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Sir, medication-related osteonecrosis of the jaw (MRONJ) is a well-documented complication associated with bone modulating therapy from various bisphosphonates and denosumab. In additional anti-angiogenic medication (tyrosine kinase inhibitors and new biologics including monoclonal antibodies) have also been implicated and hence the list of drugs continues to grow. Once patients are 'at risk' of MRONJ, well established risk factors for development of the complication include dental extractions, smoking, trauma, poor dental health and those who are immunocompromised and immunosuppressed. In this latter group certain medications such as corticosteroids, azathioprine, mycophenolate mofetil and methotrexate have been particularly identified.
Leflunomide (Arava) is a disease modifying anti-rheumatic drug (DMARD) that has been used in the treatment of rheumatoid and psoriatic arthritis for many years and can be given in combination with bisphosphonates and methotrexate. In vitro studies indicate that leflunomide selectively inhibits RANK-L-induced differentiation of osteoclast, which in turn directly affects bone remodelling as well as inhibiting several tyrosine kinases.1 These actions are exactly those targeted by the various implicated MRONJ drugs mentioned earlier.
Leflunomide has not been reported as a MRONJ drug. However, we wish to highlight this drug as a possible candidate to be added to the other immunosuppressants that have already been recognised to increase the risk of MRONJ when taken in conjunction with bone modulating and anti-angiogenic therapy. In our dedicated jaw necrosis clinic, 102 patients have been registered with MRONJ of which only two cases are from oral bisphosphonates. In these two cases one patient had bilateral maxillary MRONJ (alendronic acid two years, leflunomide six years) following dental extraction. In addition to this case a further two cases of methotrexate related jaw necrosis are also being managed. Methotrexate jaw necrosis is very rare and often preceded by lymphoproliferative disorder, however, in both our cases this was absent but both on long-term leflunomide.2 Of these two cases, one failed to heal post extraction while the other case had spontaneous necrosis in a dentate region.
Leflunomide is not a new drug and in the absence of literature reported cases of osteonecrosis of the jaw directly related to it as well as evidence of its impact on bone, it remains reasonable to consider it as a risk factor for MRONJ along with the other already recognised immunosuppressant when taken concomitantly with those drugs that have been implicated in jaw necrosis.
References
Urushibara M, Takayanagi H, Koga T et al. The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF-κB ligand–stimulated induction of nuclear factor of activated T cells c1. Arthritis Rheum 2004; 50: 794–804.
Henien M, Carey B, Hullah E, Sproat C, Patel V . Methotrexate-associated osteonecrosis of the jaw: A report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 124: e283–287.
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Patel, D., Patel, V. Pharmacology: MRONJ risk factor. Br Dent J 224, 198 (2018). https://doi.org/10.1038/sj.bdj.2018.132
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DOI: https://doi.org/10.1038/sj.bdj.2018.132
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