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 μg/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.