Reversible skeletal disease and high fluoride serum levels in hematologic patients receiving voriconazole

Gerber, Bernhard; Guggenberger, Roman; Fasler, David; Nair, Gayathri; Manz, Markus G.; Stüssi, Georg; Schanz, Urs

doi:10.1182/blood-2012-01-403030

Cited by 80 publications

(117 citation statements)

References 16 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: 79%

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: 79%

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

et al. 2015

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“…Given that voriconazole contains three fluorine atoms and clinical findings for voriconazole-induced periostitis are similar to those for skeletal fluorosis, a mechanism in which excess fluoride, liberated by voriconazole metabolism, enhances osteoblastic activity, producing clinical symptoms, has been proposed (11,13,14,16). Indeed, this would fit with the previously described effects of fluoride on osteoblast proliferation and differentiation.…”

supporting

confidence: 55%

“…Periostitis is characterized by multiple areas of periosteal ossification of bones in the axial and appendicular skeleton, which typically abate following discontinuation of therapy, suggesting a direct causative role for voriconazole. In patients with voriconazole-related periostitis, elevations in serum fluoride and bone alkaline phosphatase (ALP) levels have been observed (13,(16)(17)(18). These findings are similar to those for individuals with skeletal fluorosis, a pathological condition characterized by disturbances of bone homeostasis resulting from chronic fluoride intake, typically through endogenous water sources (19,20), and they suggest a role for free fluoride in the underlying pathology.…”

mentioning

confidence: 65%

“…More recently, reports that document painful periostitis among patients receiving voriconazole for prolonged periods are accumulating (11)(12)(13)(14)(15). Periostitis is characterized by multiple areas of periosteal ossification of bones in the axial and appendicular skeleton, which typically abate following discontinuation of therapy, suggesting a direct causative role for voriconazole.…”

mentioning

confidence: 99%

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Voriconazole Enhances the Osteogenic Activity of Human Osteoblasts In Vitro through a Fluoride-Independent Mechanism

Allen

Sánchez

Niece

et al. 2015

Antimicrob Agents Chemother

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b Periostitis, which is characterized by bony pain and diffuse periosteal ossification, has been increasingly reported with prolonged clinical use of voriconazole. While resolution of clinical symptoms following discontinuation of therapy suggests a causative role for voriconazole, the biological mechanisms contributing to voriconazole-induced periostitis are unknown. To elucidate potential mechanisms, we exposed human osteoblasts in vitro to voriconazole or fluconazole at 15 or 200 g/ml (reflecting systemic or local administration, respectively), under nonosteogenic or osteogenic conditions, for 1, 3, or 7 days and evaluated the effects on cell proliferation (reflected by total cellular DNA) and osteogenic differentiation (reflected by alkaline phosphatase activity, calcium accumulation, and expression of genes involved in osteogenic differentiation). Release of free fluoride, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) was also measured in cell supernatants of osteoblasts exposed to triazoles, with an ion-selective electrode (for free fluoride) and enzyme-linked immunosorbent assays (ELISAs) (for VEGF and PDGF). Voriconazole but not fluconazole significantly enhanced the proliferation and differentiation of osteoblasts. In contrast to clinical observations, no increases in free fluoride levels were detected following exposure to either voriconazole or fluconazole; however, significant increases in the expression of VEGF and PDGF by osteoblasts were observed following exposure to voriconazole. Our results demonstrate that voriconazole can induce osteoblast proliferation and enhance osteogenic activity in vitro. Importantly, and in contrast to the previously proposed mechanism of fluoride-stimulated osteogenesis, our findings suggest that voriconazole-induced periostitis may also occur through fluoride-independent mechanisms that enhance the expression of cytokines that can augment osteoblastic activity. Invasive fungal infections (IFIs) rarely occur in immunocompetent individuals but are potentially devastating in certain patient populations, including patients undergoing intensive chemotherapy or receiving autologous or allogeneic hematopoietic stem cell transplants for the treatment of hematological malignancies (1, 2). In recent years, there have been reports of cutaneous IFIs among immunocompetent individuals, with traumatic injuries, including motor vehicle accidents, natural disasters, and combat-related trauma, being cited as significant risk factors for infection with environmental molds, of which Aspergillus spp. are among the most commonly isolated (3-5). The recommended therapy for treatment of cutaneous IFIs involves extensive surgical debridement combined with empirical systemic antifungal therapy, for which fluorinated triazoles, including voriconazole, are important options for susceptible fungi. As the incidence rates of IFIs have been reported to be as high as 12% among immunocompromised patients (6) and up to 3.5% among U.S. military personnel admitted ...

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“…2,3 Risk factors for fluorosis include renal impairment, long-term use of voriconazole at therapeutic doses, slow drug metabolism and elevated fluoride levels. 2 Unlike voriconazole, other fluorinated triazoles (e.g., fluconazole and posaconazole) are not associated with periostitis.…”

mentioning

confidence: 99%

Voriconazole-induced periostitis

Glushko

Colmegna

2015

CMAJ

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Reversible skeletal disease and high fluoride serum levels in hematologic patients receiving voriconazole

Cited by 80 publications

References 16 publications

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

Voriconazole Enhances the Osteogenic Activity of Human Osteoblasts In Vitro through a Fluoride-Independent Mechanism

Voriconazole-induced periostitis

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