Bone Metabolism in 12-21 Year Olds Undergoing Glucagon Like Peptide (GLP)-1 Receptor Agonist Therapy

Bone Metabolism in Adolescents Undergoing GLP-1 Receptor Agonist Therapy

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:

• Take GLP-1RA as prescribed or continue to work on lifestyle management for weight loss
• Take provided calcium and vitamin D supplements

• Attend 6 study visits over 24 months with two at the beginning and then every 6 months that include:

  • History and Physical Exams
  • Lab Work
  • Imaging studies
  • Questionnaires
  • 24-hour dietary recalls

Study Overview

• Status: Recruiting
• Conditions: Obesity; Lifestyle Modification; Bone Density; Obesity in Children; Bone Strength; GLP - 1
• Intervention / Treatment: Drug: GLP-1 receptor agonist; Behavioral: Lifestyle intervention

Detailed Description

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.

Hypothesis 2: The investigators hypothesize that preservation of skeletal health despite reductions in weight, lean mass, ghrelin, insulin, oxytocin and estrone and increases in sclerostin is associated with increases in bone formation (as assessed by P1NP, a marker of bone formation) that equal or exceed those of bone resorption (as assessed by CTX, a marker of bone resorption), indicative of balanced bone turnover and net skeletal stability.

Adolescence is a critical time for bone accrual and the use of both GLP-1 RAs and MBS is increasing in youth. The study will provide novel data needed to establish whether use of GLP-1 RAs prevents the impairment in skeletal health observed following surgery in youth. Clarifying these mechanisms will identify optimal weight loss strategies in youth with obesity following lifestyle intervention.

Design:

This is a non-randomized two-group parallel observational pragmatic trial. The study will recruit 120 adolescents and young adults with obesity 12-21 years old, 60 of whom are being started clinically on GLP-1 RA therapy and 60 who will be followed with 'usual' care. Participants will be matched for BMI, sex, self-described race, age, and pubertal stage. The baseline visit will occur before starting GLP-1 RA therapy (for the active arm), and will be followed by visits 6, 12, 18, and 24-months after starting therapy. Controls will be followed at the same frequency. Participants will be counseled regarding lifestyle measures per protocol ('usual' care).

Analytical Plan:

Data generated will be longitudinal over 12 and 24-months. There are two study groups for the longitudinal component: those undergoing GLP-1 RA therapy, and adolescents with obesity followed with usual care.

Analysis of Treatment Group Comparability: Demographic and baseline characteristics will be summarized by treatment group (GLP-1 RA vs. usual care) using descriptive statistics and will be compared using a t-test or Chi-square test depending on data types.

Analysis of Aim 1:

The study is powered for analysis of the primary endpoint i.e. baseline to 24-month change in the HR-pQCT measure of total vBMD (distal radius). This analysis will include all randomized subjects according to treatment (intent to treat). The investigators will test for equivalency of the between-group treatment effects by examining if the upper limit of the 90% confidence interval of the GLP-1 RA versus 'usual care' difference in the group-specific HR-pQCT mean change is above -30 (i.e., no less than 10% below 300 mgHA/cm3) and the lower limit is below 30 (i.e., no more than 10% above 300 mgHA/cm3). The same analysis approach as that of the primary endpoint analysis will be applied to secondary endpoints. Investigators will not adjust Type-1 error for the inference of these multiple secondary endpoints.

Method to analyze longitudinal data: Although the primary analysis endpoints are 24-month change, for longitudinal data collected at multiple time points (baseline, 12 and 24 months), as parallel analyses, investigators will utilize all available repeated measures in longitudinal general linear mixed effects models with the treatment difference at 24-month as the primary contrast of interest. The subject level intercept will be considered as random. The closest pattern of time dependency will be identified by means of exploratory longitudinal plots before fitting the model. The model will include group and time as the main effects and group x time as the interaction, and the above-mentioned equivalency test method will be applied to the model-based estimate of the treatment difference at 24-month. SAS Proc Mixed procedure with exchangeable- or more appropriate correlation structure will be used. This analysis will include all data collected on all subjects irrespective of whether the subject completed all 24 months of follow up, and follows the Institute of Medicine (IOM) suggestion for analysis of data with missing observations. The investigators will adjust for confounders as necessary (the study will match participants for age, sex, race, and BMI). For Aim 2, the investigators will estimate within-group correlations (Pearson or Spearman as appropriate based on distribution) of 24-month change in weight, lean mass, and hormones with change in P1NP and CTX; and then examine if these correlations differ between the two treatment groups.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Madhusmita Misra, MD, MPH; Phone Number: 434-924-9141; Email: madhusmita.misra@uvahealth.org
• Study Contact Backup: Name: Christine Burt Solorzano, MD; Phone Number: 434-924-9084; Email: christine.burtsolorzano@uvahealth.org

