MON-800 - Early Tirzepatide-Induced Weight Loss Is Associated with Hip Bone Loss and Increased Bone Resorption: A Randomized Trial

Background: Potent incretin-based therapies induce rapid weight loss but their skeletal effects remain incompletely defined. While GLP-1 receptor agonists were initially considered bone-neutral, emerging fracture signals and profound catabolic weight loss raise concern for regional bone vulnerability, particularly with dual GIP/GLP-1 agonists such as tirzepatide.

Methods: TABFAT is a randomized, placebo-controlled trial including 34 premenopausal women with obesity (17 tirzepatide, 17 placebo). Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 6 months to assess lumbar spine, total hip, femoral neck, and whole-body bone mineral density (BMD), bone mineral content (BMC), and area. Serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) were measured to characterize bone remodeling.

Results: Median weight loss in the tirzepatide group was −13.5% (IQR −19.3 to −8.7). Tirzepatide induced a discordant skeletal response, with a modest increase in lumbar spine BMD (+2.1%, p=0.034) but significant losses at the total hip (−3.2%, p< 0.001) and femoral neck (−4.4%, p=0.020). Whole-body BMD declined slightly (−0.9%, p=0.044), accompanied by reductions in BMC and skeletal area (both p< 0.001). Between-group comparisons confirmed significantly greater hip and femoral neck BMD loss with tirzepatide (both p< 0.01). Bone remodeling shifted markedly toward resorption, with CTX increasing by 84% and PINP decreasing by 16.8%, resulting in a pronounced rise in the CTX/PINP ratio (all p< 0.001). Losses in total hip BMD and BMC correlated with weight loss magnitude (rho 0.50–0.63, p< 0.05).

Conclusion: Early tirzepatide therapy is associated with significant hip bone loss accompanied by a pronounced shift toward increased bone resorption during rapid weight reduction.

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