Frith Julie C, Rogers Michael J
Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom.
J Bone Miner Res. 2003 Feb;18(2):204-12. doi: 10.1359/jbmr.2003.18.2.204.
Nitrogen-containing bisphosphonates, such as alendronate and ibandronate, inhibit bone resorption by preventing protein prenylation in osteoclasts, whereas non-nitrogen-containing bisphosphonates, such as clodronate, are metabolized to nonhydrolyzable analogs of ATP, resulting in osteoclast apoptosis. Because these two classes of bisphosphonates have different molecular mechanisms of action, we examined in vitro whether combined treatment with clodronate and alendronate would alter antiresorptive effectiveness. Although, in cultures of rabbit osteoclasts, the antiresorptive effect of 10 microM alendronate was increased by the addition of clodronate, the effect of higher concentrations of alendronate was not altered by addition of clodronate. Furthermore, the inhibition of protein prenylation in osteoclasts caused by higher alendronate concentrations was partially prevented by cotreatment with clodronate. As in osteoclasts, the inhibition of protein prenylation in J774 cells caused by alendronate or ibandronate treatment was dose-dependently prevented by cotreatment with clodronate. Furthermore, alendronate-induced J774 apoptosis was significantly inhibited in the presence of clodronate. The presence of clodronate also decreased the short-term cellular uptake of [14C]ibandronate. These observations suggest that combined treatment with clodronate could enhance the antiresorptive effect of a low concentration of nitrogen-containing bisphosphonate, but clodronate can also antagonize some of the molecular actions and effects of higher concentrations of nitrogen-containing bisphosphonates. The exact molecular basis for the antagonistic effects between bisphosphonates remain to be determined, but could involve competition for cellular uptake by a membrane-bound transport protein.
含氮双膦酸盐，如阿仑膦酸盐和伊班膦酸盐，通过阻止破骨细胞中的蛋白质异戊二烯化来抑制骨吸收，而不含氮的双膦酸盐，如氯膦酸盐，则被代谢为ATP的不可水解类似物，导致破骨细胞凋亡。由于这两类双膦酸盐具有不同的分子作用机制，我们在体外研究了氯膦酸盐和阿仑膦酸盐联合治疗是否会改变抗吸收效果。虽然在兔破骨细胞培养物中，添加氯膦酸盐可增强10微摩尔阿仑膦酸盐的抗吸收作用，但添加氯膦酸盐不会改变更高浓度阿仑膦酸盐的作用。此外，氯膦酸盐共处理可部分阻止更高浓度阿仑膦酸盐引起的破骨细胞中蛋白质异戊二烯化的抑制。与破骨细胞一样，氯膦酸盐共处理可剂量依赖性地阻止阿仑膦酸盐或伊班膦酸盐处理引起的J774细胞中蛋白质异戊二烯化的抑制。此外，在氯膦酸盐存在下，阿仑膦酸盐诱导的J774细胞凋亡受到显著抑制。氯膦酸盐的存在还降低了[14C]伊班膦酸盐的短期细胞摄取。这些观察结果表明，氯膦酸盐联合治疗可增强低浓度含氮双膦酸盐的抗吸收作用，但氯膦酸盐也可拮抗更高浓度含氮双膦酸盐的一些分子作用和效果。双膦酸盐之间拮抗作用的确切分子基础尚待确定，但可能涉及膜结合转运蛋白对细胞摄取的竞争。
