Pamidronate prevents bone loss associated with carrageenan arthritis by reducing resorptive activity but not recruitment of osteoclasts

Abstract

Carrageenan arthritis is associated with high-turnover bone loss. We sought to determine whether the bisphosphonate pamidronate can modify this effect of inflammatory arthritis. Sixty mature, New Zealand White rabbits were randomly assigned to five groups: normal; normal with a therapeutic dose of pamidronate (300 microg/kg/day, administered subcutaneously); arthritis (induced in the right tibiofemoral joint with 10 intraarticular carrageenan injections); arthritis with a therapeutic dose of pamidronate (300 microg/kg/day, subcutaneous); and arthritis with a low dose of pamidronate (7.5 microg/kg/day, subcutaneous). All animals received the fluorochrome calcein green (0.5 g/l/day) in drinking water ad libitum from days 21 to 49. Undecalcified, transverse sections of the distal femur were photographed or imaged to determine bone volume; new bone volume; resting, eroded, osteoid, and osteoblast perimeters; and osteoclast number. Results were evaluated with analysis of variance and pairwise Bonferroni's tests. In trabecular bone adjacent to the joint affected by carrageenan arthritis, resting perimeter was substantially reduced compared with normal joints, and primary indices of osteoblast and osteoclast activity were abnormally high (p < 0.001). Daily treatment with a therapeutic dose of pamidronate (300 microg/kg/day, subcutaneous) during the induction of arthritis significantly decreased new bone volume, osteoid perimeter, and osteoblast perimeter compared with the untreated arthritis group (p < 0.001). Osteoclast number and eroded perimeter remained abnormally high despite treatment with pamidronate. The concomitant increase of bone volume and these osteoclast indices show that pamidronate prevents bone loss in this model of experimental inflammatory arthritis by inhibiting the resorptive activity, but not the formation or recruitment, of osteoclasts. These findings are relevant to the use of bisphosphonates in the treatment of rheumatoid arthritis.