18F-Sodium Fluoride PET/CT as a Tool to Assess Enthesopathies in X-Linked Hypophosphatemia

Abstract

X-linked hypophosphatemia (XLH) is a rare metabolic disorder characterized by elevated FGF23 and chronic hypophosphatemia, leading to impaired skeletal mineralization and enthesopathies that are associated with pain, stiffness, and diminished quality of life. The natural history of enthesopathies in XLH remains poorly defined, partly due to absence of a sensitive quantitative tool for assessment and monitoring. This study investigates the utility of 18F-NaF PET/CT scans in characterizing enthesopathies in XLH subjects. In 19 adult XLH subjects, enthesopathy burden was assessed by quantifying calcified sites on CT and 18F-NaF PET uptake at 16 common tendon/ligament insertion locations. Parameters obtained were (1) number of enthesopathy sites, (2) characterization of each site as CT-positive (CT +) and/or PET-positive (PET +), (3) a semiquantitative score based on severity of affected enthesopathies (CT-score_global and PET-score_global). Biochemical and self-reported questionnaires results were correlated with 18F-NaF PET/CT parameters. 18F-NaF PET/CT detected at least one enthesopathy in all subjects, with 18F-NaF PET positivity often detected before CT (19.4% of all enthesopathies). Age negatively correlated with the number of PET + /CT- enthesopathies and positively with PET-/CT + enthesopathies. PET-score_global was positively associated with ALP. While PET-score_global showed no correlation with any applied survey, CT-score_global was associated with worse functionality and pain. These associations suggest a progression from an actively mineralizing lesion to a more established, inactive lesion. Overall, although 18F-NaF PET/CT is not yet indicated for routine clinical use, it is a promising research tool for evaluating enthesopathy burden in XLH, offering valuable insights into the disease's progression and potentially enabling early therapeutic assessment.

Keywords: Enthesopathy; Extra-skeletal calcifications; Fibroblast growth factor 23 (FGF23); Osteomalacia and rickets; X‐linked hypophosphatemia (XLH).