Plasma Fluoride Level as a Predictor of Voriconazole-Induced Periostitis in Patients With Skeletal Pain

Moon, Woo J.; Scheller, Erica L.; Suneja, Anupam; Livermore, Jacob A.; Malani, Anurag N.; Moudgal, Varsha; Kerr, Lisa; Ferguson, Eric; Vandenberg, David M.

doi:10.1093/cid/ciu513

Cited by 65 publications

(87 citation statements)

References 34 publications

(65 reference statements)

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“…While voriconazole metabolism in humans is extensive and complex (less than 2% of the administered drug is excreted unchanged), free fluoride ion is only minimally liberated (approximately 5% of the dose) by voriconazole metabolism (44). In contrast to clinical studies that repeatedly noted substantial elevations in serum fluoride concentrations in periostitis (11,(16)(17)(18), we did not observe significant elevations in fluoride ion concentrations in the culture supernatants of either voriconazole-or fluconazole-exposed osteoblasts. This is not surprising, given that osteoblasts lack the enzymes responsible for the metabolism of triazoles.…”

Section: Discussioncontrasting

confidence: 92%

“…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: 56%

“…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: 64%

“…Included in these reports are observations of elevated serum fluoride and alkaline phosphatase levels, as well as radiographic abnormalities consistent with enhanced osteoblastic activity (11,(16)(17)(18). As these findings are similar to the clinical syndrome of skeletal fluorosis in humans, a pathogenic mechanism has been suggested whereby chronic daily consumption of trifluorinated voriconazole molecules leads to excess plasma fluoride, which then promotes the development of periostitis by enhancing the activity of osteoblasts (11,13,17).…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussioncontrasting

confidence: 92%

supporting

confidence: 56%

mentioning

confidence: 64%

Section: Discussionmentioning

confidence: 94%

See 2 more Smart Citations

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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“…In most previously described cases, periostitis and exostoses predominantly developed after six or more months of voriconazole treatment, and the case series described by Moon et al 9 shows that fluoride levels reflect cumulative voriconazole dose and predict the development of periostitis. However, a case report from Becce et al 10 describes development of fluorosis and periostitis within six weeks of the introduction of voriconazole.…”

Section: Discussionmentioning

confidence: 97%

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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Severe Polyarthralgia After Kidney Transplant

Allameen

Cho

2022

JAMA

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A 51-year-old woman presented with a 1-month history of intense and worsening polyarthralgia and swelling of bilateral fingers and toes. There was no history of alopecia, oral ulcers, rashes, or Raynaud phenomenon. She did not report preceding fever, diarrhea, or dysuria. There was no history of weight loss or anorexia. Medical history included tertiary hyperparathyroidism related to end-stage kidney disease from chronic glomerulonephritis. The patient had successfully received an ABO-incompatible kidney transplant 1 year ago, but this was complicated by invasive fungal (Volvariella volvacea) infection of the central nervous system. Medications included tacrolimus (0.5 mg twice daily), prednisolone (10 mg daily), cinacalcet (12.5 mg daily), and voriconazole (500 mg daily). On examination, her fingers and toes were symmetrically and diffusely swollen and tender. There was no rash, enthesitis, psoriatic nail changes, clubbing, or lower limb edema. The rest of the physical examination was unremarkable.

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Plasma Fluoride Level as a Predictor of Voriconazole-Induced Periostitis in Patients With Skeletal Pain

Cited by 65 publications

References 34 publications

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

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

Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment

Severe Polyarthralgia After Kidney Transplant

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