**3. Pathophysiology**

The pathophysiology of MRONJ is well unknown and considered to be multifactorial. Suppressed bone remodeling may contribute to the development of osteonecrosis, and in inadequate osteoclast activity disturbed cure the extraction socket. Infection is a major factor for the development of MRONJ. Bacteria stimulate bone resorption and contribute to bone necrosis [9].

#### **3.1. Incidence of MRONJ**

The reported incidence of MRONJ varies by study, and there are no reliable epidemiological data derived from evidenced-based medicine. This chapter follows the data cited by the International Task Force on ONJ [10].

#### *3.1.1. Patients with osteoporosis*

#### 1. BRONJ

The incidence is 1.04–69/100,000 patients per year treated with orally administered BPs and 0–90/100,000 patients per year treated with intravenous administration. The incidence of ONJ in patients with osteoporosis treated with oral/intravenous nitrogencontaining BPs ranges from 0.001 to 0.01%, which is estimated to be almost the same or slightly higher than the incidence (0.01%) of ONJ in the general population [10].

2. DRONJ

The incidence is 0–30.2/100,000 patients per year [10].

#### *3.1.2. Cancer patients*

The incidence of ONJ in cancer patients is higher than that in patients with osteoporosis. Prospective studies on the incidence of ONJ were conducted in cancer patients treated with zoledronic acid or denosumab. Among 5723 patients with breast, prostate, and other solid cancer and multiple myeloma, there were 89 ONJ cases in total, 52 in the denosumab, and 37 in the zoledronic acid-treated. The incidence in the denosumab-treated was 1.8% and 1.3% in the zoledronic acid [3, 11].

#### **3.2. Uniqueness of the jaw bone [12]**

There are several unique anatomical and microbiological characteristics of the jaw bone, which could be responsible for the specific occurrence of MRONJ. These characteristics are not found in bones or in other parts of the body.

The teeth erupt from the jawbone, breaking the oral epithelium, allowing infectious factors, agents, and microbes in the oral cavity to directly invade the jaw bone through the gap between the epithelium and the teeth or via root canal.


#### **3.3. Suppression of bone turnover**

BPs and denosumab inhibit osteoclast differentiation and function, increased apoptosis, and decreased bone resorption and remodeling [2, 13, 14]. Osteoclast differentiation and function act as an effective role for bone remodeling for skeletal sites, but MRONJ occurs only primarily within the alveolar bone of jaw [15]. An increased remodeling rate in the jaw may be considered for the differential predisposition of MRONJ to occur in the jaws compared with other bones in the axial or appendicular skeleton [5].

The relation between excessive suppression of C-terminal telopeptides of type I collagen (CTX), a bone resorption marker, and MRONJ incidence has been reported in several studies. However, a correlation between CTX level and severity of MRONJ has not been observed. There is still much controversy on whether a relationship exists between CTX levels and MRONJ incidence [16–18].

#### **3.4. Infection/inflammation**

The risk factors have been implicated dental disease or bacterial infection in MRONJ. Although dental extraction was performed in most reported cases of MRONJ, these teeth commonly contracted with periodontal or periapical diseases. Inflammation or infection has long been considered an important component of MRONJ [19, 20].

#### **3.5. Angiogenesis inhibition**

zoledronic acid or denosumab. Among 5723 patients with breast, prostate, and other solid cancer and multiple myeloma, there were 89 ONJ cases in total, 52 in the denosumab, and 37 in the zoledronic acid-treated. The incidence in the denosumab-treated was 1.8% and 1.3%

There are several unique anatomical and microbiological characteristics of the jaw bone, which could be responsible for the specific occurrence of MRONJ. These characteristics are

The teeth erupt from the jawbone, breaking the oral epithelium, allowing infectious factors, agents, and microbes in the oral cavity to directly invade the jaw bone through the gap

**1.** The oral mucosa covering the jawbone is thin, and infection caused by mucosal injury

**2.** More than 800 types of resident bacteria (1011 to 10<sup>12</sup> cm–3) inhabit dental plaque and can

**3.** Inflammation due to tooth decay, pulpitis, periapical lesions, or periodontal disease

**4.** The jawbone is exposed to the oral cavity following invasive dental treatments including

BPs and denosumab inhibit osteoclast differentiation and function, increased apoptosis, and decreased bone resorption and remodeling [2, 13, 14]. Osteoclast differentiation and function act as an effective role for bone remodeling for skeletal sites, but MRONJ occurs only primarily within the alveolar bone of jaw [15]. An increased remodeling rate in the jaw may be considered for the differential predisposition of MRONJ to occur in the jaws compared with

The relation between excessive suppression of C-terminal telopeptides of type I collagen (CTX), a bone resorption marker, and MRONJ incidence has been reported in several studies. However, a correlation between CTX level and severity of MRONJ has not been observed. There is still much controversy on whether a relationship exists between CTX levels and

The risk factors have been implicated dental disease or bacterial infection in MRONJ. Although dental extraction was performed in most reported cases of MRONJ, these teeth commonly

in the zoledronic acid [3, 11].

90 Osteonecrosis

extends to the jawbone.

**3.2. Uniqueness of the jaw bone [12]**

not found in bones or in other parts of the body.

between the epithelium and the teeth or via root canal.

spreads to the jawbone beneath the mucosa.

serve as a source of infection in the oral cavity.

other bones in the axial or appendicular skeleton [5].

tooth extraction, leading to infection.

**3.3. Suppression of bone turnover**

MRONJ incidence [16–18].

**3.4. Infection/inflammation**

Angiogenesis is a process that involves growth, migration, and differentiation of endothelial cells to form new blood vessels. Angiogenesis favorably influences tumor growth and influences tumor invasion of vessels, resulting in tumor metastasis. Osteonecrosis is classically considered as an interruption in vascular supply or avascular necrosis; therefore, it is not surprising that inhibition of angiogenesis is a leading hypothesis in MRONJ pathophysiology [21, 22].

#### **3.6. Soft tissue toxicity**

Although BPs primarily targets the osteoclast and bind to hydroxyapatite in bone, soft tissue toxicity has been reported. In contrast to BPs, no soft tissue toxicity has been reported with denosumab [23].
