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

描述（由申请人提供）：在过去十年中，老年前列腺癌患者使用雄激素剥夺治疗（ADT）的情况急剧增加，ADT导致睾酮几乎完全丧失。与未接受ADT治疗的年龄匹配的前列腺癌患者和未患癌症的男性相比，ADT与骨矿物质密度（BMD）损失增加5至10倍、骨折增加7倍和肌肉减少症（肌肉萎缩）显著增加相关。BMD和肌肉质量的损失与身体缺陷的高患病率相关，如福尔斯、肌肉力量降低和平衡下降。尽管ADT相关副作用的患病率很高，但治疗选择有限。双膦酸盐治疗是ADT诱导的骨丢失的有效治疗，但不适用于预防骨丢失。维生素D可以防止BMD损失和骨折，但其作用具有强烈的剂量依赖性。目前IOM推荐的补充剂（600 IU/天）和血清25-OH水平（20 ng/mL）不足以防止高危人群（如接受ADT的前列腺癌患者）的骨丢失，如血清25-OH维生素D水平e32 ng/mL时BMD增加所证明。此外，400-500 IU/天维生素D的RCT干预未能预防ADT诱导的骨丢失。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，可显著增加25-OH维生素D至改善BMD的水平。维生素D也被证明可以增加肌肉力量，减少福尔斯，改善平衡。我们在190名癌症患者中的初步数据表明，在接受治疗的前列腺癌患者中补充高剂量维生素D（e50，000 IU/周）6个月（例如，ADT， 化疗）是安全的并且耐受良好。我们小组的其他初步数据也显示，癌症患者补充高剂量维生素D（50，000 IU/周）可显著增加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。基于生物相容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治疗的前列腺癌患者将随机接受1）50，000 IU/周维生素D或2）匹配的安慰剂。所有参与者将接受每日多种维生素（600 IU维生素D）和1，000 mg/天的钙补充剂，以确保至少100% RDA。主要目的是评估高剂量维生素D补充对BMD的影响，而次要目的是评估高剂量维生素D补充对肌肉质量、福尔斯、肌肉力量和身体表现的影响。本研究旨在提供关键的初步信息和数据，为预期的R 01提案提供信息。这项研究将代表第一个临床试验之一，以检查高剂量维生素D补充剂对老年前列腺癌患者ADT相关副作用的影响。如果成功，本研究的结果是ADT在老年前列腺癌患者中减轻负担的获益可能相当可观。

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.