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Recruiting
      • University of Virginia Medical Center
      • Sub-Investigator: Christine Burt Solorzano, MD
      • Contact: Email: christine.burtsolorzano@uvahealth.org
      • Principal Investigator: Madhusmita Misra, MD, MPH
      • Contact: Melissa G Gilrain, BS; Phone Number: 434-243-6911; Email: misralab@uvahealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Study Population

Children, teenagers and adults with obesity 12-21 years old

Description

Inclusion Criteria:

• • 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.

Exclusion Criteria:

• • 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-5.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GLP-1 Receptor Agonist	Drug: GLP-1 receptor agonist; Participants prescribed a GLP-1 receptor agonist by their physician will be enrolled in this arm of the study. All participants will receive study provided calcium & vitamin D supplement to support bone health and to reduce this as a confounding factor in overall outcomes
Placebo Comparator: Lifestyle Intervention	Behavioral: Lifestyle intervention; Participants receiving usual lifestyle interventions will be enrolled in this arm of the study. All participants will receive study provided calcium & vitamin D supplement to support bone health and t

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-month change in total vBMD at the distal radius	Using repeated measures analysis, the investigators will compare change in radius vBMD after 24 months of treatment with GLP-1 RAs vs. routine care	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-month change in total vBMD at the distal tibia	Using repeated measures analysis, the investigators will compare change in radius vBMD after 24 months of treatment with GLP-1 RAs vs. routine care	24 months
24-month change in radial and tibial trabecular vBMD	Using repeated measures analysis, the investigators will compare changes in radial and tibial trabecular vBMD after 24 months of treatment with GLP-1 RAs vs. routine care	24 months
24-month change in total hip and spine areal BMD	Using repeated measures analysis, the investigators will compare changes in areal BMD at the total hip and spine after 24 months of treatment with GLP-1 RAs vs. routine care	24 months
24-month change in strength estimates (failure load) at the radius and tibia	Using repeated measures analysis, the investigators will compare changes in radial and tibial failure load after 24 months of treatment with GLP-1 RAs vs. routine care	24 months
24-month change in load-to-strength ratio at the wrist and hip	Using repeated measures analysis, the investigators will compare changes in load-to-strength ratio at the wrist and hip after 24 months of treatment with GLP-1 RAs vs. routine care	24 months
24-month change in P1NP and CTX	Using repeated measures analysis, the investigators will compare changes in P1NP and CTX after 24 months of treatment with GLP-1 RAs vs. routine care	24 months
24-month change in hormones known to impact bone (insulin, ghrelin, PYY, oxytocin, estrogens and sclerostin)	Using repeated measures analysis, the investigators will compare changes in these hormones after 24 months of treatment with GLP-1 RAs e vs. routine care and in relation to changes in bone turnover markers	24 months

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Madhusmita Misra, MD, MPH, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2025
• Primary Completion (Estimated): February 28, 2030
• Study Completion (Estimated): April 30, 2030

Study Registration Dates

• First Submitted: March 25, 2025
• First Submitted That Met QC Criteria: March 25, 2025
• First Posted (Actual): April 1, 2025

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: GLP-1; obesity; semaglutide; bone density; Lifestyle modification; liraglutide; bone strength; obesity in children
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Pediatric Obesity; Physiological Effects of Drugs; Hypoglycemic Agents; Glucagon-Like Peptide-1 Receptor Agonists
• Other Study ID Numbers: HSR302394; R01HD118635 (U.S. NIH Grant/Contract: NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Primary and secondary endpoint data, including all bone endpoints, will be submitted to the Harvard Dataverse repository to enable other researchers to analyze our study data independently. The privacy, rights, and confidentiality of human research participants will be protected by sharing only de-identified data.
• IPD Sharing Time Frame: Data sharing will occur no later than the end of performance period of the extramural award that generated the data. There is no end date planned at this time.
• IPD Sharing Access Criteria: Study investigators will make access to deidentified data available via repository without restriction to access. Data available will include deidentified demographic data and those related to primary and secondary endpoints.
• IPD Sharing Supporting Information Type: SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes