ANTIRESORPTIVE THERAPY FOR OSTEOPENIA IN GAUCHER DISEASE

戈谢病是一种常染色体隐性遗传病，由葡萄糖神经酰胺和其他鞘糖脂的细胞内水解严重减少引起。 几乎所有病例都是由于溶酶体葡萄糖脑苷脂酶（GC）缺乏症的遗传性缺乏所致，这会导致含有未水解葡萄糖神经酰胺和其他葡萄糖鞘脂的巨噬细胞在肝脏、脾脏、骨髓细胞和其他单核细胞/巨噬细胞衍生细胞中大量蓄积。 大多数患有GC缺乏症的患者用可注射形式的人GC治疗。 这种治疗导致肝脏和脾脏中的储存显著减少，但与骨相关的体征和症状，包括骨痛和骨质减少，仅在多年治疗改善后才发生，否则是难治性的。 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，戈谢病慢性衰弱性骨骼并发症的成功治疗将需要替代和/或预防性干预。 本项目的目的是确定大多数戈谢病成人中所见的骨质减少是否可以通过抗吸收治疗来纠正接受酶治疗的戈谢病患者。 为此，我们将对进入研究前已接受酶治疗至少24个月的戈谢病成人患者进行为期3年的阿仑膦酸钠40 mg/天双盲双臂对照试验。 将来自两个主要戈谢治疗中心的82名此类患者随机分为两组，分别接受阿仑膦酸钠或安慰剂酶治疗（8-60 U/kg/q 2周），持续24个月。 在进入研究时，将通过测量腰椎骨密度和骨骼X线检查对疾病严重程度进行评分，并每隔6个月进行一次，直至研究结束，以监测治疗结局。 这些研究的成功结果可能会导致新的治疗方案戈谢病，控制或逆转骨质减少，并可能导致减少剂量昂贵的酶治疗。

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.