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Treating bone deterioration associated with chronic kidney disease

治疗与慢性肾病相关的骨质恶化

基本信息

批准号：
10554260
负责人：
Matthew R Allen
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554260
关键词：
Address Adenine Affect Age Animal Diseases Animal Model Animals Area Biological Assay Bone Diseases Bone Matrix Bone Resorption Bone Tissue Cells Cessation of life Chronic Kidney Failure Clinic Clinical Collagen Combined Modality Therapy Data Deterioration Development Disease Progression Dose Effectiveness FDA approved Female Fracture General Population Goals Health Homeostasis Hospitalization Individual Intervention Kidney Diseases Laboratories Measures Mechanics Mediating Methods Minerals Modeling Modification Osteogenesis Osteoporosis Outcome PTH gene Patients Persons Population Porosity Prevalence Prevention Property Quality of life Raloxifene Raman Spectrum Analysis Rattus Regimen Resistance Risk Sex Differences Testing Time Tissues Treatment Efficacy Veterans Water Work X-Ray Computed Tomography analog bisphosphonate bone bone fragility bone mass cinacalcet clinically relevant cortical bone effectiveness evaluation experimental study fracture risk human disease improved in vivo male mechanical properties microCT military veteran mortality mortality risk nanoindentation novel novel strategies pharmacologic pre-clinical prevent sex skeletal substantia spongiosa

项目摘要

The prevalence of chronic kidney disease (CKD) in our veterans is putting them at elevated risk of fracture and fracture-associated death. Nearly 1 of every 3 veterans has CKD, fracture risk in persons with CKD is 4x higher than the age-matched general population, and persons who fracture with CKD have longer hospitalization and higher mortality rates than patients without CKD who fracture. Simply stated, interventions aimed at reducing CKD-associated fracture would have a significant impact on veteran health. Skeletal fragility in CKD is unique from conditions such as osteoporosis. The hallmark of CKD-associated bone change is that cortical bone develops porosity (holes) and also has clear changes to bone material properties Moving forward, approaches to reduce skeletal fragility in CKD will need to address both reversal of cortical porosity and improvements in material properties. The goal of this proposal is to provide foundational data on cortical bone infilling in the setting of CKD. We will test the overall hypothesis that reversal of cortical porosity with enhanced material quality can combine to improve bone mechanical properties in CKD. To achieve this goal we will use two complementary animal models of kidney disease, one, the Cy/+ rat, to allow dynamic tracking of porosity changes over time. The second, an adenine-induced model, to allow sex-based differences in porosity dynamics and treatment efficacy to be studied. Both of these models have parallels the human disease in its development of disturbed mineral homeostasis and bone fragility. This means the results from this work will have high translational capacity to the clinic. In Aim 1 we will determine the effectiveness of suppressing bone resorption with and without simultaneous PTH suppression on cortical porosity infilling in CKD. Two clinically- relevant approaches will be studied – cinacalcet (to reduce parathyroid hormone) and bisphosphonate (to reduce osteoclastic bone resorption). Using two complementary animal models of CKD that develop robust cortical porosity, we will treat both male and female animals with either low-dose bisphosphonate or cinacalcet. Key outcomes will be cortical porosity, using repeated in vivo microCT scans, combined with a novel analysis approach that permits tracking of individual cortical pores over time. These experiments will help us to understand how pore infilling occurs using clinical approaches and how this may differ between sexes. In Aim 2 we will determine the effects of porosity infilling on tissue and structural mechanical properties. Tissues from Aim 1 will be measured with Raman spectroscopy and nano-indentation to characterize the mineral and collagen properties/mechanics of the newly infilled pore tissue. Whole bone mechanical properties (monotonic and fracture toughness) will be used to assess overall bone properties as surrogate measures of fracture resistance. Finally, in Aim 3 we will determine if combination treatment, targeting both pore infilling and modification of the infilled matrix is more effective in improving mechanical properties of CKD animals compared to either monotherapy. We have shown that raloxifene, a FDA-approved agent for treating bone, specifically benefits material properties. Furthermore, we have developed a novel analog for raloxifene that maintains beneficial effects on bone matrix with reductions in traditional cell-mediated effects. The experiments proposed will determine if the combination of infilling pores with enhanced properties of the matrix will have overall benefits. Collectively, the experiments proposed and the data to be generated will provide foundational data on pore infilling and serve as a platform on which to build a clinical regimen for reducing the skeletal burden and improving the quality of life of veterans suffering from CKD.

慢性肾脏疾病（CKD）在退伍军人中的患病率增加了他们骨折和死亡的风险

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strain-specific alterations in the skeletal response to adenine-induced chronic kidney disease are associated with differences in parathyroid hormone levels.

DOI：
10.1016/j.bone.2021.115963
发表时间：
2021-07
期刊：
Bone
影响因子：
4.1
作者：
Metzger CE;Swallow EA;Stacy AJ;Allen MR
通讯作者：
Allen MR

Assessing cortical bone porosity with MRI in an animal model of chronic kidney disease.

DOI：
10.1016/j.bone.2023.116808
发表时间：
2023-05
期刊：
Bone
影响因子：
4.1
作者：
C. Newman;Rachel K. Surowiec;Elizabeth A. Swallow;Corinne E. Metzger;Jieun Kim;Andrew A. Tomaschke;N. Chen;M. Allen;Joseph M. Wallace;S. Moe;Yu-chien Wu;P. Niziolek
通讯作者：
C. Newman;Rachel K. Surowiec;Elizabeth A. Swallow;Corinne E. Metzger;Jieun Kim;Andrew A. Tomaschke;N. Chen;M. Allen;Joseph M. Wallace;S. Moe;Yu-chien Wu;P. Niziolek

Recent Advances in Understanding Bisphosphonate Effects on Bone Mechanical Properties.

了解双膦酸盐对骨机械性能影响的最新进展。