**1. Osteonecrosis of the jaws**

#### **1.1. History**

The term osteonecrosis dates back to the 1950s, when a series of cancer patients who underwent radiotherapy developed bone lesions on the jaws following the treatment [1–3]. This treatment, which is currently resulting in many complications on an oral level, makes it very hard to cure infections that are sometimes inevitable for these patients, since ischemia takes place on the jaws.

Some years later, the first article appeared citing a periapical lesion following arsenic infiltration for canal treatment. Arsenic was used as a therapeutic agent and as poison in Ancient Greek and Roman times [4]. It was also used as an agent during dental history for pulp devitalization, when anesthetics did not exist. Due to its ability to destroy cells in surrounding tissues, the use of arsenic trioxide in vital pulpectomy has been dropped progressively [5]. Dumlu's article (2007) described a case of jaw necrosis in a young patient following tooth extraction of a first failed molar after arsenic treatment of the canals [6]. Toxavit, another devitalizing agent, has also been related to bone necrosis. In any case, both agents are currently obsolete for these dental treatments [7, 8].

Another one of the causes mentioned in the history of osteonecrosis is the untreated intracapsular fracture, after several months, the described clinical symptoms were pain in the temporal-jaw articulation in the affected side and the limitation in opening the jaw. On a radiographic level, the condylar head is usually eroded and irregular [9].

Back in 1982, the first cases of osteonecrosis of the jaw in toothless patients by chemotherapy treatment were published. Specifically, the article considered the origin was a lesion on the mucosa due to a trauma caused by removable prosthesis.

The cases of aseptic osteonecrosis after jaw osteotomy following orthognathic surgeries have also been described in the literature; they have been related mostly to a complication following a surgical error [10].

In 2002, a clinical case of osteonecrosis of the jaws due to chemotherapy in a patient with myelogenous leukemia was published [11]; and, a year later, the current term bisphosphonates-related osteonecrosis of the jaws was branded (BRONJ) [12].

Despite the osteonecrosis of the jaws was exclusively related to the mouth, some rare cases in the external ear, the hip, the tibia and the femur have been documented [13, 14].

#### **1.2. Definition**

The concept of osteonecrosis of the jaws was introduced in 2003 when a series of 36 bone lesions in the mandible and the maxilla were described in patients undergoing treatment with pamidronate or zoledronate [12].

Then in 2007, the American Association of Oral and Maxillofacial Surgeons (AAOMS) described osteonecrosis of the jaws like persistent bone exposure in the mouth for over 8 weeks in patients with a history of use of bisphosphonates, without local evidence of malignancy or radiotherapeutic treatment of the affected region [15].

Despite that the term osteonecrosis has been used in numerous contexts and even in different locations (not only for the jaws); it is currently related exclusively to the chronic use of bisphosphonates. The condition is called bisphosphonate-related osteonecrosis of the jaw (BRONJ) [16], which was changed by the AAOMS in 2014 for the term medication-related osteonecrosis of the jaw (MRONJ), since this complication has also been described in relation to other antiresorptive drugs (denosumab) and antiagiogenic therapies [17].

#### *1.2.1. Prevalence and incidence*

**1. Osteonecrosis of the jaws**

obsolete for these dental treatments [7, 8].

ing a surgical error [10].

**1.2. Definition**

pamidronate or zoledronate [12].

The term osteonecrosis dates back to the 1950s, when a series of cancer patients who underwent radiotherapy developed bone lesions on the jaws following the treatment [1–3]. This treatment, which is currently resulting in many complications on an oral level, makes it very hard to cure infections that are sometimes inevitable for these patients, since ischemia takes place on the

Some years later, the first article appeared citing a periapical lesion following arsenic infiltration for canal treatment. Arsenic was used as a therapeutic agent and as poison in Ancient Greek and Roman times [4]. It was also used as an agent during dental history for pulp devitalization, when anesthetics did not exist. Due to its ability to destroy cells in surrounding tissues, the use of arsenic trioxide in vital pulpectomy has been dropped progressively [5]. Dumlu's article (2007) described a case of jaw necrosis in a young patient following tooth extraction of a first failed molar after arsenic treatment of the canals [6]. Toxavit, another devitalizing agent, has also been related to bone necrosis. In any case, both agents are currently

