TMJ and Maxillomandibular Lesions

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

[24] Kargul B, Caglar E, Kabalay U. Glass fiber-reinforced composite resin as fixed space maintainers in children: 12-Month clinical follow-up. Journal of Dentistry for Children (Chicago, Ill.). 2005;**72**:109-112

[25] Marriot-Smith C, Marino V, Heithersay GS. A preclinical dental trauma teaching module. Dental Traumatology. 2016;**32**:247-250. DOI:

[26] Yildirim Öz G, Ataoǧlu H, Kir N, Karaman AI. An alternative method

Traumatology. 2006;**22**:345-349. DOI: 10.1111/j.1600-9657.2005.00364.x

[28] Stellini E, Avesani S, Mazzoleni S, Favero L. Laboratory comparison of a titanium trauma splint with three conventional ones for the treatment of dental trauma. European Journal of Paediatric Dentistry. 2005;**6**:191-196

[29] Von Arx T, Filippi A, Lussi A. Comparison of a new dental trauma splint device (TTS) with three commonly used splinting techniques. Dental Traumatology. 2001;**17**:266-274. DOI: 10.1034/j.1600-9657.2001.170605.x

[30] Hinckfuss SE, Messer LB. Splinting duration and periodontal outcomes for replanted avulsed teeth: A systematic review. Dental Traumatology. 2009;**25**:150-157. DOI: 10.1111/j.1600-9657.2008.00761.x

[31] Qin M, Ge L, Bai R. Use of a removable splint in the treatment of subluxated, luxated and root fractured anterior permanent teeth in children. Dental Traumatology. 2002;**18**:81-85. DOI: 10.1034/j.1600-9657.2002.180207.x

[27] Filippi A, Von Arx T, Lussi A. Comfort and discomfort of dental trauma splints—A comparison of a new device (TTS) with three commonly used splinting techniques. Dental Traumatology. 2002;**18**:275-280. DOI: 10.1034/j.1600-9657.2002.00121.x

for splinting of traumatized teeth: Case reports. Dental

10.1111/edt.12251

of emergency treatment. Dental Traumatology. 2008;**24**:370-372. DOI: 10.1111/j.1600-9657.2007.00530.x

[16] Lello JL, Lello GE. The effect of interdental continuous loop wire splinting and intermaxillary fixation on the marginal gingiva. International Journal of Oral and Maxillofacial Surgery. 1988;**17**:249-252. DOI: 10.1016/

[17] Berthold C, Thaler A, Petschelt A.

Traumatology. 2009;**25**:248-255. DOI: 10.1111/j.1600-9657.2008.00683.x

[18] Oikarinen K. Comparison of the flexibility of various splinting methods for tooth fixation. International Journal of Oral and Maxillofacial Surgery. 1988;**17**:125-127. DOI: 10.1016/

[19] Oikarinen K. Tooth splinting: A review of the literature and

[20] Alexander PC. Replantation of teeth. Oral Surgery, Oral Medicine, and Oral Pathology. 1956;**9**:110-114. DOI: 10.1016/0030-4220(56)90181-5

[21] Dawoodbhoy I, Valiathan A, Lalani ZS, Cariappa KM. Splinting of avulsed central incisors with orthodontic wires: A case report. Endodontics & Dental Traumatology. 1994;**10**:149-152. DOI: 10.1111/j.1600-9657.1994.tb00541.x

[22] Croll TP, Helpin ML. Use of selfetching adhesive system and compomer for splinting traumatized incisors. Pediatric Dentistry. n.d.;**24**:53-56

[23] von Arx T. Splinting of traumatized teeth with focus on adhesive techniques.

Journal of the California Dental Association. 2005;**33**:409-414

consideration of the versatility of a wirecomposite splint. Endodontics & Dental Traumatology. 1990;**6**:237-250. DOI: 10.1111/j.1600-9657.1990.tb00426.x

s0901-5027(88)80050-x

s0901-5027(88)80166-8

Rigidity of commonly used dental trauma splints. Dental

**44**

**47**

**Chapter 5**

**Abstract**

**1. Introduction**

Medication-Related Osteonecrosis

Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of medications belonging to the antiresorptive (AR) and antiangiogenic (AA) groups. The first cases were described in the literature in 2003, and more than 1300 publications and 15,000 cases have been published since then. The incidence of MRONJ among cancer patients treated with bisphosphonates is 0–6.7%, with denosumab is 0.7–1.7% and with bevacizumab is 0.2%. Patients treated for osteoporosis have a lower risk of developing MRONJ at 0.02 and 0.04% with bisphosphonates and 0.2% with denosumab. In more than 50% of cases, tooth extraction was considered the causative factor responsible for the onset of the MRONJ. Treatment strategies

**Keywords:** medication-related osteonecrosis of the jaw, bisphosphonate-related osteonecrosis of the jaw, antiresorptive-associated osteonecrosis of the jaw,

Medication-related osteonecrosis of the jaw (MRONJ) is a side effect of some medications belonging to the antiresorptive (AR), such as bisphosphonates and denosumab, and antiangiogenic (AA) groups. The disease is present as an exposed necrotic bone in the maxilla or mandible persisting for more than 8 weeks in patients taking the aforementioned medical therapy but without a past history of radiotherapy [1, 2]. The first cases described in 2003 were thought to be a side effect of bisphosphonates (BP) alone and was termed bisphosphonate-related osteonecrosis of the jaws [3, 4]. More than 1300 publications with more than 15,000 cases have been published since then, with two new names indicating that medications other

Reports of denosumab-associated osteonecrosis began surfacing in 2010, which led the American Dental Association to revise the term 'MRONJ' to antiresorptiverelated osteonecrosis of the jaws (ARONJ) to stress the fact that other antiresorptive

Recently published literature has, however, demonstrated the implication of both antiresorptive and antiangiogenic medications in osteonecrosis of the jaws. It was known previously that the antiangiogenic medications could increase the incidence of osteonecrosis of the jaws when they were administered together with BP [12, 13]. New evidence indicates that antiangiogenic therapy can cause osteonecrosis of the jaws in patients naive to BP therapy [12]. Consequently, the American Association of Oral and Maxillofacial Surgeons (AAOMS) published an update in

of the Jaw: An Overview

*Marko Blašković and Dorotea Blašković*

include preventive, medical and surgical interventions.

than BPs could help trigger osteonecrosis of the jaws [5].

compounds could lead to osteonecrosis of the jaws [6–11].

denosumab, antiangiogenic medicamentations

## **Chapter 5**

## Medication-Related Osteonecrosis of the Jaw: An Overview

*Marko Blašković and Dorotea Blašković*

## **Abstract**

Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of medications belonging to the antiresorptive (AR) and antiangiogenic (AA) groups. The first cases were described in the literature in 2003, and more than 1300 publications and 15,000 cases have been published since then. The incidence of MRONJ among cancer patients treated with bisphosphonates is 0–6.7%, with denosumab is 0.7–1.7% and with bevacizumab is 0.2%. Patients treated for osteoporosis have a lower risk of developing MRONJ at 0.02 and 0.04% with bisphosphonates and 0.2% with denosumab. In more than 50% of cases, tooth extraction was considered the causative factor responsible for the onset of the MRONJ. Treatment strategies include preventive, medical and surgical interventions.

**Keywords:** medication-related osteonecrosis of the jaw, bisphosphonate-related osteonecrosis of the jaw, antiresorptive-associated osteonecrosis of the jaw, denosumab, antiangiogenic medicamentations

## **1. Introduction**

Medication-related osteonecrosis of the jaw (MRONJ) is a side effect of some medications belonging to the antiresorptive (AR), such as bisphosphonates and denosumab, and antiangiogenic (AA) groups. The disease is present as an exposed necrotic bone in the maxilla or mandible persisting for more than 8 weeks in patients taking the aforementioned medical therapy but without a past history of radiotherapy [1, 2]. The first cases described in 2003 were thought to be a side effect of bisphosphonates (BP) alone and was termed bisphosphonate-related osteonecrosis of the jaws [3, 4]. More than 1300 publications with more than 15,000 cases have been published since then, with two new names indicating that medications other than BPs could help trigger osteonecrosis of the jaws [5].

Reports of denosumab-associated osteonecrosis began surfacing in 2010, which led the American Dental Association to revise the term 'MRONJ' to antiresorptiverelated osteonecrosis of the jaws (ARONJ) to stress the fact that other antiresorptive compounds could lead to osteonecrosis of the jaws [6–11].

Recently published literature has, however, demonstrated the implication of both antiresorptive and antiangiogenic medications in osteonecrosis of the jaws. It was known previously that the antiangiogenic medications could increase the incidence of osteonecrosis of the jaws when they were administered together with BP [12, 13]. New evidence indicates that antiangiogenic therapy can cause osteonecrosis of the jaws in patients naive to BP therapy [12]. Consequently, the American Association of Oral and Maxillofacial Surgeons (AAOMS) published an update in

2014 establishing the new moniker 'MRONJ' to better reflect the variety of medications known to induce jaw osteonecrosis [14].

From a historical stand point, the first cases of the jaw osteonecrosis were described in the nineteenth century in matchmaking industry workers who were exposed to phosphorous compounds. The condition was known as 'phossy jaw', a painful jaw bone exposure associated with sequestration and infection. It was a very progressive condition with high mortality rate because of the absence of antibiotic therapy. The incidence of the condition "phossy jaw" decreased significantly due to the improvement of the working conditions in the matchmaking industry [15].

In the literature, this condition is known under several names and acronyms:

MRONJ—medication-related osteonecrosis of the jaw BRONJ—bisphosphonate-related osteonecrosis of the jaw BAONJ—bisphosphonate-associated osteonecrosis of the jaw ARONJ—antiresorptive-associated osteonecrosis of the jaw BON—bisphosphonate osteonecrosis ONJ—osteonecrosis of the jaw [5]

#### **1.1 Antiresorptive medicaments: bisphosphonates (BPs)**

Bisphosphonates belong to a group of antiresorptive medications often used to treat osteoporosis. Other members of the AR group are monoclonal antibodies against receptor activator of nuclear factor-ĸ denosumab (RANKL), selective oestrogen receptor modulators, estrogens and calcitonin. Only the first two members, BP and denosumab, are associated with MRONJ. Unfortunately, these are also the most commonly utilised medications for the treatment of osteoporosis. BPs are in fact considered the first-choice treatment for osteoporosis worldwide [16, 17].

The first biological use of BP dates back to the 1960s, when etidronate was used to treat heterotopic ossification. Soon after, further research led to the use of BP in the treatment of osteoporosis [18, 19]. BPs are also used to treat non-malignant diseases affecting the bone tissue such as Paget's disease of bone, fibrous dysplasia, cystic fibrosis, primary hyperparathyroidism and osteogenesis imperfecta [19–23].

They are also used to treat osseous malignant conditions such as metastases of solid tumours, malignant hypercalcemia and multiple myeloma. The literature shows that BPs have significant positive effects on the quality of life in cancer patients by reducing complications such as bone fractures, pain and serum calcium imbalances. Furthermore, some members of the BP family such as zolendronate also present antiangiogenic and antitumour features by inhibiting human endothelial cell proliferation and changes in endothelial cell migration and adhesion. Zolendronate's antitumour effects include induction of apoptosis as well as inhibition of cell invasion and adhesion. These aforementioned features are beneficial in delaying tumour growth [17, 24–29].

BPs can be divided into two groups based on the presence or absence of nitrogen atom in the side chain. The presence of nitrogen is related to the higher potency of the BP, which will clinically translate to a better antiresorptive effect and higher binding affinity to hydroxyapatite within bones. It is estimated that BPs have half lives in bone of approximately 11 years [30, 31]. Unfortunately, higher potency of the medication is also linked to a higher incidence of MRONJ. Bone resorption is achieved by two mechanisms. Non-nitrogen BPs are linked to osteoclast apoptosis. Nitrogen-containing BPs have a much more complex working mechanism that inhibits mevalonate signalling to impact osteoclastogenesis, apoptosis and cytoskeletal dynamics [32].

**49**

*Medication-Related Osteonecrosis of the Jaw: An Overview*

**1.2 Antiresorptive medicaments: denosumab**

patients with renal insufficiency [36, 38, 39].

are members of tyrosine kinase inhibitors [37].

In order to diagnose MRONJ, three diagnostic factors must be met:

symptoms as well as a history of head or neck radiotherapy [7].

1.Current or previous treatment with antiresorptive and/or antiangiogenic

2.Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for more than 8 weeks

3.No history of radiation therapy to the jaws or obvious metastatic disease to the

Radiation therapy of the jaws must be excluded since the clinical presentation of the osteoradionecrosis and MRONJ may be impossible to distinguish. A diagnosis of osteoradionecrosis should be considered in patients with the aforementioned

MRONJ diagnosis is established mainly via oral examination and review of medical history. Other more complex diagnostic tools such as imaging modalities

**3. Diagnosis of the MRONJ**

jaws [1, 7, 14, 50]

agents

**2. Antiangiogenic medications**

Denosumab is a human monoclonal antibody that inhibits receptor-activated nuclear factor-ĸB ligand (RANKL). Denosumab prevents the RANKL activation, which is crucial for osteoclast activation, function and differentiation resulting in decreased bone resorption and cancer-induced bone destruction [33–37]. It is available under two names: Prolia, which is used for treating osteoporosis, and Xgeva, which is used for treating complications in patients with bone metastases and solid tumours. The dosing used in the treatment of osteoporosis is 60 mg subcutaneous injection every 6 months. The treatment of patients with bone metastasis is 120 mg subcutaneous injection every 4 weeks [37]. Although the incidence of MRONJ is similar in patients treated with BPs and denosumab, there are some advantages of denosumab over bisphosphonates such as improved efficacy and better tolerability. Furthermore, denosumab creates no nephrotoxic effects and may be used in

Antiangiogenic medicines are used to treat patients with different types of tumours such as gastrointestinal stromal tumour, glioblastoma, hepatocellular carcinoma, hormone receptor-positive breast carcinoma, mantle cell lymphoma, metastatic colorectal carcinoma, multiple myeloma, metastatic renal cell carcinoma, non-squamous nonsmall cell lung carcinoma, pancreatic neuroendocrine tumour, renal cell carcinoma, subependymal giant cell astrocytoma and soft tissue sarcoma. They are used to inhibit or decrease neoangiogenesis which is crucial for the expansive tumour growth. It was known previously that antiangiogenic medications could increase the incidence of osteonecrosis of the jaws when administered concurrently with BP or denosumab [12, 40–43]. New evidence indicates that antiangiogenic therapy can also cause osteonecrosis of the jaws in patients naive to BP therapy [12, 41, 42, 44–49]. Many AA-associated cases of MRONJ were reported after the use of sunitinib and sorafenib, both of which

*DOI: http://dx.doi.org/10.5772/intechopen.86241*

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

MRONJ—medication-related osteonecrosis of the jaw BRONJ—bisphosphonate-related osteonecrosis of the jaw BAONJ—bisphosphonate-associated osteonecrosis of the jaw ARONJ—antiresorptive-associated osteonecrosis of the jaw

**1.1 Antiresorptive medicaments: bisphosphonates (BPs)**

tions known to induce jaw osteonecrosis [14].

BON—bisphosphonate osteonecrosis ONJ—osteonecrosis of the jaw [5]

worldwide [16, 17].

delaying tumour growth [17, 24–29].

2014 establishing the new moniker 'MRONJ' to better reflect the variety of medica-

In the literature, this condition is known under several names and acronyms:

Bisphosphonates belong to a group of antiresorptive medications often used to treat osteoporosis. Other members of the AR group are monoclonal antibodies against receptor activator of nuclear factor-ĸ denosumab (RANKL), selective oestrogen receptor modulators, estrogens and calcitonin. Only the first two members, BP and denosumab, are associated with MRONJ. Unfortunately, these are also the most commonly utilised medications for the treatment of osteoporosis. BPs are in fact considered the first-choice treatment for osteoporosis

The first biological use of BP dates back to the 1960s, when etidronate was used to treat heterotopic ossification. Soon after, further research led to the use of BP in the treatment of osteoporosis [18, 19]. BPs are also used to treat non-malignant diseases affecting the bone tissue such as Paget's disease of bone, fibrous dysplasia, cystic fibrosis, primary hyperparathyroidism and osteogenesis imperfecta [19–23]. They are also used to treat osseous malignant conditions such as metastases of solid tumours, malignant hypercalcemia and multiple myeloma. The literature shows that BPs have significant positive effects on the quality of life in cancer patients by reducing complications such as bone fractures, pain and serum calcium imbalances. Furthermore, some members of the BP family such as zolendronate also present antiangiogenic and antitumour features by inhibiting human endothelial cell proliferation and changes in endothelial cell migration and adhesion. Zolendronate's antitumour effects include induction of apoptosis as well as inhibition of cell invasion and adhesion. These aforementioned features are beneficial in

BPs can be divided into two groups based on the presence or absence of nitrogen atom in the side chain. The presence of nitrogen is related to the higher potency of the BP, which will clinically translate to a better antiresorptive effect and higher binding affinity to hydroxyapatite within bones. It is estimated that BPs have half lives in bone of approximately 11 years [30, 31]. Unfortunately, higher potency of the medication is also linked to a higher incidence of MRONJ. Bone resorption is achieved by two mechanisms. Non-nitrogen BPs are linked to osteoclast apoptosis. Nitrogen-containing BPs have a much more complex working mechanism that inhibits mevalonate signalling to impact osteoclastogenesis, apoptosis and cytoskel-

From a historical stand point, the first cases of the jaw osteonecrosis were described in the nineteenth century in matchmaking industry workers who were exposed to phosphorous compounds. The condition was known as 'phossy jaw', a painful jaw bone exposure associated with sequestration and infection. It was a very progressive condition with high mortality rate because of the absence of antibiotic therapy. The incidence of the condition "phossy jaw" decreased significantly due to the improvement of the working conditions in the matchmaking industry [15].

**48**

etal dynamics [32].

## **1.2 Antiresorptive medicaments: denosumab**

Denosumab is a human monoclonal antibody that inhibits receptor-activated nuclear factor-ĸB ligand (RANKL). Denosumab prevents the RANKL activation, which is crucial for osteoclast activation, function and differentiation resulting in decreased bone resorption and cancer-induced bone destruction [33–37]. It is available under two names: Prolia, which is used for treating osteoporosis, and Xgeva, which is used for treating complications in patients with bone metastases and solid tumours. The dosing used in the treatment of osteoporosis is 60 mg subcutaneous injection every 6 months. The treatment of patients with bone metastasis is 120 mg subcutaneous injection every 4 weeks [37]. Although the incidence of MRONJ is similar in patients treated with BPs and denosumab, there are some advantages of denosumab over bisphosphonates such as improved efficacy and better tolerability. Furthermore, denosumab creates no nephrotoxic effects and may be used in patients with renal insufficiency [36, 38, 39].

## **2. Antiangiogenic medications**

Antiangiogenic medicines are used to treat patients with different types of tumours such as gastrointestinal stromal tumour, glioblastoma, hepatocellular carcinoma, hormone receptor-positive breast carcinoma, mantle cell lymphoma, metastatic colorectal carcinoma, multiple myeloma, metastatic renal cell carcinoma, non-squamous nonsmall cell lung carcinoma, pancreatic neuroendocrine tumour, renal cell carcinoma, subependymal giant cell astrocytoma and soft tissue sarcoma. They are used to inhibit or decrease neoangiogenesis which is crucial for the expansive tumour growth. It was known previously that antiangiogenic medications could increase the incidence of osteonecrosis of the jaws when administered concurrently with BP or denosumab [12, 40–43]. New evidence indicates that antiangiogenic therapy can also cause osteonecrosis of the jaws in patients naive to BP therapy [12, 41, 42, 44–49]. Many AA-associated cases of MRONJ were reported after the use of sunitinib and sorafenib, both of which are members of tyrosine kinase inhibitors [37].

## **3. Diagnosis of the MRONJ**

In order to diagnose MRONJ, three diagnostic factors must be met:


Radiation therapy of the jaws must be excluded since the clinical presentation of the osteoradionecrosis and MRONJ may be impossible to distinguish. A diagnosis of osteoradionecrosis should be considered in patients with the aforementioned symptoms as well as a history of head or neck radiotherapy [7].

MRONJ diagnosis is established mainly via oral examination and review of medical history. Other more complex diagnostic tools such as imaging modalities or histopathological examinations are not specific enough and should be used as adjunctive tools to assess the stage and extent of the disease. The initial diagnosis of MRONJ can be made by any dentist or physician with a basic understanding of MRONJ [7, 50].

Consultations with the patient's physician are critical because many patients remain confused or forgetful regarding their current or previous antiresorptive/ antiangiogenic therapy. Furthermore, cancer patients may receive a complex therapy consisting of different medications used at different time sequences, which contributes to the overall confusion.

#### **3.1 Clinical picture of MRONJ**

A defining feature of MRONJ is the exposure of necrotic bone or fistulation that can be probed to the osseous surface which fails to heal for more than 8 weeks. This clinical finding can be anticipated by mild pain and discomfort in the affected site. As the disease progresses, the adjacent soft tissue becomes inflamed, appearing erythematosus and swollen. Purulent exudate may be present as a consequence of a secondary infection. In the later stages of the disease, oroantral fistula, oronasal fistula, oral cutaneous fistula or pathological fractures may be present [1, 7, 14, 51].

#### **3.2 Imaging**

Radiographic features of MRONJ are not pathognomonic and depend on the stage and development of the disease.

In the early stages of the disease, zones of higher and diffused radiopacity and thickening of the lamina dura can be present within the affected bone. Previous extraction sites may demonstrate minimal or complete absence of bone healing, which results in radiolucent radiographic appearance with a prominent residual lamina dura.

In more developed stages of MRONJ, the exposed bone becomes colonised by bacteria which induce focal bone demineralisation. Radiography shows a poorly circumscribed mixture of radiolucent and radiopaque zones. Other osteolytic processes with similar radiographic findings include osteomyelitis, multiple myeloma, metastatic disease and primary lymphoma of the bone [7, 52].

Further advancement of the disease can result in the formation of bony sequestra, which is visible on radiographic image as radiopaque or mottled fragments surrounded by a radiolucent border. Additionally, in some cancer patients treated with BP, a periosteal thickening (mimicking a second layer of compact bone surrounding the cortical bone) and new bone formation on the Schneiderian mucous membrane were described [7, 52, 53].

MRI and Technetium-99m imaging modalities may be more useful in detecting the presence of inflammation in patients with established MRONJ [7].

Scintigraphy may show additional benefits in cancer patients undergoing intravenous (IV) BP therapy. There exists evidence that many of those who presented with an increased tracer uptake in the jaws subsequently developed necrosis, though further research is needed to confirm these findings [54, 55].

PET imaging has low diagnostic values in MRONJ because of a low level of sensitivity and accuracy [7].

#### **3.3 Histopathology**

MRONJ specimens are composed of grey coloured hard tissue and, occasionally, friable soft tissue. Decalcification of the larger specimens can be prolonged as a result of bone sclerosis. In contrast, smaller bone specimens may have soft

**51**

*Medication-Related Osteonecrosis of the Jaw: An Overview*

tissue with or without abscess formation [7, 52].

consistency as a result of bacterial colonisation. While the necrotic fragments are devoid of osteocytes and osteoclasts, they may have bacterial debris adherent to their surfaces from bone exposure. The adjacent soft tissue consists of granulation

Although infrequently, metastatic cancer was identified in bone specimens clinically diagnosed as MRONJ in cancer patients exposed to BP therapy. Thus, all the bone specimens obtained from MRONJ cancer patients either by biopsy, sequestrectomy or segmental osteotomy should be sent for histopathological

Microbiological culture assessment of exposed bone has previously failed to identify a definite, specific microbial aetiology behind MRONJ. The samples demonstrated a polymicrobial infection caused by pathogens present in the normal

MRONJ is an uncommon disease whose frequency is generally low regardless of the type of antiresorptive or antiangiogenic medications administered. According to one study, an average general dentist can expect one new case of MRONJ every 62 years of his work among patients on oral BP [57]. The overall risk of MRONJ among patients with cancer diagnosis (primary or metastatic) is 0–6.7% if treated with IV BPs [58–60], 0.7–1.7% if treated with denosumab [58, 61, 62] and 0.2% if treated with the AA agent bevacizumab [12, 58, 63]. The risk range of MRONJ among patients who are exposed to both zolendronate (intravenous BP) and bevacizumab (antiangiogenic) is 0.9% [12]. The risk among patients treated for osteoporosis who are exposed to oral zolendronate alone is 0.02% [58, 64], while the risk for patients treated with denosumab alone is

Patients with intraosseous malignancies are treated intravenously with BP or subcutaneously with denosumab, while patients affected with osteoporosis can be treated with oral or intravenous BP medications or subcutaneously with

Oral BPs are associated with lower occurrence risk of MRONJ than intravenous BPs or denosumab. The incidence of AR therapy-associated MRONJ is signifi-

The prevalence of MRONJ increases over time, from 0.5 to 0.6% after 1 year of therapy, 0.9 to 1.1% after 2 years and 1.3 to 1.1% after 3 years [67]. For patients with osteoporosis who are exposed to oral BPs, the prevalence of MRONJ increases over time from 0 to 0.2% after 4 years. The average duration of BP

cantly lower for osteoporosis patients than for cancer patients [58].

*DOI: http://dx.doi.org/10.5772/intechopen.86241*

analysis [56].

