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.

Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid‐induced osteonecrosis

“…There was no difference in body weight of mice prior to placement on treatment (Supporting Information Figure S1). Both control and LPS‐only mice gained more weight than dexamethasone‐treated mice, consistent with our prior findings dexamethasone‐treated mice weigh less than control‐treated mice in this model . Dexamethasone plus LPS mice showed a transient delay, but not decrease, in weight gain compared with dexamethasone‐only mice (Figure A).…”

“…The severity of both osteonecrosis and arteriopathy was higher in mice treated with LPS (Figure ). These findings are consistent with our prior work, showing that proximal vasculature damage (e.g., arteriopathy) is the likely preceding and possibly causative event prior to development of osteonecrosis following dexamethasone with or without concurrent asparaginase . LPS has been shown to cause apoptosis of vascular endothelial cells and inhibition of vascular repair .…”

“…Previous studies showed that osteonecrosis occurred predominately in the distal femoral epiphysis; therefore, only the knee joints were evaluated . At necropsy, both hind limbs were collected, fixed in 10% formalin, decalcified in 10% formic acid, and processed . Hind limbs were sagittally sectioned beginning at the medial aspect of the knee.…”

Ethyl acetate fraction of Huogu formula inhibits adipogenic differentiation of bone marrow stromal cells via the BMP and Wnt signaling pathways

“…Previous studies reported that steroid caused significant enlargement of the adipocyte size and fat accumulation in the bone marrow, which contributes to the onset and progress of ONFH 20, 21. To investigate the role of HGE in repairing osteocytes damage, we performed steroid-induced ONFH rat model, which resulted in a significant osteonecrosis and extensive fat accumulation in the bone marrow, and allowed the rats to be recovered under the conditions with or without HGE treatment.…”

Genetic Biomarkers to Identify the Risk of Osteonecrosis in Children with Acute Lymphoblastic Leukemia

“…In addition, female sex is mentioned as an important determinant in most studies, especially in women of pubertal age [14]. Other anticancer agents such as methotrexate, as well as the combination of both asparaginase and corticosteroids, are suggested to be associated with osteonecrosis [3,11,14]. In addition, variability in the coagulation process is an important mechanism in the pathogenesis of osteonecrosis [1,12].…”