Stürznickel J, Rolvien T, Delsmann A, et al. - This study was sought to examine the impacts of relevant LRP5 and LRP6 variants on the clinical phenotype, bone turnover, bone mineral density, and bone microarchitecture. Early‐onset osteoporosis (EOOP) patients (n = 372) were genotyped by gene panel sequencing after exclusion of secondary osteoporosis, and segregation analysis of variants in LRP5/LRP6 was conducted. The study enrolled 50 individuals (31 EOOP index patients, 19 family members). The results of this study exhibited that the relevant variants in LRP5 and LRP6 contribute to EOOP in a substantial number of individuals, leading to a high number of fractures, low bone formation, decreased Z‐scores, and impaired microarchitecture. The outcomes suggested that this detailed skeletal characterization improves the interpretation of known and novel LRP5 and LRP6 variants.