The aim of this report was to document a rare case of medication-related osteonecrosis of the jaw (MRONJ) that developed around the already osseointegrated implants in the maxillary right molar region. A 73-year-old woman presented at our university dental hospital in May 2017 with a chief complaint of discomfort near a maxillary implant. Her first visit was in 2006, and the maintenance treatment began in 2007 after the periodontal treatment. During the implant maintenance period there were no complications; however, the patient began taking alendronate sodium hydrate (Fosamac tablets, 35 mg, once weekly), an oral bisphosphonate (BP) since 2013, for treatment of osteoporosis. Eight years after starting implant maintenance, in 2016, peri-implantitis occurred, for which mechanical cleaning and antimicrobial therapy were performed. Peri-implantitis symptoms disappeared, and the medical condition improved. Nonetheless, in 2017, MRONJ developed 4 years after she commenced taking the BP. The patient underwent implant removal and sequestrectomy. There was no postoperative recurrence. Since it was such a rare case, we performed a literature review but only discovered a few similar cases. Because various triggers may lead to the development of MRONJ, even if already osseointegrated implant, it is important to note that implants in patients taking BPs should be more carefully maintained.

Bisphosphonates (BPs) are drugs that inhibit bone resorption by suppressing osteoclasts. They have been widely used to treat osteoporosis, malignancy-associated hypercalcemia, and osteodynia associated with bone metastasis of a solid cancer (eg, breast cancer), multiple myeloma-associated bone diseases, Paget's disease of bone, and osteogenesis imperfect1 BP-related osteonecrosis of the jaw (BRONJ), which has serious side effects in the jawbone. This was first reported by Marx in 2003.2  Subsequently, osteonecrosis of the jawbone associated with the anti-receptor activator of nuclear factor-kappaB ligand antibody denosumab and angiogenesis inhibitors was reported and has been renamed medication-related osteonecrosis of the jaw (MRONJ) in a recent position paper of the American Association of Oral Maxillofacial Surgeons.1  MRONJ onset after starting a BP was slower in osteoporosis patients than in cancer patients.1,3,4  It was also reported that the incidence of ONJ in patients prescribed oral BPs for the treatment of osteoporosis ranged from 1.04 to 69.0/100 000 patient-years, whereas the incidence in patients with prescribed intravenous BPs ranged from 0 to 90/100 000 patient-years.5  The number of patients taking oral BPs for osteoporosis treatment has been increasing in recent years, and it is predicted to create serious dental problems.

Local risk factors that cause MRONJ have been identified as dental infections, such as apical lesions and untreated periodontal disease. In addition to surgical invasion due to tooth extraction, it has been reported that implant surgery during and after BP treatment is a risk factor for MRONJ.68  There have been only a few reports on the pathogenesis of MRONJ that develops around the already osseointegrated implants or that has been subsequent to peri-implantitis, and the details have not been clarified. We present a rare case of MRONJ subsequent to peri-implantitis in a patient who had been taking alendronate sodium hydrate, an oral BP, during long-term implant maintenance.

A 73-year-old woman presented at our Nihon University School of Dentistry dental hospital in May 2017 with a chief complaint of discomfort around the maxillary implant. The patient had medical histories of type 1 diabetes, subtotal gastrectomy for a gastric ulcer in 1998, and colorectal cancer in 2003. The patient did not have a smoking habit and was in good health. She had experienced menopause in her mid-50s.

Periodontal and implant treatment

The patient was first referred to our periodontology department in 2006 for periodontal disease treatment. She was diagnosed with generalized chronic severe periodontitis (stage IV, in the molar area, grade B according to the diagnostic criteria of the American Academy of Periodontology & European Federation of Periodontology9,10) (Figure 1). After the initial 7 months of periodontal treatment, with her type 1 diabetes stable, 2-stage implant surgery was planned. The implants were placed according to the manufacturer's recommended protocol under intravenous sedation (Micro Thread 4.5ST; Astra Tech AB; #14: 11 mm, #16: 9 mm, #35: 11 mm, #36: 9 mm). The superstructures were created using porcelain fused to both metal crown and bridge. Subsequently, they were fixed with a side-screw system (Figure 2). It is worth noting that the patient did not request prosthetic treatment of all second molars owing to financial reasons. After confirming that periodontal and peri-implant tissue were stable, maintenance treatment began in June 2007 (Figure 3).

Figure 1.

(a) Pretreatment intraoral photographs (February 2006). Generalized inflammation is observed, particularly between teeth #14 and #16. (b) Pretreatment radiographs. Nine dental plain radiographs show severe bone loss in the maxillary right molar regions.

Figure 1.

(a) Pretreatment intraoral photographs (February 2006). Generalized inflammation is observed, particularly between teeth #14 and #16. (b) Pretreatment radiographs. Nine dental plain radiographs show severe bone loss in the maxillary right molar regions.

Close modal
Figure 2.

Clinical situation at the delivery of prosthetic rehabilitation (April 2008). The gingival texture and peri-implant mucosa appear healthy.

Figure 2.

