Comparative Investigation of Changes in Body Composition and Bone Turnover Markers in People With Obesity After Treatment With Tirzepatide Versus Liraglutide. A Prospective Cohort Study.

Title of the study Comparative investigation of changes in body composition and bone turnover markers in people with obesity after treatment with tirzepatide versus liraglutide. A prospective cohort study.

Research Hypothesis:

The investigators hypothesize that treatment with tirzepatide versus liraglutide will yield distinct effects on markers of bone turnover and body composition, independent of the magnitude of weight loss due to different molecular mechanisms of action.

Keywords Obesity, Bone Metabolism, Body Composition, Lean mass, Free Fat Mass, Fat Mass, Tirzepatide, Liraglutide, CTX, P1NP, TRAP5b

Introduction Obesity is a growing global health concern, associated with various metabolic disorders, including hypertension, diabetes, metabolic syndrome, non-alcoholic fatty liver disease, sleep apnea and ultimately cardiovascular events. Obesity has also been linked to osteoporosis and high risk of fragility fractures. However, this relationship remains complex, as it involves multiple factors, including mechanical load from body weight, the type and distribution of adipose tissue, imbalances in nutrient intake, and a wide variety of cytokines (adipokines) and hormones secreted by the adipose tissue. On the other hand, rapid and substantial weight loss is associated with a significant reduction in bone mineral density (BMD), osteomalacia and increased risk of fragility fractures. Assessment of bone turnover status can be reliably assessed by circulating levels of bone turnover markers (BTMs) such as the bone resorption markers C-terminal telopeptide of type I (CTX), and tartrate-resistant acid phosphatase (TRAP5b), which evaluates bone resorptive capacity and is not influenced by renal clearance and bone formation markers such as procollagen type 1 N-terminal propeptide (P1NP). Clinical trials have demonstrated that diet-induced weight loss is associated with deterioration of bone metabolism, as indicated by alterations in BTMs and Dual-energy X-ray Absorptiometry (DXA) measurements of BMD. In addition, bariatric management of obesity, particularly malabsorptive surgical modalities, are known to increase the risk of fractures at two years postoperatively. Weight-loss treatments such as liraglutide, the first injectable Glucagon-like peptide-1 (GLP-1) receptor agonist approved for obesity, and tirzepatide, a dual GLP-1/Glucose-dependent insulinotropic polypeptide (GIP) receptor agonist recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for treating obesity, has shown efficacy in weight management but their effects on bone metabolism are not fully understood. Liraglutide administration in diabetic mice improves bone health, by altering the levels of BTMs CTX, osteoprotegerin (OPG), osteocalcin (OC), alkaline phosphatase (ALP), and procollagen type 1 N-terminal propeptide (P1NP), reducing the number of osteoclasts, and improving bone architecture. Similarly, in mice models with glucocorticoid-induced osteoporosis (GIOP) under liraglutide treatment, BMD and bone microarchitecture is improved, with reductions in BTMs such as Tartrate-resistant acid phosphatase type 5b (TRACP-5b) and CTX, and increases in ALP and OPG. A randomized, double-blinded, placebo-controlled clinical trial of 56 individuals with diabetes (mean age: 63 years) showed that liraglutide at a dose of 1.8 mg did not affect bone metabolism despite a reduction in body weight. Another randomized controlled study of 37 women with obesity (mean age 46 years, BMI 34kg/m2) who lost 12% of body weight after a 12-week low-calorie diet and were subsequently randomized to placebo or liraglutide at a dose of 1.2 mg, found that liraglutide increased P1NP levels by 16%, highlighting its positive effects on bone metabolism following weight loss. Nevertheless, clinical data on the effects of liraglutide on bone metabolism are limited. Regarding tirzepatide, the pronounced weight loss from its administration seems to have a neutral effect on bone mass and microarchitecture in diabetic mice, with no significant changes in BTMs. However, no clinical data are currently available regarding tirzepatide effect on bone metabolism. The concern, however, is that the combination of GLP-1 and GIP, which leads to greater weight loss, may have a different impact on bone metabolism than GLP-1 agonists alone.