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

• 批准号: 10491365
• 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
• 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/10491365
• 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 necrosis; California; Child; Childhood; Chronic; Clinical; Clinical Investigator; Complication; Cyclophosphamide; Data; Enrollment; FDA approved; Feasibility Studies; Genotype; Goals; Head; 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; Prospective cohort; Proxy; Public Health; Quality of life; Questionnaires; Replacement Arthroplasty; Reporting; Research; Research Project Grants; Research Training; 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; cohort; disability; effective therapy; 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; skills; targeted treatment; translational study; transplantation therapy

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.

项目概要/摘要 股骨头坏死 (ONFH) 是一种严重的骨骼并发症，影响 30% 的人 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 即使在治愈性造血干细胞移植治疗后，移植后患者的症状仍然存在 由于骨骼限制，他们的生活质量较差。迫切需要探索有效的 ONFH 疗法可减轻 SCD 患者的疼痛并改善与健康相关的生活质量。阿仑膦酸钠， 一种经 FDA 批准用于治疗骨质疏松症、减轻骨痛和延迟性骨痛的口服双膦酸盐 类固醇引起的外伤性 ONFH 患者股骨头塌陷的时间。治疗潜力 使用阿仑膦酸钠缓解成人 SCD 相关 ONFH 的骨痛是一个重要的知识空白 深远的公共卫生影响。 我和我的同事最近发现，骨密度低是 SCD 的另一种常见骨骼并发症， 与患有 SCD 的儿童和青少年的 ONFH 和慢性疼痛有关。我推测该协会 由于许多 SCD，低骨密度、ONFH 和镰状细胞痛在成人中更为显着 并发症随着年龄的增长而恶化。在这次 K23 重新提交中，我计划研究患有 SCD 的成人的疼痛表型 使用经过验证的患者报告的结果测量来评估低骨密度。我也会进行单臂6- 在 24 名患有 SCD 相关 ONFH 的成人前瞻性队列中进行为期一个月的阿仑膦酸钠可行性研究。初级 终点是预定的招募率和保留率。次要终点包括初步安全性 和疗效，通过不良事件报告、药物依从性、阿片类药物的使用、疼痛评分的变化来衡量 和其他替代标记。最后，我将从一组非输血者中收集血清和尿液样本 研究对象，以更好地了解如何使用骨生物标志物来代表阿仑膦酸钠的依从性和 研究骨生物标志物浓度如何与潜在的 SCD 骨病理学相关。 将阿仑膦酸钠重新用作 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。修订后的 K23 提案将为 随后 R01 申请阿仑膦酸钠 2 期多中心、随机、安慰剂对照试验 患有 SCD 并发 ONFH 的成人。我的工作将极大地促进正在进行的临床转化 减轻 SCD 患者慢性疼痛负担的研究。研究和培训计划 我的 K23 申请中详细介绍的内容将为我提供建立职业生涯所需的关键技能 独立的临床研究者，致力于为 SCD 患者开发安全有效的疗法。