0 Fig. 3 Change from baseline in serum levels of a IL-6, b TNF-alpha, c IFN-gamma, and d hs-CRP following IV zoledronic acid infusion in a subset of 96 patients receiving treatment with placebo (plac), acetaminophen (acet), or fluvastatin (fluv). Measurements were taken at baseline and at 24 and 72 h post-infusion. hs-CRP highly sensitive C-reactive protein, IFN interferon, IL interleukin, TNF tumor necrosis factor Inflammatory biomarker changes were weakly correlated with changes
in body temperature and VAS scores. IL-6, IFN-gamma, and hs-CRP levels were generally higher in patients with a major increase in symptom severity (with the exception of severe headaches). However, some asymptomatic patients also experienced biomarker elevations. The use of acetaminophen appeared to attenuate increases in IL-6 and IFN-gamma levels at 24 h in this treatment group compared with those reported for the placebo and fluvastatin learn more groups (Fig. 3a, c). Safety In safety evaluations, post-dose symptoms were not counted as AEs, since they were collected in patient diaries as secondary outcomes. The most common Vemurafenib clinical trial AEs were musculoskeletal and connective tissue disorders, general disorders and administration site conditions, and gastrointestinal disorders. AEs occurred at comparable rates across treatment groups. There were no deaths in the study. Five (0.6%) patients reported six serious
AEs (one [hypokalemia] in the placebo group, two [syncope and pleuritic pain] in the acetaminophen group, and three [convulsion, pyrexia, and uveitis] in the fluvastatin group). Ten (1.3%) patients withdrew from the study due to AEs (three in the placebo group, three in the acetaminophen group, and four in the fluvastatin group). There were no notable differences between treatment groups in serious AEs or treatment withdrawals. No clinically significant
between-group differences were observed in laboratory values MRIP or vital signs. Discussion Transient post-dose symptoms are the most frequently reported AEs following ZOL infusions in postmenopausal women . These symptoms are believed to be caused by the accumulation of IPP as a result of FPP blockade in the mevalonate pathway, a key step in the inhibition of bone resorption by ZOL . Statins block an earlier stage of this pathway and do not lead to IPP accumulation. In vitro, pretreatment of peripheral blood mononuclear cells with a statin followed by exposure of the cells to a bisphosphonate prevents the bisphosphonate-induced release of inflammatory cytokines including TNF-alpha and IFN-gamma . In this trial, we evaluated the efficacy of acetaminophen and fluvastatin in preventing or reducing post-dose symptoms following administration of a single infusion of ZOL in bisphosphonate-naive postmenopausal women with low bone mass.