High-dose Vitamin D Supplementation for ADT-Induced Bone Loss in Older Prostate Cancer Patients

补充高剂量维生素 D 治疗老年前列腺癌患者 ADT 引起的骨质流失

基本信息

批准号：
10374552
负责人：
Luke Joseph Peppone
金额：
$ 63.58万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2021-12-17 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374552
关键词：
Age Agonist Alcohols American Society of Clinical Oncology Biological Biological Markers Bone Density Calcium Cancer Center Cancer Patient Cancer Survivor Cholecalciferol Clinical Clinical Practice Guideline Community Clinical Oncology Program Country Data Distal Dose Double-Blind Method Dual-Energy X-Ray Absorptiometry Elderly Ensure Equilibrium Exercise Fracture GNRH1 gene High Prevalence Hip Fractures Hip region structure Hypercalcemia Incidence Intervention Intervention Trial Investigation Machine Learning Malignant Neoplasms Malignant neoplasm of prostate Measures Metastatic Prostate Cancer Morbidity - disease rate Muscle Muscular Atrophy Neck Nonmetastatic Oncologist Osteoporosis Outcome Participant Pathway interactions Patients Pharmacology Phase Pilot Projects Placebos Population Preparation Prevention Preventive treatment Prostate Cancer therapy Publishing Quality of life Radial Randomized Randomized Controlled Trials Regimen Research Safety Serum Site Skeletal Muscle Smoking Supplementation Testosterone Toxic effect Universities Vertebral column Vitamin D Vitamin D supplementation Vitamin D2 androgen deprivation therapy antagonist arm base bisphosphonate bone bone cell bone health bone loss clinical practice clinically relevant community setting cost design efficacy testing falls fracture risk high risk high risk population hip bone human old age (65+)improved men mortality muscle form muscle strength novel older patient placebo group prevent primary outcome programs response sarcopenia secondary outcome side effect

项目摘要

ABSTRACT: Use of androgen deprivation therapy (ADT), which causes near-total loss of testosterone, has increased dramatically in elderly prostate cancer patients over the last decade. ADT is associated with a significant increase in bone mineral density (BMD) loss (2-5% annually) and bone fractures, combined with a significant decrease in skeletal muscle mass (2-5% annually) compared to age-matched prostate cancer patients not on ADT and men without cancer. The loss of BMD and muscle mass results in a high prevalence of falls, reduced muscular strength, and decreased balance. Despite the high incidence of ADT-related side effects, treatment options are limited. Bisphosphonate therapy is commonly used for ADT-induced bone loss, but is associated with significant side effects and poor compliance. Vitamin D protects against BMD loss and fractures, but its effects are strongly dose-dependent. Current IOM recommended supplementation (600-800 IU/day) and serum 25-OH levels (20 ng/mL) are inadequate to protect against bone loss in a high risk population such as prostate cancer patients on ADT. In addition, RCT interventions of 400-500 IU/day of vitamin D fail to prevent ADT-induced bone loss. High- dose vitamin D supplementation (e.g., 50,000 IU/week) is a promising intervention that significantly increases 25-OH vitamin D to levels shown to improve BMD in other populations. Vitamin D has also been shown to increase muscular strength, reduce falls, and improve balance. In preparation for this R01, we conducted a Phase II randomized controlled trial (RCT) investigating the feasibility, safety, and preliminary efficacy of HDVD versus placebo for 24 weeks in 59 prostate cancer patients receiving ADT (NCI R21CA185678; PI: Peppone). Compelling evidence from our pilot study showed: 1) 50,000 IU/week of vitamin D (HDVD) was safe with no increase in toxicity versus low-dose vitamin D, 2) compliance was excellent at 94%, and 3) HDVD significantly increased 25-OH vitamin D levels. Those randomized to HDVD lost 1.9% BMD at the total hip versus 3.7% loss in the placebo group (p=0.03). Stratified analyses showed the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the placebo group for those with baseline vitamin D <27 ng/ml (p<0.01). Based on our preliminary data, we propose to conduct a definitive, multi-center, phase III RCT in which 366 prostate cancer patients ≥65 years old starting ADT with vitamin D <27 ng/ml will be randomized to 1) 50,000 IU/week vitamin D or 2) a matching placebo for 52 weeks. All participants will receive a daily supplementation (800 IU vitamin D/1,000 mg calcium) to ensure a minimum of 100% RDA. The primary outcomes is the change in BMD, while secondary outcomes include changes in the clinically relevant outcomes of falls, balance, quality of life and fractures. We also plan to explore the biological pathways of ADT-induced bone loss and response to HDVD using bone biomarkers. If found to be efficacious, HDVD would be a safe, low-cost, widely-available OTC treatment that could revolutionize management of ADT-induced bone loss and change clinical practice paradigms.

抽象的：雄激素剥夺疗法（ADT）导致接近睾丸激素的损失，已增加在过去的十年中，在古老的前列腺癌患者中动态动态。 ADT与大幅增加有关在骨矿物质密度（BMD）损失（每年2-5％）和骨折，结合显着下降与不参加ADT的年龄匹配的前列腺癌患者相比，骨骼肌质量（每年2-5％）没有癌症。 BMD和肌肉质量的丧失导致跌落率很高，肌肉降低力量和增加的平衡。尽管与ADT相关的副作用发生了很高的事件，但治疗选择是有限的。双膦酸盐治疗通常用于ADT诱导的骨质流失，但与显着有关副作用和依从性差。维生素D可预防BMD损失和断裂，但其作用很强剂量依赖性。当前IOM建议补充（600-800 IU/天）和血清25-OH水平（20 Ng/ml）不足以防止高风险人群（例如前列腺癌患者）的骨质流失 adt。此外，维生素D的400-500 IU/天的RCT干预无法防止ADT诱导的骨质流失。高的- 补充剂量维生素D（例如50,000 IU/周）是承诺的干预措施，可显着增加 25-OH的维生素D至显示出可改善其他人群的BMD的水平。维生素D也已显示为增加肌肉力量，减少跌倒并改善平衡。为了准备此R01，我们进行了一次 II期随机对照试验（RCT）研究了HDVD的可行性，安全性和初步效率在接受ADT的59名前列腺癌患者中与安慰剂相比24周（NCI R21CA185678； PI：PEPPONE）。我们的试点研究中有令人信服的证据显示：1）50,000 IU/周维生素D（HDVD）是安全的，没有毒性与低剂量维生素D，2）依从性在94％和3）HDVD显着出色增加了25-OH维生素D水平。那些随机到HDVD的人以总臀部损失1.9％的BMD，而3.7％的损失损失在安慰剂组中（p = 0.03）。分层分析表明，HDVD组在总髋关节上损失了2.3％BMD 安慰剂组的基线维生素D <27 ng/ml的那些安慰剂组为7.1％（p <0.01）。根据我们的初步数据我们建议进行确定的多中心，III期RCT，其中366名前列腺癌患者≥65岁使用维生素D <27 ng/ml的旧开始ADT将随机分为1）50,000 IU/周维生素D或2）匹配安慰剂持续52周。所有参与者将获得每日补充（800 IU维生素D/1,000毫克钙）确保至少100％RDA。主要结果是BMD的变化，而次要结果包括跌倒，平衡，生活质量和骨折的临床相关结果的变化。我们还计划使用骨生物标志物探索ADT诱导的骨质流失和对HDVD的反应的生物学途径。如果 HDVD发现是有效的，将是一种安全，低成本，广泛的OTC治疗 ADT引起的骨质流失和变化临床实践范例的管理。