Comments on ''Geranylgeraniol--a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw" by Ziebart T et al. (2011)

therapeutic approach to bisphosphonate associated osteonecrosis of the jaw’’ in Oral Oncology, by Ziebart T et al., and would like to compare and discuss these results with our recently published data.1 The design of the two studies is very similar: natural isoprenoids have been used to revert the mevalonate pathway inhibition induced by amino-bisphosphonates (N-BPs). Isoprenoid compounds are hypothesized to enter the mevalonate pathway after the N-BPs block, being metabolized as farnesyl-pyrophosphate and bypass the biochemical inhibition mediate by N-BPs on farnesyl- pyrophosphate synthase, restoring the metabolites flux along the pathway.2,3 Ziebart T. et al. empathized that the isoprenoid geranylgeraniol (GGOH) can antagonize the effects of N-BPs in the processes of osteoclast formation, apoptosis, bone resorption and in tumor cells (i.e. prostate cancer cells, human myeloma cells) as previously described in several studies,4,5 suggesting a therapeutic use of GGOH in bisphosphonate associated osteonecrosis of the jaw (BP-ONJ). Recently, our group demonstrated that GGOH and several other isoprenoids (farnesol, geranygeraiol, mentol, limonene) are able to revert the pro-inflammatory effect induced by the combination of N-BPs and bacterial lipoplyshaccaride (LPS) or muramyldipeptide (MDP) both in Balb/c mice and in human and murine monocytes. 2,3,6 We also proposed isoprenoid compounds as eligible treatment for the rare and still orphan disease mevalonate kinase deficiency (MKD, OMIM: 251170), characterized by genetic defect in the second enzyme of the mevalonate pathway. All this considered we would like to discuss the following issues: – We do agree with Ziebart T. et al.1 about the anti-N-BPs effect of geraniol, emphasizing that this effect is not dependent on the N-BP used on the isoprenoids. Ziebart’ group used ibandronate, pamidronate and zoledronate in their model, whereas we treated Balb/c mice and monocytes with alendronate or pamidronate obtaining comparable and reproducible findings. 2,7 Moreover geranylgeraniol, farnesol, menthol and limonene showed a comparable effect in contrasting N-BP action in our models,3 suggesting a common mechanism of action for these compounds in the context of NBP inhibition. – It is interesting to note that GGOH is able to contrast N-BP effect independently of the cellular model implied (osteoblast or monocytes) and the different outcome of N-BP inhibition. Since the block of the mevalonate pathway affects the prenylation of several signalling molecules involved in cell cycle, differentiation and cell response to extracellular stimulus, probably it results in different defects depending on the cell types. – We suggest Ziebart T. et al.1, to test other isoprenoids in addition to GGOH, such as geraniol, farnesol, menthol or limonene, in order to identify the most effective isoprenoids to treat in combination within aminobisphosphonate associated osteonecrosis of the jaw. While the dose/effect of the isoprenoid is comparable within Ziebart T. et al. and our models, additionally we would like to emphasize the importance of the timing in isoprenoid administration. – In our animal model the isoprenoid timing necessary to revert the pro-inflammatory action of alendronate or pamidronate was the critical point, because the isoprenoid must be injected the day before and/or after the N-BP.2,7 – Recently we showed that farnesyltransferase inhibitor (FTI) such as manumycin A, Tipifarnib or Lonafarnib, currently used in clinical trials as anticancer drugs, were able to contrast N-BP effect leading to a redistribution of mevalonate intermediates along its pathway.6 We propose Ziebart T. et al. to evaluate the effects of these pharmacological agents which could be an alternative therapeutic approach in the case of N-BP-induced osteonecrosis of the jaw. In summary, we do agree with the study by Ziebart T. et al., and emphasize the pivotal role of isoprenoid to rescue the phenotype inflammation induced by aminobisphosphonate treatment.