**3.4 Microbiology**

oral flora [7, 52].

**4. Frequency of MRONJ**

0.04–0.2% [58, 65, 66].

denosumab.

• Duration of BP therapy

**5. Risk factors of MRONJ**

**5.1 Risk factors connected with AR medications**

• Route of administration of AR medications

*Medication-Related Osteonecrosis of the Jaw: An Overview DOI: http://dx.doi.org/10.5772/intechopen.86241*

consistency as a result of bacterial colonisation. While the necrotic fragments are devoid of osteocytes and osteoclasts, they may have bacterial debris adherent to their surfaces from bone exposure. The adjacent soft tissue consists of granulation tissue with or without abscess formation [7, 52].

Although infrequently, metastatic cancer was identified in bone specimens clinically diagnosed as MRONJ in cancer patients exposed to BP therapy. Thus, all the bone specimens obtained from MRONJ cancer patients either by biopsy, sequestrectomy or segmental osteotomy should be sent for histopathological analysis [56].

#### **3.4 Microbiology**

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

MRONJ [7, 50].

**3.2 Imaging**

contributes to the overall confusion.

stage and development of the disease.

were described [7, 52, 53].

sensitivity and accuracy [7].

**3.3 Histopathology**

**3.1 Clinical picture of MRONJ**

or histopathological examinations are not specific enough and should be used as adjunctive tools to assess the stage and extent of the disease. The initial diagnosis of MRONJ can be made by any dentist or physician with a basic understanding of

Consultations with the patient's physician are critical because many patients remain confused or forgetful regarding their current or previous antiresorptive/ antiangiogenic therapy. Furthermore, cancer patients may receive a complex therapy consisting of different medications used at different time sequences, which

A defining feature of MRONJ is the exposure of necrotic bone or fistulation that can be probed to the osseous surface which fails to heal for more than 8 weeks. This clinical finding can be anticipated by mild pain and discomfort in the affected site. As the disease progresses, the adjacent soft tissue becomes inflamed, appearing erythematosus and swollen. Purulent exudate may be present as a consequence of a secondary infection. In the later stages of the disease, oroantral fistula, oronasal fistula, oral cutaneous fistula or pathological fractures may be present [1, 7, 14, 51].

Radiographic features of MRONJ are not pathognomonic and depend on the

In the early stages of the disease, zones of higher and diffused radiopacity and thickening of the lamina dura can be present within the affected bone. Previous extraction sites may demonstrate minimal or complete absence of bone healing, which results in radiolucent radiographic appearance with a prominent residual lamina dura. In more developed stages of MRONJ, the exposed bone becomes colonised by bacteria which induce focal bone demineralisation. Radiography shows a poorly circumscribed mixture of radiolucent and radiopaque zones. Other osteolytic processes with similar radiographic findings include osteomyelitis, multiple myeloma,

Further advancement of the disease can result in the formation of bony sequestra, which is visible on radiographic image as radiopaque or mottled fragments surrounded by a radiolucent border. Additionally, in some cancer patients treated with BP, a periosteal thickening (mimicking a second layer of compact bone surrounding the cortical bone) and new bone formation on the Schneiderian mucous membrane

MRI and Technetium-99m imaging modalities may be more useful in detecting

Scintigraphy may show additional benefits in cancer patients undergoing intravenous (IV) BP therapy. There exists evidence that many of those who presented with an increased tracer uptake in the jaws subsequently developed necrosis, though

PET imaging has low diagnostic values in MRONJ because of a low level of

MRONJ specimens are composed of grey coloured hard tissue and, occasionally, friable soft tissue. Decalcification of the larger specimens can be prolonged as a result of bone sclerosis. In contrast, smaller bone specimens may have soft

the presence of inflammation in patients with established MRONJ [7].

further research is needed to confirm these findings [54, 55].

metastatic disease and primary lymphoma of the bone [7, 52].

**50**

Microbiological culture assessment of exposed bone has previously failed to identify a definite, specific microbial aetiology behind MRONJ. The samples demonstrated a polymicrobial infection caused by pathogens present in the normal oral flora [7, 52].

## **4. Frequency of MRONJ**

MRONJ is an uncommon disease whose frequency is generally low regardless of the type of antiresorptive or antiangiogenic medications administered. According to one study, an average general dentist can expect one new case of MRONJ every 62 years of his work among patients on oral BP [57]. The overall risk of MRONJ among patients with cancer diagnosis (primary or metastatic) is 0–6.7% if treated with IV BPs [58–60], 0.7–1.7% if treated with denosumab [58, 61, 62] and 0.2% if treated with the AA agent bevacizumab [12, 58, 63]. The risk range of MRONJ among patients who are exposed to both zolendronate (intravenous BP) and bevacizumab (antiangiogenic) is 0.9% [12]. The risk among patients treated for osteoporosis who are exposed to oral zolendronate alone is 0.02% [58, 64], while the risk for patients treated with denosumab alone is 0.04–0.2% [58, 65, 66].

## **5. Risk factors of MRONJ**

#### **5.1 Risk factors connected with AR medications**

• Route of administration of AR medications

Patients with intraosseous malignancies are treated intravenously with BP or subcutaneously with denosumab, while patients affected with osteoporosis can be treated with oral or intravenous BP medications or subcutaneously with denosumab.

Oral BPs are associated with lower occurrence risk of MRONJ than intravenous BPs or denosumab. The incidence of AR therapy-associated MRONJ is significantly lower for osteoporosis patients than for cancer patients [58].

• Duration of BP therapy

The prevalence of MRONJ increases over time, from 0.5 to 0.6% after 1 year of therapy, 0.9 to 1.1% after 2 years and 1.3 to 1.1% after 3 years [67]. For patients with osteoporosis who are exposed to oral BPs, the prevalence of MRONJ increases over time from 0 to 0.2% after 4 years. The average duration of BP

therapy in patients who developed MRONJ is 4.4 years [58]. Some authors found that there were no significant increases in risk between the third and fourth years of BP therapy [59].

• Dose and potency

Zoledronic acid is considered the most potent BP medication. Its potency is estimated to be 10 times higher compared to ibandronate and 20 times higher than pamidronate [68].

## **5.2 Local factors**

• Dental treatment

Dentoalveolar surgery with bone manipulation (tooth extraction, implant placement and periodontal or endodontic surgical procedures) is the most common local risk factor for patients exposed to AR/AA with MRONJ. Tooth extraction was considered a precipitating factor in 52–61% of cases of MRONJ. In addition, exposure to zolendronate prior to tooth extraction incurred a 16- to 33-fold increase in risk of MRONJ [13, 69, 70]. The risk for patients treated with oral BPs is 0.5% or less [71, 72]. The same risk for the cancer patients treated with intravenous BPs is within the range of 1.6–14.8% [73, 74] or 1.7–4.7% [72] depending on the investigation.

Though they are considered risk factors, the exact rate of MRONJ in patients treated with AA/AR medications after periodontal, implant or endodontic surgeries is not yet certain. Anecdotal experience stipulates that they nonetheless demonstrate similar risks when compared to dental extractions [14].

• Dental or implant inflammation

The inflammatory processes associated with dentoalveolar surgery are considered a causative factor in developing MRONJ. The periodontal or periapical pathology were considered a risk factor for 50% of the cases of MRONJ [13, 14, 73, 75, 76]. Since many dental inflammatory diseases are treated via extraction, the exact degree to which surgical trauma or inflammatory changes actually contribute to the development of osteonecrosis is not yet clear [27].

## **5.3 Anatomic factors**

MRONJ appears in the mandible more often than in the maxilla. Instance in the lower jaw is 73%, in upper jaw is 22.5% and in both jaws is 4.5% [13, 14].

Denture use increases the risk of MRONJ. This is especially true in cases of cancer patients with dentures exposed to ibandronate, zolendronate or pamidronate. These patients experience a two-fold increase in risk of osteonecrosis [69, 70].

## **5.4 Demographic risk factors**

Higher prevalence of MRONJ in the female population may be associated with the prevalence of osteolytic conditions in women [14]. Women over 50 have a 50 and 12% lifetime risk of developing osteoporosis and breast cancer, respectively.

**53**

**6.2 Stage 1**

may also be present.

*Medication-Related Osteonecrosis of the Jaw: An Overview*

osteoporosis and a 17% risk of prostate cancer [16].

therapies and invasive dental treatments [77, 78].

On the other hand, men in the same age group have a 20% risk of developing

Few studies have been conducted exploring MRONJ risk in the paediatric population. However, a recent survey of the literature revealed no significant rate of MRONJ despite the fact that a number of patients were exposed to long-lasting BP

Corticosteroids [13, 75] and antiangiogenic [12, 13, 37, 40–43, 45–49, 69] medications may increase the risk of MRONJ when administered concurrently with

MRONJ, such as anaemia, diabetes [13, 75] and the type of cancer [15, 16].

Other comorbidities were inconsistently linked to elevated risk of developing

The staging system was developed primarily to guide the clinician with specific

The guidelines were first published in 2006 then updated in 2009 and 2014 as a

The initial stage includes patients exposed to AR/AA therapy with no clinical evidence of exposed or necrotic bone. Only non-specific symptoms are present which cannot be attributed to other pathological entities. Recent literature suggests

1.**Symptoms present during stage 0**: odontalgia not explained by dental cause, dull pain in the body of the mandible, sinus pain and altered neurosensory

explained by periodontal disease and fistula that is not associated with endo-

3.**Radiographic findings present during stage 0**: alveolar bone resorption not associated with periodontal disease, thickening of the maxillary sinus walls, irregular trabecular patterns, absence of bone healing and persistent lamina dura in extraction sites, thickening of the lamina dura and a decrease in the

The clinical picture of stage 1 consists of exposed necrotic bone or a fistula that can be probed to the bone. Since there is no infection, the patients typically do not experience additional symptoms. Radiographic findings mentioned in the stage 0

2.**Clinical findings present during stage 0**: increased tooth mobility not

treatment strategies according to clinical presentation. Furthermore, it helped introduce homogeneity to MRONJ literature, allowing for new advancements in the

result of new findings relevant for treatment of the disease [2, 7, 14].

that up to 50% of patients at stage 0 will progress to the subsequent stage.

*DOI: http://dx.doi.org/10.5772/intechopen.86241*

**5.5 Systemic risk factors**

**6. Staging of MRONJ**

diagnosis and treatment of the disease.

a bisphosphonate.

**6.1 Stage 0**

function.

dontic pathology.

size of the periodontal ligament space.

On the other hand, men in the same age group have a 20% risk of developing osteoporosis and a 17% risk of prostate cancer [16].

Few studies have been conducted exploring MRONJ risk in the paediatric population. However, a recent survey of the literature revealed no significant rate of MRONJ despite the fact that a number of patients were exposed to long-lasting BP therapies and invasive dental treatments [77, 78].

#### **5.5 Systemic risk factors**

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

fourth years of BP therapy [59].

depending on the investigation.

• Dental or implant inflammation

yet clear [27].

**5.3 Anatomic factors**

**5.4 Demographic risk factors**

• Dose and potency

• Dental treatment

**5.2 Local factors**

than pamidronate [68].

therapy in patients who developed MRONJ is 4.4 years [58]. Some authors found that there were no significant increases in risk between the third and

Zoledronic acid is considered the most potent BP medication. Its potency is estimated to be 10 times higher compared to ibandronate and 20 times higher

Dentoalveolar surgery with bone manipulation (tooth extraction, implant placement and periodontal or endodontic surgical procedures) is the most common local risk factor for patients exposed to AR/AA with MRONJ. Tooth extraction was considered a precipitating factor in 52–61% of cases of MRONJ. In addition, exposure to zolendronate prior to tooth extraction incurred a 16- to 33-fold increase in risk of MRONJ [13, 69, 70]. The risk for patients treated with oral BPs is 0.5% or less [71, 72]. The same risk for the cancer patients treated with intravenous BPs is within the range of 1.6–14.8% [73, 74] or 1.7–4.7% [72]

Though they are considered risk factors, the exact rate of MRONJ in patients treated with AA/AR medications after periodontal, implant or endodontic surgeries is not yet certain. Anecdotal experience stipulates that they nonetheless demonstrate similar risks when compared to dental extractions [14].

The inflammatory processes associated with dentoalveolar surgery are considered a causative factor in developing MRONJ. The periodontal or periapical pathology were considered a risk factor for 50% of the cases of MRONJ [13, 14, 73, 75, 76]. Since many dental inflammatory diseases are treated via extraction, the exact degree to which surgical trauma or inflammatory changes actually contribute to the development of osteonecrosis is not

MRONJ appears in the mandible more often than in the maxilla. Instance in the

Denture use increases the risk of MRONJ. This is especially true in cases of cancer patients with dentures exposed to ibandronate, zolendronate or pamidronate. These patients experience a two-fold increase in risk of osteonecrosis

Higher prevalence of MRONJ in the female population may be associated with the prevalence of osteolytic conditions in women [14]. Women over 50 have a 50 and 12% lifetime risk of developing osteoporosis and breast cancer, respectively.

lower jaw is 73%, in upper jaw is 22.5% and in both jaws is 4.5% [13, 14].

