Antiresorptive medications are essential in treating diseases of pathologic osteoclastic
bone resorption, including
bone cancer and
osteoporosis.
Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of
bone resorption is important in regulating unwanted malignant and metabolic
osteolysis, BP treatment is associated with potential side effects, including
osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as
denosumab, have entered the clinical arena.
Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with
tooth extraction or
dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-κB
ligand (RANKL) inhibitors
RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of
immunoglobulin G [
IgG]) and OPG-Fc (composed of the RANKL-binding domains of
osteoprotegerin [OPG] linked to the Fc portion of
IgG) to induce ONJ in mice in the presence of
periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in
RANK-Fc-treated and OPG-Fc-treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on
denosumab treatment. Histologic examination revealed that
RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae,
osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with
periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ.