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

Abstract

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 ...

A 31‐Year‐Old Man With A Fungal Infection, Elevated Alkaline Phosphatase Level, and Polyarthritis

“…There is no recommendation for measuring the bone‐specific alkaline phosphatase level to identify at‐risk patients who may develop periostitis. There also is no reported association between periostitis and the levels of bone‐specific alkaline phosphatase in patients taking voriconazole . While serum fluoride levels may be used as surrogate markers for periostitis in symptomatic patients when a bone scan is not readily available, they are not widely available, hence delaying the diagnosis .…”

“…Animal studies have shown that fluoride exposure causes aberrant activation of osteoblasts and inhibits osteoclast‐mediated bone resorption . Voriconazole promotes osteoblastic differentiation through 2 pathways, either by increasing alkaline phosphatase or by promoting the expression of runx2, a key protein associated with osteoblast differentiation.…”

“…Voriconazole promotes osteoblastic differentiation through 2 pathways, either by increasing alkaline phosphatase or by promoting the expression of runx2, a key protein associated with osteoblast differentiation. Additionally, endothelial growth factor and platelet‐derived growth factor, which are vital in angiogenesis and osteoblast proliferation and differentiation, are up‐regulated with voriconazole exposure . However, further research is needed to clarify these pathogenic processes.…”

Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections

“…Cutaneous malignancy has not been recognized to date, and hyperfluorosis with isavuconazole is unlikely given the differences in chemical structure between voriconazole and isavuconazole and that this phenomenon does not appear to be a class-effect. 67 …”

Mimicking Multiple Myeloma: Voriconazole-Induced Hyperfluorosis and Bone Lesions

“…Bony changes resemble periostitis deformans, a condition associated with drinking excessively fluoridated water [1][2][3] . Additionally, voriconazole is believed to cause bony changes in a nonfluoride mediated pathway via osteoblast activation and stimulation of cytokine release 4 . In our patient, voriconazole was replaced with posaconazole and he experienced significant improvement within weeks of this change.…”