ABSTRACT: Weight loss is associated with reduction in bone mineral density (BMD).The objective was to address the role of changes in fat mass (FM) and lean mass (LM) in BMD decline in both sexes.A 2-year randomized controlled trial, the Preventing Overweight Using Novel Dietary Strategies (POUNDS-LOST).The setting was the general community.Enrolled were 424 overweight and obese participants (mean age, 52 ± 9 y; 57% females).Intervention included weight loss diets differing in fat, protein, and carbohydrates.Main outcome measures were change in spine, total hip (TH), and femoral neck (FN) BMD and sex differences after dietary intervention.At baseline, a stronger correlation between BMD and body composition measurements was observed in women, primarily with LM (r = 0.419, 0.507, and 0.523 for spine, FN, and TH, respectively; all P < .001). In men, only LM correlated with hip BMD (r = 0.298; P < .001). Mean weight loss at 2 years was -6.9%, without differences among diets. Two-year changes in BMD were 0.005 (P = .04), -0.014 (P < .001), and -0.014 g/cm(2) (P < .001), at the spine, TH, and FN, respectively. These changes directly correlated with changes in LM in women (r = 0.200, 0.324, and 0.260 for spine, FN, and TH, respectively), whereas FM loss correlated only with changes in TH BMD (0.274; P < .001). In men, changes in LM (-0.323; P < .001) and FM (-0.213; P = .027) negatively correlated with changes in spine BMD.Weight loss diets result in sex-specific effects on BMD. Although men exhibited a paradoxical increase in spine BMD, women tended to decrease in BMD at all sites.