INTERLEUKIN-6 AND THE ACUTE-PHASE RESPONSE DURING TREATMENT OF PATIENTS WITH PAGETS-DISEASE WITH THE NITROGEN-CONTAINING BISPHOSPHONATE DIMETHYLAMINOHYDROXYPROPYLIDENE BISPHOSPHONATE

Bisphosphonates suppress bone resorption and are used in the managemen t of bone diseases with increasing frequency. In some patients treated for the first time with potent nitrogen-containing bisphosphonates, t here is a transient febrile reaction and transient hematological chang es suggestive of an acute phase response. Because IL-6 is considered t o be an important mediator of the acute phase response, we examined th e changes in circulating IL-6 bioactivity in 38 patients with Pagers d isease treated with the nitrogen-containing bisphosphonate hyl-amino-1 -hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). 16 patients wh o had never received such bisphosphonate were treated with oral dimeth yl-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 degrees C exceeding 37 degrees C associated with a s ignificant decrease in lymphocyte count and an increase in serum CRP v alues. These changes were transient and did not occur in the patients with no febrile response. In patients with a febrile reaction circulat ing IL-6 bioactivity increased significantly and this increase general ly preceeded the rise in temperature. Moreover, patients with an acute phase response had significantly higher peak IL-6 values than those w ithout (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 seru m CRP values (r = 0.49, p < 0.05). In vitro, low concentrations of dim ethyl-APD, but not of clodronate, stimulated IL-6 release from fetal m ouse bone explants and this release was markedly enhanced after treatm ent of the bones with dimethyl-APD followed by PTH. There was also a s ignificant correlation between basal plasma PTH concentrations and IL- 6 peaks (r = 0.60, p < 0.005) in the patients that improved further wh en only results from patients with first time exposure to dimethyl-APD were analyzed (r = 0.88, p < 0.002). In conclusion, an acute phase re sponse occurred only in patients treated for the first time with the n itrogen-containing bisphosphonate dimethyl-APD and IL-6 plays a role i n this response. The cellular basis of the interaction between bisphos phonates and IL-6 at the bone-bone marrow interface remains to be eluc idated.