**52**

[69, 70].

Corticosteroids [13, 75] and antiangiogenic [12, 13, 37, 40–43, 45–49, 69] medications may increase the risk of MRONJ when administered concurrently with a bisphosphonate.

Other comorbidities were inconsistently linked to elevated risk of developing MRONJ, such as anaemia, diabetes [13, 75] and the type of cancer [15, 16].

## **6. Staging of MRONJ**

The staging system was developed primarily to guide the clinician with specific treatment strategies according to clinical presentation. Furthermore, it helped introduce homogeneity to MRONJ literature, allowing for new advancements in the diagnosis and treatment of the disease.

The guidelines were first published in 2006 then updated in 2009 and 2014 as a result of new findings relevant for treatment of the disease [2, 7, 14].

#### **6.1 Stage 0**

The initial stage includes patients exposed to AR/AA therapy with no clinical evidence of exposed or necrotic bone. Only non-specific symptoms are present which cannot be attributed to other pathological entities. Recent literature suggests that up to 50% of patients at stage 0 will progress to the subsequent stage.


#### **6.2 Stage 1**

The clinical picture of stage 1 consists of exposed necrotic bone or a fistula that can be probed to the bone. Since there is no infection, the patients typically do not experience additional symptoms. Radiographic findings mentioned in the stage 0 may also be present.

## **6.3 Stage 2**

In the second stage, the exposed necrotic bone is infected and the patients experience pain. Second stage patients can present with abscess and fistulation as well. Radiographic findings mentioned in the stage 0 may also be present. The adjacent soft tissues may be swollen or secondarily infected.

## **6.4 Stage 3**

All of the symptoms and clinical findings characteristic of the second stage are also present in the third stage: infection, pain and exposed necrotic bone or fistulation that probes to bone. Furthermore, one or more of the following symptoms manifest as a result of disease progression beyond the anatomical borders of the alveolar bone:


## **7. Treatment of MRONJ**

Three different types of treatment strategies have been developed for the MRONJ: preventive, [79, 80] medical and surgical treatments [14, 81]. Preventive measures are indicated for patients who are slated for AA/AR therapy or have undergone treatment without notable symptoms of MRONJ. The latter two treatment modalities are used to treat patients with an established diagnosis of MRONJ.

## **7.1 Preventing MRONJ**

Preventive measures are undertaken to reduce risk factors and preserve oral health of the patient at risk of developing MRONJ. The incidence of MRONJ can be reduced by up to one third if preventive measures are applied. These measures differ depending on the indications of the AR/AA therapy as well as the nature of the triggering dental treatment.

Preventive measures fundamentally rely on proper communication and collaboration between the oncologist, the primary care physician, the dentist and the patient. The healthcare professionals must inform the patient of the possibility of developing MRONJ and of the importance of oral health in its prevention. Prior to initiating AR/AA treatment, the patient should be referred to a dentist for a complete clinical and radiological oral examination. It is the dentist's responsibility to evaluate the risk factors (such as dental decay, periodontal diseases and ill-fitting prostheses) for each individual patient, eliminate or decrease the risk factors, restore oral health and maintain oral health throughout and after the AA/AR treatment [79, 80].

**55**

*Medication-Related Osteonecrosis of the Jaw: An Overview*

According to some studies, only 30% of the patients taking BP are referred to a dentist because of a lack of AR/AA prescriber awareness. In addition, approximately 40–50% of dentists expressed a low-to-moderate level of knowledge of MRONJ, sometimes requesting discontinuation of medications not associated with

Before initiating AA/AR treatment, the oncologist should inform the patient about possible oral side effects and refer the patient to a dentist for comprehensive dental examination [79, 80]. Dentoalveolar surgery remains the major risk factor for developing MRONJ and extraction increases this risk, as do periodontal or periapical pathology [13, 69, 70]. As estimated above, pre-existing dental inflammatory disease is a risk factor for more than 50% of cases [13, 14, 73, 75, 76]. Thus, in accordance with the oncologists, the onset of the AR/AA therapy should be postponed until dental health is established. All extractions and dentoalveolar surgery should be performed and the surgical sites should be allowed to heal completely. Some studies advise at least 2–3 weeks of mucosal healing, while others recommend up to 45–60 days prior to initiation of AA/AR therapy [14, 79]. In the case of patients with total or partial dentures, intraoral examination for decubital areas should be performed. Old or ill-fitting dentures should be relined

If a cancer patient has already been exposed to AR/AA compounds, preventive therapy is directed towards preventing infections and avoiding dentoalveolar surgery. Consequently, good oral hygiene and frequent recalls are of paramount importance. All infected dentition should be addressed via endodontic therapy. If surgery cannot be avoided, chlorhexidine (CHX) mouth wash 0.12% should be started 7 days before the surgical procedure 2–3 times per day and should be continued for the next 2 weeks after the extraction. Antibiotic treatment should also be initiated before the extraction and continued afterwards, though there exists no current consensus [79] on the type, duration, onset and route of administration of the antibiotic therapy [84]. Some authors also recommend deep scaling of the

Again, proper communication must be established between the oncologist, the

The risk of MRONJ in osteoporosis patients on oral bisphosphonate therapy increases significantly when the duration of therapy exceeds 4 years. During the first 4 years of oral BP therapy, minor surgical procedures can typically be performed without therapy modification. Thus, prophylactic dentoalveolar surgery is not critical to the degree it is in cancer patients and/or those undergoing IV AR/AA therapies. The patient should nonetheless be monitored regularly and given proper

Patients who have been prescribed with a combination of BP, AA or corticosteroids

demonstrate an additive risk of developing MRONJ [12, 13, 37, 40–43, 45–49, 69]. There exists much discussion in the literature regarding discontinuation (drug holiday) of BP therapy prior to surgical procedures. The purpose of a 'drug holiday' is to reduce the risk of MRONJ and complications with wound healing. However, suspension of BPs may increase the risk of complications including fractures. Furthermore, BPs have long half-lives when bound to hydroxyapatite, and the efficacy of a temporary discontinuation has been questioned. The clinician must weigh the risk of MRONJ

*DOI: http://dx.doi.org/10.5772/intechopen.86241*

*7.1.1 Cancer patients with AR/AA therapy*

remaining teeth prior to surgical interventions [72].

*7.1.2 Osteoporosis patients with AR/AA therapy*

oral hygiene instruction [14, 79].

dentist and the patient to reduce the rate of complications.

osteonecrosis of the jaw [82, 83].

or replaced [69, 70].

According to some studies, only 30% of the patients taking BP are referred to a dentist because of a lack of AR/AA prescriber awareness. In addition, approximately 40–50% of dentists expressed a low-to-moderate level of knowledge of MRONJ, sometimes requesting discontinuation of medications not associated with osteonecrosis of the jaw [82, 83].

#### *7.1.1 Cancer patients with AR/AA therapy*

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

soft tissues may be swollen or secondarily infected.

In the second stage, the exposed necrotic bone is infected and the patients experience pain. Second stage patients can present with abscess and fistulation as well. Radiographic findings mentioned in the stage 0 may also be present. The adjacent

All of the symptoms and clinical findings characteristic of the second stage are also present in the third stage: infection, pain and exposed necrotic bone or fistulation that probes to bone. Furthermore, one or more of the following symptoms manifest as a result of disease progression beyond the anatomical borders of the

• Exposed necrotic bone reaching the inferior border of the mandible or the floor

• Bone resorption extending to the inferior border of the mandible or the sinus

Three different types of treatment strategies have been developed for the MRONJ: preventive, [79, 80] medical and surgical treatments [14, 81]. Preventive measures are indicated for patients who are slated for AA/AR therapy or have undergone treatment without notable symptoms of MRONJ. The latter two treatment modalities are used to treat patients with an established diagnosis of MRONJ.

Preventive measures are undertaken to reduce risk factors and preserve oral health of the patient at risk of developing MRONJ. The incidence of MRONJ can be reduced by up to one third if preventive measures are applied. These measures differ depending on the indications of the AR/AA therapy as well as the nature of

Preventive measures fundamentally rely on proper communication and collaboration between the oncologist, the primary care physician, the dentist and the patient. The healthcare professionals must inform the patient of the possibility of developing MRONJ and of the importance of oral health in its prevention. Prior to initiating AR/AA treatment, the patient should be referred to a dentist for a complete clinical and radiological oral examination. It is the dentist's responsibility to evaluate the risk factors (such as dental decay, periodontal diseases and ill-fitting prostheses) for each individual patient, eliminate or decrease the risk factors, restore oral health and maintain oral health throughout and after

**6.3 Stage 2**

**6.4 Stage 3**

alveolar bone:

of the maxillary sinuses

• Oroantral or oronasal communication

• Pathological fracture

• Extra-oral fistula

floor [7, 14, 52]

**7. Treatment of MRONJ**

**7.1 Preventing MRONJ**

the triggering dental treatment.

the AA/AR treatment [79, 80].

**54**

Before initiating AA/AR treatment, the oncologist should inform the patient about possible oral side effects and refer the patient to a dentist for comprehensive dental examination [79, 80]. Dentoalveolar surgery remains the major risk factor for developing MRONJ and extraction increases this risk, as do periodontal or periapical pathology [13, 69, 70]. As estimated above, pre-existing dental inflammatory disease is a risk factor for more than 50% of cases [13, 14, 73, 75, 76]. Thus, in accordance with the oncologists, the onset of the AR/AA therapy should be postponed until dental health is established. All extractions and dentoalveolar surgery should be performed and the surgical sites should be allowed to heal completely. Some studies advise at least 2–3 weeks of mucosal healing, while others recommend up to 45–60 days prior to initiation of AA/AR therapy [14, 79]. In the case of patients with total or partial dentures, intraoral examination for decubital areas should be performed. Old or ill-fitting dentures should be relined or replaced [69, 70].

If a cancer patient has already been exposed to AR/AA compounds, preventive therapy is directed towards preventing infections and avoiding dentoalveolar surgery. Consequently, good oral hygiene and frequent recalls are of paramount importance. All infected dentition should be addressed via endodontic therapy. If surgery cannot be avoided, chlorhexidine (CHX) mouth wash 0.12% should be started 7 days before the surgical procedure 2–3 times per day and should be continued for the next 2 weeks after the extraction. Antibiotic treatment should also be initiated before the extraction and continued afterwards, though there exists no current consensus [79] on the type, duration, onset and route of administration of the antibiotic therapy [84]. Some authors also recommend deep scaling of the remaining teeth prior to surgical interventions [72].

Again, proper communication must be established between the oncologist, the dentist and the patient to reduce the rate of complications.

#### *7.1.2 Osteoporosis patients with AR/AA therapy*

The risk of MRONJ in osteoporosis patients on oral bisphosphonate therapy increases significantly when the duration of therapy exceeds 4 years. During the first 4 years of oral BP therapy, minor surgical procedures can typically be performed without therapy modification. Thus, prophylactic dentoalveolar surgery is not critical to the degree it is in cancer patients and/or those undergoing IV AR/AA therapies. The patient should nonetheless be monitored regularly and given proper oral hygiene instruction [14, 79].

Patients who have been prescribed with a combination of BP, AA or corticosteroids demonstrate an additive risk of developing MRONJ [12, 13, 37, 40–43, 45–49, 69]. There exists much discussion in the literature regarding discontinuation (drug holiday) of BP therapy prior to surgical procedures. The purpose of a 'drug holiday' is to reduce the risk of MRONJ and complications with wound healing. However, suspension of BPs may increase the risk of complications including fractures. Furthermore, BPs have long half-lives when bound to hydroxyapatite, and the efficacy of a temporary discontinuation has been questioned. The clinician must weigh the risk of MRONJ with the risk of complications in partnership with the physician who prescribed the BP therapy [1, 11, 14, 79, 84].

According to the guidelines from the AAOMS, a pre-operative drug holiday of 2 months may be considered regardless of the total duration of BP therapy. This should also be done in partnership with the physician who has prescribed the BP therapy. All BP therapy should be resumed once all appropriate post-operative healing has occurred [14].

## **7.2 Medical management of MRONJ**

The aim of medical management is to prevent infection of the exposed bone using topical or systemic antibiotics. The use of analgesics is indicated if the patient complains of odontalgia or dull pain located in the affected areas. Since more than 50% of patients diagnosed with stage 0 progress to a higher stage, frequent recalls with oral health instructions and preventive measure can be beneficial in the long term [54, 81, 85].

Patients presenting with stage 0 and 1 of MRONJ may be treated with medical modalities only. Adjunctive therapy is used to enhance healing of the exposed bone by decreasing inflammation, improving vascularization and stimulating bone turnover.


