Effect of miglustat on bone disease in adults with type 1 Gaucher disease:: A pooled analysis of three multinational, open-label studies
Effect of miglustat on bone disease in adults with type 1 Gaucher disease:: A pooled analysis of three multinational, open-label studies
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DOI：
10.1016/j.clinthera.2007.08.006
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发表时间：
2007-08-01
影响因子：
3.2
通讯作者：
Zimran, Ari
中科院分区：
文献类型：
--
作者：
Pastores, Gregory M.;Elstein, Deborah;Zimran, Ari
背景：骨骼表现是戈谢病（GD）患者残疾的来源，也是疾病管理的重点。酶替代疗法（ERT）对GD骨病的影响可能有限，可能需要长达8年才能显现出来。麦格司他是一种葡萄糖神经酰胺合成酶抑制剂，可能对GD骨病有积极影响。目的：本分析的目的是评价麦格司他对I型GD患者骨表现和骨密度（BMD）的影响。方法：这是一项对2年观察期内从参加3项多国研究的患者中前瞻性收集的数据进行的汇总分析，评价麦格司他100 mg TID（目前获批的治疗剂量）疗效和耐受性的开放标签临床试验。定性评估骨表现，并与治疗和脾脏状态相关。通过腰椎和/或股骨颈双能X线吸收测定法评估麦格司他对BMD的影响。根据BMD Z评分从基线至第6、12和24个月的变化，骨反应定义为BMD的阳性变化。BMD的变化也进行了分析，根据脾脏状态和基线严重程度的骨质疏松症。结果：分析涉及72例，其中41例（57%）谁接受了以前的ERT和20（28%）谁经历了脾切除术。患者的平均（SD）年龄为41.2（13.1）岁。入组研究时最常见的骨相关表现为骨质疏松症（43/63 [68%]例患者）和骨痛（41165 [63%]例患者）。2年时，54/65例（83%）患者报告无骨痛。所有亚组的骨痛减轻程度相当，包括高危患者（即脾切除术患者）。未报告新的骨危象、缺血性坏死或病理性骨折病例。腰椎和股骨颈BMD Z评分在每个时间点（6、12和24个月）均较基线改善（P < 0.001）。早在麦格司他单药治疗开始后6个月，就观察到腰椎和腰椎的BMD Z评分较基线显著增加（平均值，0.15; P = 0.022）和股骨颈（0.23; P < 0.001）;在12个月内，（分别为0.19 [P = 0.012]和0.21 [P = 0.017]）和24个月（0.21 [P = 0.0151和0.18 [P = 0.039]）。脾切除患者股骨颈BMD Z评分显著增加（P < 0.001），并且在两个部位中，（腰椎：P < 0.001;股骨颈：P = 0.006）。本汇总分析了3个开放-麦格司他100 mg TID的标签研究表明，麦格司他单药治疗可降低1型GD患者的骨痛发生率并改善BMD，包括有脾切除术和/或骨质疏松症病史的患者。(Clin Tber. 2007;29：1645-1654）版权所有（c）2007 Excerpta Medica，Inc.
Background: Bone manifestations are a source of disability among patients with Gaucher disease (GD) and a focus of disease management. The effect of enzyme replacement therapy (ERT) on GD bone disease can be limited and may take up to 8 years to become manifest. Miglustat, a glucosylceramide synthase inhibitor, may have a positive influence on GD bone disease.Objectives: The aim of this analysis was to evaluate the effects of miglustat on bone manifestations and bone mineral density (BMD) in patients with type I GD.Methods: This was a pooled analysis of data collected prospectively over an observation period of 2 years from patients who participated in 3 multinational, open-label clinical trials evaluating the efficacy and tolerability of miglustat 100 mg TID (the currently approved therapeutic dose). Bone manifestations were assessed qualitatively and in relation to treatment and spleen status. The effects of miglustat on BMD were assessed by dual-energy x-ray absorptiometry at the lumbar spine and/or femoral neck. Bone response was defined as a positive change in BMD, based on the change in BMD Z-score from baseline to months 6, 12, and 24. Changes in BMD were also analyzed according to spleen status and baseline severity of osteopenia.Results: The analysis involved 72 patients, including 41 (57%) who had received previous ERT and 20 (28%) who had undergone splenectomy. Patients' mean (SD) age was 41.2 (13.1) years. The most frequent bone-related manifestations at study entry were osteoporosis (43/63 [68%] patients) and bone pain (41165 [63%] patients). At 2 years, 54/65 (83%) patients reported no bone pain. The reductions in bone pain were comparable among all subgroups, including high-risk patients (ie, splenectomized). No new cases of bone crisis, avascular necrosis, or pathologic fractures were reported. BMD Z-scores were improved from baseline at both the lumbar spine and femoral neck at each time point (months 6, 12, and 24) (P < 0.001). As early as 6 months after the initiation of miglustat mono-therapy, significant increases from baseline in the BMD Z-score were observed at both the lumbar spine (mean, 0.15; P = 0.022) and femoral neck (0.23; P < 0.001); the increases remained significant at 12 months (0.19 [P = 0.012] and 0.21 [P = 0.017], respectively) and 24 months (0.21 [P = 0.0151 and 0.18 [P = 0.039]). Significant increases in BMD Z-scores were observed at the femoral neck in splenectomized patients (P < 0.001) and at both sites in osteoporotic patients (lumbar spine: P < 0.001; femoral neck: P = 0.006).Conclusion: This pooled analysis of 3 open-label studies of miglustat 100 mg TID suggests that miglustat monotherapy may reduce the incidence of bone pain and improve BMD in patients with type 1 GD, including those with a history of splenectomy and/or osteoporosis. (Clin Tber. 2007;29:1645-1654) Copyright (c) 2007 Excerpta Medica, Inc.