A mouse model for glucocorticoid‐induced osteonecrosis: Effect of a steroid holiday

Abstract

Glucocorticoid-induced osteonecrosis is a common and dose-limiting adverse event. The goal of this study was to establish a mouse model of glucocorticoid-induced osteonecrosis suitable for testing the effects of different treatment strategies on its frequency. Fourteen murine strains were screened using various glucocorticoids, routes of administration, and diets. Four-week-old male BALB/cJ mice were treated with oral dexamethasone for up to 12 weeks either by continuous dosing or by discontinuous dosing, with or without asparaginase. Histopathological features of the distal femurs were examined by light microscopy. Osteonecrotic lesions were characterized by empty lacunae and osteocyte ghosts in trabecular bone surrounded by necrotic marrow and edema. The incidence of dexamethasone induced osteonecrosis in BALB/cJ mice was 40-45% (4/10 or 5/11) at 12 weeks. The frequency of osteonecrosis trended lower after discontinuous compared to continuous dosing for 12 weeks (8 vs. 45%) (p ¼ 0.06) despite comparable cumulative plasma exposure. Asparaginase hastened the occurrence of osteonecrosis, which was observed as early as 4 weeks and the incidence was 50% after 6 weeks. A mouse model of glucocorticoid-induced osteonecrosis was established. Discontinuous was less osteonecrotic than continuous dexamethasone treatment, consistent with the possible benefits of a ''steroid holiday'' seen in clinical settings. Moreover, asparaginase hastened osteonecrosis, indicating that drugs may interact with glucocorticoids to affect osteonecrosis risk. ß

Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia

“…Because hypoalbuminemia, a marker of asparaginase treatment, is associated with greater plasma exposure to dexamethasone, 25 we hypothesize that asparaginase treatment may potentiate glucocorticoidinduced osteonecrosis 24 and be reflected by lower serum albumin. Indeed, we report here, for the first time, that lower serum albumin was also associated with symptomatic osteonecrosis risk (Figures 3A, 6; supplemental Table 3).…”

“…Serum cortisol was determined by high-performance liquid chromatography (supplemental data). 24 High-and low-density lipoproteins, cholesterol, and triglycerides were determined using a colorimetric enzymatic assay on the Cobas Integra system (Roche Diagnostics). For dexamethasone pharmacokinetic analysis, blood was drawn before and after the morning dexamethasone doses on days 1 and 8 of reinduction I (corresponding to weeks 7 and 8 of continuation treatment), 25 and pharmacokinetic parameters were estimated for 365 patients, 214 of whom have been previously described.…”

Development of a Mouse Model of Ischemic Osteonecrosis

“…The need to cauterize all four vessels to obtain total epiphyseal osteonecrosis in this model is not surprising given that the knee region is well vascularized and has collateral circulation which can compensate for one or more vessel disruptions. In terms of a mouse model of osteonecrosis, we are aware of only one other model-a mouse model of glucocorticoid-induced osteonecrosis reported by Yang et al [47]. The pathogenesis of glucocorticoid-induced osteonecrosis is very different from that of ischemic osteonecrosis, such that the two models have different implications and utility in terms of investigating the pathophysiology of two distinct etiologies of osteonecrosis.…”

“…These models can be categorized broadly as traumatic and nontraumatic osteonecrosis [2,3,11], such as corticosteroid [17,19,46,47], lipopolysaccharide [16], alcohol [45], cryogen [20,40], and immune reaction-induced models of osteonecrosis [32,36]. The site of osteonecrosis in these models, however, is limited to the femoral head except in corticosteroid-induced models which tend to develop multifocal lesions.…”

Osteonecrosis of the femoral head: An update in year 2012

“…Cryogenic and thermal insults have been used to induce osteonecrosis in quadrupeds such as canines [60] and bipeds such as emus [61] . Intramuscular injection of methylprednisolone has been used to develop steroid-induced osteonecrosis in mouse [62] , rat [63] , rabbit [64,65] , pig [66] , and chicken models [18] , where the percent incidence of induced osteonecrosis is dependent on the amount of methylprednisolone injected. These animal models have been used to study the molecular mechanisms of osteonecrosis and assess the usefulness of several therapies over the last few decades.…”