Protection of inflammation-related bone loss by OPG and TNF-α antibodies through distinct mechanisms in collagen-induced arthritis

Background

Focal and systemic bone loss in rheumatoid arthritis (RA) involves several cytokines such as RANKL, which is secreted by both osteoblasts and activated lymphocytes, and TNF-α. Anti-TNF-α antibodies decrease articular inflammation and bone erosions, but the effect on bone remains to be elucidated. Osteoprotegerin (OPG) inhibits bone resorption.

Objective

We conducted the study to evaluate the respective and combined effect of OPG and anti-TNF-α antibodies on inflammation and on bone remodelling.

Methods

DBA/1 mice were immunized then treated at the onset of arthritis with OPG-Fc or anti-TNF-α antibodies or with both OPG-Fc + anti-TNF-α antibodies or saline; one group of mice remained untreated (naïve). Deoxypyridinoline changes (Δ D-Pyr) in urine, bone mineral density gain (Δ BMD) at the total body level, and histomorphometric parameters at the femur metaphysis were measured.

Results

Anti-TNF-α antibodies but not OPG decreased clinical and histological scores (P < 0.02 versus saline). Δ BMD was lower in saline-treated CIA mice than in naïve mice (P < 0.01), suggesting the effect of inflammation on bone loss. OPG and anti-TNF-α antibodies increased ΔBMD compared with saline (P < 0.001 and P < 0.05, respectively). ΔD-Pyr decreased by 65% with OPG and by 7% with saline (P < 0.001), but by 13% when mice were treated with TNF-α antibodies (NS). Compared with saline, OPG induced increased trabecular (Tb) bone volume (P < 0.02), decreased Tb spacing (P < 0.02) and decreased BFR/BS (P < 0.01). In contrast, the anti-TNF-α antibody treated group showed no significant changes in Tb bone volume and Tb spacing compared with saline, but Tb thickness was greater (P < 0.02), close to that in naïve mice, suggesting a protective effect on bone formation. There was no additive effect of OPG and anti-TNF-α antibodies on any parameter.

Conclusion

Administration of OPG and anti-TNF-α antibodies prevented bone loss in CIA mice through distinct mechanisms involving inhibition of bone resorption and formation. Combinations of both treatments must be further investigated.