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. Conversely, 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 (EF1α-GsαR201C) to assess whether zoledronate (ZOL) addition to anti-RANKL antibody (αRANKL) treatment could preserve the effects of RANKL inhibition after treatment discontinuation. We show that αRANKL treatment rapidly reduced bone turnover markers (BTMs) and increased bone mass in affected skeletal segments, but FD lesions recurred shortly after discontinuation. Importantly, αRANKL+ZOL combination therapy delayed disease rebound after αRANKL withdrawal, as bone density was preserved, BTM rise was prevented, and no new lesions were observed. ZOL monotherapy increased bone density and reduced BTMs but did not fully halt disease progression. Finally, both αRANKL and αRANKL+ZOL treatments reduced fracture incidence and improved 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.