ORN is produced by radiation therapy leading to infection and bone exposure. The healing function of both soft tissue and bone is impaired by hypovascularization in the irradiated area. It can be spontaneous or due to trauma, for example, an extraction. The most frequent site of appearance is the jaw. As ORN progresses, pain, dysesthesia, or anesthesia develop. It is considered one of the most serious complications in patients with head and neck cancer. Claudius Regaud documented it for the first time in 1922, describing the susceptibility of the maxillary bones to necrosis, due to the combination of infection and radiotherapy in the treatment of intraoral carcinomas (3). In 1926, James Ewing published an article on three clinical cases showing bone changes due to remarkably high applications of radiotherapy in cancer patients; he called it radiation osteitis, giving importance to tissue changes and decreased vascularity, which increases the likelihood of infection and subsequent bone necrosis. Ewing suggested administering radiation in low doses (4). In 1941, Frank Kanthak described Ewing's histological findings of the cellular damage generated in the bone due to radiotherapy and that produces alteration and devitalization. In addition, considerable reaction occurs in the vascular supply of the bone; the blood vessels tend to harden and eventually become sclerosed. He concluded that the conditions responsible for necrosis of the jaws are irradiation, infection, and trauma (5).

Robert Marx in 1983 explained that the irradiation, infection, and trauma sequence should be replaced by one more indicative of the cellular and metabolic changes, which are basic in the pathophysiology of ORN: irradiation, hypoxia, hypovascularity and hypocellularity of the tissues (principle of 3H), tissue deterioration, and lack of wound healing (6). This sequence gives a clearer view of the pathophysiology of ORN and to begin to understand the pathophysiology of ONJ.

As mentioned above, Marx in 2003 (2) reports on the appearance of avascular osteonecrosis in the jaws of 36 patients treated with intravenous bisphosphonates and who underwent dental procedures. Initially, he called it bisphosphonate-associated maxillary osteonecrosis because it was exclusive to this drug. But in 2014, Ruggiero, et al. (7) changed the terminology after finding cases in the scientific literature of maxillary osteonecrosis due to other drugs such as denosumab, an antiresorptive drug that, like the bisphosphonate, inhibits osteoclast function. It has also been seen in antiangiogenic drugs that function as inhibitors of the vascular endothelial growth factor (VEGF). Then it was called ONJ and antiresorptive and antiangiogenic drugs were associated with it.

Antiresorptive drugs are used in patients with osteoporosis and cancer. Antiangiogenic agents are used to treat patients with age-related macular degeneration (8) and in cancer patients. Many dentists and medical doctors have little or no knowledge of this pathology. Physicians sometimes prescribe antiresorptive medications to patients without having diagnostic tests for osteopenia or osteoporosis. In other situations, they prescribe them longer than standard time, which generates an effect contrary to the desired one (9). That is why it is important to know the different medications that can induce ONJ.

Antiresorptive drugs are divided into two groups:

Bisphosphonates. There are nitrogenous (pamidronate, ibandronate, risendronate, zoledronate, and alendronate) and non-nitrogenous (etidronate, tiludronate, and clodronate). Both nitrogenous and non-nitrogenous bisphosphonates are taken up by osteoclasts and damage their bone remodeling mechanism. They can be administered orally (alendronate, etidronate, tiludronate, risendronate, and ibandronate) or intravenously (pamidronate, ibandronate, and zoledronate), the last route being the most powerful. They can remain in the bone for prolonged periods (10).

Indications to use bisphosphonates (12):

Osteoporosis

Indications to use denosumab (13):

Osteoporosis

Antiangiogenic drugs (bevacizumab and sunitinib) are VEGF inhibitors. They bind to VEGF-A to inhibit cell proliferation by blocking the signal through VEGF-R1 and R2 and preventing new blood vessel formation in malignant tumors (14). Bevacizumab is the most used and, in combination with paclitaxel (chemotherapeutic), is more effective in fighting tumors than independently (15). In addition, antiangiogenic drugs are tyrosine kinase inhibitors and direct inhibitors of endothelial cell activation (16).

The pathophysiology of ONJ has been studied for years; however, it has not yet been fully understood. Bones are constantly remodeling due to osteoblast-osteoclast activity to maintain the integrity and strength of the skeleton. An imbalance of this activity affects mineral bone density and generates bone disorders such as osteoporosis, bone metastases, and other diseases. Antiresorptive medications decrease pathologic fractures, pain, and possible vertebral compression. The mechanism of action of these medications varies. Osteoclasts absorb bisphosphonates, which alters their chemotactic function and their binding to bone, suppresses the mechanism of bone resorption, and induces apoptosis. Denosumab interacts with the RANK-RANK-L-OPG (osteoprotegerin) pathway by binding to RANK-L and preventing preosteoclast maturation and differentiation, which ends up in osteoclast apoptosis. With both drugs, bone remodeling is affected. The high doses given to a patient and the prolonged time of the treatments decrease the ability of the bone to heal in the event of tissue trauma or bone exposure, which generates bone necrosis in the affected area (7,11).

