(A) TLR ligands have multiple effects on osteoblasts and osteoclasts, eliciting responses that modulate inflammation and immunity, promote bacterial killing, and shift the balance of bone remodeling toward resorption. (B) Infection of osteoblasts with S. aureus may provide the bacteria with a niche to avoid antibiotics and antibacterial responses and promote bone destruction through TRAIL, which can sequester OPG and induce osteoblast apoptosis. (C) A potential mechanism for bisphosphonate ONJ. A septic insult to bone such as a tooth extraction results in necrosis. Normally the necrotic bone is removed by osteoclasts. When osteoclast activity is blocked by bisphosphonates, bacteria produce biofilms on the necrotic tissue allowing them to evade host defense mechanisms.