Another one of the causes mentioned in the history of osteonecrosis is the untreated intracapsular fracture, after several months, the described clinical symptoms were pain in the temporal-jaw articulation in the affected side and the limitation in opening the jaw. On a

Back in 1982, the first cases of osteonecrosis of the jaw in toothless patients by chemotherapy treatment were published. Specifically, the article considered the origin was a lesion on the

The cases of aseptic osteonecrosis after jaw osteotomy following orthognathic surgeries have also been described in the literature; they have been related mostly to a complication follow-

In 2002, a clinical case of osteonecrosis of the jaws due to chemotherapy in a patient with myelogenous leukemia was published [11]; and, a year later, the current term bisphospho-

Despite the osteonecrosis of the jaws was exclusively related to the mouth, some rare cases in

The concept of osteonecrosis of the jaws was introduced in 2003 when a series of 36 bone lesions in the mandible and the maxilla were described in patients undergoing treatment with

the external ear, the hip, the tibia and the femur have been documented [13, 14].

radiographic level, the condylar head is usually eroded and irregular [9].

mucosa due to a trauma caused by removable prosthesis.

nates-related osteonecrosis of the jaws was branded (BRONJ) [12].

**1.1. History**

46 Osteonecrosis

jaws.

The prevalence of osteonecrosis of the jaws is variable according to the consulted authors, reaching approximately 7–12%, although in more recent articles it tends to be even higher (18.6%) [18].

In regards to IV bisphosphonates, the bibliography of a series of cases, case studies and controls and cohorts, the estimations of the accumulated incidence of MRONJ ranges from 0.8 to 12% [19].

In regards to oral bisphosphonates, clinical effectiveness has been proven, which is shown in over 190 million prescriptions of these drugs around the globe [20]. Despite that osteonecrosis cases have been described, these patients have a considerably lower risk of MRONJ than cancer patients who have been treated with monthly IV bisphosphonates.

According to the database of the alendronate manufacturer (Merk), the incidence of MRONJ was calculated as 0.7/100.000 people/years of exposure [21]. This derives from the number of (non-confirmed) reports of the cases that were considered as MRONJ, divided between the number of alendronate pills prescribed since the approval of the drug. Although this is the best information available to date, there could be a bias in the collection and validity of the data.

In Australia, MRONJ incidence in patients receiving weekly alendronate treatment ranges between 0.01 and 0.04% [22]

Felsenberg registered a prevalence of MRONJ among patients who underwent bisphosphonates therapy for osteoporosis of 0.00038%, based on the reports of three cases in the German Central Register for Jaw Necrosis [23].

#### **1.3. Risk factors**

#### *1.3.1. Local factors*

#### **A. Dentoalveolar surgery**

• Extractions


Cancer patients treated with IV bisphosphonates and who underwent dentoalveolar procedures had 5–21 times more risk of MRONJ than cancer patients who were treated with IV bisphosphonates and who did not undergo dentoalveolar procedures [19].

#### **B**. **Local anatomy**

B1. *Mandibular*


B2. *Maxilla*

• Palatine Torus

The lesions are located with a higher frequency on the mandible than on the superior maxilla (2:1) and more frequently in areas with thin mucosa that cover bone protrusions, such as the torus, bone exostosis and the mylohyoid edge [24–26].

**C. Concomitant oral diseases**: Dental or periodontal abscesses [27].


#### *1.3.3. Drug-related factors*


#### **1.4. Diagnosis**

• Dental implants • Periapical surgery • Periodontal surgery

48 Osteonecrosis

**B**. **Local anatomy**

B1. *Mandibular* • Lingual torus • Mylohyoid line

B2. *Maxilla*

• Palatine Torus

Cancer patients treated with IV bisphosphonates and who underwent dentoalveolar procedures had 5–21 times more risk of MRONJ than cancer patients who were treated with IV

The lesions are located with a higher frequency on the mandible than on the superior maxilla (2:1) and more frequently in areas with thin mucosa that cover bone protrusions, such as the

bisphosphonates and who did not undergo dentoalveolar procedures [19].

torus, bone exostosis and the mylohyoid edge [24–26].

