**7. Risk factors for MRONJ**

Proposed risk factors for MRONJ are listed in **Table 2** [12]. Among these factors, invasive dental treatments, such as tooth extraction, dental implant, or apical/periodontal surgery, are definitive local risk factors for MRONJ.

#### **7.1. Dental implants and MRONJ [12]**

Recent reports suggested that dental implant procedures performed in patients with cancer or osteoporosis prior to treatment with BPs are not likely associated with subsequent occurrence of MRONJ, if oral health is appropriately managed. However, dental implant performed during or after BP treatment is a potential risk factor for MRONJ [26, 27].

It is unknown whether dental implant is a risk factor in patients receiving denosumab. Implants are not advised for cancer patients who are receiving antiresorptive treatment, and alternative dental measures are recommended. On the other hand, in patients with osteoporosis, dental implant may be performed in cases in which physicians and dentists agree that dental implants are essential for improving the systemic and oral health of patients [12].

#### **7.2. Coadministered agents and MRONJ**

Antiangiogenic agents and tyrosine kinase inhibitors, which are essentially administered as adjuvants in the treatment of cancer patients, have been shown to cause MRONJ, albeit very rarely, when used alone, or to increase the incidence of MRONJ when used concomitantly with BP or denosumab [28].

1. Local

Invasive dental treatments including bone (e.g., tooth extraction, dental implants, apical/periodontal surgery) Ill-fitting dentures and excessive bite force Poor sanitation in the oral cavity, periodontal disease, and gingival abscess inflammatory disease, including apical periodontitis Common site: mandible > maxilla, mandibular torus, palatal torus, and mylohyoid line torus Root canal and orthodontic treatments are not considered to be risk factors 2. Antiresorptive agents Nitrogen-containing bisphosphonates (BPs) > nonnitrogen-containing BPs Denosumab Drugs for malignant tumor > drug for osteoporosis Drug for malignant tumor (Zometa, Aredia, Teiroc, Ranmark) Drug for osteoporosis (Didronel, Fosamac, Bonalon, Actonel, Benet, Bonoteo, Recalbon, Bonbiba and Pralia) Dose and administration period 3. Systemic Cancer (breast, prostate, lung, renal and colon cancer, multiple myeloma, and other cancers) Diabetes, rheumatoid arthritis, hypocalcemia, hypoparathyroidism, osteomalacia, vitamin D deficiency, renal dialysis, anemia, and Paget's disease of bone 4. Congenital Single-nucleotide polymorphisms (SNPs) in MMP-2 and cytochrome P450-2C genes 5. Lifestyle Smoking, drinking alcohol, and obesity 6. Coadministered agents Anticancer agents, corticosteroid, and erythropoietin Angiogenic inhibitors (e.g., thalidomide, sunitinib, and lenalidomide) Tyrosine kinase inhibitors

**Table 2.** Risk factors for MRONJ.

## **8. Prevention of MRONJ**

To minimize the development of ONJ in patients at risk, regular dental examinations are encouraged. Oral hygiene should be improved and local infection is managed as early as possible. The use of antibiotics before and after oral surgical procedures has been demonstrated to lower the risk of ONJ [29, 30]. Antimicrobial mouth rinses may also be useful in lowering the risk of ONJ [30, 31].

All necessary oral surgeries in oncology patients should ideally be completed before the initiation of high-dose antiresorptive therapy. For oncology patient requiring high-dose intravenous BPs or high-dose denosumab, dental radiographs should be completed before medication begins. Any invasive dental procedure including dental extractions or implants should ideally be completed before the initiation of antiresorptive therapy. Nonurgent procedures should be delayed if necessary. If ONJ develops, it is recommended that the antiresorptive drug therapy should be withheld until soft tissue closure with a well-epithelialized mucosa is achieved [32].

There is currently no evidence that interruption of drug therapy in patients requiring dental procedures reduces the risk of ONJ or the progression of the disease [29]. (BPs) that have long-term skeletal retention and cessation for weeks or months may not impact remodeling significantly. However, BPs do have increased skeletal uptake at the sites of local bone injury, and withholding BP therapy following oral surgery may be of use in reducing the local deposition in the mandible and maxilla after oral surgery. In individuals with significant risk factors for ONJ, including oncology patients on high-dose antiresorptive therapy as well as those individuals with multiple risk factors for ONJ, it may be of benefit to withhold BP or denosumab therapy following oral surgery until soft tissue healing occurs [32].

In determining the suitability if drug interruption, it is necessary to weigh the risks of ONJ with the risk of skeletal-related events in oncology patients and the risk of fracture in those with osteoporosis. The decision to hold therapy should be jointly made between the oral surgeon and the physician treating the underlying osteoporosis. Patients with osteoporosis receiving BP or denosumab may continue with therapy if a dental procedure including extraction and implant surgery is required [4]. The decision to continue or hold antiresorptive therapy should be made by the dental health provider in consultation with the patient's physician [32].

#### **8.1. Dental treatments and discontinuation of antiresorptive therapy**

#### *8.1.1. Dental treatments in patients who are to receive antiresorptive therapy*

Before initiation of antiresorptive therapy, it is wise to request that patients visit a dentist for control of oral health to prevent the occurrence of ONJ. Ideally, all dental treatments should be completed 2 weeks before starting antiresorptive treatment. However, in the event that antiresorptive treatment cannot be delayed due to progression of bone metastases or high risk of fracture, administration of antiresorptive agents in parallel with dental treatments may be acceptable. During antiresorptive treatment, patients should be instructed by physicians to adhere to routine dental visits for oral examination [12].

