Anti-Inflammatory Medication Linked to Osteonecrosis of the Jaw

Tumor Necrosis Factor Alpha (TNFα) inhibitors are common anti-inflammatory medications. In a review of the literature, TNFα inhibitors resulted in six patients with osteonecrosis of the jaw (ONJ) or osteomyelitis (OM) that were attributed solely to TNFα inhibitors. The most common site of ONJ was the posterior mandible (n=5). The mean (SD) duration of anti-TNF-α treatment before the development of bony lesions was 62.5 (47.4) months. Invasive surgery was reported as a precipitating factor in five cases, and the ONJ/OM resolved with conservative management in five.

Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-α) inhibitors: a systematic review. Br J Oral Maxillofac Surg. 2020 Jan;58(1):25-33. doi: 10.1016/j.bjoms.2019.09.023. Epub 2019 Oct 20.

TNFα inhibitors treat a wide range of inflammatory conditions such as rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, and psoriasis.

TNFα inhibitors currently available:
  • Enbrel (generic: etanercept)
  • Remicade (generic: infliximab)
  • Simponi (generic: golimumab)
  • Cimzia (generic: certolizumab)
  • Humira (generic: adalimumab)
  • Amjevita (generic: adalimumab)
  • Simponi Aria (generic: golimumab)
  • Inflectra (generic: infliximab)
  • Avsola (generic: infliximab)
  • Cyltezo (generic: adalimumab)
  • Erelzi (generic: etanercept)
  • Ixifi (generic: infliximab)
  • Renflexis (generic: infliximab)
Role of TNFα in Inflammation
TNFα is a powerful pro-inflammatory agent that regulates many facets of macrophage function. It is rapidly released after trauma, infection, or exposure to bacterial-derived LPS and has been shown to be one of the most abundant early mediators in inflamed tissue. Among its various functions is its pivotal role in orchestrating the production of a pro-inflammatory cytokine cascade. TNFα is considered to be a “master regulator” of pro-inflammatory cytokine production. In addition to pro-inflammatory cytokines, TNFα also increases lipid signal transduction mediators such as prostaglandins and platelet activating factor. Based on these roles, TNFα overproduction has been proposed as a central player in inflammatory cell activation and recruitment and is suggested to play a critical role in the development of many chronic inflammatory diseases.

Why Would TNFα Cause Osteonecrosis of the Jaw?
Bisphosphonates produce osteonecrosis of the jaw by killing osteoclasts that are required for the bone resorption phase of bone remodeling. When damaged bone cannot be removed by osteoclasts, necrosis persists. TNFα is intricately involved in osteoclast differentiation and function as well as in bone destruction through osteoclast activation. TNFα has been shown to promote bone resorption in vitro and in vivo and induces secretion of RANKL in osteoblastic cells. TNFα has also been shown to be an important mediator of LPS-induced osteoclastogenesis. Furthermore, TNFα alone or in combination with interleukin 1 (IL-1) increases osteoclast numbers seen at sites of bone resorption. TNFα also increases the numbers of circulating osteoclast precursors by promoting their proliferation and differentiation in the bone marrow. Moreover, it has been shown to promote the survival of differentiated osteoclasts, which generally have a short life span. Like the bisphosphates, TNFα inhibitors prevent the removal of damaged bone resulting in osteonecrosis.

In addition to the increased potential for the development of osteonecrosis of the jaw, the TNFα inhibitors also decrease the patient’s ability to fight infection making oral disease more difficult to resolve.


American Society for Bone and Mineral Research (ASBMR)

Tissue Engineering and Regenerative Medicine International Society (TERMIS)