Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long‐term voriconazole

Abstract

Azole therapy is widely utilized in hematopoietic stem cell transplant (HCT) recipients for the treatment of aspergillus. Complications of voriconazole treatment related to its elevated fluoride content have been described in adults, including reports of symptomatic skeletal fluorosis. We review fluoride levels, clinical, and laboratory data in five pediatric HCT recipients on long-term voriconazole therapy, all found to have elevated serum fluoride levels. Two patients had toxic fluoride levels, one infant had symptoms of significant pain with movement and radiographs confirmed skeletal fluorosis. Monitoring fluoride levels in children, especially with skeletal symptoms, should be considered in patients on long-term voriconazole.

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

“…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.…”

“…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.…”

“…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). Although this is consistent with the known clinical and cellular effects of fluoride (19,20,31,32,40), this hypothesis has not been directly evaluated for voriconazole-associated periostitis.…”

Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports

“…Assuming 96% bioavailability, standard voriconazole dosing can deliver more than ten times that amount [22]. Fluoride is thought to induce new bone formation by stimulating osteoblasts [7] and/or cause inflammation of the periosteum [14]. However, this raises the question as to why all patients with fluoride excess do not develop periostitis.…”

Denouement

“…[1][2][3][4][5][6] Most reported cases are in patients with malignancies or a history of transplant. It has not previously been reported in a patient with CGD.…”