Use of Geranylgeraniol to Rescue Bone Regeneration Impaired by Bisphosphonate

Objectives: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the main side effects of bisphosphonate therapy (BPT). To date, there is no effective therapy of the BRONJ. Nitrogen-containing bisphosphonates (N-BPs) target to the inhibition of pyrophosphate synthase (FPPS) in the mevalonate pathway. Consequently, decreased synthesis of the downstream metabolites, geranylgeraniol (GGOH) and farnesol (FOH), is believed to largely account for the development of BRONJ. Previous in vitro studies have shown the negative effects of N-BPs on decreased viability and migration capacity of different cell types. The aim of our study was to demonstrate that the application of downstream metabolites may reverse the negative biological effects of N-BPs.
Methods: Amputation-regeneration model of zebrafish caudal fin was employed to analyze the effects of drug administration. Alendronate (N-BP), farnesol, and geranylgeraniol at 7.5×10^-5M were used to treat the fish by incubation. The regenerated bone in the fin was documented by calcein staining. The dynamic appearance of ostelclasts during the process were observed by TRAP staining.
Results: The bone regeneration impaired by alendronate was reversed to normal in the presence of GGOH and FOH. In addition, the morphological restoration was delineated by TRAP staining to reveal the distribution of osteoclasts. The results showed that the number and distribution of osteoclasts was restored to normal. Hence, systemic application of GGOH and FOH may reduce the side effects of bisphosphonate therapy.
Conclusions: In this study, we demonstrate that the impairing effects of alendronate on bone regeneration and osteoclast activities may be reversed by application of GGOH and FOH. Our study in zebrafish provides a vivid animal model to investigate the BRONJ in vivo. And the results may further extend to the clinical applications in treating BRONJ.