Is Zoledronate Toxic to Human Periodontal Fibroblasts?

Abstract

Exposed necrotic alveolar bone is a hallmark of bisphosphonate-related osteonecrosis of the jaw. However, it is unknown whether zoledronate causes soft-tissue damage via adverse actions toward periodontal fibroblasts. We therefore examined whether zoledronate causes a cytotoxic response in fibroblasts isolated from the gingiva and the periodontal ligament. We report that micromolar concentrations of zoledronate and serum-free conditions decreased cell activity, as measured by assays for formazan formation, proliferation, and protein synthesis. Under these conditions, periodontal fibroblasts underwent apoptosis and necrosis, as indicated by cleavage of PARP and membrane disruption, respectively. However, these adverse effects of zoledronate were mitigated by the presence of serum. Moreover, zoledronate bound to calcium phosphate failed to reduce cell activity. Analysis of these data suggests that the cytotoxic responses of periodontal fibroblasts require high concentrations of zoledronate and depend on the in vitro experimental conditions. Whether these findings translate into soft-tissue damage will require further investigation.

Effects of low-level laser therapy on the proliferation and apoptosis of gingival fibroblasts treated with zoledronic acid

“…Therefore, one may speculate that the irreversible cell damage caused by ZA on the cultured fibroblasts may interfere negatively with tissue repair processes in vivo, as described in previous studies. 1,29 It appears that the intense toxic effect caused by ZA induced rapid fibroblast apoptosis, such that subsequent laser irradiation of ZA-treated cells at specific parameter levels had no positive effects, since the apoptotic process is considered an irreversible pathway. 30 In this study, we demonstrated that LLLT can biostimulate cultured gingival fibroblasts, leading to increased cell proliferation.…”

PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells

“…Most of the studies about BRONJ are focused on bone tissue [9,10]. However, oral soft tissue is extremely important, as its rupture and breakdown is necessary for the progression of this disease.…”

AnIn VitroAssessment of Fibroblast and Osteoblast Response to Alendronate-Modified Titanium and the Potential for Decreasing Fibrous Encapsulation

“…[16][17][18] In addition to the effects of BPs on osteoclasts and osteoblasts, recent studies indicated that BPs, especially the highly potent nitrogen-containing BPs, can inhibit fibroblast proliferation and increase their apoptosis. [19][20][21][22] Thus, treatment with BPs may help to reduce fibrous encapsulation and enhance implant osseointegration. However, since a number of recent studies have shown that systematic administration of BPs especially by intravenous injection may be associated with a severe bone disease, osteonecrosis of the jaws (ONJ), [23][24][25] development of strategies for local BP administration may be necessary to prevent this adverse effect.…”

“…S3). Earlier, in vitro studies indicated that the effective concentration of soluble BPs to induce significant apoptosis and suppress fibroblast proliferation is in the range of 10-100 mM, 20,22,38 but the relevant data for immobilized BPs are not available. Our results show that with a surface density of loaded alendronate of only 0.14 -0.08 mmol/cm 2 (0.046 -0.03 mg/cm 2 ) (i.e., Ti-CaPAlen0.5 substrate), a significant decrease in fibroblast proliferation was attained.…”