The first line antibiotic is a penicillin-class antibiotic such as amoxicillin. In case of allergy, clindamycin, fluoroquinolones and/or metronidazole may be used. Currently, there exists no scientific consensus on the duration of antibiotic therapy, though an empiric proposition recommends a 2-week course for patients with a persistent stage 1 disease and 4–6 weeks course therapy for more advanced stages of the disease.

• Pentoxifylline and vitamin E

The combinations of these drugs have already found some success in the treatment of osteoradionecrosis. Their specific mechanism of action in the treatment of MRONJ is not completely understood. It is believed that their ability to decrease inflammation and promote vascularization can contribute to positive outcomes. Though the duration of the treatment has not been established, some studies recommend suspension of this therapy after 3 years. Patients with all stages of osteonecrosis may benefit from pentoxifylline and vitamin E. The recommended dose of pentoxifylline is 400 mg twice daily and 1000 IU vitamin E daily.

• Teriparatide

This drug is used primarily in the treatment of osteoporosis. It may improve bone remodelling by stimulating osteoblasts, increasing bone cell signalling and activating osteoclasts. The safety, side effects, dosing and duration of the therapy for MRONJ are currently not known and additional research is warranted.

• Hyperbaric oxygen therapy

Hyperbaric oxygen therapy is used in the treatment of osteoradionecrosis because of its purported beneficial effects on wound healing. This treatment may help provide greater oxygenation to tissues with reduced vascular

**57**

**8. Conclusion**

surgery) in its treatment.

*Medication-Related Osteonecrosis of the Jaw: An Overview*

supplies, accelerating wound healing and increasing bone turnover. Currently, the clinical utility of hyperbaric oxygen therapy in the treatment of MRONJ remains unclear. Higher costs and extended therapy duration could prevent

Surgical treatment is typically indicated for the second and third stages of the disease. The degree of surgical intervention can vary from simple sequestrectomy to marginal or segmental osteotomies depending on disease dissemination, patient

Mobile bone sequestra should always be removed regardless of the disease stage. The term 'marginal resection' refers to surgical removal of the necrotic alveolar bone, preserving the inferior border of the mandible. On the other hand, segmental resection osteotomy includes removal of the inferior border of the mandible and results in a continuity defect. The former intervention may be used in the treatment of second stage MRONJ since the disease is limited to the alveolar bone. Consequently, the latter is reserved for the third stage of the disease as it is charac-

During surgical extractions or alveoplasties, the soft tissue over the bone defect should be sutured in multiple layers to ensure primary intention healing. Pre- and post-op systemic antibiotics should also be considered especially if the patient

Other adjunctive treatment modalities include platelet-rich fibrin (PRF) or other platelet concentrates as well as low level laser therapy. Platelet concentrates may aid soft tissue healing while low level laser therapy is linked to increased vascularity and osteoblastic differentiation, resulting in better bone healing [72, 86, 87, 89, 90]. Benefits of adjunctive treatments nonetheless remain controversial. Conflicting rates of healing have been reported when additional treatments were combined with surgical treatment compared to surgical treatments alone [86, 88–90].

MRONJ is an uncommon disease that can cause significant impairments and reductions in a patient's quality of life. Additional investments should be made to raise awareness and increase collaboration among patients, AR/AA prescribers and dentists. Issues that require further investigation include the exact number of medications associated with MRONJ, the role of drug holidays in its prevention and the choice of modalities (such as antibiotics, pentoxifylline, teriparatide and

terised by progression beyond the anatomical borders of the alveolar bone.

*DOI: http://dx.doi.org/10.5772/intechopen.86241*

routine use in MRONJ therapy [81].

comorbidities, medical status and treatment expectations.

already has an established diagnosis of MRONJ [81].

**7.3 Surgical treatment of MRONJ**

supplies, accelerating wound healing and increasing bone turnover. Currently, the clinical utility of hyperbaric oxygen therapy in the treatment of MRONJ remains unclear. Higher costs and extended therapy duration could prevent routine use in MRONJ therapy [81].

## **7.3 Surgical treatment of MRONJ**

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

therapy [1, 11, 14, 79, 84].

healing has occurred [14].

• Systemic antibiotics

more advanced stages of the disease.

• Pentoxifylline and vitamin E

vitamin E daily.

• Teriparatide

warranted.

• Hyperbaric oxygen therapy

**7.2 Medical management of MRONJ**

with the risk of complications in partnership with the physician who prescribed the BP

According to the guidelines from the AAOMS, a pre-operative drug holiday of 2 months may be considered regardless of the total duration of BP therapy. This should also be done in partnership with the physician who has prescribed the BP therapy. All BP therapy should be resumed once all appropriate post-operative

The aim of medical management is to prevent infection of the exposed bone using topical or systemic antibiotics. The use of analgesics is indicated if the patient complains of odontalgia or dull pain located in the affected areas. Since more than 50% of patients diagnosed with stage 0 progress to a higher stage, frequent recalls with oral health instructions and preventive measure can be beneficial in the long term [54, 81, 85]. Patients presenting with stage 0 and 1 of MRONJ may be treated with medical modalities only. Adjunctive therapy is used to enhance healing of the exposed bone by decreasing inflammation, improving vascularization and stimulating bone turnover.

• Typically, the topical antibiotic of choice is chlorhexidine gluconate 0.12%

The first line antibiotic is a penicillin-class antibiotic such as amoxicillin. In case of allergy, clindamycin, fluoroquinolones and/or metronidazole may be used. Currently, there exists no scientific consensus on the duration of antibiotic therapy, though an empiric proposition recommends a 2-week course for patients with a persistent stage 1 disease and 4–6 weeks course therapy for

The combinations of these drugs have already found some success in the treatment of osteoradionecrosis. Their specific mechanism of action in the treatment of MRONJ is not completely understood. It is believed that their ability to decrease inflammation and promote vascularization can contribute to positive outcomes. Though the duration of the treatment has not been established, some studies recommend suspension of this therapy after 3 years. Patients with all stages of osteonecrosis may benefit from pentoxifylline and vitamin E. The recommended dose of pentoxifylline is 400 mg twice daily and 1000 IU

This drug is used primarily in the treatment of osteoporosis. It may improve bone remodelling by stimulating osteoblasts, increasing bone cell signalling and activating osteoclasts. The safety, side effects, dosing and duration of the therapy for MRONJ are currently not known and additional research is

Hyperbaric oxygen therapy is used in the treatment of osteoradionecrosis because of its purported beneficial effects on wound healing. This treatment may help provide greater oxygenation to tissues with reduced vascular

**56**

Surgical treatment is typically indicated for the second and third stages of the disease. The degree of surgical intervention can vary from simple sequestrectomy to marginal or segmental osteotomies depending on disease dissemination, patient comorbidities, medical status and treatment expectations.

Mobile bone sequestra should always be removed regardless of the disease stage. The term 'marginal resection' refers to surgical removal of the necrotic alveolar bone, preserving the inferior border of the mandible. On the other hand, segmental resection osteotomy includes removal of the inferior border of the mandible and results in a continuity defect. The former intervention may be used in the treatment of second stage MRONJ since the disease is limited to the alveolar bone. Consequently, the latter is reserved for the third stage of the disease as it is characterised by progression beyond the anatomical borders of the alveolar bone.

During surgical extractions or alveoplasties, the soft tissue over the bone defect should be sutured in multiple layers to ensure primary intention healing. Pre- and post-op systemic antibiotics should also be considered especially if the patient already has an established diagnosis of MRONJ [81].

Other adjunctive treatment modalities include platelet-rich fibrin (PRF) or other platelet concentrates as well as low level laser therapy. Platelet concentrates may aid soft tissue healing while low level laser therapy is linked to increased vascularity and osteoblastic differentiation, resulting in better bone healing [72, 86, 87, 89, 90].

Benefits of adjunctive treatments nonetheless remain controversial. Conflicting rates of healing have been reported when additional treatments were combined with surgical treatment compared to surgical treatments alone [86, 88–90].

## **8. Conclusion**

MRONJ is an uncommon disease that can cause significant impairments and reductions in a patient's quality of life. Additional investments should be made to raise awareness and increase collaboration among patients, AR/AA prescribers and dentists. Issues that require further investigation include the exact number of medications associated with MRONJ, the role of drug holidays in its prevention and the choice of modalities (such as antibiotics, pentoxifylline, teriparatide and surgery) in its treatment.

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

## **Author details**

Marko Blašković1,2\* and Dorotea Blašković2

1 Department of Oral Surgery, Medical University of Rijeka, Rijeka, Croatia

2 Private Practice, Rijeka, Croatia

\*Address all correspondence to: marko\_blaskovic@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**59**

*Medication-Related Osteonecrosis of the Jaw: An Overview*

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[10] Kygridis A, Toulis KA. Denosumabrelated osteonecrosis of the jaws. Osteoporosis International. 2011;**22**(1):369-370. DOI: 10.1007/

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[12] Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I, et al. Bevacizumab and osteonecrosis of the jaw: Incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Research and Treatment. 2010;**122**:181-188. DOI:

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*DOI: http://dx.doi.org/10.5772/intechopen.86241*

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© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Oral Surgery, Medical University of Rijeka, Rijeka, Croatia

\*Address all correspondence to: marko\_blaskovic@yahoo.com

**58**

**Author details**

provided the original work is properly cited.

Marko Blašković1,2\* and Dorotea Blašković2

2 Private Practice, Rijeka, Croatia

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*Medication-Related Osteonecrosis of the Jaw: An Overview DOI: http://dx.doi.org/10.5772/intechopen.86241*

2009;**67**:1363-1372. DOI: 10.1016/j. joms.2009.03.005

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

the jaw related to sunitinib. Oral and Maxillofacial Surgery. 2011;**15**:63-66. DOI: 10.1007/s10006-010-0224-y

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10.1016/j.tripleo.2011.08.024

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[67] Henry D, Vadhan-Raj S, Hirsh V, von Moos R, Hungria V, Costa L, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: An analysis of data from patients with solid tumors. Supportive Care in Cancer. 2014;**22**:679-687. DOI: 10.1007/ s00520-013-2022-1

[68] Benford HL, Frith JC, Auriola S, Mönkkönen J, Rogers MJ. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: Biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Molecular Pharmacology. 1999;**56**:131-140

[69] Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis CG, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. Journal of Clinical Oncology. 2009;**27**:5356-5362. DOI: 10.1200/ JCO.2009.21.9584

[70] Kyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, et al. Bisphosphonaterelated osteonecrosis of the jaws: A casecontrol study of risk factors in breast cancer patients. Journal of Clinical Oncology. 2008;**26**(28):4634-4638. DOI: 10.1200/JCO.2008.16.2768

[71] R1 K, Need A, Hughes T, Goss A. Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery. 2009 Jun;**67**(6):1167-1173. DOI: 10.1016/j. joms.2009.02.004

[72] Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F. Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: A systematic review and meta-analysis. Journal of Clinical Periodontology. 2015;**42**:922-932. DOI: 10.1111/jcpe.12455

[73] Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, et al. Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: A cohort study. International Journal of Oral and Maxillofacial Surgery. 2012;**41**(11):1397- 1403. DOI: 10.1016/j.ijom.2012.06.020

[74] Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on zoledronic acid therapy. Oral Oncology. 2012;**48**(9):817-821. DOI: 10.1016/j. oraloncology.2012.03.009

[75] Tsao C, Darby I, Ebeling PR, Walsh K, O'Brien-Simpson N, Reynolds E, et al. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. Oral and Maxillofacial Surgery. 2013;**71**:1360-1366. DOI: 10.1016/j.joms.2013.02.016

[76] Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncology. 2014;**10**:257-275. DOI: 10.2217/fon.13.211

[77] Brown JJ, Ramalingam L, Zacharin MR. Bisphosphonateassociated osteonecrosis of the jaw: Does it occur in children? Clinical Endocrinology. 2008;**68**:863-867. DOI: 10.1111/j.1365-2265.2008.03189.x

[78] Hennedige AA, Jayasinghe J, Khajeh J, Macfarlane TV. Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta.

**65**

s00774-016-0810-7

*Medication-Related Osteonecrosis of the Jaw: An Overview*

[85] Fedele S Porter SR, D'Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, et al. Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: A case series. The American Journal of Medicine. 2010;**123**:1060-1064. DOI: 10.1016/j.

[86] Del Fabbro M, Gallesio G, Mozzati M. Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature. European Journal of Cancer. 2015;**51**: 62-74. DOI: 10.1016/j.ejca.2014.10.015

[87] Angiero F, Sannino C, Borloni R, Crippa R, Benedicenti S, Romanos GE. Osteonecrosis of the jaws caused by bisphosphonates: Evaluation of a new therapeutic approach using the Er:YAG laser. Lasers in Medical Science. 2009;**24**:849-856. DOI: 10.1007/

[88] Rupel K, Ottaviani G, Gobbo M, Contardo L, Tirelli G, Vescovi P, et al. A systematic review of therapeutical approaches in

oraloncology.2014.08.016

joms.2012.04.001

joms.2008.12.003

bisphosphonates-related osteonecrosis of the jaw (BRONJ). Oral Oncology. 2014;**50**:1049-1057. DOI: 10.1016/j.