Thus, why is osteonecrosis more frequent in the jaws than in other bones of the body? Five main theories have been proposed that would explain the exclusive location in the jaws: inhibition of bone remodeling; microbial oral inflammation and infection; immunosuppression; soft tissue toxicity; and inhibition of angiogenesis (11,17,18,19,20). It is likely that a combination of these factors facilitates the development of ONJ; however, inhibition of bone remodeling and angiogenesis are the most frequently cited theories.

Tooth extractions performed due to periapical or periodontal infections are the main cause of ONJ in which impaired healing with inflammatory infiltrate in the alveoli, bone exposure, and necrotic areas is observed histologically. Inflammation due to bacterial oral infection is a particularly important risk factor in the development of ONJ (21). According to Khan, et al. (15), polymorphonuclear cells and bacterial aggregates are always observed in necrotic tissue. The bacteria stimulate bone resorption and contribute to bone necrosis. Seddghizadeh, et al. and Kumar, et al. (22,23,24) have commented on the association between microbial biofilm and ONJ. Kalyan, et al. (25) describe how the oral microbiome can be an opportunistic factor and not the cause of ONJ.

Thus, periapical and periodontal infections with or without extractions increase the risk of ONJ because they can alter the function and number of osteoclasts and become an aggravating factor in the pathophysiology of ONJ (20). However, good oral hygiene and periodontal maintenance are beneficial to prevent ONJ in patients who are going to start treatment with antiresorptive agents (26).

A patient is considered to have ONJ if they have three conditions (7,17,27):

Previous or current medical treatment with antiresorptive and antiangiogenic drugs.

Common clinical conditions such as caries, neoplastic processes in the jaws, sinusitis, periodontal abscesses, periapical and temporomandibular disorders, and any lesion in the alveolar mucosa that causes regional pain (e.g., an ulcer) should be excluded (28).

There are clinical signs that could indicate the onset or an already established pathology of ONJ. They include pain, swelling, redness, or other signs of gum infection, gums or sockets that do not heal after treatment, dental mobility, numbness or sensation of jaw heaviness, drainage, and bone exposure (20,29). However, the diagnostic criteria must always be considered to avoid confusion with other pathologies such as ORN or neoplasms in the jaws.

To estimate the prognosis of patients who have used oral or intravenous antiresorptive agents and antiangiogenic drugs, the American Association of Oral and Maxillofacial Surgeons (AAOMS) in a 2014 position paper, proposes a staging system based on the clinical and radiographic findings (7) (table 1).

TABLE 1 TABLE 1 ONJ Staging System Proposed by the AAOMS (7)

A broad knowledge of the risk factors that are associated with the development of ONJ allows monitoring and surveillance of patients who are medicated with antiresorptive or antiangiogenic drugs. Three groups of key factors are presented: potential, oral, and triggers.

Potential Risk Factors (7,19,20,30,31,34)

Intravenous route of administration increases risk (higher potency than oral bisphosphonates)

Oral Risk Factors (7,30,31,32,33,34).

Extractions

The clinical signs have been widely described in the literature, but there is little reference to the radiographic ones. With a timely diagnosis of radiographic lesions, ONJ will be easier to treat and maintain, since early diagnosis plays a significant role in the definitive treatment of this pathology. Different diagnostic images are used: orthopantomograms, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET/CT). Bone sclerosis is the first imaging manifestation diagnosed; there are changes in bone density and the patient may be asymptomatic. Dentists must be attentive to these changes in order to take the necessary preventive measures (41). It should be noted that these bone sclerosis changes can also be seen in patients with ORN, osteosarcomas, chronic suppurative osteomyelitis, or metastasis. Hence, it is important to perform a good initial diagnosis of the disease.

Before starting any treatment with antiresorptive or antiangiogenic agents, the treating physician should refer the patient to the dentist for a careful examination of the oral cavity in order to minimize the risks of ONJ. The clinical history, the intraoral and extraoral examination, and the anamnesis continue to be the most valuable tool for its diagnosis and that of any other pathology. In these times of multi-medication, it is essential that the dentist review the medication history with the treating physicians to obtain the necessary and reliable information. Sometimes, the patient does not know exactly what medications they are consuming and if the necessary measures are not taken, they could make big mistakes.

Intraoral examination must be rigorous to identify sites of probable infection. At a minimum, an initial panoramic radiograph should be ordered, as well as always performing a periodontal hygiene phase to reduce the bacterial load (biofilm) that the patient presents. All surgical periodontal treatment, surgical removal of multilobed lingual tori, extractions, and endodontics should be performed at least three weeks to one month before antiresorptive or antiangiogenic therapy. Likewise, active caries must be removed and affected teeth rehabilitated.

