ANTIRESORPTIVE THERAPY FOR OSTEOPENIA IN GAUCHER DISEASE

高谢病是一种常染色体隐性遗传病，其原因是葡萄糖神经酰胺和其他鞘糖脂的细胞内水解度严重降低。几乎所有的病例都是由于溶酶体葡萄糖脑苷酶(GC)缺乏的遗传性缺陷，导致含有未水解性葡萄糖神经酰胺和其他鞘糖脂的巨噬细胞在肝、脾、骨髓细胞和其他单核/巨噬细胞来源的细胞中大量积聚。大多数GC缺乏症患者使用注射形式的人GC进行治疗。这种疗法显著减少了肝和脾的储存，但与骨有关的体征和症状，包括骨痛和骨量减少，只有在多年的治疗后才会出现，否则就会出现顽固的症状。然而，许多临床试验和最近由NIDDK赞助的技术评估会议已经认识到，成功治疗高谢病的慢性衰弱骨骼并发症将需要替代方案和/或辅助干预。该项目的目的是确定在接受酶治疗的高谢病患者中，是否可以通过抗吸收辅助治疗来纠正大多数成人高谢病患者中出现的骨量减少。为此，我们将对高谢病患者进行一项为期3年的双盲双臂对照试验，每天40毫克，在进入研究之前至少接受过酶疗法治疗的成年人。来自两个主要的Gaucher治疗中心的82名这样的患者将被随机分成两组，这两组将接受阿伦磷酸钠或安慰剂的酶疗法(8-60U/kg/q 2周)，为期24个月。治疗结果将通过在进入研究时测量腰椎骨密度和对疾病严重程度的骨骼X光进行评分来监测，并每隔6个月监测一次，直到研究结束。这些研究的成功结果可能导致控制或逆转骨量减少的高谢病的新治疗方案，并可能导致昂贵的酶疗法的剂量减少。

Gaucher disease is an autosomal recessive disease caused by severely decreased intracellular hydrolysis of glucosylceramides and other glucosphingolipids. Nearly all cases are due to heritable deficiency of lysosomal glucocerebrosidase (GC) deficiency which causes massive accumulation of macrophages containing unhydrolyzed glucosylceramides and other glucosphingolipids in the liver, spleen, bone marrow cells and other monocyte/macrophage-derived cells. Most patients with GC deficiency are treated with injectable forms of human GC. This therapy results in remarkable decreases in storage in liver and spleen, but signs and symptoms relating to bone, including bone pain and osteopenia only occur after years of therapy for improvement or else have been refractory. However, numerous clinical trials and a recent Technology Assessment Conference sponsored by NIDDK have recognized that successful treatment of chronic debilitating skeletal complications of Gaucher disease will require alternatives and/or adjunctive intervention. The purpose of this project is to determine whether the osteopenia that is seen in most adults with Gaucher disease can be corrected by antiresorptive adjunctive therapy in patients with Gaucher disease who are receiving enzyme therapy. To do so, we will perform a 3-year, double-blind, two-arm controlled trial of alendronate, 40 mg/day on adults with Gaucher disease who have been treated at least 24 months with enzyme therapy prior to entry into the study. Eighty-two such patients from two major Gaucher Treatment Centers will be randomized into two groups, which will receive enzyme therapy (8-60 U/kg/q 2 weeks) with alendronate or with placebo for 24 months. Therapeutic outcome will be monitored by measurement of bone density at the lumbar spine and scoring of skeletal x-rays for disease severity at the time of entry into the study, and at 6-month intervals until the end of the study. The successful outcome of these studies may lead to new therapeutic regimens for Gaucher disease that control or reverse osteopenia, and may lead to reduction of dosage in costly enzyme therapy.