SUN-735 - Tirzepatide Treatment in Obese Adult Mice Causes Bone Loss in the Cortical Compartment

Tirzepatide, a Glucagon-like peptide-1 (GLP-1)/ Glucose-dependent insulinotropic polypeptide dual receptor agonist (RA), is the most effective drug for obesity and is widely used to treat type 2 diabetes and obesity-related comorbidities. In humans, tirzepatide use has been associated with bone loss and fractures. Studies evaluating the skeletal impact of tirzepatide in obese adult mice that mimic the clinical scenario are lacking. To address this gap, 20-week-old C57BL/6 male mice were started on high fat diet (HFD-60 % fat) or control diet (CD). After 9 weeks, HFD fed mice increased their weight by 50% and were started on daily tirzepatide (tirz-15 nmol/kg) or vehicle (veh) injections for an additional 8 weeks. The mice on CD were treated with veh only. At 37 weeks of age, the HFD-tirz treated mice lost ~30% of their pre-injection weight, whereas HFD-veh and CD-veh treated mice gained 10% and 12% of their pre-injection weight, respectively. Fat mass, lean mass, and bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DXA). Fat mass decreased with time in HFD-tirz group compared to the HFD-veh (p < 0.0001) and CD-veh groups (p < 0.0001). Lean mass increased with time in the HFD-veh and CD-veh groups but not in the HFD-tirz group (p=0.0004 vs HFD-veh and p=0.0016 vs CD-veh). Femoral BMD declined by 15% in the HFD–tirz group compared with 7.4% in HFD-veh group (p= 0.0057) and 3.6% in the CD-veh group (p=0.0010). Similar changes were seen in total BMD. Micro-CT showed decreased femoral cortical thickness at both the midshaft and metaphysis in the HFD-tirz group compared to HFD-veh (p=0.0002 and p< 0.0001 respectively) and CD-veh (p < 0.0001 for both). Similarly, the HFD-tirz group exhibited loss of cortical thickness at the tibia (p=0.024 compared to HFD-veh; and p=0.001 compared to CD-veh). Vertebral, femoral, and tibial cancellous bone was similar between the HFD-tirz and the HFD-veh groups and lower in both groups compared to CD-veh mice, indicating that loss of cancellous bone is due to HFD and not tirz treatment. To confirm these findings, we performed two more experiments. In one study, C57BL/6 male mice were placed on HFD or CD at 6 weeks; at 23 weeks, HFD-fed mice were treated daily with tirz (30 nmol/kg) or veh for 8 weeks, while CD-fed mice received veh only. Next, we placed 23-weeks-old C57BL/6 female mice on HFD and, at 37 weeks of age, started tirz (30 nmol/kg) or veh injections every other day for 6 weeks. In both experiments we confirmed the ~ 30% weight loss and the loss of cortical bone at the femoral midshaft in the HFD-tirz group. These results indicate that in obese adult mice, tirz causes weight loss and bone loss that is limited to the cortical compartment. The bone loss replicates that of the one seen during non-pharmacological and GLP-1 RA-induced weight loss in humans. Therefore, these mouse models will be used to explore the mechanisms underlying the bone loss during tirz treatment.

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