*1.3.2. Systemic and demographic factors*

**C. Concomitant oral diseases**: Dental or periodontal abscesses [27].

**a. Age**: Advanced age is related to a higher prevalence of MRONJ.

agents (cyclophosphamide), erythropoietin and steroids [30, 31].

according to the study published by Wessel et al. [29].

treated with IV bisphosphonates [32–34].

[29, 31, 35].

**b. Sex**: This factor has not been statistically related to a higher risk of osteonecrosis.

**c. Race**: Caucasians have a higher risk of MRONJ compared to the Negro race [28].

**d. Cancer diagnosis**, with or without osteoporosis: The type of malignancy is not statistically related to a higher risk of MRONJ, although the presence of bone metastasis presents a correlation, according to Wessel's article (P = 0.051) [29]. It is related with a higher risk of osteonecrosis in the coadjuvant treatments in these patients, such as chemotherapeutic

**e. Tobacco and alcohol**: There is a possible correlation with smoking but not with drinking,

**f. Genetic factors**: It has been proven that polymorphism in the farnesyl pyrophosphate synthase or the cytochrome of gen P450 CYP2C8 increase the risk of MRONJ in patients

**g. Others:** Dialysis, low hemoglobin, obesity and diabetes are variables related to MRONJ

Patients diagnosed with MRONJ are defined by the following characteristics [17]:


With the intention of standardizing all the signs and symptoms present in the patients affected by osteonecrosis of the jaws, a protocol for MRONJ diagnosis was proposed in 2010 [36].

#### *1.4.1. Clinical diagnosis*

#### **a. Greater clinical signs** [37]

• Exposed necrotic bone in the oral cavity

#### **b. Minor clinical signs and symptoms**


#### *1.4.2. Radiographic/tomographic diagnosis*


#### **b. Late signs**


#### *1.4.3. Diagnosis through complementary testing*

The histopathologic study and microbiological culture are also tests developed on the suppuration area. Developing an antibiogram is very helpful since these patients will be treated with antibiotics during long periods of time and it is convenient to know the existing bacterial spectrum and the sensitivity of these microorganisms to different antibiotics.

#### **1.5. MRONJ staging**

The stages initially described by Ruggiero et al. [24] have been modified and adapted to classify patients with greater precision [17, 19, 39] (**Figure 1**).

**Risk patient**: Without apparent necrotic lesions in asymptomatic patients undergoing treatments with oral or IV bisphosphonates.

**Stage 0**: Patients without clinical evidence of bone necrosis, but with unspecific systems or clinical or radiographic findings.

#### **a. Symptoms**

• Dental mobility

• Trismus

50 Osteonecrosis

• Local inflammation • Bone and dental pain

**a. Initial signs** [38] • Cortical fracture

*1.4.2. Radiographic/tomographic diagnosis*

• Sclerosis of the focal bone marrow • Presence of post-extraction alveoli

• Osteolysis extended to the sinus floor

• Prominence of the lower dental nerve canal

*1.4.3. Diagnosis through complementary testing*

ments with oral or IV bisphosphonates.

• Osteosclerosis of adjacent bones (zygoma and hard palate)

sify patients with greater precision [17, 19, 39] (**Figure 1**).

The histopathologic study and microbiological culture are also tests developed on the suppuration area. Developing an antibiogram is very helpful since these patients will be treated with antibiotics during long periods of time and it is convenient to know the existing bacterial

The stages initially described by Ruggiero et al. [24] have been modified and adapted to clas-

**Risk patient**: Without apparent necrotic lesions in asymptomatic patients undergoing treat-

spectrum and the sensitivity of these microorganisms to different antibiotics.

• Trabecular engrossment

**b. Late signs**

• Diffuse sclerosis • Oro-antral fistula

• Pathological fracture

**1.5. MRONJ staging**

• Sinusitis


#### **b. Clinical findings**


#### **c. Radiographic findings**


These unspecific findings that are characteristic of State 0 can take place in patients with a prior history of more advanced phases in whom the disease has been cured and have no clinical evidence of exposed bone.

**Stage 1**: Asymptomatic bone exposure without clinical signs of inflammation or infection.

**Stage 2**: Bone exposure with infection and pain, erythema or inflammation of the mucosa, with our without suppuration.

