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

• 批准号: 10440068
• 负责人: Jamy D Ard
• 金额: $ 66.08万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440068
• 关键词: Age; Agreement; American; Animal Model; Area; Bariatrics; 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; 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; Participant; Patients; Physical Function; Physical Performance; Placebos; Positioning Attribute; Procedures; Public Health; Radial; Randomized; Reporting; Risedronate; Secondary to; Signal Transduction; Site; Skeleton; Societies; Suggestion; 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; fragility fracture; gastrointestinal; high risk; insight; middle age; mouse model; novel; osteoporosis with pathological fracture; preservation; primary outcome; prospective; skeletal; therapy design; treatment group; trial design; working group

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.

项目摘要 尽管肥胖相关的合并症得到了公认的改善，但越来越多的证据表明， 胃切除术（SG）在骨骼脆弱的发病。双膦酸盐治疗降低了骨质疏松性骨折风险 并且还可以有效地使与SG相关的骨丢失最小化。每月一次口服利塞膦酸钠是一种 具有良好胃肠道特征的常用处方双膦酸盐，其通过抑制活性起作用 破骨细胞，从而降低骨吸收率。因为SG与一个重要的 骨吸收增加，我们假设利塞膦酸钠使用将在这种临床情况下对抗骨丢失， 最终降低长期骨折风险。事实上，我们小组的试验数据表明，六个月的利塞膦酸钠 在减少骨吸收和骨矿物质密度（BMD）损失方面， SG与安慰剂相比。有趣的是，我们还观察到阑尾瘦肉保留的信号， 使用利塞膦酸钠。这一新发现与临床病理学动物模型的数据一致， 在人类中的观察数据，提示双膦酸盐诱导的瘦体重保留效应。如果是真的， 来自明确设计的试验的证实性数据有望影响SG患者的临床管理， 同时还提供了一个平台，在其上可以询问骨-肌肉串扰的机制。填补这些 知识差距，拟议研究的主要目标是明确测试利塞膦酸钠的使用是否可以 有效对抗SG相关的骨丢失。为此，我们建议随机抽取120名中年和老年人， （≥40岁）SG患者接受利塞膦酸钠或安慰剂治疗6个月，骨和肌肉结局 在基线、6个月和12个月时进行评估。由于其在SG后的稳健变化和在预测 骨折，我们的主要结果是全髋关节面积的变化（a）双能X线骨密度仪测量的BMD （DXA）的标准曲线。这将通过DXA获得的其他骨骼部位和非骨骼部位的aBMD评估进行补充。 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）和肌肉（横截面积，脂肪浸润）-允许 用于对几种最先进的生物成像指标进行干预有效性的新评估，以及 选择身体功能任务。还将评估骨转换和骨-肌肉串扰的生物标志物， 第三个目标，提供对骨-肌肉单位干预相关变化的机械见解。明确 数据有可能改变当前的临床实践，同时也提供了对潜在生物学特性的深入了解。 机制等