Radiation-Induced Osteoporosis in Women with Cancer: Mechanisms and Prevention

女性癌症患者辐射诱发的骨质疏松症：机制和预防

基本信息

批准号：
8901750
负责人：
Ted A Bateman
金额：
$ 30.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901750
关键词：
Accounting Acute Address Animal Model Binding Proteins Bone Marrow Bone Marrow Cells Bone Matrix Bone Mineral Contents Bone Resorption Cessation of life Clinical Clinical Research Clinical Treatment Clinical Trials Companions Deterioration Disease Estrogens Etanercept Event Femur Finite Element Analysis Fracture Functional disorder Goals Health Hip Fractures Hip region structure Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-1 Ionizing radiation Long-Term Effects Longitudinal Studies Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Marrow Mechanics Mediating Molecular Morbidity - disease rate Mus Osteoblasts Osteoclasts Osteoporosis Patients Pelvis Phagocytes Postmenopause Pre-Clinical Model Prevention Property Prophylactic treatment Proteins Protocols documentation Quality of life Radiation Radiation therapy Raman Spectrum Analysis Rectal Cancer Regimen Research Risedronate Risk Role Signal Transduction Soft Tissue Neoplasms Staging Structure Survivors TNF gene TNFSF11 gene Testing Transforming Growth Factor beta Translating Treatment Protocols Treatment-Related Cancer Tumor Necrosis Factor-alpha Tumor necrosis factor receptor 11b Walking Woman Zoledronate anakinra bisphosphonate bone bone loss bone mass bone quality bone strength cancer diagnosis cytokine innovation irradiation kinase inhibitor macrophage mortality mouse model neutrophil novel strategies osteoblast differentiation pre-clinical research prevent public health relevance radiation response receptor response substantia spongiosa targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): Pelvic tumors account for 25% of the 700,000 annual cancer diagnoses in women. Radiotherapy for soft-tissue tumors in the pelvic region increases hip-fracture risk, resulting in substantial patient morbidity and mortality: Treatment for rectal, cervical, and anal cancers in postmenopausal women significantly increases fracture rates by 66%, 65%, and 214%, respectively. Nearly 20% of all women who fracture their hips will not survive one year. Of those who do survive, 85% will not be walking unaided at one year, and most survivors will never return to pre-fracture quality of life. In our preclinical models, ionizing radiation rapidly activated osteoclastic bone resorption and caused a decline in trabecular-bone volume fraction of 20-30% during the seven to fourteen days after exposure. Increased expression of proinflammatory cytokines in the marrow preceded activation of osteoclasts, which was followed by evidence (indicated by phosphoSmad2) of activated transforming growth factor-beta (TGF¿) signaling. In companion studies, the loss in trabecular-bone volume fraction was prevented by the bisphosphonate risedronate. Our recently completed clinical trial confirms rapid bone loss in patients receiving radiation therapy for gynecological tumors: We observed a 14% decline in proximal femur bone mineral content (BMC). No prophylactic treatment exists for radiation therapy-induced osteoporosis, and molecular mechanisms for this rapid loss of bone mass and strength and resultant increased fracture risk are unknown. We propose that radiation therapy in women with pelvic tumors causes a rapid decline in bone mass that leads to increased fracture risk. We hypothesize that the causal mechanism for this radiation-induced deficit in bone quality is rapid activation (from bone-marrow's early inflammatory response to radiation damage) of osteoclasts via the cytokines tumor necrosis factor-alpha (TNFa) and interleukin-1 (IL-1). Estrogen suppression enhances this inflammatory response by promoting greater phagocyte infiltration. Furthermore, the subsequent release of TGF¿ from resorbed bone matrix propagates and accelerates bone loss by increasing osteoclastic bone resorption and inhibiting osteoblast differentiation. Existing therapies for osteoporosis and other disorders (e.g., the antiresorptive zoledronate, RANKL-blocking osteoprotegerin (OPG), TNFa binding protein [TNFbp], IL-1 receptor antagonist [IL-1ra], and a TGF¿ receptor I kinase inhibitor) may prevent this bone loss and could be rapidly translated to clinical treatment. To test this causal-mechanism hypothesis, the following specific Aims will determine 1) If greater levels of activated TGF¿ exacerbate radiation-induced bone loss; 2) The role of inflammatory cytokines TNFa and IL-1 in acute radiation-induced activation of osteoclastic bone resorption; 3) If osteoclast-inhibiting therapies preserve bone mass in a mouse model for radiation-induced bone loss in the setting of estrogen deficiency. By addressing an unstudied biomedical problem that we have already translated to a clinical trial, this innovative proposal's clinical impact could reduce the risk of cancer treatment-related morbidity such as radiation therapy-induced fractures. The cause of these fractures is poorly understood, and no preventative therapies are in use. If radiation therapy increases fracture risk by activating osteoclastic bone resorption, existing antiresorptive osteoporosis therapies should prevent radiation therapy-induced fractures.

