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A feasibility study of alendronate therapy for osteonecrosis of the femoral head in adults with sickle cell disease

阿仑膦酸钠治疗成人镰状细胞病股骨头坏死的可行性研究

基本信息

批准号：
10685589
负责人：
Oyebimpe Oluyemisi Adesina
金额：
$ 18.72万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685589
关键词：
Acute Adherence Adolescent Adult Adverse event Affect Age Alendronate Analgesics Arthralgia Biological Markers Blood flow Bone Density Bone Diseases Bone Pain Bone Resorption Bone Resorption Inhibition Bone necrosis California Child Childhood Chronic Clinical Clinical Investigator Complication Cyclophosphamide Data Enrollment FDA approved Feasibility Studies Genotype Goals Headache Hematopoietic Stem Cell Transplantation Incidence Knowledge Link Measurement Measures Multicenter Studies Operative Surgical Procedures Oral Oral cavity Osteogenesis Osteoporosis Outcome Measure Pain Pain management Patient Outcomes Assessments Patients Persons Pharmaceutical Preparations Phase Phase II Clinical Trials Phenotype Physical therapy Predisposition Prospective cohort Proxy Public Health Quality of life Questionnaires Replacement Arthroplasty Reporting Research Research Project Grants Roentgen Rays Safety Serum Sickle Cell Sickle Cell Anemia Specimen Steroids Study Subject Surrogate Markers Symptoms System Testing Therapeutic Time Training Programs Translational Research Transplant Recipients Trauma Type I Procollagen Urine Vertebral column Vitamin D Work arm bisphosphonate bone bone turnover career chronic pain clinical efficacy clinical translation cohort disability effective therapy femur head health related quality of life hip surgery improved insight ischemic injury medication compliance meetings non-opioid analgesic opioid use pain relief pain score post-transplant prevent primary endpoint programs randomized placebo controlled trial recruit retention rate secondary endpoint sex side effect skeletal skill acquisition skills targeted treatment translational study transplantation therapy

项目摘要

PROJECT SUMMARY/ABSTRACT Osteonecrosis of the femoral head (ONFH) is a serious skeletal complication that affects 30% of people living with sickle cell disease (SCD). ONFH causes severe chronic pain and permanent disability. ONFH symptoms persist even after curative hematopoietic stem cell transplant therapy, with post-transplant patients reporting poorer quality of life due to their skeletal limitations. There is an urgent need to explore effective therapies for ONFH to relieve pain and improve the health-related quality of life for people with SCD. Alendronate, an oral bisphosphonate that is FDA-approved for treatment of osteoporosis, decreased bone pain and delayed the time to femoral head collapse in people with steroid-induced and traumatic ONFH. The therapeutic potential of alendronate to alleviate bone pain in adults with SCD-related ONFH is an important gap in knowledge with far-reaching public health implications. My colleagues and I recently showed that low bone density, another prevalent skeletal complication of SCD, associates with ONFH and chronic pain in children and adolescents with SCD. I speculate that the association between low bone density, ONFH and sickle cell pain will be even more significant in adults since many SCD complications worsen with age. In this K23 resubmission, I plan to study the pain phenotype of adults with SCD and low bone density using a validated patient-reported outcome measure. I will also conduct a single-arm 6- month feasibility study of alendronate in a prospective cohort of 24 adults with SCD-related ONFH. The primary endpoints are predetermined recruitment and retention rates. Secondary endpoints include preliminary safety and efficacy, as measured by adverse events reporting, medication adherence, opioid use, change in pain scores and other surrogate markers. Lastly, I will collect serum and urine specimens from a subset of non-transfused study subjects to better understand how bone biomarkers can be used a proxy for alendronate adherence and to study how bone biomarker concentrations correlate with underlying SCD bone pathobiology. Repurposing alendronate as targeted therapy for SCD-related ONFH can reduce opioid use and improve health-related quality of life for people with SCD. This revised K23 proposal will lay the groundwork for a subsequent R01 application for a Phase 2 multicenter, randomized, placebo-controlled trial of alendronate in adults with SCD complicated by ONFH. My work will significantly add to ongoing clinical-translational studies to reduce the burden of chronic pain in people living with SCD. The research and training program detailed in my K23 application will provide me with the critical skills I need to build my career as an independent, clinical investigator engaged in developing safe and effective therapies for people with SCD.

项目摘要/摘要股骨头坏死(ONFH)是一种严重的骨骼并发症，影响30%的人生活患有镰状细胞病(SCD)。ONFH会导致严重的慢性疼痛和永久性残疾。ONFH 即使在根治的造血干细胞移植治疗后，移植后患者的症状仍然存在报告说，由于骨骼的限制，他们的生活质量较差。迫切需要探索有效的方法 ONFH的治疗方法可缓解SCD患者的疼痛并提高与健康相关的生活质量。阿伦磷酸钠， FDA批准的一种口服双膦酸盐，用于治疗骨质疏松症，减少骨骼疼痛和延迟激素性和创伤性股骨头坏死患者股骨头塌陷的时间。治疗潜力阿仑磷酸钠用于缓解成人SCD相关ONFH的骨痛是一个重要的知识缺口对公共卫生的深远影响。我和我的同事最近发现，SCD的另一个普遍的骨骼并发症--低骨密度，与儿童和青少年SCD的ONFH和慢性疼痛有关。我推测这个协会在低骨密度、ONFH和镰状细胞疼痛之间，成年人将更加显著，因为许多SCD 并发症会随着年龄的增长而恶化。在K23的重新提交中，我计划研究患有SCD的成年人的疼痛表型和低骨密度，使用经过验证的患者报告的结果衡量标准。我还将进行单臂6- 阿仑磷酸钠在24例SCD相关ONFH成人前瞻性队列中的月可行性研究。初级阶段终点是预先确定的招聘率和留职率。次要终端包括初步安全性疗效，通过不良事件报告、服药依从性、阿片类药物使用、疼痛评分变化来衡量和其他代孕标记。最后，我将收集一部分未输血的患者的血清和尿液样本。研究对象以更好地了解骨生物标记物如何作为阿伦磷酸钠依从性和研究骨生物标记物浓度与SCD潜在的骨病理生物学的相关性。改用阿仑磷酸钠作为SCD相关ONFH的靶向治疗可以减少阿片类药物的使用并改善 SCD患者的健康相关生活质量。这项修订后的K23提案将为随后的R01申请阿伦磷酸钠的2期多中心、随机、安慰剂对照试验成人SCD合并ONFH。我的工作将大大增加正在进行的临床翻译旨在减轻SCD患者慢性疼痛负担的研究。研究和培训计划在我的K23申请表中的详细信息将为我提供关键技能，以建立我的职业生涯独立的临床研究人员，致力于为SCD患者开发安全有效的治疗方法。