The Role of PTH in the Low Bone Mass of Anorexia Nervosa

描述（由申请人提供）：神经性厌食症（AN）影响美国0.5-1%的大学年龄女性，其特征是极端的、自我诱导的饥饿。在与AN相关的许多医学合并症中，严重的骨质流失是最常见的，并且即使体重恢复也经常持续存在。这种骨质流失很重要，因为患有AN的女性骨折的风险也会增加；一项前瞻性研究表明，与同龄对照组相比，患有AN的女性骨折风险增加了7倍。因此，预防与AN相关的严重骨质流失的治疗至关重要。目前还没有批准的治疗an相关性骨质流失的方法。在正常体重、性腺功能低下的妇女中预防骨质流失的治疗方法，如雌激素，并不能改善AN妇女的骨密度。这可能是因为营养剥夺引起的骨质流失的发病机制不同于绝经后骨质疏松症。在AN中，骨形成急剧减少。因此，一种刺激骨形成的药物将是一种重要的潜在治疗方法。目前，特立帕肽（PTH）是唯一被FDA批准用于治疗骨质疏松症的合成代谢药物。由于已知甲状旁腺激素对骨骼的影响是通过IGF-I介导的，而在营养缺乏的状态下，IGF-I水平较低，我们建议研究甲状旁腺激素对AN女性骨量的影响。我们将随机选择30名患有AN的女性，分别接受甲状旁腺激素或安慰剂治疗，并对她们进行为期6个月的前瞻性随访。我们将在基线和6个月时测量骨矿物质密度、骨微结构参数和骨强度。我们还将在基线和研究过程中每月测量骨形成和吸收标志物，IGF-I和硬化蛋白水平。Fazeli博士是哈佛医学院的医学讲师和麻省总医院（MGH）的医学助理。她是MGH神经内分泌科的一名工作人员，她的大部分时间都用于临床研究。她在研究AN激素异常方面的专业知识使她能够领导这个拟议的项目。她得到了MGH的大力支持，可以充分利用神经内分泌科、临床研究中心和哈佛催化剂CTSC资源。她的共同导师，博士。Anne Klibanski和Mary Bouxsein在Fazeli博士的研究方向上得到了充足的资金和投资。在获奖期间，Fazeli博士将在哈佛大学公共卫生学院（Harvard School of Public Health）获得生物统计学和研究设计方面的重要培训，她目前是该校公共卫生专业的硕士学生，同时还将获得确定骨骼强度的新研究方法方面的重要技能。如果获得资助，这笔资金将支持Fazeli博士在临床研究方面的培训，最终目标是成为一名独立的研究者，在神经内分泌学和骨骼生物学方面具有专业知识，以更好地了解营养不良疾病中骨质流失的病理生理学。

DESCRIPTION (provided by applicant): Anorexia Nervosa (AN) affects 0.5-1% of college-aged women in the US and is characterized by extreme, self- induced starvation. Of the many medical co-morbidities associated with AN, severe bone loss is the most common and often persists despite weight recovery. This bone loss is significant because women with AN also have an increased fracture risk; a prospective study demonstrated that women with AN have a 7-fold increased risk of fractures as compared to age-matched controls. Therefore, a treatment to prevent the severe bone loss associated with AN is critical. There are currently no approved treatments for AN-associated bone loss. Therapies which prevent bone loss in normal-weight, hypogonadal women, such as estrogen, do not improve bone mineral density in women with AN. This is likely because the pathogenesis of bone loss due to nutritional deprivation differs from that of post-menopausal osteoporosis. In AN, there is a dramatic decrease in bone formation. Therefore an agent which stimulates bone formation would be an important potential treatment. Currently teriparatide (PTH) is the only anabolic agent approved by the FDA for the treatment of osteoporosis. As the effects of PTH on bone are known to be mediated through IGF-I and IGF-I levels are low in states of nutritional deficiency, we propose to investigate the effects of PTH on bone mass in women with AN. We will randomize thirty women with AN to treatment with either PTH or placebo and follow them prospectively for 6 months. We will measure bone mineral density, parameters of bone microarchitecture and bone strength at baseline and at 6 months. We will also measure markers of bone formation and resorption, IGF-I and sclerostin levels at baseline and monthly during the course of the study. Dr. Fazeli is an Instructor in Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital (MGH). She is on staff in the Neuroendocrine Unit at MGH and devotes the majority of her time to clinical research. Her expertise in studying hormonal abnormalities in AN positions her to lead the proposed project. She is well-supported by MGH and has full access to the Neuroendocrine Unit, Clinical Research Center and Harvard Catalyst CTSC resources. Her co-mentors, Drs. Anne Klibanski and Mary Bouxsein, are well-funded and invested in the direction of Dr. Fazeli's research. During the award period, Dr. Fazeli will obtain critical trainig in biostatistics and research design at the Harvard School of Public Health, where she is currently a Master of Public Health student, as well as important skills in novel investigational methods of determining bone strength. If awarded, this grant will support Dr. Fazeli's training in clinical research, with the ultimate goal of becoming an independent investigator with an expertise in combining neuroendocrinology and bone biology to better understand the pathophysiology of bone loss in disorders of under-nutrition. PUBLIC HEALTH RELEVANCE: Anorexia nervosa, a disorder predominantly affecting women and characterized by extreme self-imposed weight loss, is associated with many medical complications including severe bone loss and an increased fracture risk. Therapies which prevent bone loss in post-menopausal women, such as estrogen, do not improve or stabilize bone mineral density in women with anorexia nervosa and there are currently no approved therapies for bone loss associated with anorexia nervosa. The goal of this study is to investigate the effects of teriparatide on bone density, bone microarchitecture and bone strength in this group of women and to better understand the pathophysiology of bone loss in anorexia nervosa.