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）的使用增加，这种疗法会导致睾酮几乎完全丧失过去十年中，老年前列腺癌患者的 ADT 显着增加。骨矿物质密度 (BMD) 损失（每年 2-5%）和骨折，同时骨密度显着下降与未接受 ADT 的年龄匹配的前列腺癌患者和男性相比，骨骼肌质量（每年 2-5%）骨密度和肌肉质量的损失导致跌倒、肌肉减少的高发生率。尽管 ADT 相关副作用的发生率很高，但治疗方案仍然存在。双膦酸盐疗法通常用于治疗 ADT 引起的骨质流失，但与显着相关。副作用和依从性差维生素 D 可以防止 BMD 损失和骨折，但其作用很强。目前 IOM 建议的补充量（600-800 IU/天）和血清 25-OH 水平（20 ng/mL）不足以防止高危人群（例如前列腺癌患者）的骨质流失此外，每日 400-500 IU 维生素 D 的 RCT 干预措施无法预防 ADT 引起的骨质流失。一定剂量的维生素 D 补充剂（例如，每周 50,000 IU）是一种很有前途的干预措施，可显着提高 25-OH 维生素 D 水平也被证明可以改善其他人群的骨密度。增加肌肉力量、减少跌倒并提高平衡能力为了准备这次 R01，我们进行了一次训练。 II 期随机对照试验 (RCT)，调查 HDVD 的可行性、安全性和初步疗效在 59 名接受 ADT 的前列腺癌患者中与安慰剂进行了 24 周的比较（NCI R21CA185678；PI：Peppone）。我们的试点研究提供了令人信服的证据：1) 每周 50,000 IU 的维生素 D (HDVD) 是安全的，不会产生任何副作用。与低剂量维生素 D 相比，毒性增加，2) 依从性极佳，达 94%，3) HDVD 显着随机接受 HDVD 的 25-OH 维生素 D 水平增加，全髋骨密度下降 1.9%，而髋部骨密度下降 3.7%。分层分析显示，与安慰剂组相比，HDVD 组的髋部总 BMD 降低了 2.3%。根据我们的初步数据，基线维生素 D <27 ng/ml 的安慰剂组为 7.1%（p<0.01）。我们建议进行一项确定性、多中心、III 期随机对照试验，其中 366 名年龄≥65 岁的前列腺癌患者维生素 D <27 ng/ml 的旧起始 ADT 将被随机分配至 1) 50,000 IU/周维生素 D 或 2) 匹配的所有参与者将接受每日补充剂（800 IU 维生素 D/1,000 毫克钙），为期 52 周。确保至少 100% RDA 主要结果是 BMD 的变化，而次要结果是包括跌倒、平衡、生活质量和骨折等临床相关结果的变化。使用骨生物标志物 If 探索 ADT 诱导的骨质流失和 HDVD 反应的生物学途径。如果发现有效，HDVD 将是一种安全、低成本、广泛使用的非处方药治疗方法，可能会彻底改变管理 ADT 引起的骨质流失并改变临床实践范式。