Phase 2b Study of Denosumab to Prevent Bone Loss in Idiopathic Osteoporosis in Premenopausal Women Treated with Teriparatide

影响年轻、健康、性腺功能完整且无继发性的女性的骨质疏松症 骨丢失的原因(特发性骨质疏松症或眼压)在美国并不常见，估计患病率 基于脆性骨折或低骨矿密度(BMD)的200,000个状态。我们之前的工作定义了 绝经前眼压患者的骨骼微结构异常：皮质变薄、疏松、变少、变薄、不相连 骨小梁减少，僵硬或强度降低。没有FDA批准的针对绝经前妇女的治疗方法 有眼压，其中许多人有多发性骨折或极低的骨密度。我们现在招收了41名校长- 有眼压的绝经妇女进入FDA孤儿疾病计划资助的随机、24个月、两个地点的试验 特立帕帝治疗绝经前妇女特发性骨质疏松症的2期研究 (FD003902；Pi，Shane)。我们假设，促进骨形成的特瑞帕帝(TPTD)将在- 降低面骨密度和体积骨密度，使异常微结构恢复正常，增加骨量 绝经前眼压的强度。然而，来自早期TPTD开放标签试点研究的新数据 绝经前眼压显示与TPTD相关的BMD增加在18-24个月后开始消失 完成了。因此，我们认为FD003902参与者在完成TPTD后将需要抗吸收治疗 以保持骨密度和质量的改善。Denosumab(Prolia®)是一种完全人源性的抗肿瘤单抗 核因子受体激活剂κβ配体抑制骨质疏松症的发生和活性 碎裂，减少骨吸收，增加骨密度，降低骨折发生率。它是FDA批准的邮递员- 绝经和男性骨质疏松症。我们假设Denosumab，在完成两年的 TPTD，将维持或改善中央和腰椎的面骨密度和体积骨密度、显微结构和硬度。 绝经前眼内压患者的虹膜骨骼。我们将在一项为期24个月的研究中验证这一假设。 苏美单抗(60 mg SC，每6个月一次)。参加FD003902的41名受试者将不会提供足够的力量 进行随机试验。因此，我们建议进行一项开放标签的IIB期研究，以评估Denosumab对 骨密度、微结构和硬度，这将为设计未来的随机研究提供初步数据。 其具体目的是通过脊柱、髋部、前部的DXA来评估Denosumab对Aim 1)区域BMD的影响。 目的2)用中心QCT和有限元方法测量脊柱骨密度和骨小梁体积 分析(FEA)；目标3)总骨密度、皮质和骨小梁体积骨密度、骨小梁微结构、皮质位置 用高分辨率外周QCT(HR-pQCT)和有限元分析测定桡骨远端和胫骨的硬度和硬度； 目的4)血清甲状旁腺激素(PTH)和骨转换指标及其与去甲肾上腺素治疗效果的关系。 关于骨密度、微结构和僵硬的Sumab。通过研究治疗和改善青少年的健康 对于患有IOP的女性，这项提案解决了孤儿产品开发补助金办公室的一个关键目标- 葛兰素史克：支持针对目前尚不存在治疗方法的罕见疾病/病症的临床开发。

Osteoporosis that affects young, otherwise healthy women with intact gonadal function and no secondary cause of bone loss (idiopathic osteoporosis or IOP) is uncommon with an estimated prevalence in the United States of <200,000, based on fragility fractures or low bone mineral density (BMD). Our prior work defined abnormal skeletal microstructure in premenopausal IOP: thin, porous cortices, fewer, thinner, disconnected trabeculae, and reduced stiffness or strength. There is no FDA-approved therapy for premenopausal women with IOP, many of whom have multiple fractures or extremely low BMD. We are currently enrolling 41 premen- opausal women with IOP into a randomized, 24-month, two-site, FDA Orphan Diseases Program-funded trial “A Phase 2 Study of Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal Women” (FD003902; PI, Shane). We hypothesize that teriparatide (TPTD), which increases bone formation, will in- crease areal and volumetric BMD, restore abnormal microarchitecture towards normal, and increase bone strength in premenopausal IOP. However, emerging data from an earlier, open-label pilot study of TPTD in premenopausal IOP indicates that TPTD-associated gains in BMD begin to dissipate by 18-24 months after completion. Thus, we believe FD003902 participants will require antiresorptive therapy after completing TPTD to maintain improvements in bone density and quality. Denosumab (Prolia®) is a fully human monoclonal anti- body to receptor activator of nuclear factor-κβ ligand (RANKL) that inhibits development and activity of osteo- clasts, decreases bone resorption, increases BMD and lowers fracture rates. It is FDA-approved for postmen- opausal and male osteoporosis. We hypothesize that denosumab, initiated after completing two years of TPTD, will maintain or improve areal and volumetric BMD, microstructure and stiffness of the central and pe- ripheral skeleton in premenopausal women with IOP. We will test this hypothesis in a 24-month study of deno- sumab (60mg SC every 6 months). The 41 subjects participating in FD003902 will not provide sufficient power for a randomized trial. Thus we propose an open-label, Phase IIB study to estimate effects of denosumab on BMD, microstructure and stiffness, which will provide preliminary data to design a future randomized study. The Specific Aims are to estimate effects of denosumab on Aim 1) Areal BMD by DXA of the spine, hip, fore- arm; Aim 2) Total and trabecular volumetric BMD and stiffness of the spine by central QCT and finite element analysis (FEA); Aim 3) Total, cortical and trabecular volumetric BMD, trabecular microarchitecture, cortical po- rosity and stiffness of the distal radius and tibia by high resolution peripheral QCT (HR-pQCT) and FEA; and Aim 4) Serum PTH and bone turnover markers and associations between these variables and effects of deno- sumab on BMD, microarchitecture and stiffness. By investigating therapy for and improving the health of young women with IOP, this proposal addresses a key goal of the Office of Orphan Product Development grant pro- gram: to support clinical development of products for rare diseases/conditions where no current therapy exists.