Abstract
A defect in the canonical Wnt-β-catenin pathway may lead to reduced bone strength and increased fracture risk. Sclerostin is a key inhibitor of this pathway by binding to low-density lipoprotein (LDL) receptor-related protein (LRP)-5/6, thereby reducing bone formation. The effectiveness of romosozumab, a human monoclonal antibody that binds sclerostin and prevents this inhibitory effect, has been questioned in patients with inactivating genetic variants in LRP5 or LRP6. We present a 67-year-old woman with severe osteoporosis with 4 grade 2 vertebral fractures due to a heterozygous pathogenic variant in LRP5. She was treated with romosozumab for 1 year, after which a routine follow-up spine x-ray revealed 5 new vertebral fractures, despite a strong increase in bone mineral density (BMD) (lumbar spine [LS] + 58%; femur neck [FN] + 23%), although overestimated at LS because of the vertebral fractures. This suggests that in patients with loss-of-function LRP5 variants, romosozumab is able to increase BMD. However, it is unclear whether the progressive vertebral fractures are due to the severe osteoporosis in relation to the start of romosozumab or a diminished responsiveness related to her LRP5 variant. Further evaluation is needed on the effect of romosozumab on BMD and fracture outcomes in patients with a likely defective LRP5/6 receptor.