Inflammation perturbs normal bone homeostasis and is known to induce bone loss, as it promotes both local cartilage degradation and local and systemic bone destruction by osteoclasts, as well as inhibits bone formation by osteoblasts. Thus, not surprisingly, inflammatory autoimmune diseases often lead to local and/or general bone loss. However, the mechanisms that target the bone in autoimmune disease are complex and diverse, as they range from a direct attack on the bone and cartilage by the immune cells to indirect consequences of disturbances of the systemic control of bone remodeling. This Review discusses current understanding of the mechanisms of autoimmune-mediated bone loss in view of new insight from two new fields of research: osteoimmunology, which analyzes the direct effect of immune cells on bone, and the integrative metabolism approach, which established the existence of neuroendocrine loops that regulate bone remodeling.