Interleukin-6 and tumor necrosis factor alpha levels after bisphosphonates treatment in vitro and in patients with malignancy

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, I-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 (TNF alpha). Moreover, pamidronate was found to slightly stimulate interleukin-6 IL-6 production, In contrast, clodronate (dichloromethylenebisphosphonate) did not increase IL-6 or TNF alpha, 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,vith an increase greater than or equal to 0.5 degrees C at 24 h, These changes were not found in the patients treated with clodronate or ibandronate, Plasma IL-6 and TNF alpha 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 TNF alpha 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 (rho = 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, TNF alpha, 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 TNF alpha, which may be responsible for the acute phase reaction observed clinically.