A new diabetes drug called tirzepatide (TZP) can make bones weaker in obese, diabetic mice. The bone loss isn’t because the drug directly harms bone cells, but because it changes gut bacteria, especially cutting down a helpful group called Lachnospiraceae that produces a compound (evodiamine) that normally slows bone‑breaking cells. Giving back the missing bacteria helped stop the bone loss.

As a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, Tirzepatide (TZP) is a recently approved medication for treating type 2 diabetes mellitus (T2DM) and obesity; however, the effect of TZP in bone remodeling remains unclear. 1. The effect of Tirzepatide on osteoblasts and osteoclasts was observed by inducing differentiation of bone marrow mesenchymal cells (BMSCs) <i>in vitro</i>. 2. Db/db mice were used as a pathological model to investigate the role of TZP on bone metabolism. After TZP intervention, the feces in the intestinal tract of mice were collected for 16s rRNA gene sequencing to select the candidate gut microbiota most related to bone mass, and the effects of gut microbiota on bone metabolism were verified through subsequent microbiota supplementation experiments. 3. Metabolomics was used to analyze the difference of fecal metabolites between mice with the candidate microbiota supplement and those without, and the effect of candidate metabolites on bone metabolism was verified by the <i>in vitro</i> intervention of differential metabolites in BMSCs induction differentiation experiments. We found that TZP intervention resulted in a significant decrease in bone mass accrual <i>in vivo</i>. TZP was not indispensable to the differentiation of osteoblasts and osteoclasts <i>in vitro</i>. Bone and fat homeostasis were modulated by gut microbiota. We further demonstrated that the biodiversity of the gut microbiota in db/db mice was strikingly altered after TZP treatment. <i>Lachnospiraceae</i>, a key pro-osteogenic component of gut microbiota was significantly reduced. As a main metabolite of <i>Lachnospiraceae</i>, evodiamine played a role in suppressing osteoclastogenesis <i>in vitro</i>. Based on this, the transplantation of the <i>Lachnospiraceae</i> effectively ameliorated bone loss that was seen in db/db mice due to TZP treatment. TZP administration leads to bone loss in the context of diabetes and obesity, and targeting the composition of gut microbiota may provide a potential way to protect bone health in type 2 diabetic patients treating with TZP. This study indicates that TZP has a negative impact on bone mass, suggesting that clinical attention should be paid to the risk of further decline in bone mass after Tirzepatide treatment, and it is necessary to follow up on their bone metabolism. Additionally, the gut microbiota plays an important role in bone metabolism regulation, and supplementing with certain probiotics may have a preventive effect on bone mass reduction associated with TZP treatment. Our research provides a reference for the prevention and treatment of drug-related osteoporosis in patients with T2DM in the future.