**Stage 3**: Bone exposure associated to pain, inflammation and infection with one or more of the following complications:


**Figure 1.** TNM Staging. (A) Stage 1; (B) Stage 2; (C) and (D) Stage 3.

#### **1.6. Treatment**

To focus on the treatment to be developed regarding this complication, it is essential to know the pathophysiology of MRONJ, only by this way we can draft an appropriate treatment plan.

To date, the source has not been adequately documented, describing a multi factor source. Suppression of bone remodeling can contribute to the development of osteonecrosis by an inadequate activity of osteoclasts that do not allow the post-extraction alveoli to heal. The presence of microflora in the mouth have also been related as an osteonecrosis-promoting factor, since numerous biopsy studies and bone sequestrations revealed the presence of *Fusobacterium*, *Eikenella*, *Bacillus*, *Actinomyces*, *Staphylococcus* and *Streptococcus* [40]. Bacterial infection produces local cytokines that promote local osteolysis that contribute to the stimulation of bone resorption and, therefore, subsequent necrosis [41–43].

Additionally, recent articles relate the presence of Actinomyces in MRONJ, although these are small studies on a series of cases having a very small impact in establishing a specific treatment strategy [28, 44–46].

Antinomyces are Gram-positive anaerobic facultative bacteria that do not form spores and are commonly filamentous. They are frequent commensals of the mucosa in the oropharynx, intestinal tract and the female genital tract, once the mucosa barrier is broken due to trauma, surgical interventions or foreign objects, they can invade deep tissue structures and compromise treatment response. Progressive chronic disease is called actinomycosis, and the treatment of this pathology is based on a prolonged antimicrobial therapy for 2–6 months in combination with surgery [47, 48].

#### *1.6.1. Conservative treatment*


**1.6. Treatment**

ment strategy [28, 44–46].

plan.

52 Osteonecrosis

To focus on the treatment to be developed regarding this complication, it is essential to know the pathophysiology of MRONJ, only by this way we can draft an appropriate treatment

To date, the source has not been adequately documented, describing a multi factor source. Suppression of bone remodeling can contribute to the development of osteonecrosis by an inadequate activity of osteoclasts that do not allow the post-extraction alveoli to heal. The presence of microflora in the mouth have also been related as an osteonecrosis-promoting factor, since numerous biopsy studies and bone sequestrations revealed the presence of *Fusobacterium*, *Eikenella*, *Bacillus*, *Actinomyces*, *Staphylococcus* and *Streptococcus* [40]. Bacterial infection produces local cytokines that promote local osteolysis that contribute to the stimula-

Additionally, recent articles relate the presence of Actinomyces in MRONJ, although these are small studies on a series of cases having a very small impact in establishing a specific treat-

Antinomyces are Gram-positive anaerobic facultative bacteria that do not form spores and are commonly filamentous. They are frequent commensals of the mucosa in the oropharynx,

tion of bone resorption and, therefore, subsequent necrosis [41–43].

**Figure 1.** TNM Staging. (A) Stage 1; (B) Stage 2; (C) and (D) Stage 3.


Numerous studies have used this therapy as an adjuvant in antibiotic treatments with good results, although further standardized studies are needed to accurately determine their effectiveness [50].


Most conservative treatments on their own do not show accurate results on their effectiveness, especially in more advance stages. Authors use them in combination with antibiotics and observe that these can help heal the patient, especially in terms of tissue regeneration; but it is always reinforced with an appropriate antibiotic treatment (**Table 1**) [55].

#### *1.6.2. Surgical treatment*

For patients in advanced stages and resistant-clinical-cases:


Numerous studies show high improvement rates in patients who underwent surgical treatment both in conservative and resective procedures (**Table 2**) [55].

#### *1.6.3. Other treatments*

The use of stem cells [58, 59], platelet-rich plasma [60], the administration of parathyroid hormone [61] or the use of leukocyte- and platelet-rich fibrin [62] are also promising proposals, but they require further clinical studies that attest to their effectiveness.

#### *1.6.4. Protocol for the treatment of MRONJ*

**Risk Patients**: They do not require treatment, but must be informed of the risks of developing MRONJ, as well as the signs and symptoms of this disease [19, 24].


