Voriconazole-induced periostitis

Voriconozole-incuded periostitis is a type of drug-induced periostitis and is a rare cause of diffuse bone pain in those on high dose or prolonged voriconozole therapy. 

Epidemiology

Voriconozole-induced periostitis primarily occurs in the immunocompromised and transplant patient populations, however it has also been described in immunocompetent hosts ¹.

Clinical presentation

Clinical presentation includes:

• diffuse bone pain ^1​
• dental fluorosis ²
  • whitish specks and discolouration
• fractures
• high serum ALP level and 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 litre ⁶; and, thus daily fluoride consumption from municipal tap water has been estimated at only 2 to 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 fluroapatite deposit causes disorganised osteoblastic reaction, resulting in periosteal thickening or ossification, exostosis, and osteosclerosis, a condition known as skeletal fluorosis ². 

Radiographic features

Voriconozole-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. 

Common locations include the clavicles, ribs, proximal long bones, scapula, hands and acetabula.

The mainstay of imaging modality include plain x-ray, CT and nuclear medicine bone scan. Advanced imaging modalities such as MRI and PET can be utilised if the diagnosis remains elusive, however is not recommended as first line ⁹.

X-ray

• 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. No known mortality has been associated with voriconazole-induced periostitis.

Differential diagnosis

General imaging differential considerations include:

• hypertrophic osteoarthropathy
• metastases
• thyroid aropachy