Voriconazole‐Associated Periostitis: New Insights into Pathophysiology and Management

Abstract

Voriconazole‐associated periostitis (VAP) is an underrecognized and unpredictable side effect of long‐term voriconazole therapy. We report two cases of VAP occurring in the post‐transplant setting: a 68‐year‐old lung transplant recipient who required ongoing voriconazole therapy, in whom urinary alkalinization was used to promote fluoride excretion and minimize voriconazole‐related skeletal toxicity, and a 68‐year‐old stem‐cell transplant recipient with a high voriconazole dose requirement, identified on pharmacogenomic testing to be a CYP2C19 ultrarapid metabolizer, the dominant enzyme in voriconazole metabolism. This is the first reported case of pharmacogenomic profiling in VAP and may explain the variability in individual susceptibility to this uncommon adverse effect. Our findings provide new insights into both the management and underlying pathophysiology of VAP. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Voriconazole-induced periostitis in a patient with HIV treated for coccidioidomycosis meningitis

“…When voriconazole is the agent of choice, these individuals can be exposed to higher cumulative doses of the drug and are at higher risk of developing periostitis. Interestingly, periostitis has only been observed with voriconazole, which has three fluoride ions compared with the difluorinated azoles, fluconazole and posaconazole 1 13. The additional fluoride ion is proposed to cause hyperfluorosis, with excess fluoride taken up by calcified tissues; this drives new periosteal bone formation.…”

“…Increased fluoride has also been shown to decrease the resorption activity of newly formed osteoclasts, causing an imbalance in bone remodelling 14 15. A study comparing fluoride levels in patients treated with different triazoles showed that mean serum fluoride levels in the voriconazole group were significantly higher than those treated with itraconazole or fluconazole but not posaconazole 13…”