Differences in osteoclast formation between proximal and distal tibial osteoporosis in rats with adjuvant arthritis: inhibitory effects of bisphosphonates on osteoclasts.

Patients with rheumatoid arthritis commonly suffer both systemic and periarticular osteoporosis. Bisphosphonates (BPs) are inhibitors of bone resorption, and several derivatives have been developed for treatment of enhanced bone resorption. We aimed to characterize osteoclast formation in two different sites, the proximal tibial and distal tibial areas, in rats with adjuvant arthritis, and to investigate the impact of amino or non-amino types of bisphosphonate. Adjuvant arthritis was initiated in rats while administering daily injections of either etidronate, a non-amino BP, or alendronate, an amino BP, for 3 weeks. On the day following the last injection, bone mineral density (BMD) was measured in the proximal tibia to assess systemic osteoporosis and in the distal tibia for periarticular osteoporosis using dual-energy X-ray absorptiometry. Subsequently, bone marrow cells from either end of the tibia were collected and incubated for 7 days before staining and counting tartrate-resistant acid phosphatase positive cells. In the rats with adjuvant arthritis, BMD of either end of the tibia was lower than in normal rats. Although etidronate prevented bone mineral loss at both ends, distal loss was significantly less than proximal. In contrast, alendronate significantly inhibited mineral loss primarily in the proximal area. Large osteoclasts, defined as having five or more nuclei, formed preferentially in the proximal tibia, while small osteoclasts with fewer than four nuclei were found mainly distally. The suppressive effect of alendronate was greater on the large osteoclasts, while etidronate had a greater effect on the small osteoclasts. These results show that the size and multinuclearity of osteoclasts and the number of osteoclasts formed are different in the distal and proximal areas of the tibia, and that alendronate and etidronate may suppress different types of osteoclasts as discriminated by the number of nuclei.

[Biological effects of bisphosphonates in patients with rheumatoid arthritis].

Loss of bone mineral density(BMD) has frequently been observed in patients with rheumatoid arthritis (RA) and main causes of osteoporosis were reported to be steroid osteoporosis, postmenoposal osteoporosis, and disuse bone atrophy associated with polyarticular impairment. It is becoming clear that the increase in bone resorption such as these osteoporosis and RA is underling the molecular mechanism; the facilitation of osteoclast differentiation and activation by the inflammatory cytokines TNFalpha and IL-1. Bisphosphonates, which are taken up by osteoclasts and macrophages to inhibit the activity of these cytokines, are expected to function as an inhibitor of inflammation induced by these cells. Bisphosphonates reduce also osteoclast numbers and activity by induction of osteoclast apoptosis, and could be a therapeutic goal for new anti-osteoclast drugs. As for the periarticular osteoporosis, bisphosphonate has also anti inflammatory effects and inhibition of bone destruction in RA.