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

摘要： 雄激素剥夺疗法（ADT）的使用，导致睾丸激素几乎完全丧失， 在过去的十年里，老年前列腺癌患者中发生了显着变化。ADT与显著增加 骨矿物质密度（BMD）损失（每年2-5%）和骨折，结合显着减少， 与年龄匹配的未接受ADT的前列腺癌患者和男性相比，骨骼肌质量（每年2-5%） 没有癌症骨密度和肌肉质量的损失导致福尔斯、肌肉萎缩和肌肉萎缩的高患病率。 力量和平衡下降。尽管ADT相关副作用的发生率很高，但治疗选择 有限公司双膦酸盐治疗通常用于ADT诱导的骨丢失，但与显著的 副作用和依从性差。维生素D可以防止骨密度损失和骨折，但其作用是强烈的。 剂量依赖性。目前IOM推荐的补充剂（600-800 IU/天）和血清25-OH水平（20 ng/mL）不足以防止高风险人群（如前列腺癌患者）的骨丢失， ADT。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- 补充维生素D的剂量（例如，50，000 IU/周）是一种有希望的干预措施， 25-OH维生素D的水平显示，以改善其他人群的BMD。维生素D也被证明 增加肌肉力量，减少福尔斯，改善平衡。为了准备这次R 01，我们进行了一次 研究HDVD可行性、安全性和初步疗效的II期随机对照试验（RCT） 与安慰剂相比，在59名接受ADT的前列腺癌患者中进行了24周的研究（NCI R21 CA 185678; PI：Peptide）。 我们的初步研究的令人信服的证据表明：1）50，000 IU/周的维生素D（HDVD）是安全的， 与低剂量维生素D相比，毒性增加，2）依从性极好，为94%，3）HDVD显著 增加25-OH维生素D水平。随机分配到HDVD组的患者全髋关节BMD丢失1.9%， 安慰剂组（p=0.03）。分层分析显示，HDVD组全髋BMD损失2.3%， 对于基线维生素D <27 ng/ml的患者，安慰剂组为7.1%（p<0.01）。根据我们的初步数据， 我们计划进行一项确定性的、多中心的III期随机对照试验，纳入366例年龄≥65岁的前列腺癌患者， 维生素D <27 ng/ml的老年起始ADT将随机分配至1）50，000 IU/周维生素D或2）匹配的 安慰剂52周。所有参与者将接受每日补充（800 IU维生素D/1，000 mg钙） 确保最低100% RDA。主要结局是BMD的变化，而次要结局 包括福尔斯、平衡、生活质量和骨折的临床相关结局的变化。我们还计划 探索ADT诱导的骨丢失的生物学途径和使用骨生物标志物对HDVD的反应。如果 HDVD被发现是有效的，它将是一种安全、低成本、广泛可用的OTC治疗方法， 管理ADT引起的骨丢失和改变临床实践模式。

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.