Oral and Maxillofacial Surgery, University Medical Centre of the Johannes Gutenberg University Mainz, Augustusplatz 2, Mainz, Germany.
J Craniomaxillofac Surg. 2011 Dec;39(8):562-9. doi: 10.1016/j.jcms.2010.10.007. Epub 2010 Oct 28.
Bisphosphonates are widely used in the clinical treatment of bone diseases with increased bone resorption. In terms of side effects, they are known to be associated with osteonecrosis of the jaw (BONJ). There are two groups of bisphosphonates: the nitrogen-containing bisphosphonates, e.g. zoledronate and ibandronate, and the non-nitrogen-containing bisphosphonates, e.g. clodronate. Their impact on bone metabolism seems to differ. The objective of this study was to compare the osteogenic differentiation potency of these two pharmacologic groups. Human osteoblasts were stimulated with zoledronate and ibandronate at concentrations of 5×10(-5) M, 5×10(-6) M and 5×10(-7) M over the experimental periods of 1, 2, 5, 10 and 14 days. Clodronate was applied with concentrations of 5×10(-3), 5×10(-5) M and 5×10(-6) M. At each time point, the cells were dissolved, the mRNA extracted, and the gene expression level of the osteoblast specific differentiation markers of the homeobox transcription factors MSX1 and MSX2, the distal-less homeobox 5 (Dlx5), the Runt-related transcription factor 2 (Runx2/CBF1a) and osteocalcin (OCN) were quantified by Real-Time PCR. The gene expression was compared to an unstimulated osteoblast cell culture as control. The results showed a significant difference between the nitrogen-containing and the non-nitrogen-containing bisphosphonates. Zoledronate and ibandronate at concentrations of 5×10(-5) M enhanced the gene expression of all differentiation markers by several hundred folds compared to unstimulated control after 10 days, whereas clodronate had less influence on gene expression, even at higher concentrations of 5×10(-3) M. Lower concentrations of zoledronate and ibandronate, however, led to a decreased gene expression. These data confirm the results of other studies which have shown the osteogenic stimulus on osteoblasts in a dose dependent manner. The nitrogen-containing bisphosphonates appear to enhance bone density by stimulation of osteoblast differentiation. Non-nitrogen-containing bisphosphonates seem to have less influence on osteoblast differentiation.
双膦酸盐广泛用于治疗骨质吸收增加的骨疾病。就副作用而言，已知其与下颌骨坏死（BONJ）有关。双膦酸盐有两类：含氮双膦酸盐，如唑来膦酸和伊班膦酸，和不含氮双膦酸盐，如氯膦酸。它们对骨代谢的影响似乎不同。本研究的目的是比较这两类药物的成骨分化能力。用唑来膦酸和伊班膦酸在浓度为 5×10(-5) M、5×10(-6) M 和 5×10(-7) M 刺激人成骨细胞，实验期为 1、2、5、10 和 14 天。氯膦酸的浓度为 5×10(-3) M、5×10(-5) M 和 5×10(-6) M。在每个时间点，溶解细胞，提取 mRNA，并通过实时 PCR 定量成骨细胞特异性分化标志物同源盒转录因子 MSX1 和 MSX2、远侧同源盒 5（Dlx5）、 Runt 相关转录因子 2（Runx2/CBF1a）和骨钙素（OCN）的基因表达水平。将基因表达与未刺激的成骨细胞培养物进行比较作为对照。结果表明，含氮和不含氮双膦酸盐之间存在显著差异。唑来膦酸和伊班膦酸在浓度为 5×10(-5) M 下，与未刺激的对照组相比，在 10 天后，所有分化标志物的基因表达均增强了数百倍，而氯膦酸对基因表达的影响较小，即使在浓度较高的 5×10(-3) M 下也是如此。然而，较低浓度的唑来膦酸和伊班膦酸导致基因表达降低。这些数据证实了其他研究的结果，这些研究表明双膦酸盐以剂量依赖的方式刺激成骨细胞产生成骨刺激。含氮双膦酸盐似乎通过刺激成骨细胞分化来增加骨密度。不含氮的双膦酸盐对成骨细胞分化的影响较小。