It is important to conduct motivation and oral hygiene education to avoid future infections. Also, oral rinses with chlorhexidine (0.12 % or 0.2 %), cetylpyridinium chloride, benzalkonium chloride, or other alcohol-free active ingredients should be used periodically.

Patients wearing full or removable dentures should have their flanks relieved to avoid pressure on the buccal and alveolar ridges. After starting treatment with antiresorptive or antiangiogenic drugs, periodontal checkups and maintenance should be performed every four months. If the patient started treatment with antiresorptive or antiangiogenic agents but was not previously referred to the dentist and requires some treatment, non-surgical endodontics should be indicated. Also, avoid extractions, although, if necessary, there should be premedication with antibiotics, curette the alveolus very well to induce bleeding, and suture well confronting the edges to obtain healing by first intention. If there are teeth with extensive caries, without mobility and they are not restorable, endodontic treatment should be performed, amputate the clinical crown, and submerge the roots to minimize the risk of ONJ. Before, during, and after any of these procedures, the patient should always perform oral rinses with chlorhexidine (0.12 % or 0.2 %) 2-3 times a day for a period of 2-3 weeks. Controls will be monthly during the first year and with x-rays (in the case of having performed extractions) every six months (7,11,21).

There is a great deal of misinformation in the medical and dental fields about the adverse effects that these drugs can have on the maxillary bones. Prior to the start of treatment, there must be communication and multidisciplinary management with the different medical groups and the dentist, when it is determined that a patient is treated with antiresorptive or antiangiogenic drugs (7,21,42,43). The most important activity is to explain and inform patients about the minimal risk associated with these drugs, but also the elevated risk of not following the recommendations or conducting preventive measures (44,45,46).

Every dentist must consider that patients with osteoporosis under oral bisphosphonates are less likely to present ONJ than those who use intravenous antiresorptives (i.e., denosumab or bisphosphonates). Likewise, cancer patients are more likely to present ONJ due to the high doses and frequency with which they are applied (11,17,21,39).

The estimated incidence in patients with osteoporosis treated with antiresorptives is 0.01 % to 0.1 % (1-10 cases per 10,000). In cancer patients treated with antiresorptive or antiangiogenic agents, the incidence is 1 % (one case per 100) (21,47). Although the percentages may seem low, the risk is always high. Women are at greater risk than men due to a higher incidence of osteoporosis and breast cancer.

During drug treatment, the oral status should be monitored, the patient should practice good oral hygiene, and periodontal maintenance should be performed. This review should be periodic, if possible, every 3, 4, or 6 months (48,49,50).

High-risk patients should always receive prophylactic or previous dental treatment. The Ontario Cancer Care group and the American Society of Clinical Oncology issued the following recommendation in 2017: “Dental evaluation is recommended, when possible, prior to initiation of BF [bisphosphonates] and any outstanding dental or oral health problems should be resolved before starting treatment” (51)

On the other hand, the Scottish National Health and Education Service in its clinical guide recommends that before starting pharmacological treatment with antiresorptive or antiangiogenic agents, or as soon as possible thereafter, ensure that the patient is in the best possible dental condition, prioritizing preventive care. Higher-risk cancer patients should preferably undergo a comprehensive dental evaluation, performing dental treatments where necessary, before starting pharmacological treatment (47). The treatment proposed by the AAOMS in 2014, based on the various stages (7), is as follows (Table 2):

TABLE 2 TABLE 2 Treatment of ONJ based on stage, according to the AAOMS (7)

The management of ONJ with several types of treatments is still under investigation. Medications such as teriparatide seem to be a possible solution (52). But side effects such as nausea, arthralgia, vomiting, psychological and, kidney problems may occur, which leads to discontinuation or interruption of treatment. Its use in the treatment of ONJ continues to be investigated (53).

It is not just about treating the patient with antiresorptive or antiangiogenic drugs; it is always imperative to take risk factors into account. If a patient has one or more of these factors, the probability of developing ONJ is higher. Figures 1,2,3 show clinical and radiographic aspects of patients with osteoporosis and cancer with ONJ generated by several factors.

FIGURE 1

Case 1) Patient diagnosed with multiple myeloma undergoing treatment with antiresorptive agents with ONJ due to extractions. Alginate impression is taken and the alveolar bone is adhered to the material. It is a favorable situation for the patient because there is scar tissue and no infection. Case 2) Patient in treatment with antiresorptive drugs for osteoporosis with ONJ due to extractions and orofacial fistula. Case 3) Four months after conservative treatment with clindamycin 300 mg and chlorhexidine 0.2 %; note the bone sequestration and healing of the gingiva.

Note: Images posted with permission from patients.