Abstract
Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 μg/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.
Highlights
Bisphosphonates (BPs) that inhibit bone resorption are frequently used to treat osteoporosis, skeletal-related events, multiple myeloma, Paget’s bone disease, and other conditions that result in bone fragility [1,2,3]
As measures for preventing BRONJ triggered by tooth extraction, infection prophylaxis, including complete removal of potential sources of infection, improvement of oral hygiene, antimicrobial medication before tooth extraction, and closing the extraction socket, have been recommended [5, 18, 19]
It is difficult to prevent the occurrence of BRONJ by infection prophylaxis alone, and the development of a new prophylactic measure is awaited
Summary
Bisphosphonates (BPs) that inhibit bone resorption are frequently used to treat osteoporosis, skeletal-related events, multiple myeloma, Paget’s bone disease, and other conditions that result in bone fragility [1,2,3]. The severity of BRONJ is classified into four stages on the basis of clinical and radiographic findings, and stage-specific treatment strategies have been proposed (Table 1). Once established, BRONJ is often refractory to treatment and tends to be progressive. In a cohort study characterizing BRONJ among patients receiving intravenous BPs over a median follow-up period of 1.5 years, 25%, 48%, and 27% of patients receiving stage-specific treatment improved, stayed within the same stage, and worsened, respectively [4]. Progression of BRONJ in terms of severity causes pathologic fractures, oral antral/oral nasal communication, extraoral fistulas, and so on, resulting in a marked decrease in quality of life [5], and sometimes in a fatal outcome due to sepsis [6]. No standard of treatment for BRONJ has been established; it is important to prevent the onset of BRONJ
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