Pérez García, Victor M.. Fernández Calvo, Gabriel. Vargas Beltran, Juan Carlos. 

Fibrous dysplasia (FD) is a rare, benign bone disorder characterized by the abnormal formation of tissue in a mosaic distribution. It can affect multiple bones, causing severe symptoms such as pathological fractures, spinal curvature, and reduced stature, as part of the so-called McCune– Albright Syndrome (MAS). FD originates from postzygotic gain-of-function mutations in the GNAS gene. While treatments for other skeletal diseases like the monoclonal antibody denosumab, used in osteoporosis, have been applied to FD, the absence of a quantitative understanding of the dynamics of lesional cell populations limits both in-depth analysis and therapy optimization. This study introduces a novel pharmacokinetic–pharmacodynamic mathematical model specifically designed for FD, enriched with in vitro/ex vivo data from denosumab assays. Our framework builds upon existing mathematical approaches for osteoporosis, focusing on two cell populations: (1) variant-bearing FD osteoprogenitors and (2) wild-type (WT) osteoprogenitors displaying transferred FD phenotypes. The resulting model paves the way for future in vitro assays targeting FD and related skeletal conditions. Our analyses reveal that abnormal cell proliferation in FD may be due to its atypical inhibition, providing new insights for potential treatment strategies. Furthermore, our simulations identify a promising biomarker for FD diagnosis.