Fluoride Excess and Periostitis in Transplant Patients Receiving Long-Term Voriconazole Therapy

Wermers, Robert A.; Cooper, Kay; Razonable, Raymund R.; Deziel, Paul J.; Whitford, Gary M.; Kremers, Walter K.; Moyer, Thomas P.

doi:10.1093/cid/ciq188

Cited by 117 publications

(167 citation statements)

References 22 publications

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“…As seen in this case, and described elsewhere, fluoride levels persist after withdrawal of voriconazole, despite symptom resolution, 3,6 which suggests that the fluoride is sequestered in, and slowly released from, the skeleton. It has been suggested that intermittent treatment with recombinant parathyroid hormone (teriparatide) to increase bone turnover might assist with removal of skeletal fluoride 11 ; however, the need for such treatment in the absence of symptoms is unclear.…”

Section: Discussionsupporting

confidence: 81%

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

et al. 2015

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We describe a case of development of painful periostitis deformans in a 39-year-old woman who was receiving long-term voriconazole treatment for Aspergillus infection as a complication of orthotopic liver transplant. Measurement of fluoride levels strongly supports fluorosis to be the mechanism of the voriconazole-induced periostitis deformans and supports the concept that such measurements might be of use in predicting this complication of long-term voriconazole treatment.

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Section: Discussionsupporting

confidence: 81%

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

et al. 2015

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“…Concerns regarding the potential toxicity of long-term triazole therapy have been raised, and recent observations have presented compelling evidence for the causal role of long-term voriconazole, a trifluorinated antifungal, as a risk factor for the development of fluoride excess and subsequent painful periostitis and exostoses in posttransplant patients (1,2,5). However, the safety and potential toxicity of fluconazole and posaconazole (difluorinated triazoles) have not been assessed, nor has hyperfluorosis been reported for nontransplant patients.…”

mentioning

confidence: 99%

Fluoride Excess in Coccidioidomycosis Patients Receiving Long-Term Antifungal Therapy: an Assessment of Currently Available Triazoles

Thompson

Bays

Cohen

et al. 2012

Antimicrob Agents Chemother

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The use of voriconazole, a trifluorinated antifungal, has been associated with the development of fluoride excess and periostitis/ exostoses. We evaluated a cohort of patients on long-term triazole therapy and found that other fluorinated triazoles (fluconazole and posaconazole) conferred no risk for the development of hyperfluorosis and its complications in our cohort. Atotal of 3 to 5% of patients with coccidioidomycosis have disseminated disease or chronic pulmonary infection requiring long-term suppressive antifungal therapy with a triazole. Concerns regarding the potential toxicity of long-term triazole therapy have been raised, and recent observations have presented compelling evidence for the causal role of long-term voriconazole, a trifluorinated antifungal, as a risk factor for the development of fluoride excess and subsequent painful periostitis and exostoses in posttransplant patients (1, 2, 5). However, the safety and potential toxicity of fluconazole and posaconazole (difluorinated triazoles) have not been assessed, nor has hyperfluorosis been reported for nontransplant patients. We have subsequently sought to determine if fluoride excess is common and if clinical sequalae consistent with hyperfluorosis are present in our cohort of chronic coccidioidomycosis patients receiving long-term antifungal therapy. This is a cohort study designed to test whether patients receiving long-term antifungal therapy (Ͼ6 months' duration) with different triazoles were at risk for hyperfluoremia and/or the clinical development of periostitis or exostoses. This study was approved by the Institutional Review Board of the University of California-Davis.Patients referred to the University of California-Davis Medical Center for chronic pulmonary, disseminated, or meningeal coccidioidomycosis as defined by existing European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria (3) who were also receiving a fluorinated triazole (fluconazole, posaconazole, or voriconazole) for greater than 6 months were included. All patient samples were collected over a 60-day enrollment period. Patients taking long-term itraconazole (a nonfluorinated triazole) were included as a control group.All patients were assessed for clinical symptoms suggestive of coccidioidal osteomyelitis or arthritis and periostitis or exostoses, and radiographic studies were obtained if suggestive symptoms were present. Demographic and laboratory data were abstracted from patient medical records, and serum fluoride levels were determined using an Accumet pH/ion meter equipped with a fluoride-specific electrode. Serum samples were buffered with TISAB prior to analysis.Analysis of variance (ANOVA) between groups with Tukey's posttest analysis was used to compare demographic characteristics, clinical factors, and laboratory values between groups. Then using the residuals from each model, Q-Q plots and ShapiroWilk's testing was performed to assess normality of the residuals.For variables found to depart significantly from normali...

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“…Fluoride is a major component of this antifungal, and is central in the pathophysiology of VIPD through stimulation of osteoblasts. 1 Classically VIPD presents with diffuse bony pain and swelling, elevated serum ALP and fluoride levels, dense periosteal reaction on radiographs, as well as multiple areas of uptake on bone scintigraphy. 2,3 Despite the aforementioned abnormalities, voriconazole troughs are often within normal limits.…”

Section: Discussionmentioning

confidence: 99%

Voriconazole-Induced Periostitis Deformans: A Mimicker of Hypertrophic Pulmonary Osteoarthropathy

Ladak¹,

Rubin²

2017

Clin Med Res

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. Calcium, vitamin D, parathyroid hormone, urate, creatinine, and inflammatory markers were normal. Serum voriconazole and beta-crosslinks (a marker of bone resorption) were normal. Given the elevated ALP, periostitis, osteophytic reactions and lack of clubbing, he was diagnosed with voriconazole-induced periostitis deformans (VIPD). Voriconazole was discontinued and symptoms and ALP improved within 3 months. DiscussionVoriconazole is a triazole antifungal used to treat invasive fungal infections which are commonly encountered in immunocompromised hosts. Fluoride is a major component of this antifungal, and is central in the pathophysiology of VIPD through stimulation of osteoblasts.1 Classically VIPD presents with diffuse bony pain and swelling, elevated serum ALP and fluoride levels, dense periosteal reaction on radiographs, as well as multiple areas of uptake on bone scintigraphy.2,3 Despite the aforementioned abnormalities, voriconazole troughs are often within normal limits. 4 It differs from hypertrophic pulmonary osteoarthropathy in its predilection for distinct areas such as the ribs, irregular and dense periosteal reactions, and lack of clubbing and joint effusions. 2,3Symptoms typically resolve soon after discontinuing voriconazole. 2,5Figure 1. Hand radiographs are notable for multifocal periosteal reaction involving the metacarpals, and proximal and middle phalanges in an asymmetrical manner. The patient is skeletally immature. Anatomic alignment and joint spaces are preserved.

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Fluoride Excess and Periostitis in Transplant Patients Receiving Long-Term Voriconazole Therapy

Abstract: Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in post-transplant patients with long-term voriconazole use.

Cited by 117 publications

References 22 publications

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

Fluoride Excess in Coccidioidomycosis Patients Receiving Long-Term Antifungal Therapy: an Assessment of Currently Available Triazoles

Voriconazole-Induced Periostitis Deformans: A Mimicker of Hypertrophic Pulmonary Osteoarthropathy

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