X-Linked Hypophosphatemia: A Review of Pathophysiology, Clinical Manifestations, Current Management, and Emerging Therapeutic Strategies

X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorders, caused by pathogenic variants in the PHEX gene that result in excess fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia. Historically considered a pediatric disease characterized by rickets and growth impairment, XLH is now recognized as a lifelong condition with substantial adult morbidity including osteomalacia, fractures, enthesopathy, osteoarthritis, and reduced quality of life. The discovery of FGF23 as the central mediator of phosphate wasting transformed understanding of disease pathophysiology and enabled development of burosumab, a monoclonal antibody that neutralizes FGF23 and restores phosphate homeostasis. While burosumab represents a paradigm shift in therapy, accumulating evidence indicates that XLH involves FGF23-independent mechanisms, including osteopontin accumulation, ASARM peptide generation, and pyrophosphate dysregulation, which contribute to persistent skeletal abnormalities despite biochemical correction. This review integrates current insights into the molecular genetics, pathophysiology, and lifelong clinical features of XLH, with particular attention to emerging concepts involving local bone matrix abnormalities and their impact on therapeutic innovation. We trace the transition from conventional phosphate and active vitamin D supplementation to targeted FGF23 inhibition, highlight the limitations of existing treatment strategies, and explore future directions such as small‑molecule inhibitors, anti‑sclerostin therapy, gene-based approaches, and ultimately PHEX‑focused repair. A comprehensive understanding of XLH as both a systemic endocrine disorder and an intrinsic defect of osteocyte biology is critical for optimizing patient care and steering the development of curative therapies.