Bone metabolism in adolescents undergoing GLP-1 receptor agonist therapy

University Of Virginia, Charlottesville VA

Investigators

Abstract

Abstract Obesity is now epidemic, and as a consequence, the use of weight loss medications and surgery to manage obesity is increasing in both adults and adolescents. Metabolic and bariatric surgery (MBS) effectively enables sustained weight loss. However, our data in adolescents and young adults indicate that it causes marked loss of bone density, structure, and strength estimates. This is particularly alarming during adolescence, a time of rapid bone accrual towards attainment of peak bone mass, a key determinant of fracture risk across the lifespan. With the increasing use of weight loss medications, particularly glucagon-like-peptide 1 receptor agonists (GLP-1 RA), in adolescents, it is essential to determine whether weight loss following use of these medications is associated with similar detrimental effects on bone accrual. Interestingly, our preliminary data in adults and adolescents indicate preservation of skeletal health despite significant weight loss following use of GLP-1 RA. GLP-1 RAs have direct bone anabolic effects, as demonstrated in both rodent and human studies, and also anti-resorptive effects. Thus, a GLP-1 RA might mitigate the deleterious effects of weight loss on skeletal health through a direct impact on bone formation and resorption. Data from the literature are conflicting with one study reporting no change or improved bone outcomes following use of semaglutide (a commonly used GLP-1 RA) in adults with obesity, while another reported deterioration in bone outcomes following semaglutide use. Whether GLP-1 RA use preserves critical bone anabolic activity during adolescence merits investigation and is the focus of our proposal. If our hypotheses prove correct and use of GLP-1 RAs preserves bone accrual in youth with obesity, the results of this study will be paradigm shifting in the management of obesity in youth, favoring GLP-1 RA treatment over MBS following lifestyle management. Our overall hypothesis is that despite marked weight loss in adolescents and young adults with obesity receiving semaglutide (commonly used and FDA approved for use in children 12 and older) over 2 years, study participants will demonstrate preservation of areal and volumetric BMD, bone geometry, structure and estimated strength, and improvements in estimated fracture risk. In Aim 1, we will determine to what extent semaglutide alters bone density, geometry, structure, and strength, and load-to-strength ratio prospectively over 2 years in youth ages 12-21 years with obesity compared to controls of similar weight followed with lifestyle management. In Aim 2, we will investigate whether alterations in bone turnover markers explain how semaglutide impacts skeletal health. Our multi-center study will provide novel data needed to establish whether use of a GLP-1 RA prevents the impairment in skeletal health observed following MBS in youth. Clarifying these mechanisms will identify optimal weight loss strategies in youth with obesity following lifestyle intervention.