Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children

The formation of functional bone requires a delicate interplay between osteogenesis and osteolysis. Disturbances in this subtle balance result in an increased risk for fractures. Besides its mechanical function, bone tissue represents a key player in the regulation of calcium homeostasis. Impaired bone formation results in bone fragility, which is especially pronounced in osteogenesis imperfecta (OI). This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. The current classification of OI includes 23 distinct types. In recent years, several new mutations in different genes have been identified, although the exact pathomechanisms leading to the clinical presentation of OI often remain unclear. While bisphosphonates are still the standard of care, novel therapeutic approaches are emerging. Especially, targeted antibody therapies, originally developed for osteoporosis, are increasingly being investigated in children with OI and represent a promising approach to alleviate the consequences of impaired osteogenesis and improve quality of life in OI patients. This review aims to provide insight into the pathophysiology of OI and the consequences of distinct disease-causing mutations affecting the regulation of bone homeostasis. In this context, we describe the four most recently identified OI-causing genes and provide an update on current approaches for diagnosis and treatment.