Potent suppression of bone remodeling by denosumab does not blunt the anabolic response to romosozumab in mice

Histological analyses suggest that sclerostin inhibition increases bone mass primarily by stimulating modeling-based bone formation. However, clinical studies show that anti-resorptive therapies, which inhibit bone remodeling, blunt the anabolic effect of the anti-sclerostin antibody romosozumab. Moreover, suppressing remodeling inhibits bone formation in Sost-deficient mice. These latter studies suggest that bone remodeling is required for the full anabolic effect of sclerostin suppression. To address this, we suppressed bone remodeling in mice using the anti-RANKL antibody denosumab and then administered romosozumab, along with continued denosumab. Controls received either vehicle, denosumab alone, or romosozumab alone. The romosozumab-induced increase in bone was not blunted by denosumab. Similarly, the romosozumab-induced increases in osteoblast number and bone formation were not altered by denosumab. The anabolic effect of romosozumab was also not altered in a mouse model of rebound resorption caused by denosumab discontinuation. Nonetheless, denosumab reduced bone formation in Sost-deficient mice. These results demonstrate a striking difference in the dependence on bone remodeling for the anabolic effects of sclerostin suppression versus genetic inactivation of Sost and suggest distinct mechanisms drive osteoblast production in the two conditions. In addition, they suggest that the blunted response to romosozumab in clinical studies is not due to suppressed remodeling.