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. BPs downregulate bone remodeling but their effects on FD lesions and pain are variable. Contrarily, denosumab converts FD tissue into mineralized bone and prevents disease progression, but disease rebound occurs upon treatment withdrawal. The combination of these two drugs may represent an effective and safe strategy for FD treatment. We used a FD mouse model (EF1-GsR201C) to assess whether zoledronate (ZOL) addition to anti-RANKL antibody (RANKL) treatment could preserve the effects of RANKL inhibition after treatment discontinuation. We show that RANKL treatment rapidly reduced bone turnover markers (BTMs) and increased bone mass in affected skeletal segments, but FD lesions recurred shortly after discontinuation. Importantly, RANKL+ZOL combination delayed disease rebound after RANKL withdrawal, as bone density was preserved, BTMs rise was prevented, and no new lesions were observed. ZOL monotreatment increased bone density and reduced BTMs but did not fully halt disease progression. Finally, both RANKL and RANKL+ZOL treatments reduced fracture incidence and ameliorated pain-like behavior in FD mice. These results demonstrate that combining zoledronate 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 zoledronate would slow down the resumption of the disease and the rebound effect.