Engineering patient-derived organotypic bone model to understand osteoanabolic therapy in skeletal disease

Bone-forming therapies often fail in genetic skeletal disorders, highlighting critical gaps in mechanistic understanding and therapy evaluation. We developed 3D bioprinted organotypic bone models using primary cells from a patient with FKBP10-mutant osteogenesis imperfecta (OI) and from metabolically healthy controls obtained via femoral osteotomy (FO). The platform combines cyclic mechanical loading and reseeding to recreate the cellular heterogeneity of bone tissue, enabling parallel assessment of gene expression, extracellular matrix formation, mineralization and mechanical function. We tested Dickkopf-1 antibody (DKK1Ab), a Wnt pathway modulator, to evaluate therapy response. OI constructs showed elevated interferon-stimulated gene (ISG) activity and hypermineralization with structural fragility, hallmark features of OI bone. Unlike FO constructs, treatment in OI resulted in a limited transcriptional response marked by ISG downregulation and increased proliferative activity. These changes improved matrix secretion, enhanced construct stability, and reduced fracture scores. These findings show that patient-derived models can reveal multi-scale drug responses.