Pregnancy and lactation associated osteoporosis: Bone microstructure and metabolism, genotypic characteristics, natural history and biomarkers of disease severity

妊娠和哺乳相关性骨质疏松症（PLO）是骨质疏松症的严重早期表现，其中 年轻女性在晚期经历低创伤或自发性骨折，最常见的是椎骨骨折， 怀孕或哺乳。有关特征和管理的信息仅来自病例报告， 小系列4 -25.在开发出治疗PLO的方法之前，有必要解决我们研究中的几个关键空白。 了解这种疾病。目前，关于其自然历史和风险的信息很少。 PLO的因素，这种急性骨折综合征的病理生理机制， 严重程度和随后怀孕时骨折的风险。在我们的发病机制研究中（AR 49896）26-31 治疗组（FD 003902; FD 005114）32，33例绝经前特发性骨质疏松症（IOP），66例中仅10例 女性有PLO 34。绝经前IOP是一种罕见的孤儿疾病， 美方我们的数据表明，PLO代表绝经前IOP的一个小子集（~15%）， 被认为是一种罕见的孤儿病。我们发现了妇女与巴解组织之间的几个重要差异 而那些与妊娠或哺乳无关的IOP患者; PLO患者有更多的骨折， 骨折，更深刻的皮质骨缺损，骨重建比IOP 34。这些数据 使我们假设PLO的病理生理学不同于其他形式的IOP， 涉及骨形成和结构的持续缺陷， 开发有效的治疗方法。这项研究的目标是确定巴解组织的自然历史， 其表型，包括临床特征、激素特征、骨骼结构和重塑，以及 疾病严重程度的预测因子。我们还将调查潜在的遗传病因的PLO。我们将招募 绝经前女性发生骨质疏松性骨折，与无创伤或轻度创伤相关， 怀孕或哺乳期间或6个月内。我们将根据参与者的时间进行分类 相对于就诊时间的评估：近期PLO受试者评估的初始骨折时间<6个月 远侧PLO受试者在其初始骨折后>6个月进行评估。将两个群体都包括在内， 我们来比较处于疾病发展不同阶段的患者。在目标1中，我们将进行一次在线 调查，以获得信息的临床特点和自然历史的巴解组织，利用我们的长期 与一个大型（>135名妇女）国际脸书巴解组织支持团体建立关系。在目标2和3中，我们将 巴解组织招募了50名妇女，这是迄今为止人数最多的一批。参与者将在以下时间进行详细的表型分析： 哥伦比亚大学在历史、生物化学、成像和髂间动脉活检特征方面，以及 通过全外显子组测序进行基因分型。所有指标将作为疾病的潜在生物标志物进行研究 严重性。这项研究将提供巴解组织的第一个全面的特点， 设计未来的靶向治疗策略研究，以改善骨骼恢复和骨质量。

Pregnancy and lactation associated osteoporosis (PLO) is a severe early presentation of osteoporosis in which young women experience low trauma or spontaneous fractures, most commonly vertebral fractures, during late pregnancy or lactation. Information on characteristics and management is derived only from case reports and small series4-25. Before therapies for PLO can be developed, it is necessary to address several key gaps in our knowledge about this disorder. Currently, there is little information available on the natural history of and risk factors for PLO, the pathophysiological mechanisms of this acute fracturing syndrome, any biomarkers of severity, and risk of fracture with subsequent pregnancies. In our studies of the pathogenesis (AR49896)26-31 and treatment (FD003902; FD005114)32,33 of premenopausal idiopathic osteoporosis (IOP), only 10 of 66 women had PLO34. Premenopausal IOP is a rare orphan disease with an estimated prevalence <200,000 in the US. Our data indicate that PLO represents a small subset (~15%) of premenopausal IOP, and should also be considered a rare orphan disease. We detected several important differences between women with PLO and those with IOP unrelated to pregnancy or lactation; those with PLO had more fractures, more vertebral fractures, more profound cortical bone deficits, and lower bone remodeling than those with IOP34. These data lead us to hypothesize that the pathophysiology of PLO is distinct from other forms of IOP and may involve persistent deficits in bone formation and structure, hypotheses with important implications for the development of effective therapies. The goals of this study are to define the natural history of PLO and its phenotype, including clinical features, hormonal characteristics, skeletal structure and remodeling, and predictors of disease severity. We will also investigate potential genetic etiologies of PLO. We will recruit premenopausal women who experience osteoporotic fracture(s), associated with no trauma or low trauma, during or within 6 months of pregnancy or lactation. We will categorize participants according to time of evaluation relative to time of presentation: Recent PLO subjects evaluated <6 months of their initial fracture(s) and Distant PLO subjects evaluated >6 months after their initial fracture(s). Inclusion of both groups will allow us to compare patients who are at different stages of disease evolution. In Aim 1, we will conduct an online survey to obtain information on clinical characteristics and natural history of PLO, capitalizing on our long-term relationship with a large (>135 women), international Facebook PLO support group. In Aims 2 and 3, we will recruit 50 women with PLO, the largest cohort to date. Participants will undergo detailed phenotyping at Columbia University in terms of historical, biochemical, imaging and transiliac biopsy characteristics, and genotyping by whole exome sequencing. All indices will be investigated as potential biomarkers of disease severity. This study will provide the first comprehensive characterization of PLO, an essential step towards the design of future studies of targeted treatment strategies to improve skeletal recovery and bone quality.