Hypophosphatasia (HPP) is an inborn disease that causes a rare form of osteomalacia, a mineralization disorder affecting mineralized tissues. Identification of patients at high risk for fractures or other skeletal manifestations (such as insufficiency fractures or excessive bone marrow edema) by bone densitometry and laboratory tests remains clinically challenging. Therefore, we examined two cohorts of patients with variants in theALPLgene grouped by bone manifestations. These groups were compared by means of bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) and simulated mechanical performance utilizing finite element analysis (FEA). Whereas the incidence of skeletal manifestations among the patients could not be determined by dual energy X-ray absorptiometry (DXA) or laboratory assessment, HR-pQCT evaluation showed a distinct pattern of HPP patients with such manifestations. Specifically, these patients had a pronounced loss of trabecular bone mineral density, increased trabecular spacing, and decreased ultimate force at the distal radius. Interestingly, the derived results indicate that the non-weight-bearing radius is superior to the weight-bearing tibia in identifying deteriorated skeletal patterns. Overall, the assessment by HR-pQCT appears to be of high clinical relevance due to the improved identification of HPP patients with an increased risk for fractures or other skeletal manifestations, especially at the distal radius.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00223-023-01082-3.