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，没有继发性骨丢失原因。在男性中，眼压与成骨细胞功能障碍和骨形成不足有关，这与胰岛素样生长因子1(IGF-1)缺乏有关，IGF-1是一种对生长激素(GH)的反应产生的激素，生长激素是成骨细胞的合成代谢物质。在我们最近完成的由国立卫生研究院资助的针对患有眼压的绝经前女性的骨活检研究中，与患有眼压的男性相比，其中一组患者的骨形成率非常低，而胰岛素样生长因子-1水平显著升高。此外，眼压低、骨形成低和血清IGF-1水平高的女性对Teriparatide(TPTD)没有反应，TPTD是一种骨合成代谢药物，通过IGF-1依赖的机制刺激骨形成，从而增加骨密度(BMD)。这些发现使我们假设，眼压、低骨形成和高IGF-1的女性存在IGF-1抵抗，这使得她们在骨骼(成骨细胞)水平对IGF-1和TPTD的反应较差。我们还假设，这些女性可能在非骨骼组织中有IGF-1抵抗的证据。IGF-1抵抗，无论是与激素本身、其结合蛋白或其受体的异常有关，预计都会具有类似于成年垂体源性生长激素缺乏症的临床特征：骨密度和瘦体重减少，内脏脂肪增加，胰岛素抵抗，血清低密度脂蛋白胆固醇(LDL)胆固醇和心血管风险标记物，如C反应蛋白(CRP)，白细胞介素6(IL-6)和同型半胱氨酸。这项初步研究的目标是确定患有眼压和低骨形成的绝经前妇女是否在骨骼和非骨骼组织中存在IGF-1抵抗的证据，以及IGF-1抵抗的骨骼和非骨骼标记物是否可以预测她们对TPTD的反应。我将在FDA孤儿疾病计划(FD003902)资助的TPTD治疗绝经前眼压的新的随机、双盲、安慰剂对照的第二阶段试验的背景下实现这些目标。这项试验的主要结果变量仅限于骨密度、微结构和重塑。这项R03资助将利用并利用招募40名患有眼压的绝经前妇女来调查一组与父母资助不同的研究问题，重点是IGF-1抵抗在绝经前眼压发病机制中的作用，以及通过12个月脊柱骨密度增加来评估TPTD的反应。这项工作具有创新性，因为它是第一次研究生长激素/胰岛素样生长因子-1轴和内脏肥胖症对骨合成代谢剂TPTD在人类中作用机制的影响。此外，相当大比例的患有骨质疏松症的绝经后妇女对TPTD没有反应，原因尚不清楚。R03将为未来的R01应用提供试点数据，重点关注绝经后骨质疏松症中GH/IGF-1轴、脂肪分布和对TPTD的反应之间的相互作用。绝经后骨质疏松症是一种临床影响很大的疾病，远比眼压更常见。

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.