Pathogenic variants in COL1A1 and COL1A2, encoding the two chains of type I procollagen, account for the majority of OI cases and are inherited in an autosomal dominant pattern. De novo mutations are common, particularly in more severely affected individuals without a family history. A growing number of rarer autosomal recessive forms have been identified, caused by variants in genes encoding proteins involved in collagen post-translational modification, folding, and intracellular transport, including CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, BMP1, and several others. These recessive forms are associated with specific subtypes and may produce distinct clinical profiles, including severe kyphoscoliosis and pulmonary involvement. The genetic architecture of OI continues to expand as molecular sequencing technologies identify additional causative loci across the collagen biosynthesis pathway.

Diagnosis is established through clinical assessment integrating fracture history, family history, physical examination findings, and skeletal radiography. Bone mineral density measurement via dual-energy X-ray absorptiometry (DXA) documents reduced bone mass and supports clinical characterization. Biochemical collagen analysis performed on cultured dermal fibroblasts can identify qualitative and quantitative defects in type I collagen production, though this approach has largely been supplanted in clinical practice by molecular genetic testing. Next-generation sequencing panels targeting OI-related genes or broader skeletal dysplasia panels identify pathogenic variants in the majority of affected individuals. Prenatal diagnosis is achievable via ultrasound identification of fractures or limb shortening, with molecular confirmation from amniocentesis or chorionic villus sampling in families with a known variant.

No curative therapy exists for OI. Bisphosphonate therapy, particularly intravenous pamidronate and oral risedronate or alendronate, has been used extensively to reduce fracture frequency and improve bone mineral density in pediatric and adult populations, though evidence for reduction in fracture incidence is more robust in children. Orthopedic surgical interventions, including intramedullary rodding of long bones, are used to stabilize deformed bones and prevent recurrent fracture. Physical rehabilitation and physiotherapy are important components of care at all ages, supporting mobility and muscle strength. Several investigational agents are in clinical development, including an anti-Siglec-15 monoclonal antibody, an anti-TGF-beta monoclonal antibody (based on fresolimumab), romosozumab (a human anti-sclerostin monoclonal antibody), allogeneic fetal mesenchymal stem cells, and allogeneic bone marrow-derived osteoblastic cells. Denosumab, a RANK ligand inhibitor, carried orphan designation for OI but that designation was subsequently withdrawn.

Prognosis in OI is closely tied to subtype and the degree of skeletal involvement. Individuals with mild subtypes, characterized by normal height or mild short stature and infrequent fractures, often achieve independent ambulation and typical life expectancy. Those with moderate subtypes typically sustain more frequent fractures and may develop progressive deformity limiting mobility. Severely affected individuals face substantial orthopedic disability and, in forms with thoracic cage restriction, risk of respiratory complications that may reduce life expectancy. Fracture frequency generally decreases after puberty in many cases, attributable in part to the relative increase in bone mass with skeletal maturation. Hearing loss, if present, tends to be progressive across adulthood.

Active clinical trials in osteogenesis imperfecta include Phase 2 and Phase 3 studies evaluating romosozumab for its effects on bone density and fracture outcomes, as well as dose-finding studies of novel anti-resorptive agents in pediatric populations. Research areas reflected in the published literature include gene therapy approaches targeting collagen gene expression, with a notable proportion of publications categorized as basic science and preclinical work, alongside biomarker studies and case series. Cell-based therapeutic strategies using allogeneic mesenchymal stem cells and osteoblastic cell infusions are in early-stage clinical investigation. The expanding genetic characterization of OI subtypes continues to inform the development of subtype-directed molecular interventions.