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Bisphosphonates that lack a nitrogen-containing side chain do not cause osteonecrosis of the jaws, regardless of their effect on STAT3 phosphorylation and SOCS3 expression

      To the Editor:
      The article by Jayne S. Reuben et al.
      • Reuben J.S.
      • Dinh L.
      • Lee J.
      • Stateson J.
      • Kamara H.
      • Xiang L.
      • Opperman L.A.
      Bisphosphonates inhibit phosphorylation of signal transducer and activator of transcription 3 and expression of suppressor of cytokine signaling 3: implications for their effects on innate immune function and osteoclastogenesis.
      hails a discovery of immunologic and pharmacologic significance that is largely irrelevant to the understanding of bisphosphonate-related osteonecrosis of the jaws. These nondentist researchers have made a very significant and novel discovery that bisphosphonates, with and without a nitrogenous side chain, are inflammatory cytokine modulators vis-à-vis the downregulation of macrophage suppressor of cytokine signaling 3 (SOCS3). They successfully induced this effect in vitro with macrophages exposed to clodronate and ibandronate. However, in speculating that this effect may have a “key role” in osteonecrosis, they fail to note that clodronate, and all non-aminobisphosphonates, do not cause osteonecrosis. Nonetheless, these researchers have discovered a novel, and perhaps “druggable,” structure-activity relationship that may function to suppress inflammatory bone resorption. For in the downregulation of this STAT3/SOCS3 pathway by a bisphosphonate moiety, there is an altered immune response characterized by reduced production of osteoclasts.
      The article infers that downregulation of osteoclastogenesis along with induction of apoptosis of osteoclasts by clodronate and ibandronate explains how these compounds induce osteonecrosis of the jaws. The underlying assumption seems to be that a decrease in osteoclasts, and therefore bone “turnover,” is the cause of this perplexing malady. This popular assumption is without merit. Furthermore, this article adds one more piece of evidence that proves that bisphosphonate-related osteonecrosis of the jaws is unrelated to a decrease in osteoclasts and bone “turnover.” Clodronate does not cause osteonecrosis of the jaws, although it does decrease osteoclastic function and population, as demonstrated in this study.
      The most important finding of this study is easily overlooked by the failure to see an error in attributing causation of osteonecrosis to clodronate. That is, this study proves once again that osteonecrosis of the jaws is not related to decreased function of osteoclasts and therefore bone “turnover.” Rather, it is more likely caused by inhibition of the mevalonate pathway by nitrogen-containing bisphosphonates that act primarily to inhibit the enzyme farnesyl pyrophosphate synthase. It was the discovery that a nitrogen substituent on the alkyl side chain, several carbons remote from the central bisphosphonate carbon, made these compounds sufficiently potent as mevalonate pathway inhibitors to avoid cytotoxic accumulation of ATP analogues in clinical practice. It was this discovery that has resulted in the “blockbuster” sales of aminobisphosphonates as drugs for the treatment of low bone mineral density and osteolytic lesions of metastatic cancer. These nitrogen-containing bisphosphonates function far differently from their nitrogen-free predecessors like clodronate, especially in the induction of osteonecrosis of the jaws.
      The finding that both ibandronate and clodronate inhibit a pathway essential to osteoclastogenesis, yet only the nitrogen-containing mevalonate pathway inhibitors are known to cause osteonecrosis of the jaws, gives further evidence that a decrease in osteoclastic bone resorption and bone “turnover” has nothing to do with the etiology of bisphosphonate-related osteonecrosis of the jaws.

      Reference

        • Reuben J.S.
        • Dinh L.
        • Lee J.
        • Stateson J.
        • Kamara H.
        • Xiang L.
        • Opperman L.A.
        Bisphosphonates inhibit phosphorylation of signal transducer and activator of transcription 3 and expression of suppressor of cytokine signaling 3: implications for their effects on innate immune function and osteoclastogenesis.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011; 111: 196-204

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