Medication-Related Osteonecrosis of the Jaw: History
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Subjects: Dentistry, Oral Surgery & Medicine
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Riham M Fliefel

Medication-related osteonecrosis of the jaw (MRONJ) has become a well-known side effect of antiresorptive, and antiangiogenic drugs commonly used in cancer management.

  • medication-related osteonecrosis of the jaw
  • MRONJ
  • bisphosphonates
  • denosumab
  • infection

1. Introduction

Bisphosphonates are stable analogues of inorganic pyrophosphate (PPi) which bind to hydroxyapatite crystals at sites of active bone remodeling. They impair intracellular signaling in osteoclasts interfering with osteoclast-mediated bone resorption and therefore are considered one of the most effective antiresorptive drugs (ARDs). Despite the great benefits of bisphosphonates in management of bone metastasis and osteoporosis, a rare but serious side effect, osteonecrosis of the jaw, was reported in 2003. Since then, the number of reported cases has increased dramatically to the point that a causal link has been established between osteonecrosis of the jaw and bisphosphonates intake and the condition was then named bisphosphonate-related osteonecrosis of the jaw (BRONJ). Maxillofacial surgeons observed this complication and thus, a position paper was developed by the American Association of Maxillofacial Surgery (AAOMS) in 2007 to set strategies for treatment and prevention of BRONJ [1][2].

In 2010, osteonecrosis of the jaw was reported in association with the new antiresorptive, denosumab, a monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL) [3]. The same complication was also observed after administration of antiangiogenic medications and tyrosine kinase inhibitors, however there is still little scientific evidence to confirm the association between these medications and osteonecrosis of the jaw [4]. Based on the increasing number of medications that cause osteonecrosis of the jaw, AAOMS proposed the name medication-related osteonecrosis of the jaw (MRONJ) in its last position paper in 2014 in which MRONJ was defined as exposed bone in the jaws or the maxillofacial region that persisted for a minimum period of two months in a patient who has a history of current or previous ARDs or antiangiogenic agents in absence of radiotherapy or metastasis to the jaw [5]. However, recently, the definition of MRONJ has been updated being not only due to the intake of bisphosphonate drugs (current or past), but also further pharmacological therapies such as other antiresorptive agents, or drugs with anti-angiogenic activity. It is also important to perform a thorough physical examination and medical history, together with targeted radiologic examinations. Furthermore, it is important to take into the account not only the presence of exposed necrotic bone but consider also other clinical signs and first/second-level imaging and consider that pain may not always be present in MRONJ cases, especially in the early stages as well as considering that some cases of MRONJ can arise from the presence of dental–periodontal diseases or spontaneously, without any relation to invasive dental procedures [6].

Despite the enormous research efforts made in relation to MRONJ, its pathogenesis is still not fully elucidated. Many hypotheses have been postulated, such as suppression of bone remodeling, inhibition of angiogenesis, constant microtraumas and local infection. However, none of them can fully explain the exact mechanism of MRONJ development and, generally, the process seems to be multifactorial [5]. Clinical observations support ARDs type, dose and frequency as absolute risk factors for MRONJ [5]. Nevertheless, MRONJ does not occur in all patients under ARDs and it is clear that other factors are involved in its onset. Indeed, a considerable and growing body of evidence has accumulated over the last few years and suggests a substantial role of local infection of the jaw bones in initiation of MRONJ. Management of MRONJ can be quite complex and challenging and it is totally agreed that prevention is the best way to face MRONJ, especially in cancer patients under long-term antiresorptive therapy. For this reason, it is crucial to develop a clear understanding of the exact pathophysiology of MRONJ to aid in implementing preventive measures before and after ARDs administration.

2. Summary

Many mechanisms have been suggested, including over-suppression of bone remodelling, anti-angiogenic properties or direct tissue toxicity of antiresorptive drugs, hyper-occlusal forces and local infection. All of the proposed mechanisms might play a part; however, local infection of the jawbone seems to play a major role in the pathogenesis of MRONJ [7][8]. Recently, other etiopathogenetic theories have been suggested such as the effect of ARDs on mesenchymal precursors of components of the periodontium and alveolar bone [9]. Indeed, no other bone in the human body is as frequently affected by infections compared to the jawbones: more than 50% of young adults suffer from moderate to severe periodontitis. The risk increases with aging to reach 75% of the population aged 65 years or more [10]. It is well-known that osteoclasts play a key role in the physiologic response to bone infections. Not only the phagocytosis’ capability of cell detritus but also the ability to resorb small necrotic bone fragments make osteoclasts an irreplaceable player in this battle.

