Bone homeostasis is maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoclast maturation requires stimulation by RANKL expressed on osteoblasts and other cells. During the processes, pro-inflammatory cytokines such as TNF-alpha cause an imbalance in bone metabolism via direct and/or indirect effects on osteoclasts. These inflammatory signals originate from the immune system, the largest source of cell-derived regulatory signals and such immunological signals to the bone results in secondary osteoporosis and bone destruction. Actually, such phenomena mainly occur at the interface between proliferating synovium and bone tissue in rheumatoid arthritis (RA). Thus, therapeutic strategies using biologics including infliximab and etanercept, effective for treating RA disease activity, also reduce joint destruction. Based on an improved understanding of immune signals, investigation of the suppression of cell functions may lead to improved understanding and better treatment of bone destruction and osteoporosis.