[89] Freiberger JJ, Padilla-Burgos R, McGraw T, Suliman HB, Kraft KH, Stolp BW, et al. What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: A randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. Journal of Oral and Maxillofacial Surgery. 2012;**70**:1573-1583. DOI: 10.1016/j.

[90] Freiberger JJ. Utility of hyperbaric oxygen in treatment of bisphosphonaterelated osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery. 2009;**67**:96-106. DOI: 10.1016/j.

amjmed.2010.04.033

s10103-009-0654-7

*DOI: http://dx.doi.org/10.5772/intechopen.86241*

Journal of Oral & Maxillofacial Research. 2014;**4**:e1. DOI: 10.5037/jomr.2013.4401

[79] Di Fede O, Panzarella V, Mauceri R, Fusco V, Bedogni A, Lo Muzio L, et al. The dental management of patients at risk of medication-related osteonecrosis of the jaw: New paradigm of primary

International. 2018;**2018**:2684924. DOI:

[80] Abed HH, Al-Sahafi EN. The role of dental care providers in the management of patients prescribed bisphosphonates:

prevention. BioMed Research

Brief clinical guidance. General Dentistry. 2018;**66**:18-24

[81] Williams WB, O'Ryan F. Management of medication-related osteonecrosis of the jaw. Oral and Maxillofacial Surgery Clinics of North America. 2015;**27**:517-525. DOI:

10.1016/j.coms.2015.06.007

[82] Taguchi A, Shiraki M, Sugimoto T, Ohta H, Soen S, Japan Osteoporosis Society. Lack of cooperation between physicians and dentists during osteoporosis treatment may increase fractures and osteonecrosis of the jaw. Current Medical Research and Opinion. 2016;**32**:1261-1268. DOI: 10.1185/03007995.2016.1170005

[83] Yoo JY, Park YD, Kwon YD, Kim DY, Ohe JY. Survey of Korean dentists on the awareness on bisphosphonaterelated osteonecrosis of the jaws. Journal of Investigative and Clinical Dentistry. 2010;**1**:90-95. DOI: 10.1111/j.2041-1626.2010.00024.x

[84] Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, et al. Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on osteonecrosis of the jaw. Journal of Bone and Mineral Metabolism. 2017;**35**:6-19. DOI: 10.1007/

10.1155/2018/2684924

*Medication-Related Osteonecrosis of the Jaw: An Overview DOI: http://dx.doi.org/10.5772/intechopen.86241*

Journal of Oral & Maxillofacial Research. 2014;**4**:e1. DOI: 10.5037/jomr.2013.4401

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

[72] Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F. Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: A systematic review and meta-analysis. Journal of Clinical Periodontology. 2015;**42**:922-932. DOI:

[73] Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, et al. Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: A cohort study. International Journal of Oral and Maxillofacial Surgery. 2012;**41**(11):1397- 1403. DOI: 10.1016/j.ijom.2012.06.020

[74] Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on

oraloncology.2012.03.009

10.2217/fon.13.211

[77] Brown JJ, Ramalingam L, Zacharin MR. Bisphosphonateassociated osteonecrosis of the jaw: Does it occur in children? Clinical Endocrinology. 2008;**68**:863-867. DOI: 10.1111/j.1365-2265.2008.03189.x

[78] Hennedige AA, Jayasinghe J, Khajeh J, Macfarlane TV. Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta.

zoledronic acid therapy. Oral Oncology. 2012;**48**(9):817-821. DOI: 10.1016/j.

[75] Tsao C, Darby I, Ebeling PR, Walsh K, O'Brien-Simpson N, Reynolds E, et al. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. Oral and Maxillofacial Surgery. 2013;**71**:1360-1366. DOI: 10.1016/j.joms.2013.02.016

[76] Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncology. 2014;**10**:257-275. DOI:

10.1111/jcpe.12455

denosumab exposure in women with postmenopausal osteoporosis: Results from the FREEDOM extension. The Journal of Clinical Endocrinology and Metabolism. 2013;**98**:4483-4492. DOI:

[67] Henry D, Vadhan-Raj S, Hirsh V, von Moos R, Hungria V, Costa L, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: An analysis of data from patients with solid tumors. Supportive Care in Cancer. 2014;**22**:679-687. DOI: 10.1007/

[68] Benford HL, Frith JC, Auriola S, Mönkkönen J, Rogers MJ. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: Biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Molecular Pharmacology. 1999;**56**:131-140

[69] Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis CG, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. Journal of Clinical Oncology. 2009;**27**:5356-5362. DOI: 10.1200/

10.1210/jc.2013-1597

s00520-013-2022-1

JCO.2009.21.9584

[70] Kyrgidis A, Vahtsevanos K,

[71] R1 K, Need A, Hughes T, Goss A. Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery. 2009 Jun;**67**(6):1167-1173. DOI: 10.1016/j.

Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, et al. Bisphosphonaterelated osteonecrosis of the jaws: A casecontrol study of risk factors in breast cancer patients. Journal of Clinical Oncology. 2008;**26**(28):4634-4638. DOI: 10.1200/JCO.2008.16.2768

**64**

joms.2009.02.004

[79] Di Fede O, Panzarella V, Mauceri R, Fusco V, Bedogni A, Lo Muzio L, et al. The dental management of patients at risk of medication-related osteonecrosis of the jaw: New paradigm of primary prevention. BioMed Research International. 2018;**2018**:2684924. DOI: 10.1155/2018/2684924

[80] Abed HH, Al-Sahafi EN. The role of dental care providers in the management of patients prescribed bisphosphonates: Brief clinical guidance. General Dentistry. 2018;**66**:18-24

[81] Williams WB, O'Ryan F. Management of medication-related osteonecrosis of the jaw. Oral and Maxillofacial Surgery Clinics of North America. 2015;**27**:517-525. DOI: 10.1016/j.coms.2015.06.007

[82] Taguchi A, Shiraki M, Sugimoto T, Ohta H, Soen S, Japan Osteoporosis Society. Lack of cooperation between physicians and dentists during osteoporosis treatment may increase fractures and osteonecrosis of the jaw. Current Medical Research and Opinion. 2016;**32**:1261-1268. DOI: 10.1185/03007995.2016.1170005

[83] Yoo JY, Park YD, Kwon YD, Kim DY, Ohe JY. Survey of Korean dentists on the awareness on bisphosphonaterelated osteonecrosis of the jaws. Journal of Investigative and Clinical Dentistry. 2010;**1**:90-95. DOI: 10.1111/j.2041-1626.2010.00024.x

[84] Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, et al. Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on osteonecrosis of the jaw. Journal of Bone and Mineral Metabolism. 2017;**35**:6-19. DOI: 10.1007/ s00774-016-0810-7

[85] Fedele S Porter SR, D'Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, et al. Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: A case series. The American Journal of Medicine. 2010;**123**:1060-1064. DOI: 10.1016/j. amjmed.2010.04.033

[86] Del Fabbro M, Gallesio G, Mozzati M. Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature. European Journal of Cancer. 2015;**51**: 62-74. DOI: 10.1016/j.ejca.2014.10.015

[87] Angiero F, Sannino C, Borloni R, Crippa R, Benedicenti S, Romanos GE. Osteonecrosis of the jaws caused by bisphosphonates: Evaluation of a new therapeutic approach using the Er:YAG laser. Lasers in Medical Science. 2009;**24**:849-856. DOI: 10.1007/ s10103-009-0654-7

[88] Rupel K, Ottaviani G, Gobbo M, Contardo L, Tirelli G, Vescovi P, et al. A systematic review of therapeutical approaches in bisphosphonates-related osteonecrosis of the jaw (BRONJ). Oral Oncology. 2014;**50**:1049-1057. DOI: 10.1016/j. oraloncology.2014.08.016

[89] Freiberger JJ, Padilla-Burgos R, McGraw T, Suliman HB, Kraft KH, Stolp BW, et al. What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: A randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. Journal of Oral and Maxillofacial Surgery. 2012;**70**:1573-1583. DOI: 10.1016/j. joms.2012.04.001

[90] Freiberger JJ. Utility of hyperbaric oxygen in treatment of bisphosphonaterelated osteonecrosis of the jaws. Journal of Oral and Maxillofacial Surgery. 2009;**67**:96-106. DOI: 10.1016/j. joms.2008.12.003

**67**

**Chapter 6**

*Ahmet Baki*

**Abstract**

and nosebleeds.

**1. Introduction**

lymphatics [1].

and cell types [2].

**2. Hemangiomas**

the nasal region is a rare disease [3].

Nasal Cavity Hemangiomas

**Keywords:** hemangioma, nasal septum, paranasal sinus

Hemangiomas are benign tumors originating from vascular structures in the body. Although it is common in the head and neck region, it is rarely seen in the nasal cavity and paranasal sinuses. Histologically, there are three types of hemangiomas including capillary, cavernous, and mixed types, the most common being a cavernous hemangioma. Cavernous hemangiomas in the nasal cavity usually originate from the lateral nasal wall and cause symptoms such as nasal congestion

Vascular lesions in the head and neck region originate from blood vessels or

Nasal hemangioma was first described by Poncet and Dor in 1897 as human botryomycosis. More than half of the hemangioma affects the head and neck region, rarely the nasopharynx. Therefore it is safe to presume that hemangioma in

Hemangiomas are common, benign endothelial lesions of the skin and mucous membranes. Hemangiomas have capillary, cavernous, mixed, and hypertrophic subtypes. Capillary hemangioma is the most common subtype and is mostly seen on anterior septal cartilage. Capillary hemangioma is seen mostly in the first years of

Cavernous hemangioma is seen mostly in adulthood, and traumatic etiology is present. Cavernous hemangioma is rare and seen in the bone septum or lateral nasal wall. On macroscopic examination, hemangiomas can be observed to have a polypoid, smooth surface and a lobed pattern, whereas in the microscopic examination, it consists of capillaries covered with flat epithelium separated by collagen stroma. Cavernous hemangioma shows large proliferation of thin-walled blood vessels of various sizes covered with endothelium, while the mixed endothelial vascular areas

life and may show spontaneous regression (**Figure 1**) [4, 6].

While the terminology used to describe vascular lesions was related to the clinical appearance of the lesions rather than their physiopathological development, the first distinction that formed the basis of today's classification was made by Mulliken and Glowacki in 1982 according to the clinical and histochemical findings

## **Chapter 6** Nasal Cavity Hemangiomas

*Ahmet Baki*

## **Abstract**

Hemangiomas are benign tumors originating from vascular structures in the body. Although it is common in the head and neck region, it is rarely seen in the nasal cavity and paranasal sinuses. Histologically, there are three types of hemangiomas including capillary, cavernous, and mixed types, the most common being a cavernous hemangioma. Cavernous hemangiomas in the nasal cavity usually originate from the lateral nasal wall and cause symptoms such as nasal congestion and nosebleeds.

**Keywords:** hemangioma, nasal septum, paranasal sinus

## **1. Introduction**

Vascular lesions in the head and neck region originate from blood vessels or lymphatics [1].

While the terminology used to describe vascular lesions was related to the clinical appearance of the lesions rather than their physiopathological development, the first distinction that formed the basis of today's classification was made by Mulliken and Glowacki in 1982 according to the clinical and histochemical findings and cell types [2].

Nasal hemangioma was first described by Poncet and Dor in 1897 as human botryomycosis. More than half of the hemangioma affects the head and neck region, rarely the nasopharynx. Therefore it is safe to presume that hemangioma in the nasal region is a rare disease [3].

## **2. Hemangiomas**

Hemangiomas are common, benign endothelial lesions of the skin and mucous membranes. Hemangiomas have capillary, cavernous, mixed, and hypertrophic subtypes. Capillary hemangioma is the most common subtype and is mostly seen on anterior septal cartilage. Capillary hemangioma is seen mostly in the first years of life and may show spontaneous regression (**Figure 1**) [4, 6].

Cavernous hemangioma is seen mostly in adulthood, and traumatic etiology is present. Cavernous hemangioma is rare and seen in the bone septum or lateral nasal wall. On macroscopic examination, hemangiomas can be observed to have a polypoid, smooth surface and a lobed pattern, whereas in the microscopic examination, it consists of capillaries covered with flat epithelium separated by collagen stroma. Cavernous hemangioma shows large proliferation of thin-walled blood vessels of various sizes covered with endothelium, while the mixed endothelial vascular areas

## *Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

form the large endothelium. These pathologies do not always differentiate from other forms of inflammatory pseudotumor (**Figure 2**) [5, 6].