Although antiresorptive drugs in particular denosumab and bisphosphonates possess completely different mechanisms of action and pharmacokinetics, both drugs have the same target cell, namely osteoclasts.

It is well-known and proven in different studies that the osteoclast activity is significantly reduced under antiresorptive treatment [11]. Thus, simultaneous presence of local infection and MRONJ is not a coincidence but rather indicates a significant correlation between the two.

The molar area of the mandible is known to be frequent site of dental and periodontal infections. Furthermore, the disease process of MRONJ in dentate patients usually starts by infected tooth bearing areas of alveolar process or areas of dento–alveolar surgeries without adequate preventive measures. In edentulous patients, pressure sores might increase the need for remodeling beyond the capacities of patients treated with antiresorptive drugs. Clinical presentation of MRONJ is similar to osteomyelitis and basically all clinical signs of MRONJ are well-known signs of infection [12][13].

The risk factors, namely diabetes mellitus, smoking, poor oral hygiene, steroid intake, immunosuppression, may contribute to an increased risk of infection. Bacterial colonization of MRONJ tissue samples by different bacterial species also underlines the plausible link to local infection as a triggering event [14][15].

Similarly, MRONJ was reported other than the jaw, in the ear canal, which is also characterized by bacterial colonization and only a very thin epithelial layer covering the bone. This underscores the role of infection in the pathogenesis of MRONJ. Imaging and animal studies have also shown the central role of the infection [16][17][18]. Likewise, prevention of MRONJ aims to prevent infection and thus to eliminate the potential key factor of MRONJ pathogenesis. The decisive role of infection is also evidenced by the drop in incidence of MRONJ in cancer patients who managed to improve their dental hygiene, which thereby prevented potential inflammation and infection [19][20]. Of note, the current treatment of MRONJ is based on controlling existing infection to avoid rapid osteonecrosis progression.

Another aspect is the blood supply of infected bone. There are also other conditions that require stronger remodeling activities and vessel ingrowth especially following surgical procedures.

It is also no coincidence that other drugs which might interfere with host defense and wound healing, especially antiangiogenic drugs, have been recently connected to the development of MRONJ. These drugs (e.g., bevacizumab, Sunitinib, mTOR inhibitors) may act as additional risk factors/co factors for the development of MRONJ in patients receiving antiresorptive drugs [21]. The growing number of studies and models has strengthened the claim that assigns infection as the key trigger in the pathogenesis of MRONJ.

No agreement has been reached in the treatment of MRONJ. Some recommendations focus on the administration of antibiotics, oral antibacterial mouth rinse or surgical debridement or a segmental mandibulectomy and partial maxillectomy with mandibular reconstruction with the fibula flap and covering the exposed areas with tissue flaps. Hyperbaric oxygen (HBO) therapy, fluorescence-guided bone resection, and low-intensity laser therapy have also been studied as therapeutic tools. Other treatment modalities that increase bone wound healing using growth factors had been studied. More recently, teriparatide (N-terminal 34-amino acid recombinant human para-thyroid hormone) has been reported for the medical treatment of MRONJ. Pentoxifylline and a-tocopherol in addition to antimicrobial therapy has been shown to decrease the area of bone exposure and symptoms in MRONJ patients. The use of ozone in combination with antibiotics and surgery for patients with exposed bone lesions has also been the subject of a clinical investigation [22].

The intention of this paper is to stress and reinforce the role of infection in the pathogenesis of MRONJ by collecting pieces of evidence that have been published since the introduction of our hypothesis almost 10 years ago [7]. However, that does by no means disprove any other theory. The infection theory might in fact tie all of the other potentially involved factors and co-factors such as remodeling suppression, inhibition of angiogenesis, inhibition of immunocompetent cells and soft tissue toxicity together. Thus, as detailed above, the infection theory can conclusively explain many of the clinical and radiological features of MRONJ as well as the reasons behind all of the relevant prophylactic and therapeutic measurements.

