Effectiveness and limitations of anti-sclerostin therapy in osteogenesis imperfecta: A systematic review

Sclerostin inhibition is a potential anabolic therapy for osteogenesis imperfecta (OI). We systematically evaluated whether anti-sclerostin therapy improves bone quantity, bone quality, mechanical performance, and fracture-related outcomes in preclinical and clinical studies of OI.

PubMed, Embase, and Web of Science were searched for randomized controlled trials and controlled animal studies investigating sclerostin inhibition in OI. 3 reviewers independently screened studies, extracted data using a standardized template, and assessed methodological quality with Joanna Briggs Institute appraisal tools.

18 studies were included:15 controlled experimental studies in mouse models of OI and 2 clinical trials in adults with OI, plus one ancillary iliac crest biopsy study derived from a trial cohort. Across murine models, anti-sclerostin consistently increased bone quantity (e.g., trabecular bone volume, cortical thickness, bone mineral density), often increased whole-bone strength, and sometimes reduced fracture incidence. However, efficacy varied by genotypes, ages, skeletal sites, or outcome levels. In several collagen-related murine OI models (e.g. Brtl/+, Crtap-deficient and the severe Col1a1^Jrt/+ model), tissue-level material properties such as elastic modulus, hardness and mineralization indices remained abnormal despite structural gains. Clinical studies in adults with OI similarly demonstrated increases in areal bone mineral density, whereas microarchitectural and biopsy-based matrix-level outcomes were more variable and frequently failed to normalize.

Anti-sclerostin therapy elicits an anabolic response in OI, improving overall bone mass and whole-bone strength. However, it does not consistently restore intrinsic tissue-level material properties. Current clinical evidence supports skeletal responses in adults with COL1A1/COL1A2-related OI types I, III, and IV, without a demonstrated difference between type I and pooled types III/IV; it does not identify a preferentially responsive individual genotype or an optimal pediatric age. Future trials should prespecify molecular and skeletal-maturity strata and prioritize fractures and whole-bone strength, supported by axial DXA, weight-bearing-site HR-pQCT/microFE, and tissue-level bone-quality outcomes.