Osteogenesis imperfecta: Pathophysiology and current treatment strategies

Osteogenesis imperfecta (OI) is a hereditary disease of the bones and fascia. It is associated with an increased tendency to fracture, deformities of the extremities, and extra-skeletal signs. A short description of the clinical course, diagnostic recommendations and the current treatment are followed by an extensive overview of the genetic and pathophysiological background of the disease and future therapeutic options. Approximately 80% of patients present with mutations in genes coding for collagen (COL1A1/A2). In these patients, no clear correlation between phenotype and genotype is described for the collective. Stop mutations usually cause a quantitative collagen defect, which results in less normal collagen and a mild phenotype. Missense mutations lead to structurally changed collagen (qualitative defect) and to a more severe phenotype. Nonetheless, there is high variability and it is difficult to predict the course of an individual patient. In addition to changes in the collagen coding genes, there are mutations that affect the modification and secretion of collagen. A specific group consists of genes involved in the differentiation of osteoblasts. As with the other genes (which are not referred to in more detail), these are often superior genes, whose function in osteogenesis is not fully understood. Based on the pathophysiological principles, existing treatments may well be more precisely deployed in the future. An example is the receptor activator of nuclear factor kappa-B ligand (RANKL) antibody denosumab, which is more specific than bisphosphonates, and is already used in OI type VI (SERPINF1). Further treatments such as antisclerostin or stem cell therapies are currently being investigated with a focus on pathophysiology.