Individualized antiresorptive therapy in fibrous dysplasia and McCune-Albright syndrome: A retrospective cohort study.

Abstract

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare benign bone disorder caused by postzygotic mutations in <i>GNAS</i>, characterized by skeletal lesions leading to pain, deformities, and fractures. Although antiresorptive agents such as denosumab and zoledronate are used, evidence remains limited, and denosumab carries a well-known rebound risk. Given the heterogeneous disease activity in FD/MAS, standardized treatment approaches are frequently insufficient, raising the need for individualized treatment strategies. We therefore evaluated the effects and safety of individualized denosumab-zoledronate therapy with clinically guided treatment adjustments. A single-center FD/MAS cohort (<i>n</i> = 42) managed between 2014 and 2025 was retrospectively analyzed. Clinical, radiographic, histopathological, and baseline biochemical characteristics were assessed in the overall cohort, whereas longitudinal analyses of treatment response, laboratory markers, pain scores, and adverse events were restricted to an antiresorptive-treated subgroup of 11 patients. Compared with untreated patients, the treated subgroup showed higher skeletal lesion burden and elevated osteocalcin levels. During therapy, elevated bone turnover markers decreased, particularly ALP (-44.3%, <i>p</i> = 0.016). Most treated patients showed stable biochemical trajectories and reported pain reduction under therapy. One young MAS patient experienced severe rebound hypercalcemia (4.43 mmol/L) with renal failure after delayed denosumab administration. In conclusion, individualized antiresorptive therapy with denosumab and zoledronate was associated with symptomatic improvement and largely stable clinical courses in most treated FD/MAS patients. However, denosumab treatment may carry a clinically relevant rebound risk, particularly in young MAS patients with extensive skeletal burden and high bone turnover. Further studies are needed to establish specific, safe and effective treatment strategies.