Cavernous hemangiomas are uncommon in the paranasal sinuses and nose. It has been defined to originate from the inferior turbinate, vomer, lamina perpendicularis, and sinus maxillaris. Nasal mucosal hemangiomas ought to be distinguished from hemangiomas that originate from the maxilla or nasal bones which are primary osseous lesions, of which the symptoms and surgical approach are entirely different [7–12].

**Figure 1.** *Capillary Hemangioma of the Nasal Septum [5].*

**69**

**3. Conclusion**

*Nasal Cavity Hemangiomas*

vestibule [14].

much less common [16].

differentiated [18].

malignant transformations.

absence of coagulated blood [14, 19–22].

loma should be kept in mind [3, 17].

*DOI: http://dx.doi.org/10.5772/intechopen.90137*

septum and the lateral nasal wall [13].

Although nasal hemangiomas common in the head and neck region, it is uncommonly seen in the nasal mucosa. In the nasal cavity, the most common cause is the

Although nasal hemangiomas commonly affect the anterior septum as described

The most common symptom in hemangiomas located in the nasal cavity is nose bleeding; also other rare visible symptoms are nasal obstruction, runny nose, and epiphora [15]. Epistaxis and unilateral nasal obstruction were the most common presenting symptoms, followed by other nasal symptoms such as rhinorrhea. Epistaxis is the most common symptom, as demonstrated by previously published studies. In addition, extra nasal symptoms, such as facial pain and headache, are

In differential diagnosis, lymphangioma, venous hemangioma, angiofibroma, hemangioendothelioma, glomus tumor, and malignant nasal cavity tumors, metastatic malignancies, Wegener granulomatosis, angiofibroma, and sinonasal papil-

The diagnosis of cavernous hemangioma can be made based on the patient's history and clinical features of the lesion. Cavernous hemangiomas are tumors composed of vascular ectasia. They can be placed deeper in the skin, and mucous membranes additionally can involve deeper structures such as subcutaneous tissue, muscle, and bone. Hemangiomas may be localized in an area or may be common. All midline lesions such as subcutaneous cavernous hemangioma, nasal gliomas, meningocele or meningoencephaloceles, teratomas, sebaceous cysts, dermoid cysts, and fibromas, which have atypical clinical features in the nasal dorsum, should be

Imaging tests such as ultrasonography (USG), computed tomography (CT), or magnetic resonance imaging (MRI) are needed to confirm vascular pathology and to demonstrate venous, arterial, or lymphatic components and whether deeper structures are involved. CT can be performed to exclude bone erosion or possible

According to some authors, MRI is more effective in evaluating the connection with soft tissue and intracranial. Also, there is no radiation exposure. MRI is the first diagnostic tool that should be used for screening in patients with midline nasal mass. Negative results on imaging studies, even with contrast, do not exclude the intracranial communication. Phlebitis is typical for cavernous hemangiomas. Hypointense on T1-weighted images on MRI and hyperintense on T2 indicate the

According to their histopathological appearance, it is possible to examine them as cavernous and capillary hemangiomas. They generally occur on the skin, and on the mucosal surfaces of the body, capillary hemangioma is a capillary ball that is located close to each other, separated by a connective tissue stroma [23]. Cavernous hemangiomas should be treated because they will never undergo involution [24].

Hemangiomas should be treated because they have the potential to cause bleeding problems and complications such as infection in the head and neck, especially in the face, ear, and nose. Agents such as steroids, interferon, and vincristine may be used in the medical treatment of hemangiomas. The use of these agents is limited due to the large number of serious toxic side effects. Propranolol, which is

in prior literature, nasal hemangioma has also been reported in other nasal sites such as middle turbinates, inferior turbinates, posterior part of the septum, and

**Figure 2.** *Nasal septal cavernous hemangioma [6].*

#### *Nasal Cavity Hemangiomas DOI: http://dx.doi.org/10.5772/intechopen.90137*

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

other forms of inflammatory pseudotumor (**Figure 2**) [5, 6].

entirely different [7–12].

*Capillary Hemangioma of the Nasal Septum [5].*

**Figure 1.**

form the large endothelium. These pathologies do not always differentiate from

Cavernous hemangiomas are uncommon in the paranasal sinuses and nose. It has been defined to originate from the inferior turbinate, vomer, lamina perpendicularis, and sinus maxillaris. Nasal mucosal hemangiomas ought to be distinguished from hemangiomas that originate from the maxilla or nasal bones which are primary osseous lesions, of which the symptoms and surgical approach are

**68**

**Figure 2.**

*Nasal septal cavernous hemangioma [6].*

Although nasal hemangiomas common in the head and neck region, it is uncommonly seen in the nasal mucosa. In the nasal cavity, the most common cause is the septum and the lateral nasal wall [13].

Although nasal hemangiomas commonly affect the anterior septum as described in prior literature, nasal hemangioma has also been reported in other nasal sites such as middle turbinates, inferior turbinates, posterior part of the septum, and vestibule [14].

The most common symptom in hemangiomas located in the nasal cavity is nose bleeding; also other rare visible symptoms are nasal obstruction, runny nose, and epiphora [15]. Epistaxis and unilateral nasal obstruction were the most common presenting symptoms, followed by other nasal symptoms such as rhinorrhea. Epistaxis is the most common symptom, as demonstrated by previously published studies. In addition, extra nasal symptoms, such as facial pain and headache, are much less common [16].

In differential diagnosis, lymphangioma, venous hemangioma, angiofibroma, hemangioendothelioma, glomus tumor, and malignant nasal cavity tumors, metastatic malignancies, Wegener granulomatosis, angiofibroma, and sinonasal papilloma should be kept in mind [3, 17].

The diagnosis of cavernous hemangioma can be made based on the patient's history and clinical features of the lesion. Cavernous hemangiomas are tumors composed of vascular ectasia. They can be placed deeper in the skin, and mucous membranes additionally can involve deeper structures such as subcutaneous tissue, muscle, and bone. Hemangiomas may be localized in an area or may be common. All midline lesions such as subcutaneous cavernous hemangioma, nasal gliomas, meningocele or meningoencephaloceles, teratomas, sebaceous cysts, dermoid cysts, and fibromas, which have atypical clinical features in the nasal dorsum, should be differentiated [18].

Imaging tests such as ultrasonography (USG), computed tomography (CT), or magnetic resonance imaging (MRI) are needed to confirm vascular pathology and to demonstrate venous, arterial, or lymphatic components and whether deeper structures are involved. CT can be performed to exclude bone erosion or possible malignant transformations.

According to some authors, MRI is more effective in evaluating the connection with soft tissue and intracranial. Also, there is no radiation exposure. MRI is the first diagnostic tool that should be used for screening in patients with midline nasal mass. Negative results on imaging studies, even with contrast, do not exclude the intracranial communication. Phlebitis is typical for cavernous hemangiomas. Hypointense on T1-weighted images on MRI and hyperintense on T2 indicate the absence of coagulated blood [14, 19–22].

According to their histopathological appearance, it is possible to examine them as cavernous and capillary hemangiomas. They generally occur on the skin, and on the mucosal surfaces of the body, capillary hemangioma is a capillary ball that is located close to each other, separated by a connective tissue stroma [23]. Cavernous hemangiomas should be treated because they will never undergo involution [24].

## **3. Conclusion**

Hemangiomas should be treated because they have the potential to cause bleeding problems and complications such as infection in the head and neck, especially in the face, ear, and nose. Agents such as steroids, interferon, and vincristine may be used in the medical treatment of hemangiomas. The use of these agents is limited due to the large number of serious toxic side effects. Propranolol, which is

a nonselective beta blocker, was first introduced by Leaute-Lebeze, and it has been reported that it can be used safely in many later studies [25, 26].

Surgical excision is the treatment of choice for the treatment of nasal hemangiomas. Various surgical methods can be employed for this lesion such as excisional surgery, laser ablation, cryotherapy, and electrocoagulation. Surgical excision is a key for confirmation via histological examination and should be and remains the mode of choice of treatment for nasal hemangiomas. Surgical operation of cavernous hemangioma depends on the nature and localization of the lesion, but it should not cause functional and esthetic problems. All the patients can be successfully treated with adequate endoscopic surgical excision from the site of origin and no complications. Endoscopic resection of midline nasal tumors without intracranial extension can be performed because external approaches cause postoperative esthetic problems. Tumor resection can be removed endoscopically, leaving a safe margin. Endoscopic technique provides better esthetic results. Sclerotherapy and laser are commonly used treatment modalities. Embolization with super-selective arteriography can be used in cases with arterial component or arteriovenous fistula [14, 18, 24].

Midline elliptical incision has good functional outcomes and maintains the nasal contours, although the surgical technique for these lesion outcomes marked a scar on the midline. Treated with inferior rhinotomy and achieved excellent results [27, 28].

Lesions in the nasal type region are easily accessible after incision where transcolumellar and alarm rim incisions are combined, but it is difficult to reach larger and more complex lesions because the incision does not extend cranially [29]. A central wedge excision with vertical closure, removing excess skin, leads to a marked scar on the tip of the nose and columella, and as a result, it is recommended to avoid this wedge excision if possible [30].

Open rhinoplasty approach, and put forward that the extra skin will not be removed but rather left in place to let for contraction, which may take many months. In this approach, the excess skin remaining after the treatment of hemangioma can be considered as a disadvantage [31].

## **Author details**

Ahmet Baki Otorhinolaryngology Clinic, Uskudar State Hospital, Istanbul, Turkey

\*Address all correspondence to: dr.ahmet170@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**71**

*Nasal Cavity Hemangiomas*

2010;**26**(10):1417-1433

1982;**69**:412-422

balkanmedj.2014.13178

SCS.0000000000004220

2006;**33**(4):475-478

[2] Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: A classification based on endothelial characteristics. Plastic and Reconstructive Surgery.

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.90137*

[10] Graumüller S, Terpe H, Hingst V, Dommerich S, Pau HW. Intraossäres

perpendicularis ossis ethmoidalis.

[11] Engels T, Schörner W, Felix R, Witt H, Jahnke V, Kavernöses

Hämangiom d. Sinus maxillaris. HNO.

[12] Osborn DA. Hemangiomas of the nose. The Journal of Laryngology and

[13] Çaylakli F, Çagici AC, Hürcan C, Bal N, Kizilkiliç O, Kiroglu FMD. Cavernous hemangioma of the middle turbinate: A case report. Ear, Nose, & Throat Journal. 2008;**87**(7):391-393

[14] Puxeddu R, Berlucchi M, Ledda GP, Parodo G, Farina D, Nicolai P. Lobular capillary hemangioma of the nasal cavity: A retrospective study on 40 patients. American Journal of Rhinology. 2006;**20**(4):480-484

[15] Işılay D, Fuat B. Nazal Septumda Pyojenik Granülom: Olgu Sunumu. Acıbadem Üniversitesi Sağlık Bilimleri

[16] Fasunla AJ, Adebola OS, Okolo CA, Adeosun AA. Nasal septal lobular capillary haemangioma in West Africa sub-region: A case report. Cases Journal.

[17] Batsakis JG. Tumors of the head and neck. In: Clinical and Pathological Considerations. 2nd ed. Baltimore, MD: Williams & Wilkins; 1979. pp. 291-312

[18] Harley EH. Pediatric congenital nasal masses. Ear, Nose, & Throat

[19] Reilly JR, Koopman CF, Cotton R. Nasal mass in a pediatric patient. Head

Journal. 1991;**70**:28-32

& Neck. 1992;**14**:415-418

Dergisi. 2011;**2**(1):8

2009;**8, 2**:8952

Hämangiom der Lamina

HNO. 2003;**5**:142-145

1990;**38**:342-344

Otology. 1959;**73**:174-179

[3] Chi TH, Yuan CH, Chien ST. Lobular capillary hemangioma of the nasal cavity: A retrospective study of 15 cases in Taiwan. Balkan Medical Journal. 2014;**31**(1):69-71. DOI: 10.5152/

[4] Journal of Medical Case Reports. Elmer Press Inc. ISSN: 1923-4155 print, 1923-4163 online, Open Access; Journal website: http://www.journalmc.org

[5] Journal of Craniofacial Surgery. Mar 2018;**29**(2):e135-e136. DOI: 10.1097/

treatment of nasal septum hemangioma with the harmonic scalpel: A case report. Auris, Nasus, Larynx.

[7] Kim HJ, Kim JH, Kim JH, Hwang EG. Bone erosion caused by sinonasal cavernous hemangioma: CT findings in two patients. American Journal of Neuroradiology. 1995;**16**:1176-1178

[8] Hayden RE, Luna M, Goepfert H. Hemangiomas of the sphenoid sinus. Otolaryngology and Head and Neck

[9] Nakahira M, Kishimoto S, Miura T, Saito H. Intraosseous hemangioma of the vomer: A case report. American Journal of Rhinology. 1997;**11**:473-477

Surgery. 1980;**88**:136-138

[6] Kodama S, Yoshida K, Nomi N, Fujita K, Suzuki M. Successful

[1] Puttgen KB, Pearl M, Tekes A, Mitchell SE. Update on pediatric extracranial vascular anomalies of the head and neck. Child's Nervous System.

