骨质疏松症严重影响老年人，美国在研基金侧重这个领域（2024）
Bringing medical advances from the lab to the clinic.
骨质疏松症（Osteoporosis）是一种骨骼疾病，其特征是骨密度降低、骨结构恶化、骨骼脆弱性增加，导致骨折风险显著增高。这种疾病常见于老年人，尤其是绝经后的女性。
早期诊断：由于骨质疏松症在早期阶段往往无明显症状，早期诊断仍然是一个挑战。需要开发更有效的筛查工具和方法来早期识别高风险个体。 治疗反应的个体差异：当前治疗方法（如钙补充、维生素D、抗吸收药物和骨吸收抑制剂）在不同患者中的效果存在差异。研究如何根据个体的生物标志物和遗传背景来优化治疗方案是必要的。 新治疗药物的研发：目前的治疗药物虽多，但对某些患者的治疗效果有限，需要开发新的药物和治疗方法来改善骨质疏松症患者的预后。 长期治疗的安全性和副作用：骨质疏松症的治疗往往需要长期服用药物，如何减少长期服药的副作用，提高患者的生活质量，是另一个需要关注的问题。
TULANE UNIVERSITY OF LOUISIANA 的 DENG, HONG-WEN
MASSACHUSETTS GENERAL HOSPITAL 的 WEIN, MARC NATHAN UNIVERSITY OF PITTSBURGH AT PITTSBURGH 的 GREENSPAN, SUSAN L OSTEODX INC. 的 DICK, ANDREW BROWN UNIVERSITY 的 HAYES, KALEEN NICOLE
路易斯安那州杜兰大学
麻省总医院
匹兹堡大学匹兹堡分校
OSTEODX INC.
布朗大学等
Our Overall Objective is to comprehensively identify/characterize in vivo, in humans (epi-)genes/gut bacterial species/environmental factors and their functional interactions/mechanisms/mediators for sex-/ethnic-general/specific osteoporosis risk. To do so, we will investigate the human genome and gut microbiome, for their impacts via cells and cell-cell interactions (CCIs) in both osteoclastogenic and osteoblastogenic lineages.
Based on the solid progress made on our current U19 (AG055373) and leveraging the resources accumulated through other support (e.g., Louisiana Osteoporosis Study; LOS), we propose to fulfill the following Specific Aims:
Pioneer a comprehensive and highly innovative project to identify osteoporosis risk (epi-)genes in vivo simultaneously with human genome/gut microbiome (Proj 1), epigenome and single-cell transcriptome of osteoblast/osteoclast lineage cells (Proj 2), and metabolome (Proj 3), while assessing age/sex/ethnicity- specificity/generality of the identified molecular features (Proj 1-3). We will study BMD (both areal & volumetric–aBMD & vBMD), bone strength/quality (by finite element analyses – FEA and trabecular bone score - TBS), and OF.
Leverage the omics profiles to be generated in this U19 renewal and those accumulated in the ongoing U19 and LOS to impute (in Proj 2 & 3) to the full dataset all the omics features studied (in >5,600 subjects).
Efficiently/innovatively generate/integrate trans-omics interaction networks (Proj 1-3 & Core C), making causal inference to re-construct functional gene regulatory networks (GRN) within and across cells (for CCIs) and across our genome and gut microbiome. We will test these re-constructed GRNs to illuminate their functional significance and mechanisms for osteoporosis from the aspects of osteoblasto- and osteoclasto-genic lineages in vivo in humans.
Pursue in-depth follow-up functional studies (Proj 1 & 3) for specific molecular mechanisms and confirmation of the identified novel molecules, gut bacterial species, functions, and pathways.
This U19 will include three Cores (Administrative, Clinical, Biostatistics/Bioinformatics) to efficiently support the necessary synergy among projects for the above analyses that all address age/sex/ethnicity-specific/general effects.
This Phase IIB SBIR grant application proposes to continue development and commercialization of OsteoDx’s Cortical Bone Mechanics Technology™ (CBMT™), a novel osteoporosis related diagnostic device that non- invasively measures the mechanical properties of cortical bone and provides direct information about bone strength and quality that is not accessible by other diagnostic modalities. OsteoDx has already successfully illustrated commercial feasibility and demonstrated that CBMT can accurately and efficiently estimate ulna bone bending strength (R2=0.99). OsteoDx also established that CBMT is sensitive to detecting change in bone strength and provides information about cortical bone that is unique and independent of Bone Mineral Density (BMD), which suggests CBMT may yield clinically significant information about osteoporotic fracture potential.
Osteoporosis is a common medical condition causing progressive weakening of bones, eventually leading to nontraumatic or fragility fractures. These fractures are painful and, in many cases, cause prolonged or life-long disability, and dramatically increases mortality rates up to 8x within 3 months post fracture. The Bone Health and Osteoporosis Foundation projects that by 2025, there will be 3 million osteoporosis related fractures every year in the US, resulting in healthcare costs of more than $57 billion. Numerous treatments with varying mechanisms of action exist for osteoporosis and, if given to high-risk individuals, could dramatically reduce the risk of fracture. However, current osteoporosis treatment decisions are heavily driven by X-ray based measurements of BMD and risk surveys. Unfortunately, these tools lack sufficient discriminatory sensitivity and accuracy to identify many individuals at high risk of experiencing a fragility fracture. For instance, <50% of the variation in whole-bone strength is attributable to variations in BMD, and the vast majority of patients who sustain fragility fractures do not have low BMD (i.e., they have T-score’s above −2.5). Thus, there is a large unmet need to better diagnose patients who are at risk of fracture, so that physicians can accurately identify individuals who would benefit from osteoporosis medications and to better monitor the effectiveness of treatment.
OsteoDx’s market research, interviews with key opinion leaders, and prior meetings with the FDA have identified the most important and immediate commercialization milestones necessary for FDA approval and market adoption: a study that demonstrates the accuracy (aim 1) and clinical precision (aim 2) of the final design production version of the medical device, and advances safety and regulatory compliance (aim 3). Thus, in this Phase II application we propose a series of experiments, tests, and approaches to accomplish the above-mentioned aims.
Upon successful achievement of these aims, OsteoDx will be positioned to submit a Class II de novo medical device application to the FDA for noninvasively quantifying flexural rigidity of cortical bone in the ulna.