Bullock George, Miller Cheryl, McKechnie Alasdair, Hearnden Vanessa
Department of Materials Science and Engineering, The University of Sheffield, Sheffield S3 7HQ, UK.
School of Clinical Dentistry, The University of Sheffield, Sheffield S10 2TA, UK.
Materials (Basel). 2020 May 1;13(9):2086. doi: 10.3390/ma13092086.
Medication-related osteonecrosis of the jaw (MRONJ) is a side effect of bisphosphonate therapy, characterised by exposed necrotic bone. The soft tissues of the oral mucosa no longer provide a protective barrier and MRONJ patients experience pain, infections and difficulties eating. We hypothesised that hydroxyapatite (Ca(PO)(OH)) could reduce bisphosphonate concentrations and protect the oral mucosa by exploiting bisphosphonate's calcium binding affinity. The effect of zoledronic acid (ZA) and pamidronic acid (PA) on the metabolism of oral fibroblasts, oral keratinocytes and three-dimensional oral mucosa models was investigated and then repeated in the presence of hydroxyapatite granules. Without hydroxyapatite, ZA and PA significantly reduced the metabolic activity of oral cells in a dose-dependent manner. Both drugs reduced epithelial thickness and 30 µM ZA resulted in loss of the epithelium. Hydroxyapatite granules had a protective effect on oral cells, with metabolic activity retained. Oral mucosa models retained their multi-layered epithelium when treated with ZA in the presence of hydroxyapatite granules and metabolic activity was comparable to controls. These results demonstrate hydroxyapatite granules protected oral soft tissues from damage caused by bisphosphonate exposure. Porous hydroxyapatite granules are currently used for socket preservation and this data suggests their potential to prevent MRONJ in at-risk patients.
药物相关性颌骨坏死（MRONJ）是双膦酸盐治疗的一种副作用，其特征为暴露的坏死骨。口腔黏膜的软组织不再提供保护屏障，MRONJ患者会经历疼痛、感染和进食困难。我们假设羟基磷灰石（Ca(PO)(OH)）可以通过利用双膦酸盐的钙结合亲和力来降低双膦酸盐浓度并保护口腔黏膜。研究了唑来膦酸（ZA）和帕米膦酸（PA）对口腔成纤维细胞、口腔角质形成细胞和三维口腔黏膜模型代谢的影响，然后在存在羟基磷灰石颗粒的情况下重复进行。在没有羟基磷灰石的情况下，ZA和PA以剂量依赖的方式显著降低口腔细胞的代谢活性。两种药物均降低上皮厚度，30 µM ZA导致上皮丧失。羟基磷灰石颗粒对口腔细胞具有保护作用，代谢活性得以保留。在存在羟基磷灰石颗粒的情况下用ZA处理时，口腔黏膜模型保留了其多层上皮，且代谢活性与对照组相当。这些结果表明羟基磷灰石颗粒可保护口腔软组织免受双膦酸盐暴露所致的损伤。多孔羟基磷灰石颗粒目前用于牙槽窝保存，该数据表明其在预防高危患者发生MRONJ方面的潜力。
