Background: Bariatric surgery is an effective and therapeutic way for different metabolic diseases. It has become a focus of attention about the effects and molecular mechanisms to bone metabolism. Objective: We aim to assess the changes of bone mineral density (BMD) among Chinese obese individuals with type 2 diabetes who have undergone Roux-en-Y gastric bypass surgery (RYGB). Two ghrelin gene products, namely unacylated ghrelin (UAG) and obestatin, were evaluated the roles in this pathologic process. Setting: University-affiliated hospital, China. Methods: Thirty patients who had received RYGB were enrolled in the study. Changes in anthropometric parameters, metabolic indexes, and serum UAG and obestatin were assessed preoperatively, 6, 12, and 24 months postoperatively. BMD at lumbar spine (LS), femoral neck (FN), and total hip (TH) were identified. Results: RYGB resulted in statistical reductions of BMD in 3 different skeletal parts. After the first 6 months, BMD began to reduce and maintained a declining trend until 24 months postoperatively. Comparing to baseline, the maximal reduction of BMD was as high as 10.28% in total hip. The plasma concentration of UAG increased after 6 months (51.61 6 55.21 versus 71.95 6 64.91 pg/mL; P ,.01), as well as the serum obestatin level (1.65 6 0.88 versus 1.71 6 0.99 ng/mL; P. .05). Although there was a slight drop of both peptides in the first year, they were still above the baseline. Notably, in the second year, UAG and obestatin rose to their peak values, respectively (91.90 6 77.11 pg/mL and 1.74 6 1.09 ng/mL). There was a negative correlation between UAG and BMD in all sites. Multiple linear regression analysis showed that the UAG level was the independent parameter associated with BMD at baseline (FN: b 5-.407, P 5 .012 and TH: b 5-0.396, P 5 .030 respectively), as well as the changes of UAG that were independently related with reduction percentage of LS BMD after 24 months (b 5-.379, P 5.046). Conclusion: The reduction of BMD in obese Chinese with type 2 diabetes was observed after RYGB. The pronounced increase of serum UAG acts as an independent risk factor for the decrease of BMD.