Abstract
AIM: Weight-loss therapy often results in an unintended loss of muscle and bone mass. Inhibitors of the activin receptor signaling pathway, such as bimagrumab, an anti-activin receptor antibody (αActRIIA/IIB ab), are under investigation to counteract weight-loss induced muscle loss, but their skeletal effects in obesity remain unclear. This study investigates αActRIIA/IIB ab on bone in mice exposed to a high-fat diet (HFD) model of obesity or standard chow. MATERIALS AND METHODS: Male C57BL/6 J mice were stratified into four groups (n = 10/group, standard chow or HFD for 10 weeks ± αActRIIA/IIB ab). αActRIIA/IIB ab (10 mg/kg) was administered twice weekly during the final three weeks. The femur and vertebral body were assessed using DEXA, μCT, mechanical testing, and histomorphometry. RESULTS: HFD did not affect bone density, microstructure, or strength but reduced histological bone formation markers. In standard chow mice, αActRIIA/IIB ab increased trabecular bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD) by 36 %. In HFD mice, the effect of αActRIIA/IIB ab was less pronounced but still increased BV/TV (+16 %) and vBMD (+13 %). For cortical bone, μCT parameters remained largely unaffected by αActRIIA/IIB ab, while the treatment increased periosteal mineralizing bone surfaces in standard chow mice (+217 %), but not in HFD mice. CONCLUSIONS: αActRIIA/IIB ab enhanced trabecular bone properties in standard chow-fed mice, but its anabolic effects were blunted in HFD-fed mice. Furthermore, αActRIIA/IIB ab improved cortical histological bone formation markers, while morphology remained unaffected, suggesting a site- or time-specific difference. Thus, αActRIIA/IIB ab holds potential for mitigating weight-loss-associated bone deterioration.