**2. Etiopathogenesis**

There are a number of theories concerning the cause of this complication. They are mostly related to the formation of necrotic bone caused by the inhibition of bone remodeling with bisphosphonates and an antiangiogenic therapy. However, several studies on the development of the disease indicate that the bone remodeling inhibition itself cannot cause bone exposure. It is necessary for local risk factors to also be present.

The most significant theories about the possible cause are based on the following arguments:


According to a theory, keratinocytes undergo bisphosphonate-induced apoptosis resulting in diminished mucous barrier in the oral cavity, which plays a role in the development of MRONJ. If an infection in the oral cavity is caused by the naturally occurring post-surgery bacteria (*Actinomyces israelii*, *Escherichia coli*), they will cause the drop in the wound area pH, and will release bisphosphonates and calcium salts. The hypothesis is that high concentrations of bisphosphonates increase apoptosis of keratinocytes in the attached gingiva and consequently, allow the penetration of bacteria into deeper tissues. This hypothesis may explain why MRONJ occurs only in maxilla and mandible, but not in other bones of the skeleton.

Numerous similar longitudinal studies confirm the significant role of infectious agents in the oral cavity with expressed osteonecrosis [10]. Surgical procedures conducted during a bisphosphonate therapy or a periodontal pathology indicating bone remodeling of the alveolar bone make it easier for bisphosphonates to accumulate in maxilla or mandible. After bisphosphonates in a bone reach the critical concentration, a trigger (tooth extraction) activates the bone remodeling, simultaneously releasing local deposits of bisphosphonates that inhibit the bone healing process. Necrotic osteomyelitis is induced by the slowed-down repair

Osteonecrosis of the Jaws

73

http://dx.doi.org/10.5772/intechopen.75878

Hence, efficient debridement, application of antimicrobial mouthwash and application of ATB directly on the bone defect and the wound play a very important role in the treatment of ONJ.

In the past, osteonecrosis of the jaw proved to be a serious problem not only in the view of possible treatments, but also in the view of the diagnosis itself. Such lesions and conditions were usually considered to be osteitis, osteomyelitis or alveolitis, which were thought to have

Complications in the oral cavity in patients with MRONJ are usually diverse. The complications may emerge due to the progression of the disease, or as a result of medical procedures, which produce functional problems such as diminished chewing function, loss of teeth and limited rehabilitation of the chewing function. In addition, aesthetic obstructions may also emerge due to the loss of teeth, facial contour defects (owing to partial bone resections) or due to enduring oroantral fistulas. Patients experience sore mouth, impaired wound healing and drug-induced mucositis.

The most common clinical sign of MRONJ (up to 93.9%) is an exposed necrotic bone. The scope of bone exposure may vary greatly and is directly connected neither with the scope of the necrosis nor with the severity of the disease. Signs of infection such as swelling of soft tissues, intra/extra oral purulent discharge or abscesses may also be present. Patients may suffer from severe pain if the infection breaks out of the necrotic tissue, although this symptom is not a requirement many patients do not report any pain. In severe cases, local infection may develop into abscesses in the deeper areas of the head and neck, resulting in life-threatening conditions. It may even lead to an abscess in brain tissues. Some rare cases of septic systemic infection have been documented. Rare, although typical, symptom of MRONJ is the paresis of alveolar nerve, also known as the Vincent's symptom. It is interesting that it manifests itself in the earlier and in the advanced stages of MRONJ. Reduced sensitivity of nervus alveolaris inferior can also be a sign of metastatic infiltration. Histologic examination is recommended. Other symptoms associated with MRONJ include loss of teeth due to structural changes within the necrotic bone and bad

Loss of teeth is the result of a progress of the necrotic damage to the alveolar bone. Bad breath as a symptom commonly occurs in patients suffering from MRONJ based on previous changes within the necrotic bone and the surrounding soft tissues. This can also be the result

process, accompanied by a bone wound contamination by the Actinomyces bacteria.

**3. Clinical picture**

been the result of a preceding extraction.

breath due to bacterial inflammation.

Another theory considers the unique role of bone remodeling rate. Both maxilla and mandible are examples of a bone that is subject to an increased bone remodeling, mainly in the alveolar socket area and periodontal area, as a result of intensive mechanical stress acting on teeth during chewing and other movements of the teeth. It turns out that the bone turnover is constant during the life of an individual, regardless of their age [5].

The suppression of remodeling and decrease of bone turnover results from bisphosphonates directly affect osteoclasts and their function. Studies examining osteogenesis imperfecta in kids reveal that bisphosphonates do not always reduce the level of osteoclasts, but contrary to that, under certain conditions, they tend to increase their levels [6, 7]. Suppression of bone remodeling could therefore occur through other mechanisms such as intravenous bisphosphonate application.

Longitudinal animal studies with long-term application of bisphosphonates revealed increased number of multilocular phosphatase-positive cells in jaw and long bones. On the surface of the bone, however, the number of osteoclasts is decreased, while the number of osteoclasts in the woven bone is increased [8]. A traumatized alveolar compact bone with damaged periosteal and endosteal covering and diminished osteoprogenitor cells will activate osteoclasts and start the bone remodeling process. However, osteoclasts are unable to bind themselves to the bone surface and resorp the bone matrix as a result of incorporated bisphosphonates. Traumatized bone can hold the attempted osteoclast activation signal, and the osteoclasts then accumulate near the bone surface. The purpose of these accumulated unconnected osteoclasts in bone tissue is currently unclear [9].

#### **2.1. Infectious agents**

The oral cavity is colonized by a number of microorganisms that may become pathogenic even after the slightest superficial trauma to the oral mucosa, which then acts as a gateway for jaw bone infection. An organism treated with ARM has altered immune response and is unable to react efficiently against infectious agents and curb the spread of infection to surrounding tissues of the oral cavity and alveolar processes.

Various in vivo studies on rats describe a link between the periodontal infection and the osteonecrosis development. Young adult rats have been administered bisphosphonates for 15 weeks and had a circumdental wire applied to the first molar for 3 weTeks to induce an aggressive periodontitis. Osteonecrosis of the jaw diagnosed in this study had the identical course and histological finding to the human manifestations of the disease, with bone sequestration, numerous empty osteocyte lacunas and an expression of inflammation. Culture results proved that Fusobacterium nucleatum were present. After the subsequent ATB application, the signs of osteonecrosis have subsided; however, the healing ad integrum did not happen.

Numerous similar longitudinal studies confirm the significant role of infectious agents in the oral cavity with expressed osteonecrosis [10]. Surgical procedures conducted during a bisphosphonate therapy or a periodontal pathology indicating bone remodeling of the alveolar bone make it easier for bisphosphonates to accumulate in maxilla or mandible. After bisphosphonates in a bone reach the critical concentration, a trigger (tooth extraction) activates the bone remodeling, simultaneously releasing local deposits of bisphosphonates that inhibit the bone healing process. Necrotic osteomyelitis is induced by the slowed-down repair process, accompanied by a bone wound contamination by the Actinomyces bacteria.

Hence, efficient debridement, application of antimicrobial mouthwash and application of ATB directly on the bone defect and the wound play a very important role in the treatment of ONJ.
