IGF-1, bone turnover and response to teriparatide in premenopausal women with IOP

描述（由申请人提供）：特发性骨质疏松症（IOP）影响其他健康的年轻男性和女性，性腺功能完整，没有继发性骨质流失的原因。在男性中，IOP与成骨细胞功能障碍和低骨形成相关，这与胰岛素样生长因子1（IGF-1）缺乏有关，IGF-1是一种响应于生长激素（GH）产生的激素，生长激素对骨形成成骨细胞具有合成代谢作用。在我们最近完成的NIH资助的64例绝经前IOP女性骨活检研究中，与IOP男性相比，一个子集的骨形成率非常低，IGF-1水平显著较高。此外，患有IOP、低骨形成和高血清IGF-1水平的女性对特立哌酮（TPTD）没有反应，特立哌酮是一种骨合成代谢药物，通过IGF-1依赖性机制刺激骨形成来增加骨矿物质密度（BMD）。这些发现使我们假设，患有IOP、低骨形成和高IGF-1的女性具有IGF-1抗性，这使得她们在骨骼（成骨细胞）水平上对IGF-1和TPTD的反应较低。我们还假设，这些妇女可能有证据表明，IGF-1的非骨骼组织的阻力。IGF-1抵抗，无论是否与激素本身、其结合蛋白或其受体的异常有关，预期具有与垂体源性成人生长激素缺乏症相似的临床特征：BMD和瘦体重降低，内脏肥胖增加，胰岛素抵抗，血清低密度脂蛋白（LDL）胆固醇和心血管风险标志物如C-反应蛋白（CRP）升高，白细胞介素-6（IL-6）和同型半胱氨酸。这项初步研究的目的是确定绝经前IOP和低骨形成女性是否有骨骼和非骨骼组织中IGF-1抵抗的证据，以及IGF-1抵抗的骨骼和非骨骼标志物是否可预测其对TPTD的反应。我将在一项由FDA孤儿病项目（FD 003902）资助的新的TPTD治疗绝经前IOP的随机、双盲、安慰剂对照、II期试验中实现这些目标。本试验的主要结果变量仅限于BMD、微结构和重塑。该R 03基金将利用和利用招募的40名绝经前IOP女性，调查一组与母基金不同的研究问题，重点关注IGF-1抵抗对绝经前IOP发病机制的贡献以及通过12个月脊柱BMD增加评估的TPTD反应。这项工作是创新的，因为它是第一项研究，以调查GH/IGF-1轴和内脏肥胖对骨合成代谢剂，TPTD，在人类的作用机制的影响。此外，相当一部分绝经后骨质疏松症妇女对TPTD无反应，原因尚不清楚。该R 03将为未来的R 01应用提供试点数据，重点关注GH/IGF-1轴、脂肪分布和绝经后骨质疏松症（一种临床影响较大的疾病，远比IOP更常见）对TPTD的反应之间的相互作用。

DESCRIPTION (provided by applicant): Idiopathic osteoporosis (IOP) affects otherwise healthy young men and women with intact gonadal function and no secondary cause of bone loss. In men, IOP is associated with osteoblast dysfunction and low bone formation that is related to deficient insulin-like growth factor 1 (IGF-1), a hormone produced in response to growth hormone (GH) that is anabolic to the bone-forming osteoblast. In our recently completed NIH-funded bone biopsy study of 64 premenopausal women with IOP, a subset had very low bone formation rates and significantly higher IGF-1 levels, in contrast to men with IOP. Moreover, women with IOP, low bone formation and high serum IGF-1 levels did not respond to teriparatide (TPTD), an osteo-anabolic medication that increases bone mineral density (BMD) by stimulating bone formation via IGF-1-dependant mechanisms. These findings lead us to hypothesize that women with IOP, low bone formation and high IGF-1 have IGF-1 resistance that renders them less responsive to IGF-1 and also TPTD, at the skeletal (osteoblast) level. We also hypothesize that such women may have evidence of IGF-1 resistance in non-skeletal tissues. IGF-1 resistance, whether related to abnormalities with the hormone itself, its binding proteins or its receptors, would be expected to have clinical features similar to those of adult growth hormone deficiency of pituitary origin: decreased BMD and lean body mass, increased visceral adiposity, insulin resistance, and elevated serum low-density-lipoprotein (LDL) cholesterol and cardiovascular risk markers such as C-reactive protein (CRP), interleukin-6 (IL-6) and homocysteine. The goals of this pilot study are to determine whether premenopausal women with IOP and low bone formation have evidence of IGF-1 resistance in skeletal and non-skeletal tissues, and whether skeletal and non-skeletal markers of IGF-1 resistance predict their response to TPTD. I will accomplish these goals in the context of a new randomized double-blind placebo-controlled phase 2 trial of TPTD for the treatment of premenopausal IOP funded by the FDA Orphan Diseases Program (FD003902). The primary outcome variables of this trial are limited to BMD, micro- architecture and remodeling. This R03 grant will capitalize upon and leverage the recruitment of 40 premenopausal women with IOP to investigate a set of research questions distinct from the parent grant and focused upon the contribution of IGF-1 resistance to the pathogenesis of premenopausal IOP and the response to TPTD assessed by 12 month increase in spine BMD. This work is innovative because it is the first study to investigate the influence of the GH/IGF-1 axis and visceral adiposity on the mechanism of action of the osteo-anabolic agent, TPTD, in humans. Moreover, a substantial proportion of postmenopausal women with osteoporosis do not respond to TPTD, for reasons that are not clear. This R03 will provide pilot data for a future R01 application focused on the interplay between the GH/IGF-1 axis, adipose distribution and response to TPTD in postmenopausal osteoporosis, a disease of high clinical impact that is far more common than IOP.