ABSTRACTMutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%–90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygousoim/oimmice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB‐mFc (sActRIIB‐mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF‐β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole‐body metabolism effect of treating 5‐week‐old wildtype (Wt) andoim/oimmice for 11 weeks with either control antibody (Ctrl‐Ab) or monoclonal anti‐activin A antibody (ActA‐Ab), anti‐myostatin antibody (Mstn‐Ab), or a combination of ActA‐Ab and Mstn‐Ab (Combo). We demonstrated that ActA‐Ab treatment minimally impacts muscle mass inoim/oimmice, whereas Mstn‐Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment inoim/oimmice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.