We have shown that the bisphosphonate pamidronate (P) given to children <10d post-burn prevents resorptive bone loss and muscle protein breakdown. We have also shown in vitro that Ca modulates the inflammatory response by altering mononuclear cell chemokine production. We hypothesized that P affects muscle protein breakdown by altering cytokine or chemokine concentration directly or indirectly by lowering blood ionized (i) Ca. We retrospectively analysed biomarkers of inflammation and iCa obtained during the randomized controlled trial of P (1.5 mg/kg IV <10d post-burn) in children 218 years, all obtained in the first 100d post-admission. The relationships between each biomarker and treatment group, each biomarker and iCa were modelled as mixed ANOVA and between iCa and treatment group by mixed multiple regression, in each analysis adjusting for age at burn, body surface area burned, and time from admission, allowing for an interaction between time and group, while blocking on subject to control for repeated measures. Cytokine concentrations were log (natural base) transformed to improve approximations of normality. Time was log (base 2) transformed for better centering and interpretation. Only IL-7 was marginally different between treatment groups (P=0.048) and iCa was not. However, IL-4 was inversely correlated with iCa (P=0.049) and IL-6 and IL-7 were directly correlated with blood iCa (P=0.036 and P=0.032 respectively). IL-4 stimulates myotube differentiation from muscle satellite cells; IL-6 is associated with muscle wasting, and IL-7 may impair myotube differentiation from satellite cells. Thus in a high Ca environment such as high bone resorption, the resulting biomarker pattern is consistent with muscle wasting and failure to differentiate. Pamidronate may act in conjunction with known up-regulation of the parathyroid CaSR to lower circulating iCa and reverse these effects.
14 May 2016 - 17 May 2016