Ossification of the Posterior Longitudinal Ligament (OPLL) and Diffuse Idiopathic Skeletal Hyperostosis (DISH) are debilitating conditions characterized by pain, stiffness, myelopathy, and impaired mobility due to progressive enthesopathies and spinal fractures. These disorders worsen with age and may lead to hemiplegia. The underlying mechanisms of these diseases remain poorly understood, and effective treatments are currently lacking. To elucidate the pathogenesis of OPLL, we conducted a prospective study involving plasma analyte measurement in 50 consecutive OPLL and 25 consecutive cervical osteoarthritic (OA) patients who presented for surgical correction within the same time frame, followed by exome sequencing of 19 genes associated with phosphate wasting and spinal ligament enthesopathy/ossification. Our study identified a significant association between OPLL and ENPP1 deficiency. Specifically, we observed that OPLL patients exhibited decreased plasma levels of inorganic pyrophosphate (PPi) while maintaining unaltered alkaline phosphatase levels. Additionally, 17% of OPLL patients harbored monoallelic pathogenic variants in ENPP1, the mammalian enzyme responsible for extracellular PPi. Using Enpp1-deficient mice (Enpp1asj) to model the condition, we discovered pathologic mineralization of the spine, long bones, and tendons, alongside increased long bone and spinal fracture risk by 17 wk of age. We further assessed the therapeutic potential of two forms of ENPP1 enzyme replacement therapies. Bone-targeted ENPP1 significantly ameliorated the spinal hyperostosis, improved or normalized spinal and long bone fragility, ameliorated tendon enthesopathies, and improved trabecular microarchitecture. Meanwhile, soluble ENPP1 prevented tendon enthesopathies, normalized cortical bone microarchitecture, and improved long bone fragility. Our findings establish a clear link between decreased plasma PPi, ENPP1 deficiency, and OPLL, unveiling additional therapeutic targets to more effectively manage this poorly treated condition.