**Table 1.** Summary of studies with a conservative focus for the management of ONJ-related osteonecrosis [55].

Osteonecrosis of the Jaws. Prevalence, Risk Factors and Role of Microbiota and Inflammation... http://dx.doi.org/10.5772/intechopen.69315 55


**Table 2.** Summary of studies with a surgical focus for the treatment of MRONJ.

**Stage 0**: Symptomatic treatment and control of local factors, such as cavities and periodontal disease.

**Stage 1**: Daily rinses with antimicrobial agents (chlorhexidine at 0.12%) and regular control visits.

**Stage 2:** Oral antimicrobial rinses (chlorhexidine at 0.12%) in combination with antibiotic therapy.

**Stage 3**: Combination of different protocols:


Most conservative treatments on their own do not show accurate results on their effectiveness, especially in more advance stages. Authors use them in combination with antibiotics and observe that these can help heal the patient, especially in terms of tissue regeneration; but

**a. Conservative surgery**: Includes the remotion of the necrotic bone (sequestration) and/or

**b. Resective surgery**: Destined to patients in whom previous treatments have not been effective or have very advanced stages. This process has been questioned since it is difficult to guarantee complete resection of the necrosed bone sectioned at the healthy

Numerous studies show high improvement rates in patients who underwent surgical treat-

The use of stem cells [58, 59], platelet-rich plasma [60], the administration of parathyroid hormone [61] or the use of leukocyte- and platelet-rich fibrin [62] are also promising proposals,

**Risk Patients**: They do not require treatment, but must be informed of the risks of developing

**Type of treatment Author/Year No. patients healed/No.** 

Van den Wyngaert et al. (2009) 16/33 (53%) Scoletta et al. (2010) 18/30 (62%) Nicolatou-Galitis et al. (2011) 7/47 (14.9%)

Antibiotic treatment Melea et al. (2014) 23/38 (60%)

T Antibiotic treatment + hyperbaric oxygen Freiberger et al. (2012) 13/25 (52%) Antibiotic treatment + ozone therapy Ripamonti et al. (2011) 10/10 (100%) Pentoxifylline + α-tocopherol Magremanne et al. (2014) 1/1 (100%)

**Table 1.** Summary of studies with a conservative focus for the management of ONJ-related osteonecrosis [55].

**patients treated (%)**

superficial unbinding associated to antibiotic therapy and chlorhexidine rinses.

it is always reinforced with an appropriate antibiotic treatment (**Table 1**) [55].

For patients in advanced stages and resistant-clinical-cases:

ment both in conservative and resective procedures (**Table 2**) [55].

but they require further clinical studies that attest to their effectiveness.

MRONJ, as well as the signs and symptoms of this disease [19, 24].

*1.6.2. Surgical treatment*

54 Osteonecrosis

bone [56, 57].

*1.6.3. Other treatments*

*1.6.4. Protocol for the treatment of MRONJ*

• Daily rinses with antimicrobial agents (chlorhexidine at 0.12%)

Regardless of the state of the patient, mobile bone sequestration segments must be retrieved. Extraction of affected teeth with symptoms within the exposed necrotic bone must be considered, since it is improbable that the extraction exacerbates the established necrotic process.

#### **1.7. Prevention**

Despite all the treatments proposed above, the latest articles agree that none of these are completely effective for all cases, therefore, the main goal in these patients is prevention of this complication.

Back in 2009, AAOMS [16] determined that prevention was the main goal in the management of these patients, recommending that patients are evaluated and treated before initiating bisphosphonate therapy.

There are several studies that document that preventative dental treatment decreases the risk of MRONJ among patients with malignant tumors treated with IV bisphosphonates [63, 64]. These findings suggest that, although MRONJ is not eliminated, evaluations and dental treatment prior to beginning bisphosphonate therapy in cancer patients reduces the risk of MRONJ.

Furthermore, they advise revising the doses prescribed to the patients, since it has been proven that [65] the accumulative doses can increase the risk of suffering complications.

