Clinical spectrum of rare bone fragility disorders and response to bisphosphonate treatment: a retrospective study

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85-90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.In this study, we investigated the clinical characteristics of 38 patients with a bone fragility disorder that had variants in non-COL1A1/COL1A2 genes in order to study genotype-phenotype correlations, as the natural history of these rare forms is still not well known. We then studied the usefulness of bisphosphonate treatment by evaluating the effects on LS BMD, annual non-vertebral fracture rate, bone turnover markers and height. This study enabled us to better define the natural history of patients with non-COL1 pathogenic variants. Patients with CRTAP and TMEM38B variants consistently had a prenatal presentation with a short (<3^rd p) and bowed femur. Importantly, this prenatal involvement does not predict the postnatal severity of the disease. Regarding treatment by bisphosphonates, all patients showed a significant increase in LS BMD while treated and this increase was dependent on the dose received. The increase in LS BMD also translated in a reduction of fracture rate during treatment. Finally, our study showed that the earlier bisphosphonates are initiated, the greater the fracture rate is reduced.