High-dose Vitamin D Supplementation for ADT-induced Side Effects

补充高剂量维生素 D 治疗 ADT 引起的副作用

• 批准号: 8637300
• 负责人: Luke Joseph Peppone
• 金额: $ 20.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-04 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637300
• 关键词: Activities of Daily Living; Adverse effects; Age; Aged, 80 and over; Androgens; Aromatase Inhibitors; Atrophic; Biological; Bone Density; Bone necrosis; Calcium; Cancer Patient; Cholecalciferol; Clinical; Clinical Trials; Controlled Clinical Trials; Data; Dose; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Elderly; Ensure; Equilibrium; Fracture; High Prevalence; Incidence; Intervention; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Multivitamin; Muscle; Participant; Performance; Placebos; Population; Prevention; Questionnaires; Randomized; Randomized Controlled Trials; Recommended Daily Allowances; Recording of previous events; Regimen; Research; Schedule; Serum; Supplementation; Testing; Testosterone; Therapeutic Intervention; Time; Vitamin D; Vitamin D2; Vitamins; aged; arm; base; bisphosphonate; bone health; bone loss; chemotherapy; deprivation; design; effective intervention; effective therapy; efficacy testing; falls; high risk; hormone therapy; human old age (65+); improved; indicated prevention; innovation; long bone; malignant breast neoplasm; men; muscle form; muscle strength; prevent; public health relevance; sarcopenia

DESCRIPTION (provided by applicant): 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 5- to 10-fold greater loss of bone mineral density (BMD), a 7-fold increase in bone fractures, and a significant increase in sarcopenia (muscle mass atrophy) compared to age-matched prostate cancer patients not on ADT and men without cancer. The loss of BMD and muscle mass is associated with a high prevalence of physical deficits such as falls, reduced muscular strength, and decreased balance. Despite the high prevalence of ADT-related side effects, treatment options are limited. Bisphosphonate therapy is an effective treatment for ADT-induced bone loss, but is not indicated for the prevention of bone loss. Vitamin D protects against BMD loss and fractures, but its effects are strongly dose-dependent. Current IOM recommended supplementation (600 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, as evidenced by increased BMD with serum 25-OH vitamin D levels e32 ng/mL. In addition, RCT interventions of 400-500 IU/day of vitamin D failed 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. Vitamin D has also been shown to increase muscular strength, reduce falls, and improve balance. Preliminary data from our group in 190 cancer patients demonstrates high-dose vitamin D supplementation (e50,000 IU/week) for 6 months in prostate cancer patients receiving treatment (e.g., ADT, chemotherapy) is safe and well-tolerated. Other preliminary data from our group also show high-dose vitamin D supplementation (50,000 IU/week) in cancer patients significantly increases 25-OH vitamin D levels while low-dose vitamin supplementation (7,000 IU/week) does not. Based on biological plausibility and our preliminary data, we propose to conduct a two-arm randomized controlled trial in which 76 prostate cancer patients 65 years old and older on ADT will be randomized to receive 1) 50,000 IU/week vitamin D or 2) a matching placebo. All participants will receive a daily multivitamin (600 IU vitamin D) and a 1,000 mg/day calcium supplement to ensure a minimum of 100% RDA. The primary aim will evaluate the effect of high-dose vitamin D supplementation on BMD, while the secondary aims will evaluate the effect of high-dose vitamin D supplementation on muscle mass, falls, muscle strength, and physical performance. The study proposed herein is designed to provide critical preliminary information and data to inform an anticipated R01 proposal. This study would represent one of first clinical trials to examine the effect of high-dose vitamin D supplementation on ADT-related side effects in older prostate cancer patients. If successful, the benefit of a reduced burden from ADT in older prostate cancer patients as a result of this study could be considerable.

描述（由申请人提供）：在过去十年中，老年前列腺癌患者中雄激素剥夺疗法（ADT）的使用急剧增加，这种疗法会导致睾酮几乎完全丧失。与年龄匹配的未接受 ADT 的前列腺癌患者和未患癌症的男性相比，ADT 导致骨矿物质密度 (BMD) 损失增加 5 至 10 倍，骨折发生率增加 7 倍，肌少症（肌肉质量萎缩）显着增加。 BMD 和肌肉质量的损失与身体缺陷的高发生率有关，例如跌倒、肌肉力量下降和平衡能力下降。尽管 ADT 相关副作用的发生率很高，但治疗选择仍然有限。双磷酸盐治疗是 ADT 引起的骨质流失的有效治疗方法，但不适用于预防骨质流失。维生素 D 可防止 BMD 损失和骨折，但其作用具有强烈的剂量依赖性。目前 IOM 建议的补充剂（600 IU/天）和血清 25-OH 水平（20 ng/mL）不足以防止高危人群（例如接受 ADT 的前列腺癌患者）发生骨质流失，血清 25-OH 维生素 D 水平达到 e32 ng/mL 时 BMD 增加就证明了这一点。此外，每日 400-500 IU 维生素 D 的随机对照试验干预措施未能预防 ADT 引起的骨质流失。高剂量维生素 D 补充剂（例如 50,000 IU/周）是一种很有前途的干预措施，可显着增加 25-OH 维生素 D 至可改善 BMD 的水平。维生素 D 还被证明可以增强肌肉力量、减少跌倒并改善平衡。我们小组对 190 名癌症患者进行的初步数据表明，接受治疗（例如 ADT、ADT、 化疗）是安全且耐受性良好的。我们小组的其他初步数据还显示，癌症患者补充高剂量维生素 D（50,000 IU/周）可显着提高 25-OH 维生素 D 水平，而补充低剂量维生素 D（7,000 IU/周）则不会。根据生物学合理性和我们的初步数据，我们建议进行一项双臂随机对照试验，其中 76 名 65 岁及以上接受 ADT 的前列腺癌患者将被随机分配接受 1) 50,000 IU/周维生素 D 或 2) 匹配的安慰剂。所有参与者将每天服用多种维生素（600 IU 维生素 D）和 1,000 毫克/天的钙补充剂，以确保至少 100% RDA。主要目标是评估大剂量维生素 D 补充剂对 BMD 的影响，次要目标是评估大剂量维生素 D 补充剂对肌肉质量、跌倒、肌肉力量和身体表现的影响。本文提出的研究旨在提供关键的初步信息和数据，为预期的 R01 提案提供信息。这项研究将成为检验高剂量维生素 D 补充剂对老年前列腺癌患者 ADT 相关副作用影响的首批临床试验之一。如果成功，这项研究的结果将是减轻老年前列腺癌患者 ADT 负担的益处可能是相当大的。