The risk of developing MRONJ due to oral bisphosphonate treatment is minimal, but it seems to increase when the duration of the treatment is more than 3 years. This period of time can be reduced in the presence of certain concomitant diseases, such as the chronic use of corticosteroids. Systemic conditions permitting the clinician should consider interrupting oral bisphosphonate treatments for a 3-month period before and another 3 months after elective invasive dental surgery with the purpose of reducing the risk of MRONJ. The justification of this focus is based on extrapolated data that show fluctuations depending on osteoclasts, which is related to the treatment with bisphosphonates, and recent studies show that there is a better result in the treatment of MRONJ after eliminating the drug [66]. In the long term, prospective studies will be necessary to establish the efficacy of suppression period of these drugs to reduce the risk of MRONJ in patients undergoing oral bisphosphonate treatments.

#### *1.7.1. Patients about to begin bisphosphonate treatment*

The goal is to reduce the risk of developing MRONJ to the minimum despite that a small percentage of patients who receive IV bisphosphonate therapy can develop osteonecrosis spontaneously [19]. Thus, if the medical conditions of the patient allow, the start of the treatment must be delayed until their dental health is optimal [63, 64]. This decision must be made by the doctor, together with the dentist and other specialists involved in the patient's care.

Untreatable teeth and those with bad prognosis must be extracted. Additionally, other necessary dentoalveolar surgeries should also be performed at this time. The start of the treatment with bisphosphonates, if possible, should be delayed until complete healing of the mucosa (14–21 days) or until there is an appropriate bone healing.

Dental prophylaxis, cavity control and restorative-conservative odontology are essential to maintain dental health. This level of attention should be maintained indefinitely. The patients with complete or partial prosthesis should be examined to avoid the trauma areas of the mucosa, especially in the border of the tongue. It is essential that patients are trained in regards to the importance of oral hygiene and regular dental evaluations, and instructed specifically to report any pain, swelling or exposed bone area.

### *1.7.2. Asymptomatic patients who receive IV bisphosphonates*

Regardless of the state of the patient, mobile bone sequestration segments must be retrieved. Extraction of affected teeth with symptoms within the exposed necrotic bone must be considered, since it is improbable that the extraction exacerbates the established necrotic process.

Despite all the treatments proposed above, the latest articles agree that none of these are completely effective for all cases, therefore, the main goal in these patients is prevention of

Back in 2009, AAOMS [16] determined that prevention was the main goal in the management of these patients, recommending that patients are evaluated and treated before initiating

There are several studies that document that preventative dental treatment decreases the risk of MRONJ among patients with malignant tumors treated with IV bisphosphonates [63, 64]. These findings suggest that, although MRONJ is not eliminated, evaluations and dental treatment prior to beginning bisphosphonate therapy in cancer patients reduces the

Furthermore, they advise revising the doses prescribed to the patients, since it has been proven that [65] the accumulative doses can increase the risk of suffering complications.

The risk of developing MRONJ due to oral bisphosphonate treatment is minimal, but it seems to increase when the duration of the treatment is more than 3 years. This period of time can be reduced in the presence of certain concomitant diseases, such as the chronic use of corticosteroids. Systemic conditions permitting the clinician should consider interrupting oral bisphosphonate treatments for a 3-month period before and another 3 months after elective invasive dental surgery with the purpose of reducing the risk of MRONJ. The justification of this focus is based on extrapolated data that show fluctuations depending on osteoclasts, which is related to the treatment with bisphosphonates, and recent studies show that there is a better result in the treatment of MRONJ after eliminating the drug [66]. In the long term, prospective studies will be necessary to establish the efficacy of suppression period of these drugs to reduce the risk of MRONJ in patients undergoing oral bisphospho-

The goal is to reduce the risk of developing MRONJ to the minimum despite that a small percentage of patients who receive IV bisphosphonate therapy can develop osteonecrosis spontaneously [19]. Thus, if the medical conditions of the patient allow, the start of the treatment must be delayed until their dental health is optimal [63, 64]. This decision must be made by the doctor, together with the dentist and other specialists involved in the patient's care.

Untreatable teeth and those with bad prognosis must be extracted. Additionally, other necessary dentoalveolar surgeries should also be performed at this time. The start of the treatment with bisphosphonates, if possible, should be delayed until complete healing of the mucosa

**1.7. Prevention**

56 Osteonecrosis

this complication.

risk of MRONJ.

nate treatments.

*1.7.1. Patients about to begin bisphosphonate treatment*

(14–21 days) or until there is an appropriate bone healing.

bisphosphonate therapy.

