The novel selective glucocorticoid receptor modulator compound A maintains osteoblast function and the RANKL/OPG ratio in mice

Long-term administration of glucocorticoids (GC) is associated with an increased fracture risk. Compound A (CpdA) is a novel GC receptor modulator with a potentially improved benefit/risk profile. Here, we tested the anti-inflammatory potential and the effects of CpdA on bone in comparison to a classical GC. To determine the effects of CpdA on bone, mice received slow-release pellets containing either placebo, prednisolone (PRED; 3.5 mg), or CpdA (3.5 mg) and after 4 weeks effects on the skeleton were examined. Although PRED reduced total bone density in the femur by 9% (p < 0.05) and in the vertebral body by 11% (p < 0.01), CpdA did not impair these parameters. Histomorphometry showed that CpdA maintained osteoblast function while PRED decreased the mineralization rate, which was paralleled by a decline in serum P1NP and other osteoblast markers (Runx2, ALP, osteocalcin). Moreover, osteoclast number, serum CTX-1 and the femoral RANKL/OPG ratio only increased with PRED. Strikingly, CpdA did not affect the RANKL/OPG ratio in osteocytic MLO-Y4 cells, whereas dexamethasone (DEX) increased it 40-fold. Finally, CpdA failed to transactivate Dkk-1 expression in bone tissue and bone marrow stromal cells whereas DEX increased its expression about 2-fold (p < 0.05). The anti-inflammatory effects of CpdA were studied in a collagen type II arthritis mice model. DBA/1 arthritic mice were treated with either PBS, DEX (100 µg/mouse), or CpdA (300 µg/mouse) for 10 days. While CpdA tended to reduce paw swelling by 12% (p = 0.06), the clinical score by 43% (p < 0.05) and the paw temperature by 7%, DEX significantly reduced those parameters. Furthermore CpdA did not influence bone mineral density but was unable to prevent inflammation-induced bone loss. In conclusion, our study shows that CpdA exerts bone-sparing effects, but is a less potent anti-inflammatory compound, compared to DEX.