Abstract

Excerpt:

1. Introduction

Voriconazole is a frequently used antifungal in the post-transplant setting and has been associated with periostitis with long-term use.^{( 1 )} The true prevalence of voriconazole-associated periostitis (VAP) is unknown; however, retrospective studies suggest this adverse effect may occur in up to 15% of patients on voriconazole.^{( 1 , 2 , 3 )} Risk factors for developing VAP are poorly understood, and treatment options are limited. VAP shares common clinical features with subacute fluoride intoxication, including generalized bone pain, raised alkaline phosphatase (ALP), diffuse periostitis/exostoses on X-ray, and multifocal uptake on radionuclide bone scintigraphy.^{( 2 , 4 , 5 , 6 , 7 )}

Each voriconazole molecule contains three fluorine atoms and 5% of the dose is metabolized to free fluoride.^{( 5 )} Demonstration of elevated plasma fluoride concentration is essential when diagnosing VAP.^{( 2 )} Fluoride ions have a similar size and electrical charge as hydroxide ions but greater affinity for calcium, resulting in fluorapatite replacing hydroxyapatite in the bone matrix, stimulating excess bone formation.^{( 8 , 9 )} Voriconazole may also directly induce fluoride-independent osteoblast proliferation.^{( 10 )} No association between serum voriconazole concentration and plasma fluoride level has been observed.^{( 1 )}

Discontinuation of voriconazole rapidly normalizes plasma fluoride concentration and resolves clinical and radiological features;^{( 2 , 5 , 6 )} however, cessation is not always feasible. Regardless of treatment course, factors underlying individual susceptibility to this seemingly unpredictable and severe adverse drug effect are poorly understood. Herein, we report two cases with unique insights into VAP pathophysiology and management.

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