Voriconazole is a fluorinated drug from the triazole group that is widely used in the prophylaxis and treatment of fungal infections in immunosuppressed patients. Chronic use of this medication can generate, as an adverse effect, a multifocal, asymmetric, diffuse and nodular periosteal reaction, associated with severe and disabling skeletal pain and elevated alkaline phosphatase and serum fluoride. Radiography is the imaging technique of choice for periostitis diagnosis. In general, clinical manifestations and radiographic findings disappear, when the drug is discontinued. We report the clinical case of a 44 year-old woman diagnosed with acute myeloid leukemia, who developed an invasive fungal infection treated with voriconazole after a stem cell transplant. Nine months after starting antifungal treatment, she manifested symptoms and radiological signs compatible with periostitis. Due to clinical suspicion, we decided to suspend voriconazole, with consequent resolution of clinical manifestations and radiological findings.
The main hypothesis that explains how voriconazole can generate or trigger this periostitis is subacute fluoride toxicity, secondary to the use of the antifungal agent. Voriconazole contains in its structure three fluorine atoms that represent 16.25% of its molecular weight. This means that a dose of 400 mg contains 65 mg of fluorine (6). In addition, 5% is metabolized into free fluorine. The risk of skeletal effects is elevated in patients with fluoride intakes greater than 6 mg/day (7). When present in large quantities, fluoride can be integrated into the extracellular matrix in the form of fluorapatite, increasing bone density and giving it more resistance to resorption, but increasing bone brittleness. Fluoroapatite may stimulate the activity of osteoblasts leading to exostosis and secondary periostitis (8).
Reference 6: Rad B, Saleem M, Grant S, et al. Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment. Ann Clin Biochem. 2015; 52: 611-4
Reference 7: Geneva WHO. WHO (2010). Preventing disease through healthy environments inadequate or excess fluoride: a major public health concern [Internet]. [cited 2020 Nov 7]. Available from:
Reference 8: Tan I, Lomasney L, Stacy GS, et al. Spectrum of voriconazole-induced periostitis with review of the differential diagnosis. Am J Roentgenol. 2019; 212: 157-65.
**Full study in pdf at http://fluoridealert.org/wp-content/uploads/fernandez-avila-2021.pdf