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

Area of Science:

• Bone Biology
• Pharmacology
• Osteoporosis Research

Background:

• Sclerostin inhibition is thought to increase bone mass via modeling.
• Clinical data suggest anti-resorptive therapies blunt romosozumab's anabolic effect.
• Studies in Sost-deficient mice indicate remodeling is necessary for sclerostin suppression's anabolic effect.

Purpose of the Study:

• To investigate the role of bone remodeling in the anabolic effects of sclerostin inhibition.
• To determine if suppressing bone remodeling with denosumab affects romosozumab's efficacy.
• To compare the dependence on bone remodeling for sclerostin suppression versus genetic inactivation of Sost.

Main Methods:

• Mice were treated with denosumab (anti-RANKL) to suppress bone remodeling.
• Romosozumab (anti-sclerostin antibody) was administered concurrently with denosumab.
• Bone mass, osteoblast number, and bone formation were assessed in various treatment groups, including controls and Sost-deficient mice.

Main Results:

• Denosumab did not blunt the romosozumab-induced increase in bone mass or bone formation.
• Osteoblast number and bone formation rates were not altered by denosumab co-administration.
• Denosumab reduced bone formation in Sost-deficient mice, but not in wild-type mice treated with romosozumab.

Conclusions:

• The anabolic effects of sclerostin suppression by romosozumab are independent of bone remodeling.
• There is a distinct difference in remodeling dependence between sclerostin suppression and genetic Sost inactivation.
• The blunted response to romosozumab observed in clinical studies is likely not due to suppressed bone remodeling.