ABSTRACTEarly‐onset osteoporosis (EOOP) has been associated with several genes, includingLRP5, coding for a coreceptor in the Wnt pathway. Variants inLRP5were also described in osteoporosis pseudoglioma syndrome, combining severe osteoporosis and eye abnormalities. Genomewide‐association studies (GWAS) showed thatLRP5p.Val667Met (V667M) variant is associated with low bone mineral density (BMD) and increased fractures. However, despite association with a bone phenotype in humans and knockout mice, the impact of the variant in bone and eye remains to be investigated. Here, we aimed to evaluate the bone and ocular impact of the V667M variant. We recruited 11 patients carrying the V667M variant or other loss‐of‐function variants ofLRP5and generated anLrp5V667Mmutated mice. Patients had low lumbar and hip BMDZ‐score and altered bone microarchitecture evaluated by HR‐pQCT compared with an age‐matched reference population. Murine primary osteoblasts fromLrp5V667Mmice showed lower differentiation capacity, alkaline phosphatase activity, and mineralization capacity in vitro. Ex vivo, mRNA expression ofOsx,Col1, andosteocalcinwas lower inLrp5V667Mbones than controls (allp< 0.01).Lrp5V667M3‐month‐old mice, compared with control (CTL) mice, had decreased BMD at the femur (p< 0.01) and lumbar spine (p< 0.01) with normal microarchitecture and bone biomarkers. However,Lrp5V667Mmice revealed a trend toward a lower femoral and vertebral stiffness (p= 0.14) and had a lower hydroxyproline/proline ratio compared with CTL, (p= 0.01), showing altered composition and quality of the bone matrix. Finally, higher tortuosity of retinal vessels was found in theLrp5V667Mmice and unspecific vascular tortuosity in two patients only. In conclusion,Lrp5V667Mvariant is associated with low BMD and impaired bone matrix quality. Retinal vascularization abnormalities were observed in mice. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.