Voriconazole-induced periostitis is similar to fluorosis and is most likely due to the high fluoride content in the drug. The side-effect is related to the dose and duration of treatment and resolves rapidly after drug cessation 1.
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Epidemiology
Voriconazole-induced periostitis primarily occurs in the immunocompromised and transplant patient populations, particularly in lung transplant patients due the high incidence of invasive aspergillosis and consequent long-term voriconazole prophylaxis and treatment.
In immunocompetent hosts, high-dose voriconazole is used to treat intracranial fungal disease 1.
Voriconazole dose is adjusted to maintain satisfactory trough levels. Patients with CYP2C19 genetic polymorphism metabolize the drug more rapidly and require higher doses.
Clinical presentation
The effects on bone are related to dose and duration of treatment, usually months but sometimes as little as 6 weeks. Clinical features include:
diffuse bone pain 1
dental fluorosis: whitish specks and discolouration 2
high serum total ALP and bone ALP levels and high plasma fluoride concentration 3,4
Pathology
Voriconazole is a broad-spectrum triazole antifungal medication. Triazole antifungal agents contain varying amounts of fluorine. Voriconazole contains three fluorine atoms, and a 400 mg dose of voriconazole contains a substantial 65 mg of fluoride 5. In comparison, the fluoride content of the municipal tap water is 1 mg per liter 6; thus, daily fluoride consumption from municipal tap water has been estimated at 2-4 mg per day 6.
Absorbed excess fluoride is incorporated into the crystal structure of bony matrix called hydroxyapatite, forming fluorapatite 7. Unlike normal calcium hydroxyapatite, high fluorapatite deposit causes disorganized osteoblastic reaction, resulting in periosteal thickening or ossification, exostosis, osteosclerosis and decreased bone strength similar to skeletal fluorosis 2.
Common locations include the shoulder girdle, pelvis, limbs, ribs and teeth 1.
Radiographic features
Voriconazole-induced periostitis has been described as having a variable appearance of periosteal reaction including a fluffy, feathery, nodular or irregular morphology on imaging with an asymmetric distribution 8.
The mainstay of imaging includes x-ray, CT and isotope bone scan. Advanced imaging modalities such as MRI and PET can be utilized if the diagnosis remains elusive, however, are not recommended as first-line 9.
Plain radiograph
periosteal reaction with elevation and thickening 1
Nuclear medicine
technetium-99m bone scan demonstrates high radiotracer uptake due to increased osteoblastic activity 1
Treatment and prognosis
Discontinuation of voriconazole usually results in rapid resolution of symptoms. Itraconazole (which does not contain fluoride) may be substituted. No known mortality has been associated with voriconazole-induced periostitis 1.
Differential diagnosis
General imaging differential considerations include ref:
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