Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-2794, USA.
Blood. 2011 Feb 24;117(8):2340-7; quiz 2556. doi: 10.1182/blood-2010-10-311969. Epub 2010 Dec 10.
Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10(-6), odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation.
骨坏死是急性淋巴细胞白血病治疗中一种严重的糖皮质激素诱导并发症。我们前瞻性地对髋膝关节进行磁共振成像筛查儿童（n=364），无论是否有症状；任何（1-4 级）与有症状（2-4 级）骨坏死的累积发生率分别为 71.8%和 17.6%。我们研究了年龄、种族、性别、急性淋巴细胞白血病治疗臂、体重、血脂、白蛋白和皮质醇水平、地塞米松药代动力学以及全基因组种系遗传多态性是否与有症状的骨坏死有关。年龄超过 10 岁（比值比，=4.85；95%置信区间，2.5-9.2；P=0.00001）和更强化的治疗（比值比=2.5；95%置信区间，1.2-4.9；P=0.011）是危险因素，并在所有分析中都作为协变量。较低的白蛋白（P=0.05）和升高的胆固醇（P=0.02）与有症状的骨坏死相关，严重（3 或 4 级）骨坏死与地塞米松清除不良相关（P=0.0005）。调整临床特征后，调节脂质水平和成骨细胞分化的 ACP1 基因多态性（如 rs12714403，P=1.9×10（-6），比值比=5.6；95%置信区间，2.7-11.3）与骨坏死风险以及低白蛋白和高胆固醇相关。总的来说，年龄较大、白蛋白水平较低、血脂水平较高和地塞米松暴露与骨坏死相关，并且可能与遗传基因组变异有关。
