A study on mevalonic acid pathway-targeting therapy to recovery osteoclasts damaged with bisphosphonate

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Nitrogen-containing bisphosphonate (BP) is used as effective therapeutic agent for managing bone-resorbing diseases such as osteoporosis and cancer bone metastasis. It is well know n that osteonecrosis of the jaw occasionally occurs in the patients treated with nitrogen-containing bisphosphonate after tooth extraction, which is called as BRONJ. Although BRONJ is quite difficult to treat and annoys both the patients and dentists for a long time, any effective therapies for BRONJ have not been established. The target cell of BP is osteoclast. BP inhibits the mevalonic acid pathway of osteoclast to inhibit osteoclastic bone-resorbing activity. In order to recover the BP-induced inhibition of osteoclast activity, the effects of geranylgeraniol (GGOH), an intermediate of mevalonic acid pathway, on BP-induced inhibition of osteoclast activity was investigated in this study. As a result, the addition of GGOH to cultured osteoclasts restored multinucleation, TRAP expression, cell migratinability and the expression of cell fusion-promoting factor STAMP of BP-inhibited osteoclasts. This study suggests that GGOH may neutralize the adverse effects of BP in osteoclasts.