TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis

Introduction: Rheumatoid arthritis (RA) is associated with focal and systemic bone loss involving cytokines such as RANKL and TNF-α. RANK-L promotes focal and systemic osteoporosis, whereas osteoprotegerin (OPG) inhibits bone resorption. Although anti-TNF-α antibodies (anti-TNF-α Ab) decrease joint inflammation and bone erosions, their effects on bone loss are unknown. The aim of this study was to evaluate the effects of OPG and anti-TNF-α Ab, separately or in combination, on inflammation and bone remodeling in collagen-induced arthritis (CIA), a model of RA. Methods: DBA/1 mice ( n = 28) were immunized with bovine type II collagen and treated with OPG-Fc or anti-TNF-α Ab or both, or saline. One group of mice ( n = 7) was not immunized (naive group). Urinary deoxypyridinoline (D-pyr) and whole-body bone mineral density (BMD) were measured at baseline and at sacrifice. Histomorphometric parameters were evaluated at the femoral metaphysis. Results: Anti-TNF-α Ab, but not OPG, decreased the clinical arthritis score ( P < 0.02 vs. saline) and the histological score of inflammation. The BMD change from baseline to sacrifice (ΔBMD) was significantly smaller in CIA mice than naive mice. OPG and anti-TNF-α Ab significantly increased ΔBMD versus saline, and the effect was greater with OPG ( P < 0.003). ΔD-pyr decreased by 65% with OPG and 13% with anti-TNF-α Ab. Compared with saline, OPG increased trabecular bone volume (BV/TV) ( P < 0.02), decreased trabecular separation ( P < 0.02), and decreased the bone formation rate (BFR) ( P < 0.01). Anti-TNF-α Ab produced no significant changes in bone volume or trabecular separation but increased trabecular thickness ( P < 0.02 vs. saline) to a value close to that in naive mice, suggesting preservation of bone formation. No additive effects of OPG and anti-TNF-α Ab were found. Conclusions: Systemic OPG and anti-TNF-α Ab therapy prevented bone loss in CIA mice through distinct mechanisms involving decreased bone resorption and preserved bone formation. Combining these two agents might help to prevent bone loss in inflammatory diseases.