Bisphosphonate Use to Mitigate Bone Loss Secondary to Bariatric Surgery

使用双膦酸盐减轻减肥手术继发的骨质流失

基本信息

批准号：
10624846
负责人：
Jamy D Ard
金额：
$ 64.43万
依托单位：
WAKE FOREST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-20 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624846
关键词：
Age Agreement American Animal Model Area Biological Biological Markers Body Weight decreased Bone Density Bone Resorption Cells Clinical Clinical Management Clinical Pathology Complement Cyclophosphamide Data Distal Dual-Energy X-Ray Absorptiometry Effectiveness of Interventions Etiology Fatty acid glycerol esters Femur Fracture GDF8 gene Gastrectomy Health Benefit Hip region structure Human Infiltration Intervention Intervention Trial Knowledge Measures Metabolic Monitor Morbid Obesity Muscle Muscular Atrophy Musculoskeletal Neck Obesity Operative Surgical Procedures Oral Osteoclasts Outcome Assessment Participant Patients Physical Function Physical Performance Placebos Positioning Attribute Procedures Public Health Radial Randomized Recommendation Reporting Risedronate Secondary to Signal Transduction Site Skeleton Societies TNFSF11 gene Task Performances Testing Thick Thinness Transforming Growth Factor beta United States Vertebral column Walking X-Ray Computed Tomography animal data bariatric surgery bioimaging bisphosphonate bone bone loss bone turnover clinical practice comorbidity density design fracture risk gastrointestinal high risk improved insight middle age mouse model novel osteoporosis with pathological fracture preservation primary outcome prospective skeletal therapy design treatment group trial design working group

项目摘要

PROJECT SUMMARY Despite well recognized improvements in obesity-related comorbidities, mounting evidence implicates sleeve gastrectomy (SG) in the onset of skeletal fragility. Bisphosphonate therapy reduces osteoporotic fracture risk and may also be effective in minimizing bone loss associated with SG. Once-monthly oral risedronate is a commonly prescribed bisphosphonate with a favorable gastrointestinal profile that acts by inhibiting the activity of osteoclast cells, thereby decreasing the rate of bone resorption. Because SG is associated with a significant increase in bone resorption, we hypothesize that risedronate use will counter bone loss in this clinical scenario, ultimately reducing long-term fracture risk. Indeed, pilot data from our group signal that six months of risedronate use is both feasible and likely effective at reducing bone resorption and bone mineral density (BMD) loss post- SG as compared to placebo. Intriguingly, we also observe a signal for appendicular lean mass preservation with risedronate use. This novel finding aligns with data from animal models of clinical pathology and limited observational data in humans, suggestive of a bisphosphonate-induced lean-mass sparing effect. If true, confirmatory data from a definitively designed trial is poised to influence clinical management of the SG patient, while also providing a platform upon which to interrogate mechanisms of bone-muscle crosstalk. To fill these knowledge gaps, the main objective of the proposed study is to definitively test whether risedronate use can effectively counter SG associated bone loss. To do this, we propose to randomize 120 middle-aged and older (≥40 years) SG patients to six months of risedronate or placebo treatment, with bone and muscle outcomes assessed at baseline, six, and 12 months. Due to its robust change following SG and clinical utility in predicting fracture, our primary outcome is change in total hip areal (a)BMD measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and appendicular lean mass, as well as quantitative computed tomography (QCT) derived changes in bone (volumetric BMD, cortical thickness, and strength) and muscle (cross sectional area, fat infiltration) at the hip and spine — allowing for novel assessment of intervention effectiveness on several state of the art bioimaging metrics — as well as select physical function tasks. Biomarkers of bone turnover and bone-muscle crosstalk will also be assessed in a tertiary aim, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Definitive data has the potential to shift current clinical practice while also offering insight into underlying biologic mechanisms.

项目概要尽管肥胖相关合并症的改善已得到公认，但越来越多的证据表明袖子骨骼脆性发作时进行胃切除术（SG）可降低骨质疏松性骨折风险。每月一次口服利塞膦酸盐也可能有效减少与 SG 相关的骨质流失。常用的双膦酸盐具有良好的胃肠道特性，通过抑制活性发挥作用破骨细胞，降低骨吸收率，因为 SG 与显着相关。骨吸收增加，我们发现利塞膦酸盐的使用将在这种临床情况下抵消骨质流失，事实上，我们小组的试验数据表明，六个月的利塞膦酸盐。使用在减少骨吸收和骨矿物质密度（BMD）损失方面既可行又可能有效。有趣的是，与安慰剂相比，我们还观察到了保留阑尾瘦肉块的信号。这一新发现与临床病理学动物模型的数据一致并且有限。人体观察数据表明双膦酸盐引起的瘦体重节约效应如果属实，来自最终设计的试验的验证性数据将影响 SG 患者的临床管理，同时还提供了一个平台来询问骨-肌肉串扰的机制来填补这些问题。由于知识差距，拟议研究的主要目的是明确测试利塞膦酸盐的使用是否可以有效对抗 SG 相关的骨质流失为此，我们建议对 120 名中老年人进行随机分组。（≥40 岁）SG 患者接受六个月的利塞膦酸盐或安慰剂治疗，具有骨骼和肌肉结果由于其在 SG 和预测中的临床效用后的强劲变化，在基线、6 个月和 12 个月进行了评估。骨折，我们的主要结果是通过双能 X 射线骨密度测定法测量的髋部总面积 (a)BMD 的变化 (DXA) 将通过 DXA 获得的其他骨骼部位和阑尾的 aBMD 评估来补充。瘦体重以及定量计算机断层扫描 (QCT) 衍生的骨变化（体积 BMD、皮质厚度和强度）以及臀部和脊柱处的肌肉（横截面积、脂肪渗透）——允许对几种最先进的生物成像指标的干预效果进行新颖的评估 - 以及还将评估骨转换和骨肌肉串扰的选择身体功能任务。第三个目标是提供对骨肌肉单位干预相关变化的机制洞察。数据有可能改变当前的临床实践，同时也提供对基础生物学的洞察机制。