title: Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model.
abstract: Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Department of Pharmacy Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jitesh D
authors.initials: JD
authors.lastname: Kawedia
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Cai
authors.affiliation: HARP Pharma Consulting, Mystic, Connecticut, United States of America.
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Mattano
authors.affiliation: Department of Pathology Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Animal Resource Center (Veterinary Services), St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Funk
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000494:pharmacology*; D003907:Dexamethasone / Q000009:adverse effects*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004926:Escherichia coli / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010020:Osteonecrosis / Q000139:chemically induced* / Q000201:enzymology*; D012307:Risk Factors
chemical_list: D003907:Dexamethasone; D001215:Asparaginase