Krüger Tormod B, Herlofson Bente B, Lian Aina M, Syversen Unni, Reseland Janne E
Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Norway.
Clinical Oral Research Laboratory, Faculty of Dentistry, University of Oslo, Norway.
Bone Rep. 2021 Jan 26;14:100750. doi: 10.1016/j.bonr.2021.100750. eCollection 2021 Jun.
Due to gastrointestinal side effects of oral bisphosphonates (BPs), proton pump inhibitors (PPIs) are often prescribed. PPIs may enhance the risk of osteonecrosis of the jaw, a rare side effect of BPs. Therefore, the objective of this study was to evaluate the effects of the oral BP alendronate (ALN) and the PPI omeprazole (OME) alone and in combination on primary human osteoblasts and gingival fibroblasts in vitro.
Human gingival fibroblasts and normal human osteoblasts were incubated with either 5 μM of ALN or 1 μM of OME, or ALN + OME for 1, 3, 7 or 14 days. Effect on viability was evaluated by the lactate dehydrogenase activity in the medium and on proliferation by quantifying 3H-thymidin incorporation. Multianalyte profiling of proteins in cell culture media was performed using the Luminex 200TM system to assess the effect on selected bone markers and cytokines.
The proliferation of osteoblasts and fibroblasts was reduced upon exposure to ALN + OME. ALN induced an early, temporary rise in markers of inflammation, and OME and ALN + OME promoted a transient decline. An initial increase in IL-13 occurred after exposure to all three options, whereas ALN + OME promoted IL-8 release after 7 days. OME and ALN + OME promoted a transient reduction in vascular endothelial growth factor (VEGF) from osteoblasts, whereas ALN and ALN + OME induced a late rise in VEGF from fibroblasts. Osteoprotegerin release was enhanced by ALN and suppressed by OME and ALN + OME.
ALN + OME seemed to exaggerate the negative effects of each drug alone on human osteoblasts and gingival fibroblasts. The anti-proliferative effects, modulation of inflammation and impairment of angiogenesis, may induce unfavorable conditions in periodontal tissue facilitating development of osteonecrosis.
由于口服双膦酸盐（BP）会产生胃肠道副作用，质子泵抑制剂（PPI）常被开具处方。PPI可能会增加颌骨坏死的风险，这是BP的一种罕见副作用。因此，本研究的目的是评估口服BP阿仑膦酸盐（ALN）和PPI奥美拉唑（OME）单独及联合使用对原代人成骨细胞和牙龈成纤维细胞的体外影响。
将人牙龈成纤维细胞和正常人成骨细胞分别与5μM的ALN或1μM的OME，或ALN + OME孵育1、3、7或14天。通过培养基中的乳酸脱氢酶活性评估对细胞活力的影响，并通过定量3H-胸腺嘧啶核苷掺入评估对增殖的影响。使用Luminex 200TM系统对细胞培养基中的蛋白质进行多分析物分析，以评估对选定的骨标志物和细胞因子的影响。
暴露于ALN + OME后，成骨细胞和成纤维细胞的增殖减少。ALN诱导炎症标志物早期短暂升高，而OME和ALN + OME促进短暂下降。暴露于所有三种处理后，IL-13最初都会增加，而ALN + OME在7天后促进IL-8释放。OME和ALN + OME促进成骨细胞中血管内皮生长因子（VEGF）短暂减少，而ALN和ALN + OME诱导成纤维细胞中VEGF后期升高。ALN增强骨保护素释放，而OME和ALN + OME抑制骨保护素释放。
ALN + OME似乎会夸大每种药物单独对人成骨细胞和牙龈成纤维细胞的负面影响。抗增殖作用、炎症调节和血管生成受损，可能会在牙周组织中诱发不利条件，促进骨坏死的发展。
