SAT-770 - GLP-1 Receptor Agonist Use and Clinical Outcomes in Older Adults with Osteoporosis: Insights into the Bone-Obesity Axis

Obesity and osteoporosis, once considered metabolically distinct, share overlapping pathophysiology involving adipokine dysregulation, chronic inflammation, and altered bone remodeling. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, have shown pleiotropic effects on bone metabolism in preclinical models. However, real-world data on their impact in osteoporotic populations remains limited, particularly among older adults concurrently treated with osteoporosis medications.

Using the TriNetX Research Network, we identified adults ≥ 65 years with osteoporosis and active therapy (bisphosphonate, denosumab, raloxifene, or teriparatide) between 2005–2025. Cohort A included patients prescribed a GLP-1RA (n = 2,130); Cohort B included matched controls without GLP-1RA exposure (n = 2,130). Propensity-score matching balanced demographics, comorbidities (including diabetes, obesity, cardiovascular disease), and BMI. Outcomes analyzed over a 5-year window were hospitalization, mortality, and subsequent osteoporotic fracture encounters. Risk ratios and Kaplan–Meier survival analyses were calculated.

After matching (mean age 72.6 years, 84% female, Cohort A Mean BMI 31 kg/m²,Cohort B mean BMI 25.4 kg/m²), GLP-1RA users demonstrated lower hospitalization risk (30.0% vs 41.1%, RR 0.73, 95% CI 0.67–0.79, p< 0.001) and lower mortality (10.7% vs 19.4%, RR 0.55, 95% CI 0.47–0.64, p< 0.001) compared with non-users. However, subsequent fracture encounters were slightly higher in the GLP-1RA cohort (25.9% vs 20.9%, RR 1.24, 95% CI 1.11–1.38, p< 0.001). Survival analyses confirmed reduced all-cause mortality (HR 0.70) but increased fracture recurrence (HR 1.37).
GLP-1 receptor agonist (GLP-1RA) therapy was associated with favorable survival and hospitalization outcomes, despite a modestly higher rate of subsequent osteoporotic fractures. Baseline BMI remained higher among GLP-1RA users after matching, likely reflecting treatment indication, and fracture events occurred more frequently in this cohort. These findings underscore the interplay between the metabolic benefits of GLP-1 signaling and skeletal consequences. Further research is needed to determine whether the observed fracture risk reflects a direct pharmacologic effect versus weight loss.

Proposed mechanisms include rapid weight loss–induced mechanical unloading, transient acceleration of bone turnover, and direct GLP-1 receptor–mediated modulation of osteoblast and osteoclast activity through cAMP and calcitonin pathways. Clinicians should weigh the cardiometabolic advantages of GLP-1RAs against potential skeletal vulnerability, particularly in frail or underweight patients. Future mechanistic and longitudinal studies are warranted to further delineate the bone–metabolism crosstalk underlying these observations.

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