Engineering osteoporosis-related bone organoids: a mechanism-module-functional readout framework for disease...

Osteoporosis is a systemic skeletal disorder characterised by reduced bone mass, microarchitectural deterioration and increased fracture risk. Its pathogenesis extends beyond an imbalance between bone formation and resorption and involves osteoimmune dysregulation, vascular insufficiency, oxidative and inflammatory stress, and altered mechanical signalling within the bone microenvironment. Conventional two-dimensional cultures cannot adequately reproduce the three-dimensional matrix organisation, spatial multicellular interactions and mechanical properties of bone tissue, whereas animal models are limited by species-specific differences in bone remodelling, immune regulation and disease progression. Bone organoids integrating human stem/progenitor cells, bone-resident cells, immune and endothelial components, biomimetic matrices and dynamic culture systems provide a promising intermediate platform for modelling osteoporosis-related microenvironmental dysfunction. Unlike previous reviews that broadly summarised bone organoid construction and applications across skeletal diseases, this review focuses specifically on osteoporosis and proposes a mechanism-module-functional readout framework. This framework translates osteogenic suppression, RANKL/RANK/OPG-mediated osteoclast activation, immune-inflammatory amplification, vascular impairment and mechanical unloading into selectable organoid modules with measurable endpoints, including matrix formation, mineralisation, osteoclast resorption, inflammatory and oxidative-stress responses, vascular network function and mechanosensitive signalling. We further discuss how these models could connect candidate molecular signals with human-relevant three-dimensional functional phenotypes, thereby supporting biomarker discovery, drug-response assessment and patient stratification. However, organoid-derived candidates should not be regarded as clinically validated biomarkers without confirmation in independent patient cohorts and prospective clinical studies. Standardised construction, reproducible quality control, functional maturation and clinically anchored validation will therefore be essential for advancing osteoporosis-related bone organoids from experimental disease models towards biomarker translation and precision medicine.