Cyclic Versus Daily Teriparatide on Bone Mass, Microstructure and Strength

循环与每日特立帕肽对骨量、微观结构和强度的影响

• 批准号: 8142823
• 负责人: ROBERT LINDSAY
• 金额: $ 34.58万
• 依托单位: HELEN HAYES HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142823
• 关键词: Address; Alendronate; Biochemical; Biochemical Markers; Bone Density; Bone Formation Stimulation; Cells; Chronology; Clinical Research; Clinical Trials; Data; Defect; Dose; Dual-Energy X-Ray Absorptiometry; Evaluation; Exposure to; Forteo; Fosamax; Fracture; Funding; Hip region structure; Individual; Label; Long-Term Effects; Modeling; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Osteoblasts; Osteogenesis; Osteoporosis; Outcome; Patients; Phase; Population; Postmenopause; Protocols documentation; Radial; Recovery; Recruitment Activity; Regimen; Research Design; Resolution; Rest; Stimulus; Structure; Tachyphylaxis; Techniques; Teriparatide; Testing; Tetracyclines; Time; Vertebral column; Woman; bone; bone mass; bone strength; bone turnover; clinically relevant; cohort; high risk; interest; novel; public health relevance; response; theories; tibia; trial comparing

DESCRIPTION (provided by applicant): The introduction of 1-34rhPTH (TPTD) for treatment of individuals with osteoporosis at high risk of fracture changed the paradigm and gave clinicians an agent that has the capacity to correct the underlying architectural defect that is the hallmark of osteoporosis. Our group has a long-standing interest in the effects of TPTD on bone and have an ongoing study designed to look mechanistically at TPTD effects on bone, into which we have recruited 150 women with osteoporosis who were either treatment na¿ve or who had been previously treated with alendronate. These individuals are being followed for 2 yrs (4 three TPTD month cycles or 2 yrs daily treatment). This application is a logical extension of that ongoing study and takes advantage of this unique population of TPTD-treated patients to compare the effects of teriparatide given cyclically (8 three month cycles) over 4 years with teriparatide given daily for 2 years on BMD of the spine and hip by DXA and QCT and BMD and microstructure of the radius and tibia assessed by high resolution pQCT. The specific aims are to determine in treatment na¿ve and alendronate-treated subjects: 1. If TPTD given cyclically (3months on, 3 months off) over a 4 year period produces a clinically meaningful greater increase in BMD by DXA than 2 years of daily TPTD. 2. If QCT (hip, spine, radius and tibia), and FEA modeling of CT data, show enhanced effects of TPTD treatment or simply mirror DXA data. 3. If the tachyphylaxis seen with daily TPTD is caused by depletion of osteoblast precursors, and if it can be obviated by cyclic administration of TPTD. There is no other cohort, and nor will there be, any similar cohort in which these important and clinically relevant aims can be addressed. We believe that our population of subjects treated with TPTD allows us a unique opportunity to determine these clinically important long-term outcomes, since fracture studies with these TPTD regimens are unlikely to be undertaken. The issue of tachyphylaxis to ongoing TPTD administration, will be able to be assessed using the novel technique of an evaluation of the size of the circulating osteoblast pool in cyclic versus daily therapy. PUBLIC HEALTH RELEVANCE: In this clinical study we will determine the long-term effects of Teriparatide (Forteo or TPTD) on bone structure and strength, in a population of subjects already recruited into a 2 year clinical trial. This study will extend this unique trial by comparing the effects of 2 years of daily TPTD followed by alendronate (Fosamax) with a novel cyclic regimen in which TPTD is given for 3 month intervals followed by 3 month rest periods. The study will also compare the outcomes in women already on alendronate at the start of the protocol and continued on alendronate while being treated cyclically or continuously with TPTD. We will examine whether cyclic treatment can produce repeated stimuli to bone formation over 8 cycles and thus a greater increment in bone strength than 2 years of daily treatment where we know that the effects of TPTD generally decline. We will also test one theory for why this decline occurs, namely that the supply of the bone forming cells (osteoblasts) becomes depleted during the course of the daily regimen. We believe that the periods where no TPTD is given in the cyclic regimen will allow for ongoing recovery of the supply of osteoblasts and will ultimately results in greater gains in bone mass and strength.

描述（由申请人提供）：引入1- 34 rhPTH（TPTD）治疗骨折高危骨质疏松症患者改变了模式，并为临床医生提供了一种能够纠正骨质疏松症标志性基础结构缺陷的药物。我们小组长期以来一直对TPTD对骨骼的影响感兴趣，并且正在进行一项旨在从机制上研究TPTD对骨骼的影响的研究，我们招募了150名骨质疏松症女性，这些女性要么是未经治疗的，要么以前曾接受过阿仑膦酸钠治疗。对这些个体进行2年随访（4个3个TPTD月周期或2年每日治疗）。本申请是该正在进行的研究的逻辑延伸，并利用这一独特的TPTD治疗患者人群，比较了4年周期性给药（8个3个月周期）的特立哌酮与2年每日给药的特立哌酮对脊柱和髋关节BMD（DXA和QCT）的影响，以及对桡骨和胫骨BMD和微结构（高分辨率pQCT）的影响。具体目的是确定初治和阿仑膦酸钠治疗受试者：1.如果TPTD在4年内周期性给药（3个月给药，3个月停药），通过DXA测定的BMD增加具有临床意义，大于2年的每日TPTD。2.如果QCT（髋关节、脊柱、桡骨和胫骨）和CT数据的FEA建模显示TPTD治疗的增强效应或仅反映DXA数据。 3.如果每日TPTD观察到的快速耐受是由成骨细胞前体细胞耗竭引起的，并且如果可以通过TPTD的周期性给药来消除。没有其他队列，也不会有任何类似的队列可以解决这些重要的临床相关目标。我们认为，我们的受试者人群接受TPTD治疗，使我们有一个独特的机会，以确定这些临床上重要的长期结果，因为骨折研究与这些TPTD方案是不太可能进行的。使用评价循环与每日治疗中循环成骨细胞池大小的新技术，将能够评估持续TPTD给药的快速耐受性问题。 公共卫生相关性：在本临床研究中，我们将在已招募进入2年临床试验的受试者人群中确定特立帕鲁肽（Forteo或TPTD）对骨结构和强度的长期影响。本研究将通过比较2年每日TPTD随后阿仑膦酸钠（福善美）与一种新的周期方案（TPTD间隔3个月，随后休息3个月）的效果来扩展这一独特的试验。该研究还将比较在方案开始时已经接受阿仑膦酸钠治疗的女性和在周期性或连续性TPTD治疗期间继续接受阿仑膦酸钠治疗的女性的结局。我们将检查周期性治疗是否可以在8个周期内对骨形成产生重复刺激，从而比2年的日常治疗更大地增加骨强度，我们知道TPTD的作用通常会下降。我们还将测试为什么会发生这种下降的一个理论，即在日常生活中，骨形成细胞（成骨细胞）的供应变得枯竭。我们认为，在周期方案中不给予TPTD的时期将允许持续恢复成骨细胞的供应，并最终导致骨量和强度的更大增加。