#### *8.1.2. Dental treatments in patients receiving antiresorptive agents*

#### **1.** Discontinuation of BPs before starting dental treatment

**8. Prevention of MRONJ**

1. Local

100 Osteonecrosis

periodontitis

Denosumab

3. Systemic

4. Congenital

5. Lifestyle

2. Antiresorptive agents

Dose and administration period

dialysis, anemia, and Paget's disease of bone

Smoking, drinking alcohol, and obesity

Anticancer agents, corticosteroid, and erythropoietin

Angiogenic inhibitors (e.g., thalidomide, sunitinib, and lenalidomide)

6. Coadministered agents

Tyrosine kinase inhibitors

**Table 2.** Risk factors for MRONJ.

Ill-fitting dentures and excessive bite force

Drugs for malignant tumor > drug for osteoporosis

Drug for malignant tumor (Zometa, Aredia, Teiroc, Ranmark)

lowering the risk of ONJ [30, 31].

To minimize the development of ONJ in patients at risk, regular dental examinations are encouraged. Oral hygiene should be improved and local infection is managed as early as possible. The use of antibiotics before and after oral surgical procedures has been demonstrated to lower the risk of ONJ [29, 30]. Antimicrobial mouth rinses may also be useful in

Invasive dental treatments including bone (e.g., tooth extraction, dental implants, apical/periodontal surgery)

Drug for osteoporosis (Didronel, Fosamac, Bonalon, Actonel, Benet, Bonoteo, Recalbon, Bonbiba and Pralia)

Diabetes, rheumatoid arthritis, hypocalcemia, hypoparathyroidism, osteomalacia, vitamin D deficiency, renal

Common site: mandible > maxilla, mandibular torus, palatal torus, and mylohyoid line torus

Cancer (breast, prostate, lung, renal and colon cancer, multiple myeloma, and other cancers)

Single-nucleotide polymorphisms (SNPs) in MMP-2 and cytochrome P450-2C genes

Root canal and orthodontic treatments are not considered to be risk factors

Nitrogen-containing bisphosphonates (BPs) > nonnitrogen-containing BPs

Poor sanitation in the oral cavity, periodontal disease, and gingival abscess inflammatory disease, including apical

All necessary oral surgeries in oncology patients should ideally be completed before the initiation of high-dose antiresorptive therapy. For oncology patient requiring high-dose intravenous BPs There is a considerable controversy around the question of whether discontinuation (drug holiday) of BPs for a certain period of time before invasive dental treatment is effective in preventing or reducing occurrence of BRONJ. A BP drug holiday before starting invasive dental treatment is not logically supported from background information [12]. The American Association of Oral and Maxillofacial (AAOMS) and other groups have described an increased incidence of BRONJ who were treated with BPs for longer than 4 years. From these results, AAOMS recommended that, for patients receiving antiresorptive therapy for longer than 4 years and who have low fracture risk but potentially high risk for BRONJ, discontinuation of antiresorptive treatment for approximately 2 months before invasive dental treatment should be considered, in consultation with the physician [5]. Thus, no consensus has yet been reached regarding whether a BP drug holiday before invasive dental treatment is appropriate and necessary for prevention of BRONJ [12].

**2.** Suggested dental treatment in patients with cancer and osteoporosis who are receiving BPs

Dental experts will need to educate patients on the importance of daily oral sanitation, including how to clean the oral cavity after each meal and rinse their mouths with antibacterial mouthwash. Subsequently, dentists begin conservative dental treatment without discontinuation of BPs. In the case that invasive dental treatment such as removal of the teeth responsible for BRONJ is inevitable, however, antibacterial agents will be administered to the patients in advance, and invasive dental treatments should be restricted to the minimum extent and area possible to avoid discontinuation of BP treatment [12].

3. Suggested dental treatment in patients with cancer and osteoporosis who are receiving denosumab

For cancer patients with bone metastases, studies have found that the benefits of denosumab are highly superior to those of zoledronic acid [11]. The incidence of DRONJ and BRONJ, however, was found to be similar in patients with cancer [3]. Similar to case of patients treated with BPs, dentists perform conservative dental treatment without drug holiday. Invasive dental treatments, if inevitable, can be conducted without a drug holiday following appropriate infection control. Given that denosumab is administered to osteoporotic patients once every 6 months and the half-life of denosumab is approximately 1 month, there is an ample window of time within the 6-month interval to plan for dental treatments [12].

**4.** Discontinuation of antiresorptive therapy after invasive dental treatment

Antiresorptive agents may interfere with the healing of surgical wounds, especially epithelialization [33]. The decision to continue or discontinue antiresorptive treatment must be made jointly by the physician and dentist based on fracture risk, and the status of healing of surgical wounds in the oral cavity.

**5.** Timing of resumption of antiresorptive therapy

The time at which to resume antiresorptive administration after a drug holiday is dependent on the balance between the healing of surgical wounds and control of the primary disease. If fracture risk or bone metastasis is well-controlled, resumption of antiresorptive treatment is recommended approximately 2 months after invasive dental procedure, when the damaged alveolar bones are expected to have healed. However, if fracture risk is high or bone metastasis progresses during the drug holiday and resumption of antiresorptive therapy is urgent, it may resume antiresorptive drug with no sign of infection around surgical wounds and epithelialization of the surgical site at 2 weeks after invasive dental treatment, when epithelialization of the surgical site is almost complete, may be the earliest possibility [12].
