Osteoporosis represents an increasing health and socioeconomic burden on aging societies. Current therapeutic options often come with potentially severe side effects or lack long-term efficacy, highlighting the urgent need for more effective treatments. Identifying novel drug targets requires a thorough understanding of their physiological roles. Genome-wide association studies in humans have linked gene variants of the adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) to variations in bone mineral density and body height. In this study, we explore the impact of GPR133/ADGRD1 on osteoblast differentiation and function. Constitutive and osteoblast-specific knockouts of Gpr133/Adgrd1 in mice lead to reduced cortical bone mass and trabecularization in the femurs and vertebrae - features characteristic of osteoporosis. This osteopenic phenotype in receptor-deficient mice is caused by impaired osteoblast function, which, in turn, promotes increased osteoclast activity. At the molecular level, GPR133/ADGRD1 regulates osteoblast function and differentiation through a combined activation mechanism involving interaction with its endogenous ligand, protein tyrosine kinase 7 (PTK7), and mechanical forces. This is demonstrated in vitro through stretch assays and in vivo via a mechanical loading experiment. Further in vitro analysis shows that GPR133/ADGRD1-mediated osteoblast differentiation is driven by cAMP-dependent activation of the β-catenin signaling pathway. Activation of GPR133/ADGRD1 with the receptor-specific ligand AP-970/43482503 (AP503) enhances osteoblast function and differentiation, both in vitro and in vivo, significantly alleviating osteoporosis in a mouse ovariectomy model. These findings position GPR133/ADGRD1 as a promising therapeutic target for osteoporosis and other diseases characterized by reduced bone mass.