiquantitative method, revealed a significant (P < 0.05) reduction in the extent of erosions in all treatment groups (OPG: -56%; pamidronate: -53%; OPG + pamidronate: -81%; infliximab -46%) when compared to controls. These data suggest that anti-resorptive treatment may have a significant potential in TNF-mediated bone destruction.