ESPE Yearbook of Paediatric Endocrinology

In brief: This retrospective study reports on the relationship between serum phosphorus and fibrous dysplasia-related skeletal complications (fractures, orthopaedic surgery, and scoliosis) in a large cohort of patients (n=240).

Commentary: Fibrous dysplasia (FD) / McCune-Albright syndrome (MAS) is a rare mosaic disorder caused by postzygotic gain-of-function mutations in Gαs, resulting in continuous receptor activation. FD can range from an isolated, asymptomatic monostotic lesion to severe polyostotic disease associated with an increased risk of fracture, deformity, functional impairment, and pain. FD lesions are related to proliferation of abnormally differentiated osteoprogenitor cells and replacement of normal bone and marrow with expansile fibro-osseous tissue. Abnormal osteoprogenitor cells overproduce FGF23, resulting in hyperphosphaturia with or without hypophosphatemia. Several studies have reported that patients with hypophosphatemia are at increased risk of FD-related complications, suggesting that dysplastic, poorly mineralised FD tissue may be particularly vulnerable to the effects of low phosphorus levels. The current study demonstrates that both, frank hypophosphatemia (Z-score ≤−2) and low-normophosphatemia (>−2 to ≤−1), are associated with increased skeletal complications in patients with FD. These findings confirm FGF23 excess as an important contributor to skeletal morbidity, and provide support for a robust approach to monitoring and treatment.

Studies of FGF23 excess disorders, such as X-linked hypophosphatemia (XLH), have shown that burosumab, a monoclonal antibody to FGF23, can robustly and safely correct serum phosphorus into the normal range. A phase 2 trial of burosumab in patients with FD is ongoing (NCT05509595); based on the results reported here, it has been designed to target high-normophosphatemia and will titrate burosumab to achieve phosphorus levels between Z-score > -1 and ≤ 2. The results of that trial will hopefully improve our understanding of the safety and feasibility of therapeutically targeting high normal phosphorus levels.