Bone Metabolism in Adolescents Undergoing GLP-1 Receptor Agonist Therapy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Change in total volumetric bone mineral density (vBMD) the distal radius measured by HR-pQCT
研究概览
简要总结
The goal of this clinical trial is to compare bone health markers over 24 months in participants 12 - 21 years of age with obesity who are starting the glucagon-like peptide-1 receptor agonists (GLP-1RAs) as compared to those with similar weight followed by lifestyle management.
Participants will:
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Take GLP-1RA as prescribed or continue to work on lifestyle management for weight loss
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Take provided calcium and vitamin D supplements
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Attend 6 study visits over 24 months with two at the beginning and then every 6 months that include:
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History and Physical Exams
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Lab Work
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Imaging studies
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Questionnaires
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24-hour dietary recalls
详细描述
Obesity is now epidemic, and as a consequence, the use of weight loss medications and surgery to manage obesity is increasing. Weight loss surgery is associated with significant bone loss, concerning during the adolescent years of peak bone accrual. With the increasing use of weight loss medications, particularly glucagon-like-peptide 1 receptor agonists (GLP-1 RAs), in adolescents, it is essential to determine whether weight loss following use of these medications is associated with detrimental effects on skeletal health. Data from the literature are conflicting following use of GLP-1 RA in adults with obesity. Whether GLP-1 RA use preserves bone anabolic activity during adolescence merits investigation and is the focus of the proposal. If the investigators' hypotheses prove correct and use of GLP-1 RAs preserves bone accrual and skeletal health in youth with obesity, the results of this study may favor GLP-1 RA treatment over surgery following lifestyle management. Multiple mechanisms contribute to bone loss after surgery in youth including mechanical unloading of bone from weight loss, loss of lean mass, and changes in hormones that stimulate anabolic bone activity and/or are anti-resorptive. Weight loss following use of GLP1-RAs should similarly lead to skeletal unloading, reductions in lean mass, and changes in hormones. However, GLP-1 RAs have direct bone anabolic effects, and anti-resorptive effects as demonstrated in both rodent and human studies. Thus, GLP-1 RAs might mitigate deleterious effects of weight loss on skeletal health through a direct impact on bone formation and resorption. DXA-based BMD measurements have limitations in obesity and during weight loss, being susceptible to artifactual changes from a reduction in soft tissue thickness after severe weight loss. The study will therefore use advanced 3D imaging techniques to overcome limitations of DXA in the context of the marked soft tissue changes following weight loss. The investigators' overall hypothesis is that despite marked weight loss in adolescents with obesity receiving GLP-1 RAs over 24 months, study participants will demonstrate preservation of areal and volumetric BMD, bone geometry, structure and estimated strength, and improvements in estimated fracture risk.
Aim 1: To determine to what extent GLP-1 RA therapy alters bone density, geometry, structure, strength and load-to-strength ratio prospectively over 24 months in adolescents and young adults ages 12-21 years with obesity compared to controls of similar weight followed with lifestyle management. The investigators hypothesize that following GLP-1 RA therapy vs. lifestyle management:
Hypothesis 1A: Volumetric BMD of the distal radius (a non-weight bearing site) (primary endpoint) and distal tibia (a weight-bearing site) by HRpQCT, and areal BMD of the hip and spine by DXA will be preserved.
Hypothesis 1B: Cortical and trabecular geometry and structure at the distal radius and tibia (by HR-pQCT), and bone strength estimates (by μFEA) will be preserved; load-to-strength ratio will improve.
Aim 2: To investigate novel physiologic mechanisms mediating maintenance of skeletal integrity following use of GLP-1RAs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
盲法说明
Participants prescribed GLP-1 receptor agonists or lifestyle intervention by their treating physician will be followed over 24 months
入排标准
- 年龄范围
- 12 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •• Adolescents and young adults with obesity 12-21 years old starting GLP-1 RA therapy (except for dulaglutide or exenatide) or followed with 'usual' care.
- •Diagnosis of obesity (BMI ≥ 95th percentile for age and sex). The FDA has approved the use of GLP-1 RAs (liraglutide and semaglutide) for adolescents ≥ 12 years old with BMI ≥ 95th percentile for age and sex, and tirzepatide for adults with obesity. Those in the GLP-1 RA arm must have demonstrated efforts at weight loss with 'usual' care, and consistent compliance with appointments and recommendations.
- •Participants must demonstrate sufficient maturity, psychological stability and cognitive capacity to recognize the significance of being on medical therapy and implement required behavioral changes
- •Patients taking orlistat as a precursor to GLP-1 RA therapy due to insurance requirements may be included given minimal effects on weight.
- •Use of the following contraceptive methods is permitted: Combine oral contraceptives (COCs); continuous oral progestin; Progestin-releasing intrauterine device (IUD); Progestin implant; transdermal patch.
