Asier Eguia del Valle Associate Professor at the University of the Basque Country (UPV/EHU). Member of the board of the SECIB. 

Rafael Martínez-Conde Full professor at the University of the Basque Country (UPV/EHU). Associate member of SECIB. 

SUMMARY 

Medication-related Osteonecrosis of the Jaw (MRONJ) is an adverse effect of certain drugs, rare but serious in some cases. Among the medications related to this pathology, the best known are the bisphosphonates. However, MRONJ is also associated with other antiresorptive, antiangiogenic and immunomodulatory medications. 

The first cases of Osteonecrosis of the Jaw (ONJ) associated with bisphosphonates were described just over 15 years ago. However, this pathology has been documented for almost two centuries and at different times in history, in phosphorus, fireworks and ammunition factory workers who handled white phosphorus, which is associated with poisoning by pyrophosphate vapour emanations. 

INTRODUCTION 

Osteonecrosis of the Jaw (ONJ) is a pathology produced by the effects of bisphosphonates (BPH) and other medications, most frequently in the lower jaw bone, and occurring spontaneously or after surgery involving the bone^(1-3). It is manifested by the presence of one or several areas of necrotic bone, exposed (or not) in the oral cavity, and it persists for at least eight weeks^(1-3) (Figure 1). 

In 2003, R. E. Marx⁽¹⁾ published an article in which the appearance of 36 cases of ONJ was associated for the first time with the use of intravenous BPH (zoledronate and pamidronate) in patients with multiple myeloma or metastatic breast cancer. There have since been numerous cases published of ONJ associated with both the use of systemic and oral BPH ^(1-3). The relationship between BPH and ONJ is now well documented, so several entities and associations have developed guidelines and protocols for the prevention and treatment of this pathology⁽³⁾. 

In addition to BPH, this disease is also associated with other antiresorptive drugs (denosumab) and certain antiangiogenic drugs (bevacizumab, sunitinib, aflivercept) ^(4,5). 

Several cases of ONJ associated with other types of drugs—mainly immunomodulators⁽⁶⁾ (table 1)—have recently been published. With the discovery that other medications could also produce this side effect, the term BRONJ (Biphosphonate-Related OsteoNecrosis of the Jaw), which was initially established to refer to this pathology, was replaced in 2014 by MRONJ (Medication-Related OsteoNecrosis of the Jaw)⁽³⁾ based on the recommendation of the American Association of Oral and Maxillofacial Surgeons (AAOMS). 

At present, the list of drugs that may—with a greater or lesser degree of evidence—potentially favour the development of ONJ continues to grow. The risk of occurrence of ONJ varies significantly between the different medications associated with it, but also depending on other factors such as administration and dosage guidelines, cumulative time of intake and the existence of concomitant systemic disease⁽⁴⁾. 

HISTORY OF OSTEONECROSIS OF THE JAW 

Although ONJs associated with medications were first described just over 15 years ago, there have been numerous documented cases of ONJs "not associated with medications" for almost two centuries^(7-9). The history of ONJ is a long one and it has been documented at different moments in history, in matchstick, fireworks and ammunition factory workers who handled white phosphorus and other substances containing pyrophosphates. The condition has been given several names, including phosphorous necrosis of the jaw, or phossy jaw ^(7-9). 

ONJ was first described in 1838 by Lorinser⁽¹⁰⁾ as phosphorismus chronicus. Lorinser presented several cases of matchstick factory workers who suffered considerable jaw bone sequestrum whose aetiology was related to their work. In the first matchstick factories, one of the raw materials used was white phosphorus. 

White phosphorus is an allotrope (a chemical element with various molecular structures) of phosphorus, which is still used in the chemical industry and as an incendiary agent, and must be handled with caution, as it emits highly toxic fumes^(7-9). Indeed, the direct aspiration of phosphorus fumes meant that high concentrations of pyrophosphates would accumulate in the bones of women, children and adolescents (the majority of workers in the old matchstick factories). Pyrophosphates have a very similar molecular structure to that of BPH and a similar biological effect regarding the aetiology of ONJ^(7-9) (Figure 2). 

Given the poor oral health of these women and children, coupled with a poor diet and terrible working conditions, it was very common for them to develop extensive severe ONJ. At the end of the 19th century, several authors, including Kocher and von Schulthess-Rechberg^(11,12), compiled the clinical characteristics of a series of cases. 

Furthermore, pyrophosphates also have toxic effects on the liver, the kidneys and the nervous system⁽¹³⁾. In addition to the numerous occupational accidents, all this meant the workers there showed amongst the lowest life expectancies. In London's East End, this circumstance led to the birth of the feminist-union movement and the so-called Matchgirls’ strike. 

Its use was finally limited at the Bern Convention of 1906, and other less harmful forms of phosphorus, such as red phosphorus, began to be used in factories, and working conditions improved, thereby reducing the number of ONJ cases. 

Later on, in the nineteen-fifties and -sixties, there were some isolated cases of ONJ among workers in the fireworks and weapons industries, again associated with exposure to white phosphorus⁽¹⁴⁾. 

PRESENT & FUTURE 

We now know that it is not only BPH, denosumab and certain antiangiogens that can bring about the development of ONJ. There is a growing list of drugs that are likely to contribute, to a greater or lesser extent, to this side effect. Although there is not yet full evidence to relate many of these drugs to the disease, from a preventive standpoint, it is important that the same or similar precautionary clinical protocols are applied for ONJ prevention. 

Special caution is advisable in the future when treating patients with new antiresorptive, biological anti-inflammatory or biosimilar drugs, and with any new antiangiogenics or immunosuppressives.