This entry is adapted from the peer-reviewed paper 10.3390/medicina57050463

References

  1. Von Moos, R.; Costa, L.; Gonzalez-Suarez, E.; Terpos, E.; Niepel, D.; Body, J.J. Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody. Cancer Treat. Rev. 2019, 76, 57–67.
  2. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws AAoOaMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J. Oral Maxillofac. Surg. 2007, 65, 369–376.
  3. Aghaloo, T.L.; Felsenfeld, A.L.; Tetradis, S. Osteonecrosis of the jaw in a patient on Denosumab. J. Oral Maxillofac. Surg. 2010, 68, 959–963.
  4. Otto, S.; Pautke, C.; van den Wyngaert, T.; Niepel, D.; Schiodt, M. Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat. Rev. 2018, 69, 177–187.
  5. Ruggiero, S.L.; Dodson, T.B.; Fantasia, J.; Goodday, R.; Aghaloo, T.; Mehrotra, B.; O’Ryan, F. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J. Oral Maxillofac. Surg. 2014, 72, 1938–1956.
  6. Campisi, G.; Mauceri, R.; Bertoldo, F.; Bettini, G.; Biasotto, M.; Colella, G.; Consolo, U.; di Fede, O.; Favia, G.; Fusco, V.; et al. Medication-related osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian consensus update 2020. Int. J. Environ. Res. Public Health 2020, 17, 5998.
  7. Kumar, S.K.; Gorur, A.; Schaudinn, C.; Shuler, C.F.; Costerton, J.W.; Sedghizadeh, P.P. The role of microbial biofilms in osteonecrosis of the jaw associated with bisphosphonate therapy. Curr. Osteoporos. Rep. 2010, 8, 40–48.
  8. Otto, S.; Hafner, S.; Mast, G.; Tischer, T.; Volkmer, E.; Schieker, M.; Sturzenbaum, S.R.; von Tresckow, E.; Kolk, A.; Ehrenfeld, M.; et al. Bisphosphonate-related osteonecrosis of the jaw: Is pH the missing part in the pathogenesis puzzle? J. Oral Maxillofac. Surg. 2010, 68, 1158–1161.
  9. Di Vito, A.; Chiarella, E.; Baudi, F.; Scardamaglia, P.; Antonelli, A.; Giudice, D.; Barni, T.; Fortunato, L.; Giudice, A. Dose-dependent effects of zoledronic acid on human periodontal ligament stem cells: An in vitro pilot study. Cell Transplant. 2020, 29, 963689720948497.
  10. Jordan, R.A.; Bodechtel, C.; Hertrampf, K.; Hoffmann, T.; Kocher, T.; Nitschke, I.; Schiffner, U.; Stark, H.; Zimmer, S.; Micheelis, W. The fifth German oral health study (funfte Deutsche mundgesundheitsstudie, DMS V)—Rationale, design, and methods. BMC Oral Health 2014, 14, 161.
  11. Russell, R.G.; Watts, N.B.; Ebetino, F.H.; Rogers, M.J. Mechanisms of action of bisphosphonates: Similarities and differences and their potential influence on clinical efficacy. Osteoporos. Int. 2008, 19, 733–759.
  12. Mast, G.; Otto, S.; Mucke, T.; Schreyer, C.; Bissinger, O.; Kolk, A.; Wolff, K.D.; Ehrenfeld, M.; Sturzenbaum, S.R.; Pautke, C. Incidence of maxillary sinusitis and oro-antral fistulae in bisphosphonate-related osteonecrosis of the jaw. J. Craniomaxillofac. Surg. 2012, 40, 568–571.
  13. Aljohani, S.; Gaudin, R.; Weiser, J.; Troltzsch, M.; Ehrenfeld, M.; Kaeppler, G.; Smeets, R.; Otto, S. Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series. J. Craniomaxillofac. Surg. 2018, 46, 1515–1525.
  14. Panya, S.; Fliefel, R.; Probst, F.; Troltzsch, M.; Ehrenfeld, M.; Schubert, S.; Otto, S. Role of microbiological culture and polymerase chain reaction (PCR) of actinomyces in medication-related osteonecrosis of the jaw (MRONJ). J. Craniomaxillofac. Surg. 2017, 45, 357–363.
  15. De Ceulaer, J.; Tacconelli, E.; Vandecasteele, S.J. Actinomyces osteomyelitis in bisphosphonate-related osteonecrosis of the jaw (BRONJ): The missing link? Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33.
  16. Otto, S.; Pautke, C.; Jurado, O.M.; Nehrbass, D.; Stoddart, M.J.; Ehrenfeld, M.; Zeiter, S. Further development of the MRONJ minipig large animal model. J. Craniomaxillofac. Surg. 2017, 45, 1503–1514.
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  18. Aguirre, J.I.; Akhter, M.P.; Kimmel, D.B.; Pingel, J.E.; Williams, A.; Jorgensen, M.; Kesavalu, L.; Wronski, T.J. Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J. Bone Miner. Res. 2012, 27, 2130–2143.
  19. Ripamonti, C.I.; Maniezzo, M.; Campa, T.; Fagnoni, E.; Brunelli, C.; Saibene, G.; Bareggi, C.; Ascani, L.; Cislaghi, E. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann. Oncol. 2009, 20, 137–145.
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