- •Patients with celiac disease will be included if the condition is well controlled and they are on a gluten free diet with normal 25(OH)D levels confirmed by clinical labs within 3 months of enrollment in the study. If a patient does not have recent 25(OH)D results, we will add this to the screening labs.
排除标准
- •• Current or previous history of pregnancy and breast feeding.
- •Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 if in the GLP-1 RA group.
- •> 5 kg weight loss over 3 months given the known impact of significant weight loss on bone density.
- •Use of dulaglutide and exenatide (of the GLP-1 RAs) given minimal weight loss with these drugs.
- •Use of medications such as metformin, phentermine, or topiramate that may cause weight loss, or obesogenic antipsychotic medications if treated for <3 months, or if dosage is not stable for >2 months.
- •Medications other than calcium or vitamin D that affect bone, such as systemic glucocorticoids, phenytoin, phenobarbitone (unless there is a washout period of 3 months prior to enrollment if discontinuation is medically permissible)
- •Female participants on hormonal contraception will be excluded if this involves use of depot medroxyprogesterone acetate (DMPA). DMPA has profound deleterious effect on bone density, which could confound study outcomes related to bone health. Rationale: DMPA has a well-documented deleterious effect on bone density, which could confound study outcomes related to bone health or metabolic parameters.
- •Untreated thyroid dysfunction or on stable dose for <3 months. Primary thyroid dysfunction will be defined as: a TSH ≥ 10 IU/L or low per given reference range with unknown thyroid antibody status, or an abnormal TSH if known positive antibodies. Patients with known hypothyroidism will be included if appropriately treated with levothyroxine and have a normal TSH. For patients with secondary hypothyroidism (deficient production of TSH from the pituitary gland causing hypothyroidism), normal free T4 concentrations (and not TSH alterations) will be used for study inclusion, and recent adjustments in the levothyroxine dose will be permissible as long as free T4 concentrations are in the normal range at dose adjustment (as dose adjustments are often made to get free T4 concentrations in the upper half of the normal range when assessed levels are in the lower half of the normal range). Patients with hyperthyroidism will be excluded given known deleterious effects on both weight and bone metabolism.
- •Medical conditions known to impact weight or bone density, such as chronic gastrointestinal disorders (including inflammatory bowel disease), other inflammatory conditions, such as rheumatoid arthritis or ankylosing spondylitis, untreated thyroid disease, and hypercortisolemia.
- •HbA1C >8% (to avoid deleterious effects on bone from uncontrolled T2DM).
- •Smoking >10 cigarettes/day given deleterious effects on bone; substance abuse per DSM-
- •Weight >450 lbs due to limits for DXA scanners.
- •History of metabolic and bariatric surgery.
- •Judged by the investigators to be inappropriate for the study for other reasons not detailed above.
研究组 & 干预措施
Lifestyle Intervention
干预措施: Lifestyle intervention (Behavioral)
GLP-1 Receptor Agonist
干预措施: GLP-1 receptor agonist (Drug)
结局指标
主要结局
Change in total volumetric bone mineral density (vBMD) the distal radius measured by HR-pQCT
时间窗: 24 months
To assess the effect of GLP-1 RA (semaglutide) therapy on vBMD at a non-weight-bearing site (distal radius) in adolescents and young adults with obesity, compared to matched controls receiving lifestyle management.
24-month change in total vBMD at the distal radius
时间窗: 24 months
Using repeated measures analysis, the investigators will compare change in radius vBMD after 24 months of treatment with GLP-1 RAs vs. routine care
次要结局
- Change in total volumetric bone mineral density (vBMD) the distal tibia measured by HR-pQCT(24 months)
- Change in trabecular vBMD of the distal tibia and radius assessed by HR-pQCT(24 months)
- Change in areal BMD of the lumbar spine and total hip measured by DXA(24 months)
- Change in estimated bone strength (radius and tibia) using micro finite element analysis (μFEA)(24 months)
- Change in load-to-strength ratio at the radius and hip(24 months)
- Change in bone turnover markers (P1NP and CTX)(24 months)
- Changes in gut related and sex hormones(24 months)
- 24-month change in total vBMD at the distal tibia(24 months)
- 24-month change in radial and tibial trabecular vBMD(24 months)
- 24-month change in total hip and spine areal BMD(24 months)
- 24-month change in strength estimates (failure load) at the radius and tibia(24 months)
- 24-month change in load-to-strength ratio at the wrist and hip(24 months)
- 24-month change in P1NP and CTX(24 months)
- 24-month change in hormones known to impact bone (insulin, ghrelin, PYY, oxytocin, estrogens and sclerostin)(24 months)
研究者
Madhusmita Misra
Professor of Pediatrics
University of Virginia