Effects of anti-RANKL antibodies administered to pregnant mice on bone and tooth development in neonates.

Objectives: This study examined how the anti-bone resorptive agent denosumab, which comprises anti-receptor activator of nuclear factor kappa B ligand (anti-RANKL) monoclonal antibodies, administered during pregnancy affected neonatal development. Anti-RANKL antibodies, which are known to bind to mouse RANKL and inhibit osteoclast formation, were administered to pregnant mice. Following this, the survival, growth, bone mineralization, and tooth development of their neonates were analyzed.

Methods: Anti-RANKL antibodies (5 mg/kg) were injected into pregnant mice on day 17 of gestation. After parturition, their neonatal offspring underwent microcomputed tomography at 24 h and at 2, 4, and 6 weeks after birth. Three-dimensional bone and teeth images were subjected to histological analysis.

Results: Approximately 70% of the neonatal mice born to mice who received anti-RANKL antibodies died within 6 weeks after birth. These mice had a significantly lower body weight and significantly higher bone mass compared with the control group. Furthermore, delayed tooth eruption and abnormal tooth morphology (eruption length, enamel surface, and cusps) were observed. Conversely, while the tooth germ shape and mothers against decapentaplegic homolog 1/5/8 expression remained unchanged at 24 h after birth in the neonatal mice born to mice that received anti-RANKL antibodies, osteoclasts were not formed.

Conclusions: These results suggest that anti-RANKL antibodies administered to mice in the late stage of pregnancy results in adverse events in their neonatal offspring. Thus, it is speculated that administering denosumab to pregnant humans will affect fetal development and growth after birth.