Therapeutic targeting of osteoclasts by osteoprotegerin and bisphosphonates leads to a reduction of TNFalpha-mediated bone resorption

Rheumatoid arthritis (RA) is characterized by a cytokine-triggered chronic inflammation and the progressive destruction of bone. TNF-α has been recognized as a crucial inflammatory signal in RA; however, its influence on the destruction of bone is less clear, although it may involve the formation of osteoclasts. In this study, using a TNF-α transgenic mouse model, the effects of osteoclast-targeted therapies, such as osteoprotegerin and pamidronate, were examined on joint inflammation and bone destruction. Mice were divided into five groups receiving either osteoprotegerin, pamidronate, a combination of both agents, infliximab, as a positive control, or phosphate-buffered saline, as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter the clinical, radiological and histological outcomes were assessed. A significant improvement of clinical symptoms, as assessed by the reduction of paw swelling was only found in the infliximab group, whereas all other treatment groups failed to show a significant improvement. However, when assessing structural damage by X-ray analysis, a significant retardation of joint damage was evident in animals treated with osteoprotegerin the combination therapy of osteoprotegerin and pamidronate, and also with infliximab, whereas the reduction of radiologic damage in the pamidronate group was evident, albeit not significant. Quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups when compared to the control group. These data suggest that osteoprotegerin alone or its combination with bisphophonates are effective therapeutical tools to prevent TNF-α-mediated destruction of bone.