## **References**

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

reported that it can be used safely in many later studies [25, 26].

component or arteriovenous fistula [14, 18, 24].

to avoid this wedge excision if possible [30].

gioma can be considered as a disadvantage [31].

a nonselective beta blocker, was first introduced by Leaute-Lebeze, and it has been

Surgical excision is the treatment of choice for the treatment of nasal hemangiomas. Various surgical methods can be employed for this lesion such as excisional surgery, laser ablation, cryotherapy, and electrocoagulation. Surgical excision is a key for confirmation via histological examination and should be and remains the mode of choice of treatment for nasal hemangiomas. Surgical operation of cavernous hemangioma depends on the nature and localization of the lesion, but it should not cause functional and esthetic problems. All the patients can be successfully treated with adequate endoscopic surgical excision from the site of origin and no complications. Endoscopic resection of midline nasal tumors without intracranial extension can be performed because external approaches cause postoperative esthetic problems. Tumor resection can be removed endoscopically, leaving a safe margin. Endoscopic technique provides better esthetic results. Sclerotherapy and laser are commonly used treatment modalities.

Embolization with super-selective arteriography can be used in cases with arterial

Open rhinoplasty approach, and put forward that the extra skin will not be removed but rather left in place to let for contraction, which may take many months. In this approach, the excess skin remaining after the treatment of heman-

Midline elliptical incision has good functional outcomes and maintains the nasal contours, although the surgical technique for these lesion outcomes marked a scar on the midline. Treated with inferior rhinotomy and achieved excellent results [27, 28]. Lesions in the nasal type region are easily accessible after incision where transcolumellar and alarm rim incisions are combined, but it is difficult to reach larger and more complex lesions because the incision does not extend cranially [29]. A central wedge excision with vertical closure, removing excess skin, leads to a marked scar on the tip of the nose and columella, and as a result, it is recommended

**70**

**Author details**

Otorhinolaryngology Clinic, Uskudar State Hospital, Istanbul, Turkey

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: dr.ahmet170@gmail.com

provided the original work is properly cited.

Ahmet Baki

[1] Puttgen KB, Pearl M, Tekes A, Mitchell SE. Update on pediatric extracranial vascular anomalies of the head and neck. Child's Nervous System. 2010;**26**(10):1417-1433

[2] Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: A classification based on endothelial characteristics. Plastic and Reconstructive Surgery. 1982;**69**:412-422

[3] Chi TH, Yuan CH, Chien ST. Lobular capillary hemangioma of the nasal cavity: A retrospective study of 15 cases in Taiwan. Balkan Medical Journal. 2014;**31**(1):69-71. DOI: 10.5152/ balkanmedj.2014.13178

[4] Journal of Medical Case Reports. Elmer Press Inc. ISSN: 1923-4155 print, 1923-4163 online, Open Access; Journal website: http://www.journalmc.org

[5] Journal of Craniofacial Surgery. Mar 2018;**29**(2):e135-e136. DOI: 10.1097/ SCS.0000000000004220

[6] Kodama S, Yoshida K, Nomi N, Fujita K, Suzuki M. Successful treatment of nasal septum hemangioma with the harmonic scalpel: A case report. Auris, Nasus, Larynx. 2006;**33**(4):475-478

[7] Kim HJ, Kim JH, Kim JH, Hwang EG. Bone erosion caused by sinonasal cavernous hemangioma: CT findings in two patients. American Journal of Neuroradiology. 1995;**16**:1176-1178

[8] Hayden RE, Luna M, Goepfert H. Hemangiomas of the sphenoid sinus. Otolaryngology and Head and Neck Surgery. 1980;**88**:136-138

[9] Nakahira M, Kishimoto S, Miura T, Saito H. Intraosseous hemangioma of the vomer: A case report. American Journal of Rhinology. 1997;**11**:473-477

[10] Graumüller S, Terpe H, Hingst V, Dommerich S, Pau HW. Intraossäres Hämangiom der Lamina perpendicularis ossis ethmoidalis. HNO. 2003;**5**:142-145

[11] Engels T, Schörner W, Felix R, Witt H, Jahnke V, Kavernöses Hämangiom d. Sinus maxillaris. HNO. 1990;**38**:342-344

[12] Osborn DA. Hemangiomas of the nose. The Journal of Laryngology and Otology. 1959;**73**:174-179

[13] Çaylakli F, Çagici AC, Hürcan C, Bal N, Kizilkiliç O, Kiroglu FMD. Cavernous hemangioma of the middle turbinate: A case report. Ear, Nose, & Throat Journal. 2008;**87**(7):391-393

[14] Puxeddu R, Berlucchi M, Ledda GP, Parodo G, Farina D, Nicolai P. Lobular capillary hemangioma of the nasal cavity: A retrospective study on 40 patients. American Journal of Rhinology. 2006;**20**(4):480-484

[15] Işılay D, Fuat B. Nazal Septumda Pyojenik Granülom: Olgu Sunumu. Acıbadem Üniversitesi Sağlık Bilimleri Dergisi. 2011;**2**(1):8

[16] Fasunla AJ, Adebola OS, Okolo CA, Adeosun AA. Nasal septal lobular capillary haemangioma in West Africa sub-region: A case report. Cases Journal. 2009;**8, 2**:8952

[17] Batsakis JG. Tumors of the head and neck. In: Clinical and Pathological Considerations. 2nd ed. Baltimore, MD: Williams & Wilkins; 1979. pp. 291-312

[18] Harley EH. Pediatric congenital nasal masses. Ear, Nose, & Throat Journal. 1991;**70**:28-32

[19] Reilly JR, Koopman CF, Cotton R. Nasal mass in a pediatric patient. Head & Neck. 1992;**14**:415-418

[20] Lusk RP, Lee PC. Magnetic resonance imaging of congenital midline nasal masses. Otolaryngology and Head and Neck Surgery. 1986;**95** (3 Pt 1):303-306

[21] Barkovich AJ, Vandermarck P, Edwards MS, Cogen PH. Congenital nasal masses: CT and MR imaging features in 16 cases. AJNR. American Journal of Neuroradiology. 1991;**12**:105-116

[22] Itoh K, Nishimura K, Togashi K, Fujisawa I, Nakano Y, Itoh H, et al. RM imaging of cavernous hemangioma of face and neck. Journal of Computer Assisted Tomography. 1986;**10**:831-835

[23] Chawla OP, Oswal VH. Hemangiopericytoma of the nose and paranasal sinuses. The Journal of Laryngology and Otology. 1987;**101**:729-737

[24] Yokoyama M, Inouye N, Mizuno F. Endoscopic management of nasal glioma in infancy. International Journal of Pediatric Otorhinolaryngology. 1999;**51**:51-54

[25] Evans SE. İnfantil Hemanjiyomlar. Türk Derm. 2011;**45**:133-137

[26] Hsu TC, Wang JD, Chen CH, Chang TK, Wang TM, Chou CM, et al. Treatment with propranolol for infantile hemangioma in 13 Taiwanese newborns and young infants. Pediatrics and Neonatology. 2012;**53**:125-132

[27] Pitanguy I, Machado BH, Radwanski HN, Amorim NF. Surgical treatment of hemangiomas of the nose. Annals of Plastic Surgery. 1996;**36**(6):586-592

[28] Demiri EC, Pelissier P, Genin-Etcheberry T, Tsakoniatis N, Martin D, Baudet J. Treatment of facial haemangiomas. British Journal of Plastic Surgery. 2001;**54**(8):665-674

[29] Faguer K, Dompmartin A, Labbé D, Barrellier MT, Leroy D, Theron J. Early surgical treatment of Cyrano-nose haemangiomas with Rethi incision. British Journal of Plastic Surgery. 2002;**55**(6):498-503

[30] Mc Carthy JG, Borud LJ, Schreiber JS.Hemangiomas of the nasal tip. Plastic and Reconstructive Surgery. 2002;**109**(1):31-40

[31] Jackson IT, Sosa J. Excision of nasal tip hemangioma via open rhinoplasty: A skin-sparing technique. European Journal of Plastic Surgery. 1998;**21**:265-268

**73**

categories:

**Chapter 7**

**Abstract**

**1. Introduction**

Structural and Functional

Temporomandibular Joint

**Keywords:** TMJ, internal disorders, signs, symptoms, therapy

• deviations in the form of articular surfaces,

• disorders in the functions of the condyle-disc complex,

There are many factors that can cause damage to the temporomandibular joint (TMJ) structures or impair normal functional relationships between condyle, disc and eminence. The main symptoms associated with TMJ dysfunction are pain, limited mobility of the mandible, spasticity of the masticatory muscles and sound that is produced in the joint during mandibular movement. Pain originates from nociceptors located in soft tissue of the joint. If the soft tissue structures are not in inflammation, the pain is sharp, sudden and intense tightly connected to the movements in the TMJ. If the inflammation is presented, the pain is constant and increases with the movements in the joint. TMJ dysfunction is manifested by feeling stiffness of the joint, limited and/or altered opening of the mouth with deviation or deflection of the mandible. Individual or multiple sound produced by the TMJ are most often the consequence of the disturbed function of the condyle-disc complex, the morphological incompatibility of the joint surfaces or degenerative changes in them. The signs and symptoms of disease and dysfunction of TMJ are different and depend on the duration of the disorders and its chronicity as well as on the individual sensitivity of the patients. Proper identification of symptoms and precise diagnosis are therefore essential for future treatment.

Temporomandibular joint (TMJ) is susceptible to various diseases affecting other synovial joints. Due to its position it is exposed to trauma, and its functional link with the occlusal complex which makes it very sensitive to any occlusal disorders. Any force that overloads the TMJ complex can cause damage to the joint structures or disrupt the normal functional relationship between condyle, disc and articular eminence, resulting in dysfunction or pain, or both. Systemic joint disorders may also affect TMJ.

Diseases and functional disorders of the TMJ can be globally divided into several

Disorders of the

(Internal Disorders)

*Nedeljka Ivkovic and Maja Racic*

## **Chapter 7**

*Maxillofacial Surgery and Craniofacial Deformity - Practices and Updates*

[29] Faguer K, Dompmartin A, Labbé D, Barrellier MT, Leroy D, Theron J. Early surgical treatment of Cyrano-nose haemangiomas with Rethi incision. British Journal of Plastic Surgery.

Schreiber JS.Hemangiomas of the nasal tip. Plastic and Reconstructive Surgery.

rhinoplasty: A skin-sparing technique. European Journal of Plastic Surgery.

[31] Jackson IT, Sosa J. Excision of nasal tip hemangioma via open

2002;**55**(6):498-503

2002;**109**(1):31-40

1998;**21**:265-268

[30] Mc Carthy JG, Borud LJ,

[20] Lusk RP, Lee PC. Magnetic resonance imaging of congenital midline nasal masses. Otolaryngology and Head and Neck Surgery. 1986;**95**

[21] Barkovich AJ, Vandermarck P, Edwards MS, Cogen PH. Congenital nasal masses: CT and MR imaging features in 16 cases. AJNR. American

[22] Itoh K, Nishimura K, Togashi K, Fujisawa I, Nakano Y, Itoh H, et al. RM imaging of cavernous hemangioma of face and neck. Journal of Computer Assisted Tomography. 1986;**10**:831-835

[24] Yokoyama M, Inouye N, Mizuno F. Endoscopic management of nasal glioma in infancy. International Journal of Pediatric Otorhinolaryngology.

[25] Evans SE. İnfantil Hemanjiyomlar.

Türk Derm. 2011;**45**:133-137

[27] Pitanguy I, Machado BH,

1996;**36**(6):586-592

Radwanski HN, Amorim NF. Surgical treatment of hemangiomas of the nose. Annals of Plastic Surgery.

[28] Demiri EC, Pelissier P, Genin-Etcheberry T, Tsakoniatis N,

Surgery. 2001;**54**(8):665-674

Martin D, Baudet J. Treatment of facial haemangiomas. British Journal of Plastic

[26] Hsu TC, Wang JD, Chen CH, Chang TK, Wang TM, Chou CM, et al. Treatment with propranolol for infantile hemangioma in 13 Taiwanese newborns and young infants. Pediatrics and Neonatology. 2012;**53**:125-132

Journal of Neuroradiology.

[23] Chawla OP, Oswal VH. Hemangiopericytoma of the nose and paranasal sinuses. The Journal of Laryngology and Otology.

(3 Pt 1):303-306

1991;**12**:105-116

1987;**101**:729-737

1999;**51**:51-54

**72**
