The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw

Abstract

Medication-related osteonecrosis of the jaw (ONJ) is a rare but significant adverse side effect of antiresorptive drugs. Bisphosphonate-related ONJ (BRONJ) is the most prevalent condition due to the extensive use of the drug in cancer and osteoporosis treatment. Nitrogen-containing bisphosphonates suppress osteoclastic resorption by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway, leading to deficiency of the substrate for GTPase prenylation. The bone remodelling process is uncoupled, subsequently impairing bone healing and causing ONJ. Targeted administration of geranylgeraniol (GGOH) represents a promising approach to mitigate BRONJ because GGOH is a substrate for GTPase prenylation. In the current review, the in vitro effects of GGOH on osteoclasts, osteoblasts and other related cells of the jaw are summarised. We also present and appraise the current in vivo evidence of GGOH in managing BRONJ in animal models. Lastly, several considerations of using GGOH in the clinical management of BRONJ are highlighted. As a conclusion, GGOH is a promising topical agent to manage BRONJ, pending more research on an effective delivery system and validation from a clinical trial.

Biomimetic Collagen Membranes as Drug Carriers of Geranylgeraniol to Counteract the Effect of Zoledronate

“…These effects have been attributed to the inhibition of farnesyl pyrophosphate (FPP) synthase, GGPP synthase, or both [42]. It has been previously shown that the induction of cell apoptosis is produced due to the formation of ATP analogues by suppressing the mevalonate pathway [43]. In the present study, zoledronate did not exert this detrimental effect on the osteoblasts grown on GG-M (p < 0.001) (Figure 1).…”

“…It seems that GGOH can even rescue cells from the apoptotic effects of nitrogen-containing BPs. GGOH inhibits caspase-3 activation, and thus apoptosis, by inhibiting geranylgeranyl transferase I through an increase in the amount of substrate available for GTPase prenylation [43]. It has also been described that at low doses, GGOH (10-40 µM) may promote osteoblasts' viability [25,43].…”

“…GGOH inhibits caspase-3 activation, and thus apoptosis, by inhibiting geranylgeranyl transferase I through an increase in the amount of substrate available for GTPase prenylation [43]. It has also been described that at low doses, GGOH (10-40 µM) may promote osteoblasts' viability [25,43]. These results are in agreement with other authors who found that the treatment of osteoblasts with GGOH in combination with other BPs produced an attenuation of the detrimental effect of BPs on osteoblast viability [24,25,42].…”

“…This fact results in changes in genes encoding for bone proteins, such as fibroblast growth factor-2, VEGF, COL-I, and osteopontin. In addition, VEGF exerts its action as a modulator of bone repairing, promoting osteoblast maturation/differentiation and angiogenesis [43].…”

The Biomedical Importance of the Missing Pathway for Farnesol and Geranylgeraniol Salvage

“…As mentioned above, the polyprenol salvage pathway was first observed more than 25 years ago, but the enzymes responsible in animals or any pathogen are still unident ified [72,80]. Despite this, the interest in this pathway for the treatment of several human pathologies, ranging from osteonecrosis to infectious diseases, is increasing [92,93]. As a consequence, it is impractical to mention here everything published in this field, and we needed to make a selection of those reports that best illustrated the topics discussed, with a focus on biomedical problems.…”