Effects of anti-RANKL, Zoledronate or combination therapy in a mouse model of fibrous dysplasia: a preclinical study

Bone fragility and pain are major clinical issues in fibrous dysplasia (FD) of bone, a genetic disorder characterized by increased bone resorption and lytic lesions. Both bisphosphonates (BPs) and denosumab are currently used to treat FD patients, although important concerns remain unsolved. Bisphosphonates downregulate bone remodeling but their effects on FD lesions and pain are variable. Conversely, denosumab converts FD tissue into mineralized bone and prevents disease progression, but disease rebound occurs upon treatment withdrawal. The combination of these 2 drugs may represent an effective and safe strategy for FD treatment. We used a FD mouse model (EF1 alpha-Gs alpha R201C) to assess whether zoledronate (ZOL) addition to anti-RANKL antibody (alpha RANKL) treatment could preserve the effects of RANKL inhibition after treatment discontinuation. We show that alpha RANKL treatment rapidly reduced bone turnover markers (BTMs) and increased bone mass in affected skeletal segments, but FD lesions recurred shortly after discontinuation. Importantly, alpha RANKL+ZOL combination therapy delayed disease rebound after alpha RANKL withdrawal, as bone density was preserved, BTM rise was prevented, and no new lesions were observed. Zoledronate monotherapy increased bone density and reduced BTMs but did not fully halt disease progression. Finally, both alpha RANKL and alpha RANKL+ZOL treatments reduced fracture incidence and improved pain-like behavior in FD mice. These results demonstrate that combining ZOL with denosumab may effectively treat FD. This strategy could particularly benefit patients with severe, rapidly progressive disease, in which RANKL inhibition would block lesion expansion and reduce bone turnover, while ZOL would slow down the resumption of the disease and the rebound effect.Fibrous dysplasia (FD) is a genetic disorder causing bone deformities, fractures, and pain. The commonly used treatments bisphosphonates (BPs) and denosumab each have important limitations: BPs show inconsistent results, while denosumab is effective but disease rebounds at treatment discontinuation. Our preclinical study tested whether combining both drugs could overcome these drawbacks. We show that, in a mouse model of FD, combining zoledronate with a murine analogue of denosumab delayed disease relapse while reducing fracture incidence and pain. These findings provide proof-of-concept supporting this drug combination as a promising therapeutic strategy for FD with immediate translational potential in clinical practice.