Geranylgeraniol (GGOH), incorporated into a bone cement pellet promotes osteoclast function and healing in a model of medication-related osteonecrosis of the jaw.

INTRODUCTION

There is no cause -based treatment for Medication-Related Osteonecrosis of the Jaw (MRONJ). MRONJ is a morbid condition including exposed, infected bone and mandibular fractures in osteoporotic individuals and metastatic cancers patients treated with nitrogen containing bisphosphonates (NBP). NBPs inhibit farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, depriving osteoclasts and other bone cells of small GTPases necessary for their function and survival. We test the hypothesis that geranylgeraniol (GGOH),a metabolite downstream of FDPS, when incorporated into a bone cement pellet, enhances osteoclast function and promotes local bone healing in in vitro and in a proven animal model of MRONJ.

METHODS

3H labelled GGOH (2 mM) was incorporated into a Hydroset bone cement pellet and release from the cement was assessed over time. To assess the effect on bone cell function, the GGOH-loaded cement was placed in a porous filter above cultured osteoclasts treated with bisphosphonate and the effect on osteoclast survival and function were measured. In a pilot study the effect of GGOH on osteotomy microstructure was measured in a rat model of MRONJ using a split mouth design.

RESULTS

The release of GGOH from bone cement increased osteoclast survival/metabolic activity, and promoted resorption of the calcified substrate. In vivo released GGOH limited the effects of the bisphosphonate and promoted healing. In an animal pilot study, GGOH from the infused cement carrier stabilizes bone structure and restores the ability of osteoclasts to remodel.

CONCLUSION

These initial findings point to GGOH in a bone cement carrier as a useful therapeutic approach to prevent or mitigate the pathogenesis of MRONJ.