Of the U.S. population, 65% is either overweight or obese, and weight loss is recommended to reduce co-morbid conditions. However, bone mobilization and loss may also occur with weight loss. The risk for bone loss depends on initial body weight, age, gender, physical activity, and conditions of dieting such as the extent of energy restriction and specific levels of nutrient intake. Older populations are more prone to bone loss with weight loss; in women, this is due at least in part to a reduced dietary Ca intake and/or efficiency of absorption. Potential hormonal mechanisms regulating bone loss during weight loss are discussed, including decreases in estrogen, leptin, glucagon-like peptide-2, growth hormone, and insulin-like growth factor-1, or an increase in cortisol. In contrast, the rise in adiponectin and ghrelin with weight reduction should not be detrimental to bone. Combining energy restriction with exercise does not necessarily prevent bone loss, but may attenuate loss as was shown with additional Ca intake or osteoporosis medications. Future controlled weight loss trials should be designed to further address mechanisms influencing the density and quality of bone sites vulnerable to fracture, in the prevention of osteoporosis.