Abstract: Hypophosphatasia (HPP), a rare metabolic disorder caused by mutations in the ALPL gene, leads to deficient alkaline phosphatase activity and presents unique clinical challenges for adult patients, including fractures, chronic pain, and dental issues. This disorder is often underdiagnosed due to its variable clinical presentation and overlap with other conditions, further complicating timely intervention. Early diagnosis is critical for effective management; however, current diagnostic criteria have limitations, often resulting in delays. Insights from the Global HPP Registry reveal significant disease burden and treatment gaps in treated and untreated adults. These insights underscore the importance of multidisciplinary approaches in addressing HPP-related complications, including musculoskeletal and systemic manifestations. Enzyme replacement therapy (ERT) with asfotase alfa has proven effective in reducing disease burden and improving quality of life. Recent clinical evidence suggests that ERT not only alleviates symptoms but may also prevent disease progression when initiated early. Emerging therapies and alternative regimens like teriparatide dosing adjustments are being explored for their potential benefits. In addition, advanced imaging modalities and biomarker studies are improving diagnostic accuracy and monitoring of therapeutic outcomes. This comprehensive review highlights the significant challenges and advances in diagnosing and treating HPP in adults. Ongoing research aims to enhance diagnosis and treatment through genetic testing and personalized medicine, focusing on identifying and addressing knowledge gaps to improve care for adult HPP patients. Collaborative efforts between researchers, clinicians, and patient advocacy groups are crucial for driving innovation and improving access to care. Continued research and innovation are essential, and healthcare professionals must stay informed about the latest advancements in HPP diagnosis and treatment to ensure optimal patient care. By addressing these challenges, the field can move closer to improving the lives of adults living with HPP.Abstract: Hypophosphatasia (HPP), a rare metabolic disorder caused by mutations in the ALPL gene, leads to deficient alkaline phosphatase activity and presents unique clinical challenges for adult patients, including fractures, chronic pain, and dental issues. This disorder is often underdiagnosed due to its variable clinical presentation and overlap with ot...Show More