Osteogenesis Imperfecta from Historical Nosology to Gene-directed Therapy: A Critical Narrative Review of Mechanism, Evidence and Translational Uncertainty

Abstract

Osteogenesis imperfecta is the prototypical heritable disorder of bone fragility, and the last three decades have transformed it from a clinically defined syndrome into a molecularly stratified group of conditions involving more than twenty genes. That transformation has not been matched by comparable progress in classification, outcome measurement or therapeutic evidence, and the resulting mismatch is the central concern of this review. The purpose of the article is to evaluate critically how historical nosology, molecular pathology and emerging gene-directed interventions relate to one another, and to determine which conclusions the accessible evidence can currently sustain. Literature was identified through open scholarly databases, citation searching and a clinical trials registry, with appraisal directed at study design, cohort ascertainment, endpoint selection and the distance between mechanistic plausibility and demonstrated clinical benefit. Three critical findings emerge. First, competing nosological frameworks now coexist without prospective validation against clinical outcomes, so classification supports communication more than it supports prognosis or treatment selection. Second, the dominant-negative mechanism that accounts for most disease produces a hypermineralised yet mechanically inferior matrix, which explains why densitometric gains have repeatedly failed to translate into proportionate fracture reduction and why surrogate endpoints have misdirected therapeutic expectation. Third, cell and gene therapy remain overwhelmingly preclinical or exploratory: published editing work is largely confined to cell models and rodent studies, mesenchymal stromal cell evidence rests on small uncontrolled series, and no completed clinical gene therapy trial for this condition was identified. Major unresolved questions concern the qualification of surrogate endpoints, the penetrance of pathogenic variants in unselected populations, allele-specific correction of private dominant-negative variants, and durable delivery to skeletal progenitors in a growing skeleton. Progress will depend less on new mechanistic detail than on trial designs and outcome measures capable of detecting clinically meaningful change in a rare, heterogeneous and slowly evolving disorder.