Review Question - QID 5883

Interleukin-10 (IL-10) inhibits proinflammatory cytokine production, osteoclastogenesis, and osteolysis. Anakinra is a receptor antagonist of IL-1, a proinflammatory cytokine.

Periprosthetic osteolysis is a common mode of total hip arthroplasty failure. It is initiated by wear debris from prosthetic implants. Debris triggers activation of macrophages, which subsequently secrete many cytokines and inflammatory mediators, including TNF-alpha, IL-1, IL-6 and prostaglandins. The resulting inflammatory cascade ultimately promotes osteoclastic bone resorption and fibrous tissue formation.

Talmo et al. detailed the basic science behind osteolysis and potential pharmacologic agents in the prevention and treatment of osteolysis. In addition to anti-RANK-ligand antibodies, TNF-alpha agents and COX-2 inhibitors, bisphosphonates and growth factors can also target osteolysis. Bisphosphonates incorporate into bone and prevent osteoclastic resorption. Growth factors such as TGF-beta and BMP-2 promote osteoblastic bone ingrowth into implant porosities, enhancing implant stability.

Bukata et al. performed in vitro experiments with fibroblasts derived from wild-type (WT), COX-1 deficient and COX-2 deficient mice. Loss of COX-2 function resulted in decreased PGE2 production, as well as IL-6 production. This was replicated by addition of a COX-2 inhibitor to WT cells. Therefore, COX-2 inhibitors such as celecoxib may decrease osteolysis beyond direct inhibition of prostaglandin synthesis, by inhibiting the downstream pro-inflammatory cytokine cascade.

Illustration A is a figure from Talmo et al that depicts the pathophysiology of osteolysis and the site of action for potential pharmacologic agents in the prevention and management of osteolysis.

Incorrect Responses:
Answer 1: RANK ligand stimulates osteoclastogenesis, promoting osteolysis and is inhibited by denosumab, a monoclonal antibody.
Answer 2: TNF-alpha is a proinflammatory cytokine that promotes osteolysis and is inhibited by etanercept, a decoy receptor.
Answer 3: COX-2 produces PGE2, which stimulates production of IL-6 and promotes osteolysis. Celecoxib is a selective COX-2 inhibitor.
Answer 4: IL-6 is a proinflammatory cytokine that promotes osteolysis and is inhibited by tocilizumab, a monoclonal antibody.