ABSTRACT
Intravenous bisphosphonate therapy is associated with acute phase reaction characterized by fever and musculoskeletal pain. Bisphosphonates have been shown in vitro to activate gammadeltaT-cells to proliferate and produce cytokines, suggesting a role in acute phase reaction, which can be effectively blocked by statins. We conducted a double-blind randomized crossover placebo controlled study in 12 children (12.1 +/- 4.2 yr; 10 girls and 2 boys) receiving intravenous bisphosphonates to evaluate whether statins can be used to prevent acute phase reaction associated with therapy. Children received two cycles given 3-4 mo apart of intravenous bisphosphonate given on 2 consecutive days in each cycle. Atorvastatin 10 mg or placebo was given orally once a day for 3 days, starting the day before intravenous bisphosphonate therapy and on the 2 infusion days. We measured pain using a visual analog pain scale at five time points in 0-48 h, oxycodone use for pain, acetaminophen for fever, C-reactive protein (CRP), and total and percent gammadeltaT-cells. There was a nonsignificant decrease in pain, oxycodone use, and acetaminophen use with Atorvastatin compared with placebo. There was no difference in CRP and total or percent gammadeltaT-cells between the two groups. The results remained unchanged after adjustment for Atorvastatin versus placebo given with the first cycle. We conclude that in vivo Atorvastatin may not be as effective in modulating the acute phase reaction associated with intravenous bisphosphonate as would have been anticipated from in vitro studies.
Subject(s)
Acute-Phase Reaction/drug therapy , Diphosphonates/administration & dosage , Diphosphonates/therapeutic use , Heptanoic Acids/administration & dosage , Heptanoic Acids/therapeutic use , Pyrroles/administration & dosage , Pyrroles/therapeutic use , Acetaminophen/administration & dosage , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , Atorvastatin , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/therapeutic use , C-Reactive Protein/metabolism , Child , Female , Humans , Infusions, Intravenous , Male , Oxycodone/administration & dosage , Oxycodone/therapeutic use , Pain/drug therapy , PlacebosABSTRACT
We studied if the beneficial effects of bisphosphonates are maintained after their discontinuation, and whether adverse effects may develop. Seventeen children in whom I.V. bisphosphonates were discontinued for at least 12 months were included. Fracture rate (FR), skeletal pain, bone mineral density of total body (TB) and spine L(2-4), skeletal radiographs, bone markers and kidney functions were compared between: (a) before treatment, (b) end of treatment, and (c) last follow-up. Mean treatment duration was 22+/-2 months (6-43) and follow-up 26+/-2 months (18-44). FR (mean +/- SD) decreased from 0.74+/-0.21/year before treatment to 0.35+/-0.11/year after treatment and 0.20+/-0.09/year at follow-up (p<0.05). Three children had bone pain before treatment, six during treatment and none at end of follow-up (p<0.05). TB Z-score increased from -1.24+/-0.50 at baseline to -0.37+/-0.44 at end of treatment and -0.39+/-0.37 at follow-up (p<0.05). Spinal Z-score increased from -1.65+/-0.57 to -0.34+/-0.56 and 0.19+/-0.49, respectively (p<0.05). Bone turnover markers showed sustained effect of bisphosphonates. No adverse effects on kidney functions or skeletal radiographs were noted. We conclude that I.V. bisphosphonates continue to exert their beneficial effect for a mean of 26+/-2 months after their discontinuation; therefore, once therapeutic goals are achieved, the medication can be withheld, followed by periodic re-evaluation.
