Sauty A, Pecherstorfer M, Zimmer-Roth I, Fioroni P, Juillerat L, Markert M, Ludwig H, Leuenberger P, Burckhardt P, Thiebaud D
Department of Internal Medicine, University Hospital, Lausanne, Switzerland.
Bone. 1996 Feb;18(2):133-9. doi: 10.1016/8756-3282(95)00448-3.
Bisphosphonates are potent inhibitors of bone resorption and are widely used in the treatment of bone diseases. One of the side effects of administered aminobisphosphonates is transient fever and some biological changes that are suggestive of an acute phase response. Pamidronate [(3-amino-1-hydroxypropylidene).1, 1-bisphosphonate] and ibandronate [1-hydroxy-3-(methylpentylamino) propylidenebisphosphonate] incubated in heparinized whole blood at doses of 10(-4) and 10(-5) mol/L, induced the production of tumor necrosis factor alpha (TNFalpha). Moreover, pamidronate was found to slightly stimulate interleukin-6 IL-6 production. In contrast, clodronate (dichloromethylenebisphosphonate) did not increase IL-6 or TNFalpha. To investigate these phenomena in vivo, acute phase reaction was assessed in patients with malignant disease treated with 60 mg of pamidronate (n = 29), 1500 mg of clodronate (n = 8), or 0.5-2 mg of ibandronate (n = 6), all given intravenously. A significant decrease in lymphocyte and leukocyte count was observed in the pamidronate group. In the same group, seven patients (24%) showed a transient increase of body temperature above 37 degrees C with an increase > or = 0.5 degrees C at 24 h. These changes were not found in the patients treated with clodronate or ibandronate. Plasma IL-6 and TNFalpha levels increased significantly after pamidronate treatment, whereas no change was seen after clodronate infusion. The peak of IL-6 level (53.7 +/- 14.1 [SEM] pg/mL) was observed at 24 h, and that of TNFalpha level (26.9 +/- 3.4 pg/mL) at 48 h after the beginning of pamidronate administration (values before treatment, respectively: 28.6 +/- 7.1 pg/mL, p < 0.006; and 13.1 +/- 1.5 pg/mL, p = 0.0001). The peak of C-reactive protein (CRP) level was found at 48 h (41.0 +/- 7.8 vs. 25.5 +/- 5.6 mg/L before treatment, p < 0.01) and CRP levels were strongly correlated with IL-6 levels (p = 0.65,p < 0.001). Only one patient treated with ibandronate showed an increase in IL-6 and CRP levels. Patients treated with pamidronate, whose body temperatures were increased at 24 h, had a greater increases of circulating IL-6, TNFalpha, and CRP at 24 h and 48 h than patients without temperature increase. These results suggest that pamidronate treatment, but not clodronate and possibly not ibandronate at the doses used, induced an increase in the plasma levels of IL-6 and TNFalpha, which may be responsible for the acute phase reaction observed clinically.
双膦酸盐是强效的骨吸收抑制剂，广泛用于治疗骨疾病。给予氨基双膦酸盐的副作用之一是短暂发热以及一些提示急性期反应的生物学变化。帕米膦酸[(3 - 氨基 - 1 - 羟基亚丙基).1,1 - 双膦酸盐]和伊班膦酸[1 - 羟基 - 3 - (甲基戊基氨基)亚丙基双膦酸盐]以10(-4)和10(-5) mol/L的剂量在肝素化全血中孵育，可诱导肿瘤坏死因子α（TNFα）的产生。此外，发现帕米膦酸可轻微刺激白细胞介素 - 6（IL - 6）的产生。相比之下，氯膦酸（二氯亚甲基双膦酸盐）不会增加IL - 6或TNFα。为了在体内研究这些现象，对接受60 mg帕米膦酸（n = 29）、1500 mg氯膦酸（n = 8）或0.5 - 2 mg伊班膦酸（n = 6）静脉注射治疗的恶性疾病患者进行急性期反应评估。在帕米膦酸组中观察到淋巴细胞和白细胞计数显著下降。在同一组中，7名患者（24%）体温短暂升高超过37℃，在24小时时升高≥0.5℃。在接受氯膦酸或伊班膦酸治疗的患者中未发现这些变化。帕米膦酸治疗后血浆IL - 6和TNFα水平显著升高，而氯膦酸输注后未见变化。帕米膦酸给药开始后24小时观察到IL - 6水平峰值（53.7±14.1[SEM] pg/mL），48小时观察到TNFα水平峰值（26.9±3.4 pg/mL）（治疗前值分别为：28.6±7.1 pg/mL，p < 0.006；和13.1±1.5 pg/mL，p = 0.0001）。C反应蛋白（CRP）水平峰值在48小时时出现（41.0±7.8 vs.治疗前25.5±5.6 mg/L，p < 0.01），且CRP水平与IL - 6水平密切相关（p = 0.65，p < 0.001）。仅1名接受伊班膦酸治疗的患者IL - 6和CRP水平升高。在24小时体温升高的接受帕米膦酸治疗的患者，在24小时和48小时时循环IL - 6、TNFα和CRP的升高幅度大于体温未升高的患者。这些结果表明，帕米膦酸治疗（但氯膦酸以及所用剂量的伊班膦酸可能不会）会导致血浆IL - 6和TNFα水平升高，这可能是临床上观察到的急性期反应的原因。
