Background: Several reports indicated that intentional weight loss can result in reduction in bone mineral density (BMD), particularly in postmenopausal women, and older individuals. This is a post-hoc analysis of a prospective multidisciplinary weight loss trial, in search of predictors of bone loss in the Metabolic Syndrome (MS). Methods: 73 MS subjects (ATPIII criteria; F/M = 34/39) participated in a 1-year intensive multidisciplinary treatment, based on personalized physical training and a low calorie/high protein Mediterranean diet. Baseline (±SD): age 53.3 ± 11.2 years; weight 98.6 kg ± 16.8; BMI 34.4 ± 3.8 kg/m2; lean body mass (LBM) 55.48 kg ± 11.66 kg; Spine BMD 1.21 ± 016 g/cm2, femur neck BMD 0.99 ± 0.13 g/cm2. Results: By the end of 1-year BMI declined by 9.1% (p < 0.001); LBM declined by 2.68% (p < 0.001). There were no significant overall changes in spine or femur BMD; no difference in the change in BMD between participants under the age of 50 years or above 51 years, and between male and female subjects. Despite the lack of overall change in BMD during weight loss, when individual changes in spinal BMD were analyzed, participants who clustered above the median post-treatment versus pre-treatment BMD level, showed a higher initial BMI compared to participants whose change in spinal BMD was below the median level (BMI 35.6 ± 3.6 vs. 32.5 ± 3.52 kg/m2, respectively (p < 0.0001). Conclusions: In subjects with MS undergoing intensive and closely supervised multidisciplinary intentional 1 year weight loss program, higher initial weight is associated with lesser spine bone loss.