描述（由适用提供）：骨盆肿瘤占女性每年癌症诊断的25％。骨盆区域软组织肿瘤的放射疗法增加了髋骨骨折的风险，导致了大量患者的发病率和死亡率：绝经后女性直肠，宫颈和肛门癌的治疗显着增加了骨折率，分别将骨折率显着增加66％，65％和214％。在骨折的所有臀部骨折的女性中，近20％将无法生存一年。在那些生存下来的人中，有85％的人不会在一年后独立行走，大多数幸存者将永远不会回到骨折前的生活质量。在我们的临床前模型中，电离辐射迅速激活的破骨骨骨分辨率，并在暴露后的七至14天内导致小梁骨体积分数下降20-30％。在骨髓中激活破骨细胞的促炎细胞因子的表达增加，随后是激活转化的生长因子β（TGF。）信号传导的证据（用磷酸化的证据表明）。在合作伙伴研究中，双膦酸酯偶合酸酯酯可以预防小梁骨体积分数的损失。我们最近完成的临床试验证实，接受妇科肿瘤放射治疗的患者的骨质流失迅速：我们观察到近端股骨骨矿物质含量（BMC）下降了14％。没有预防性治疗用于放射治疗诱导的骨质疏松症，也不存在这种快速骨骼质量损失和强度以及增加骨折风险增加的分子机制，这是未知的。我们提出，骨盆肿瘤女性的放射治疗会导致骨骼质量迅速下降，从而导致骨折风险增加。我们假设通过细胞因子肿瘤坏死因子因子因子因子 - 阿尔法（TNFA）和Iltleukinkin-1（IL-1）（IL-1），通过细胞因子肿瘤坏死因子因子因子因子 - α（IL-1）来激活这种辐射引起的骨骼质量不足的灾难性机制是快速激活（来自骨row对辐射损伤的早期炎症反应）。雌激素抑制通过促进大吞噬细胞浸润来增强这种炎症反应。此外，随后从吸附骨基质中释放TGF，通过增加破骨骨骨骼的分辨率并抑制成骨细胞分化，从而繁殖并加速骨质流失。现有的骨质疏松症和其他疾病的疗法（例如，抗吸收性的丧失型酸球酸，RANKL阻断骨蛋白蛋白蛋白蛋白蛋白（OPG），TNFA结合蛋白[TNFBP] [TNFBP]，IL-1受体受体拮抗剂[IL-1RA]，以及TGF的受体损失可能会受到损失的损失。为了检验这种因果力学假设，以下特定目标将确定1）如果激活的TGF水平更高，则加剧了辐射诱导的骨质流失； 2）炎性细胞因子TNFA和IL-1在急性辐射诱导的破骨骨溶液激活中的作用； 3）如果破骨细胞抑制疗法将在小鼠模型中保留骨骼质量，以用于雌激素缺乏症的辐射诱导的骨质损失。通过解决我们已经转化为临床试验的未研究的生物医学问题，该创新提案的临床影响可以降低与癌症治疗相关的发病率（例如放射治疗诱导的骨折）的风险。这些碎片的原因很少了解，也没有使用预防性疗法。如果放射治疗通过激活骨碎屑骨的分辨率增加骨折风险，则现有的抗吸收性骨质疏松疗法应防止放射治疗引起的骨折。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: a model of long-duration spaceflight.

DOI：
10.1016/j.bone.2012.07.001
发表时间：
2012-10
期刊：
BONE
影响因子：
4.1
作者：
Lloyd, Shane A.;Bandstra, Eric R.;Willey, Jeffrey S.;Riffle, Stephanie E.;Tirado-Lee, Leidamarie;Nelson, Gregory A.;Pecaut, Michael J.;Bateman, Ted A.
通讯作者：
Bateman, Ted A.

Effects of combined insulin-like growth factor 1 and macrophage colony-stimulating factor on the skeletal properties of mice.

胰岛素样生长因子 1 和巨噬细胞集落刺激因子联合使用对小鼠骨骼特性的影响。

DOI：
发表时间：
2011
期刊：
In vivo (Athens, Greece)
影响因子：
0
作者：
Lloyd,ShaneA;Simske,StevenJ;Bogren,LoriK;Olesiak,SaraE;Bateman,TedA;Ferguson,VirginiaL
通讯作者：
Ferguson,VirginiaL

Changes in mouse thymus and spleen after return from the STS-135 mission in space.

DOI：
10.1371/journal.pone.0075097
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Gridley DS;Mao XW;Stodieck LS;Ferguson VL;Bateman TA;Moldovan M;Cunningham CE;Jones TA;Slater JM;Pecaut MJ
通讯作者：
Pecaut MJ

A Mouse Model for Skeletal Structure and Function Changes Caused by Radiation Therapy and Estrogen Deficiency.

放射治疗和雌激素缺乏引起的骨骼结构和功能变化的小鼠模型。

DOI：
10.1007/s00223-019-00617-x
发表时间：
2020
期刊：
Calcified tissue international
影响因子：
4.2
作者：
Sullivan,LindsayK;Livingston,EricW;Lau,AnthonyG;Rao-Dayton,Sheila;Bateman,TedA
通讯作者：
Bateman,TedA

Microgravity control of autophagy modulates osteoclastogenesis.

DOI：
10.1016/j.bone.2014.01.004
发表时间：
2014-04
期刊：
BONE
影响因子：
4.1
作者：
Sambandam, Yuvaraj;Townsend, Molly T.;Pierce, Jason J.;Lipman, Cecilia M.;Haque, Azizul;Bateman, Ted A.;Reddy, Sakamuri V.
通讯作者：
Reddy, Sakamuri V.