Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate

Bisphosphonates suppress bone resorption and are used in the management of bone diseases with increasing frequency. In some patients treated for the first time with potent nitrogen-containing bisphosphonates, there is a transient febrile reaction and transient hematological changes suggestive of an acute phase response. Because IL-6 is considered to be an important mediator of the acute phase response, we examined the changes in circulating IL-6 bioactivity in 38 patients with Paget's disease treated with the nitrogen-containing bisphosphonate (3-dimethyl- amino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). 16 patients who had never received such bisphosphonate were treated with oral dimethyl-APD (100–400 mg/day) and 22 (9 for the first time) with intravenous dimethyl-APD 4 mg/day. Treatment was given for 10 days. Eleven of 38 patients, all first treatments, showed an increase in body temperature of more than 0.5°C exceeding 37°C associated with a significant decrease in lymphocyte count and an increase in serum CRP values. These changes were transient and did not occur in the patients with no febrile response. In patients with a febrile reaction circulating IL-6 bioactivity increased significantly and this increase generally preceeded the rise in temperature. Moreover, patients with an acute phase response had significantly higher peak IL-6 values than those without (128 ± 30 vs. 31 ± 4 U/ml, p < 0.001). The peaks in plasma IL-6 were further correlated with the peaks in temperature and in serum CRP values (r = 0.49, p < 0.05). In vitro, low concentrations of dimethyl-APD, but not of clodronate, stimulated IL-6 release from fetal mouse bone explants and this release was markedly enhanced after treatment of the bones with dimethyl-APD followed by PTH. There was also a significant correlation between basal plasma PTH concentrations and IL-6 peaks (r = 0.60, p < 0.005) in the patients that improved further when only results from patients with first time exposure to dimethyl-APD were analyzed (r = 0.88, p < 0.002). In conclusion, an acute phase response occurred only in patients treated for the first time with the nitrogen-containing bisphosphonate dimethyl-APD and IL-6 plays a role in this response. The cellular basis of the interaction between bisphosphonates and IL-6 at the bone-bone marrow interface remains to be elucidated.