AN IN-VITRO AND IN-VIVO STUDY OF CYTOKINES IN THE ACUTE-PHASE RESPONSE ASSOCIATED WITH BISPHOSPHONATES

We studied the acute phase response, including specific cytokine produ ction, [interleukin-l (IL-1), interleukin-6 (IL-6), tumor necrosis fac tor alpha(TNF alpha)] following a single dose of Aredia (disodium pami dronate) in patients with increased bone turnover and, in vitro, the r ole played by specific cytokines in the acute-phase reaction which may follow the administration of aminobisphosphonates. An in vivo explora tory study was done on 24 in-and outpatients with increased bone turno ver given a single intravenous dose of pamidronate 60 mg. Measurements were taken at baseline and at 24, 48, and 72 hours. The main outcome measures were changes from baseline in serum IL-l, IL-6, and TNF alpha . In addition, C-reactive protein (CRP), white blood cell count (WCC), lymphocyte count, and elastase concentration were measured. Symptomat ic evaluation was made of fever, bone pain, and rigors. In vitro, whol e blood from eight healthy volunteers was exposed to various concentra tions of the three bisphosphonates-pamidronate, clodronate, and zoledr onate. Measurements were taken immediately before and at 3, 6, and 10 hours after exposure to drugs. The main outcome measures were changes in serum IL-1, IL-6, and TNF alpha. In vivo, there was a statistically significant (P < 0.001) increase in median values of TNF alpha in all post-baseline measurements. Median values for IL-6 also showed a sign ificant (P < 0.001) increase at 24 hours after dosing. There were no s tatistically significant changes in median IL-1 values. Few patients s howed any change from baseline in total WCC or in lymphocyte count, bu t 62.5% of patients with normal range baseline values for CRP increase d to above normal levels after treatment. Fourteen patients experience d fever; 2 reported rigors. There was no correlation between fever and changes in cytokines. There were no serious adverse experiences or pr emature discontinuations due to poor tolerability, and 91% of the pati ents expressed willingness to receive pamidronate again. In vitro, an increase in TNF alpha and a mild increase in IL-6 was seen with all bi sphosphonates, with the greatest effects seen with the highest concent ration of both pamidronate and zoledronate. No changes were observed i n IL-1 with any agent. Significant changes in both TNF alpha and IL-6 were observed within 3 days of a single dose of pamidronate in patient s treated for the first time confirming previous findings. However, th e lack of change in IL-1 in vivo and in vitro does not support the hyp othesis that this cytokine plays a major role in the acute phase react ion. The cellular mechanism of the interaction among aminobisphosphona tes, Il-6, and TNF alpha requires further investigations. The results of the in vitro study are consistent with the in vivo findings.