Procedures that imply direct bone lesion should be avoided, therefore, unrestorable teeth should be treated by eliminating the crown and the endodontic treatment of root fragments [21]. The placement of dental implants must be avoided in cancer patients exposed to higher potency bisphosphonates (zoledronic acid and pamidronate) with a frequent dose program (4–12 times/year).

#### *1.7.3. Asymptomatic patients who receive oral bisphosphonate treatments*

In general terms, these patients seem to have less severe manifestations of necrosis and respond promptly to the described treatments [67, 68]. Elective alveolodental surgery does not seem to be contraindicated in this group, although it is advisable that the patients are appropriately informed on the small risk of complications in bone healing. The use of levels in the bone exchange markers and a drug break in the treatment have been documented as additional tools that guide in making treatment decisions in patients exposed to oral bisphosphonates [68]. Currently, the effectiveness of the systemic markers of bone exchange to assess the risk of developing jaw necrosis in risk patients is being questioned, which requires more research before considering it as a valid risk evaluation tool. In the long term, prospective studies will be necessary to establish the efficacy of suppression period of these drugs (drug holidays) to reduce the risk of MRONJ in these patients.

The risk of MRONJ seems to be more associated to the duration of the treatment (≥3 years) than the dosage, since there has not been any information indicating that the monthly dosage of bisphosphonates is related, with a high or reduced risk of MRONJ when it is compared with the weekly dose program.

There a no solid recommendations based on clinical research for patients who take oral bisphosphonates. The Task Force strategies described above have remained essentially unchanged and are based on the clinical experience of the physicians (expert opinions) who participate in the care of these patients [24, 64, 68–70].

#### *1.7.3.1. Patients who have taken oral bisphosphonates for less than 3 years and have no clinical risk factors, alterations and have the possibility of programmed surgery*

Includes all the common procedures for oral and maxillofacial surgeons, periodontists and specialists.

If dental implants are placed, an informed consent must be presented in regards to possible implant failure and the possible osteonecrosis of the jaws, if the patient continues the oral bisphosphonate treatment. It is also advisable to contact the doctor who initially prescribed the oral bisphosphonate to suggest monitoring of these patients and consider a possible alternative dose to the bisphosphonate, temporary suppression of the drug or an alternative to the medication.

#### *1.7.3.2. Patients who have been administered oral bisphosphonates for less than 3 years associated with corticosteroids*

If systemic conditions allow, the physician must be contacted to consider the interruption of the oral treatment for at least 3 months prior to the oral surgery. Reinstatement of bisphosphonate therapy should not take place until complete bone healing. These strategies are based on the opinion of experts with significant clinical experience and the hypothesis that concomitant treatment with corticosteroids can increase the risk of developing MRONJ.

### *1.7.3.3. Patients who have been administered oral bisphosphonates for less than 3 years, with or without corticosteroids*

If systemic conditions allow, the physician must be contacted to consider the interruption of the oral treatment for at least 3 months prior to the oral surgery and, similarly, bisphosphonate therapy should not be reinstated until complete bone healing.

#### *1.7.4. CTXs (C-terminal telopeptide in serum)*

This bone resorption biomarker has been used for years as a predictive factor for the development of bisphosphonate-related osteonecrosis when deciding on the dental treatments for this type of patients [71]. In a study by Marx et al. (2007), they observed CTXs in fasting samples to correlate the values and the period of use of oral bisphosphonates and to demonstrate if the increase in value could indicate a recovery in bone remodeling when suspending oral bisphosphonate treatment. Risk stratification was determined according to the obtained values, CTX under 100 pg/ml represented high risk, CTX between 100 pg/ml and 150 pg/ml represented moderate risk, while CTX above 150 pg/ml represented minimal risk. CTX values increased between 25.9 and 26.4 pg/ml for each drug holiday month from the bisphosphonates, which indicated a recovery of the bone remodeling and a directive in terms of when the oral surgical procedures could be developed at a lower risk. Additionally, it was observed that in terms of the drug suppression periods associated to CTX values, the latter rose above the threshold of 150 pg/ml, which coincides with spontaneous bone healing or a better response to complete healing after debridement. [68].

