Serum Phosphorus as a Driver of Skeletal Morbidity in Fibrous Dysplasia

Fibrous dysplasia (FD) results in fractures, pain, and deformities. Abnormal osteoprogenitor cells overproduce FGF23, leading to hyperphosphaturia in most patients and frank hypophosphatemia in a subset. Studies suggest hypophosphatemia is associated with increased FD-related morbidity. However, the relationship between phosphorus and skeletal complications has not been investigated, and the optimal therapeutic target has not been determined.

Characterize the impact of serum phosphorus on FD-related morbidity and identify levels associated with increased skeletal complications.

Natural history study with 240 subjects at a clinical research center who had ≥1 fasting phosphorus level, determined as age- and sex-adjusted Z-scores. Subjects were categorized based on frank hypophosphatemia (Z-score ≤ -2; n = 48); low-normophosphatemia (> -2 to ≤ -1; n = 66); and high-normophosphatemia (> -1 to ≤ 2; n = 125). Main outcomes were fractures, orthopedic surgeries, and scoliosis.

Subjects with frank and low-normophosphatemia had increased fracture and surgery rates vs high-normophosphatemia. The prevalence of moderate to severe scoliosis was similarly higher in the frank and low-normophosphatemia groups. In a subanalysis of patients matched for Skeletal Burden Score ≥35, fracture and surgery rates remained higher in the frank hypophosphatemia group, suggesting association between phosphorus and skeletal complications is not explained by differences in FD burden alone.

Both frank hypophosphatemia and low-normophosphatemia are associated with increased FD-related complications. This supports FGF23-mediated hypophosphatemia as a driver of skeletal morbidity, which may impact a larger proportion of the FD/McCune-Albright syndrome population than previously recognized. These findings enable clinicians to identify at-risk patients and will inform development of prospective studies to determine optimal therapeutic targets.