An In Vitro and In Vivo Study of Cytokines in the Acute-Phase Response Associated with Bisphosphonates

Abstract

We studied the acute phase response, including specific cytokine production, [interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha(TNF alpha)] following a single dose of Aredia (disodium pamidronate) in patients with increased bone turnover and, in vitro, the role played by specific cytokines in the acute-phase reaction which may follow the administration of aminobisphosphonates. An in vivo exploratory study was done on 24 in- and outpatients with increased bone turnover 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-1, IL-6, and TNF alpha. In addition, C-reactive protein (CRP), white blood cell count (WCC), lymphocyte count, and elastase concentration were measured. Symptomatic evaluation was made of fever, bone pain, and rigors. In vitro, whole blood from eight healthy volunteers was exposed to various concentrations of the three bisphosphonates--pamidronate, clodronate, and zoledronate. 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 significant (P < 0.001) increase at 24 hours after dosing. There were no statistically significant changes in median IL-1 values. Few patients showed any change from baseline in total WCC or in lymphocyte count, but 62.5% of patients with normal range baseline values for CRP increased to above normal levels after treatment. Fourteen patients experienced fever; 2 reported rigors. There was no correlation between fever and changes in cytokines. There were no serious adverse experiences or premature discontinuations due to poor tolerability, and 91% of the patients expressed willingness to receive pamidronate again. In vitro, an increase in TNF alpha and a mild increase in IL-6 was seen with all bisphosphonates, with the greatest effects seen with the highest concentration of both pamidronate and zoledronate. No changes were observed in 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 patients treated for the first time confirming previous findings. However, the lack of change in IL-1 in vivo and in vitro does not support the hypothesis that this cytokine plays a major role in the acute phase reaction. The cellular mechanism of the interaction among aminobisphosphonates, IL-6, and TNF alpha requires further investigations. The results of the in vitro study are consistent with the in vivo findings.

Alendronate prevents bone loss and improves tendon‐to‐bone repair strength in a canine model

“…Nitrogen-containing bisphosphonates (such as alendronate) induce various inflammatory reactions via interleukin dependent mechanisms. [27][28][29][30] Bisphosphonate-induced inflammation exacerbates pathologic conditions such as arthritis 31 and atherosclerosis. 32 Blockage of matrix metalloproteinases improves anterior cruciate graft healing in the bone tunnels.…”

Circulating γδ T cells and the risk of acute-phase response after zoledronic acid administration

“…(1)(2)(3) The fever was noted to be associated with a fall in circulating lymphocyte number (1,4) and increases in circulating IL-6 (4) and tumor necrosis factor-alpha (TNF-a) (4)(5)(6) but not interleukin (IL)-1. (6) This is referred as the acute phase response (APR). N-BPs inhibit osteoclastic bone resorption by blocking farnesyl-pyrophosphate-synthase, an enzyme in the mevalonate pathway.…”

Calcium phosphate drug delivery system: influence of local zoledronate release on bone implant osteointegration

“…Different studies have shown the positive effect of systemic bisphosphonate treatment in protecting the peri-implant bone, either around cemented [15] or around uncemented implants [42]. However, side effects like fever [29,40], throat, or stomach ulcers [9] as well as a low bioavailability [16] are generally observed for systemic bisphosphonate treatment. In order to avoid these adverse effects and to increase the bisphosphonate bioavailability, the systemic treatment following a total hip replacement (THR) could be replaced by a local delivery with the implant selectively coated with bisphosphonate.…”