After years of research, a meta-analysis of nine controlled studies did not reveal significant differences in the mean values of CTXs among patients with MRONJ and controls (mean difference, −31.417; 95% confidence interval [CI], −91.560 to 28.726; P = 0.306). Additionally, a second meta-analysis of four studies did not show significant differences in the risk of osteonecrosis with CTX values below 150 pg/ml for patients with MRONJ in comparison with the controls (risk ratio, 1.892; 95% CI, 0.636–5.626; P = 0.251) [71].

The term **"Drug Holiday"** has appeared recently as a preventative measure when certain risk odontological treatment must be performed or to improve healing after the appearance of osteonecrosis. There are several proposals but there is no clear consensus regarding bisphosphonate suppression periods (**Table 3**) [72].

bisphosphonate treatment. It is also advisable to contact the doctor who initially prescribed the oral bisphosphonate to suggest monitoring of these patients and consider a possible alternative dose to the bisphosphonate, temporary suppression of the drug or an alternative to the

*1.7.3.2. Patients who have been administered oral bisphosphonates for less than 3 years associated* 

tant treatment with corticosteroids can increase the risk of developing MRONJ.

nate therapy should not be reinstated until complete bone healing.

or a better response to complete healing after debridement. [68].

controls (risk ratio, 1.892; 95% CI, 0.636–5.626; P = 0.251) [71].

*1.7.4. CTXs (C-terminal telopeptide in serum)*

*1.7.3.3. Patients who have been administered oral bisphosphonates for less than 3 years, with or* 

If systemic conditions allow, the physician must be contacted to consider the interruption of the oral treatment for at least 3 months prior to the oral surgery and, similarly, bisphospho-

This bone resorption biomarker has been used for years as a predictive factor for the development of bisphosphonate-related osteonecrosis when deciding on the dental treatments for this type of patients [71]. In a study by Marx et al. (2007), they observed CTXs in fasting samples to correlate the values and the period of use of oral bisphosphonates and to demonstrate if the increase in value could indicate a recovery in bone remodeling when suspending oral bisphosphonate treatment. Risk stratification was determined according to the obtained values, CTX under 100 pg/ml represented high risk, CTX between 100 pg/ml and 150 pg/ml represented moderate risk, while CTX above 150 pg/ml represented minimal risk. CTX values increased between 25.9 and 26.4 pg/ml for each drug holiday month from the bisphosphonates, which indicated a recovery of the bone remodeling and a directive in terms of when the oral surgical procedures could be developed at a lower risk. Additionally, it was observed that in terms of the drug suppression periods associated to CTX values, the latter rose above the threshold of 150 pg/ml, which coincides with spontaneous bone healing

After years of research, a meta-analysis of nine controlled studies did not reveal significant differences in the mean values of CTXs among patients with MRONJ and controls (mean difference, −31.417; 95% confidence interval [CI], −91.560 to 28.726; P = 0.306). Additionally, a second meta-analysis of four studies did not show significant differences in the risk of osteonecrosis with CTX values below 150 pg/ml for patients with MRONJ in comparison with the

If systemic conditions allow, the physician must be contacted to consider the interruption of the oral treatment for at least 3 months prior to the oral surgery. Reinstatement of bisphosphonate therapy should not take place until complete bone healing. These strategies are based on the opinion of experts with significant clinical experience and the hypothesis that concomi-

medication.

58 Osteonecrosis

*with corticosteroids*

*without corticosteroids*

Cancer patients benefit mainly from the therapeutic effects of bisphosphonates, such as the control of bone pain and the incidence of pathological fractures. An interruption of IV bisphosphonate therapy does not offer short-term benefits. However, if systemic conditions allow, long-term suspension can be beneficial in the stabilization of the areas affected by MRONJ, which reduces the risk of necrosis in other locations and minimizes clinical symptoms [63, 64]. The oncologist's role is very important to assess the risks and benefits of suppressing the treatment.

Regarding the interruption of oral bisphosphonate treatment in patients with MRONJ, a gradual improvement of the disease has been proven [68]. The interruption of oral bisphosphonates for 6–12 months may favor healing, after the removal of a bone sequestration or after


**Table 3.** Proposals in the bisphosphonates suppression rate [72].

debridement. The decision to suppress the drug must be assessed by the physician and the patient, as long as the systemic conditions allow.
