Fenofibrate reduces osteonecrosis without affecting antileukemic efficacy in dexamethasone-treated mice

Abstract

Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (>1000 mg/dL) during therapy is associated with an increased frequency of symptomatic osteonecrosis. Interventions to lower triglycerides have been considered, but there have been no preclinical studies investigating the impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone-induced osteonecrosis to determine whether fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic efficacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced by fenofibrate throughout the period of treatment, with the most pronounced, 4.5-fold, decrease at week 3 (P<1x10-6). Both frequency (33% vs. 74%, P=0.006) and severity (median necrosis score of 0 vs. 75; P=6x10-5) of osteonecrosis were reduced with fenofibrate. Fenofibrate had no impact on BCR-ABL+ ALL survival (P=0.65) nor on the antileukemic properties of dexamethasone (P=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexamethasone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials.