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

妊娠期和哺乳期相关性骨质疏松症(PLO)是一种严重的早期骨质疏松表现， 年轻女性在晚期经历低创伤或自发性骨折，最常见的是脊椎骨折 怀孕或哺乳。有关特征和管理的信息仅来自案例报告和 小系列4-25。在开发PLO的治疗方法之前，有必要解决我们在 关于这种疾病的知识。目前，几乎没有关于自然历史和风险的信息。 PLO的因素，这种急性骨折综合征的病理生理机制，任何生物标志物 严重程度和再次怀孕时发生骨折的风险。在我们对发病机制的研究中(AR49896)26-31 和治疗(FD003902；FD005114)32，33绝经前特发性骨质疏松症(IOP)，66例中仅10例 女性患有PLO34。绝经前眼压是一种罕见的孤儿疾病，估计患病率为20万 美国。我们的数据表明，PLO只占绝经前眼压的一小部分(~15%)，也应该 被认为是一种罕见的孤儿疾病。我们发现患有PLO的女性之间有几个重要的区别 与怀孕或哺乳无关的眼压；患有PLO的人骨折更多，脊椎更多 与IOP34组相比，IOP34组骨折更严重，皮质骨缺损更严重，骨重塑更低。这些数据 这使我们假设PLO的病理生理学与其他形式的眼压不同，并可能 涉及骨形成和结构的持续性缺陷，具有重要意义的假说 开发有效的治疗方法。这项研究的目标是定义巴解组织和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指标。我们还将调查PLO的潜在遗传病因。我们将招募 经历骨质疏松性骨折的绝经前妇女(S)，无创伤或轻度创伤， 在怀孕或哺乳期间或在怀孕或哺乳期6个月内。我们将根据时间对参与者进行分类 相对于出现时间的评估：最近的PLO受试者在他们最初骨折的6个月后进行评估(S) 远端PLO受试者在初次骨折6个月后进行评估(S)。将这两个群体包括在内将使 我们来比较处于疾病演变不同阶段的患者。在目标1中，我们将进行一次在线 调查以获取有关PLO的临床特征和自然病史的信息，利用我们的长期经验 与一个大型(&gt；135名女性)的国际Facebook PLO支持小组的关系。在目标2和目标3中，我们将 招募50名患有PLO的女性，这是迄今为止最大的队列。参与者将接受详细的表型鉴定，网址为 哥伦比亚大学在病史、生化、成像和暂时性活检方面的特征，以及 外显子全测序进行基因分型。所有指标都将作为潜在的疾病生物标记物进行调查。 严肃性。这项研究将提供PLO的第一个全面特征，这是迈向 设计未来的靶向治疗策略，以改善骨骼恢复和骨骼质量。

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.