Incident Vertebral Fractures During Romosozumab Treatment in a Patient With a Pathogenic <i>LRP5</i> Variant

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 <i>(LRP)-5/6</i>, 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 <i>LRP5</i> or <i>LRP6</i>. We present a 67-year-old woman with severe osteoporosis with 4 grade 2 vertebral fractures due to a heterozygous pathogenic variant in <i>LRP5</i>. 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 <i>LRP5</i> 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 <i>LRP5</i> variant. Further evaluation is needed on the effect of romosozumab on BMD and fracture outcomes in patients with a likely defective <i>LRP5/6</i> receptor.