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

描述(由申请人提供)：雄激素剥夺疗法(ADT)的使用，导致睾丸激素几乎全部丧失，在过去的十年中，在老年前列腺癌患者中急剧增加。与没有服用ADT的年龄匹配的前列腺癌患者和非癌症男性相比，ADT与骨密度(BMD)损失增加5到10倍，骨折增加7倍，骨质疏松症(肌肉萎缩)显著增加。BMD和肌肉质量的丧失与身体缺陷的高发有关，如摔倒、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，但治疗选择有限。双膦酸类药物治疗ADT引起的骨丢失是一种有效的治疗方法，但不适用于预防骨丢失。维生素D可以预防骨密度丢失和骨折，但其效果强烈地依赖于剂量。目前IOM推荐的补充剂(600IU/天)和血清25-OH水平(20 ng/毫升)不足以预防高危人群的骨丢失，如服用ADT的前列腺癌患者，血清25-OH维生素D水平E32 ng/毫升的骨密度增加就是明证。此外，每天400-500IU维生素D的RCT干预未能预防ADT引起的骨丢失。大剂量维生素D补充剂(例如，50000国际单位/周)是一种很有希望的干预措施，可以显著增加25-OH维生素D到显示出的改善BMD的水平。维生素D还被证明可以增加肌肉力量，减少跌倒，改善平衡。我们小组在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，连续6个月服用大剂量维生素D补充剂(e50000 IU/周)(例如，ADT， 化疗)是安全和耐受性良好的。我们小组的其他初步数据也表明，癌症患者服用高剂量维生素D补充剂(50000国际单位/周)可显著提高25-羟基维生素D水平，而低剂量维生素D补充剂(7000国际单位/周)则不会。基于生物学上的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，在该试验中，76名服用ADT的65岁及以上前列腺癌患者将随机接受1)50,000 IU/周的维生素D或2)匹配的安慰剂。所有参与者每天将获得一种复合维生素(600IU维生素D)和每天1000毫克的钙补充剂，以确保最低100%的RDA。主要目的是评估大剂量补充维生素D对骨密度的影响，次要目标是评估大剂量补充维生素D对肌肉质量、跌倒、肌肉力量和体能的影响。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提案提供参考。这项研究将是检验大剂量维生素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，这项研究将减轻老年前列腺癌患者的ADT负担，这可能是相当大的好处。

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.