Stürznickel J, Rolvien T, Delsmann A, et al. - Early‐onset osteoporosis (EOOP) is characterized by decreased bone mineral density (BMD, ie, Z‐score ≤ ‐2.0) occurring at a young age (ie, premenopausal women, men < 50 years) in the absence of secondary osteoporosis. Researchers here analyzed how relevant LRP5 and LRP6 variants affect the clinical phenotype, bone turnover, BMD and bone microarchitecture. Using gene panel sequencing, they genotyped EOOP patients (n = 372), and performed segregation analysis of variants in LRP5/LRP6. They detected relevant variants affecting LRP5 or LRP6 (42 LRP5 and 8 LRP6 variants), including 10 novel variants, in 50 individuals (31 EOOP index patients, 19 family members). They classified 17 variants as disease causing; identified 14 variants of unknown significance; identified 19 variants as BMD‐associated SNPs. Findings overall suggest that in a substantial number of individuals, relevant variants in LRP5 and LRP6 contribute to EOOP, resulting in a high number of fractures, low bone formation, reduced Z‐scores, and impaired microarchitecture. This comprehensive skeletal characterization enhances the interpretation of known and novel LRP5 and LRP6 variants.