Clinical situation at the delivery of prosthetic rehabilitation (April 2008). The gingival texture and peri-implant mucosa appear healthy.

Close modal
Figures 3–5.

Figure 3. Re-evaluation radiographs (August 2011). No bone resorption is seen around the 4 implants.

Figure 4. Peri-implantitis at #14 and #16 (April 2016). (a) Purulent discharge from the pocket. (b) The probing depth was 6 mm all around with bleeding. (c) Vertical, diffuse bone resorption can be seen.

Figure 5. Peri-implant medication-related osteonecrosis of the jaw (May 2017). (a) The #16 implant has mobility. (b) Lost implant with bone-like tissue.

Figures 3–5.

Figure 3. Re-evaluation radiographs (August 2011). No bone resorption is seen around the 4 implants.

Figure 4. Peri-implantitis at #14 and #16 (April 2016). (a) Purulent discharge from the pocket. (b) The probing depth was 6 mm all around with bleeding. (c) Vertical, diffuse bone resorption can be seen.

Figure 5. Peri-implant medication-related osteonecrosis of the jaw (May 2017). (a) The #16 implant has mobility. (b) Lost implant with bone-like tissue.

Close modal

Papillary thyroid carcinoma and hyperparathyroidism

The patient's papillary thyroid carcinoma was diagnosed in 2012, and hemithyroidectomy and conservative neck dissection were performed at a university hospital. Postoperative thyrotropin-suppression therapy with levothyroxine sodium hydrate (Thyradin-S tablets 75 μg; ASKA Pharmaceutical Co, Ltd) once daily was prescribed to prevent recurrence. Additionally, oral BP was prescribed for hypercalcemia and osteoporosis due to hyperparathyroidism. Alendronate sodium hydrate (Fosamac tablets, 35 mg; Merck & Co) once for a week was also prescribed and not stopped until she was seen by us in 2017.

Peri-implantitis (#14, #16 implants)

The patient complained of discomfort in the right upper molar region during maintenance in April 2016. Intraoral examination revealed diffuse redness and swelling in the #14 and #16 peri-implant mucosa. Purulent discharge from the pocket of #14 implant was also recognized (Figure 4a). To simplify our evaluation, we removed the superstructure, during which the depth of the probing was 6 mm all around it, resulting in bleeding (Figure 4b). Radiological findings showed diffuse vertical bone resorption extending one-third of the implant length at mesial and distal sites (Figure 4c). These findings led to a diagnosis of peri-implantitis.11  Later, the superstructure was again removed to make it easier to access the implant surface for non-surgical debridement using a titanium hand scaler. After healing had been ensured via systemic antibacterial therapy, the cleaned superstructure was reset, and maintenance treatment began.

Peri-implant MRONJ

One year after treatment for peri-implantitis of the maxillary right molar (May 2017), the patient contacted us because the implant superstructure had detached from its abutment. Clinical findings were redness, mucosal swelling around the implant, and #16 implant mobility. The #16 implant was easily and painlessly removed using a finger. It was observed that bone-like tissue was attached to the implant's rough surface (Figure 5). Dental cone-beam computerized tomography (CBCT) revealed that the alveolar bone around the #16 implant was largely absorbed, with partial rupture of cortical bone continuity, and reaching the sinus with thickening of the sinus mucosa. Additionally, a rough, opacity resembling sequestrum was seen around the #14 implant (Figure 6). The necrotic bone tissue was sent for pathological examination. The results showed lamellar bone with an empty osseous lacuna and necrotic tissue with a bacterial clot in the area of the bone marrow cavity. Granulation tissue with partial epithelialization was also found (Figure 7). MRONJ (stage 2) subsequent to peri-implantitis was diagnosed.

Figures 6–8.

Figure 6. Dental cone-beam computerized tomography images of peri-implant medication-related osteonecrosis of the jaw. (a) Sagittal image, (b) Horizontal image. (c) Coronal image. Arrows indicate sequestrum around #14 implant. The bone resorption of #16 region extends to the bottom of the maxillary sinus and the palatal wall of the maxillary alveolar process.

Figure 7. Hematoxylin and eosin staining of the hard and soft tissue specimens around #16 implant. (a, b) Arrowheads indicate necrotic tissue with bacterial accumulation in empty marrow space. (c) Arrows indicate epithelial and granulation tissue. Scale bar 200 μm (a) and 50 μm (b, c).

Figure 8. (a) Intraoral photographs at 1 year postoperatively (August 2018). (b) Removable partial denture.

Figures 6–8.

Figure 6. Dental cone-beam computerized tomography images of peri-implant medication-related osteonecrosis of the jaw. (a) Sagittal image, (b) Horizontal image. (c) Coronal image. Arrows indicate sequestrum around #14 implant. The bone resorption of #16 region extends to the bottom of the maxillary sinus and the palatal wall of the maxillary alveolar process.

Figure 7. Hematoxylin and eosin staining of the hard and soft tissue specimens around #16 implant. (a, b) Arrowheads indicate necrotic tissue with bacterial accumulation in empty marrow space. (c) Arrows indicate epithelial and granulation tissue. Scale bar 200 μm (a) and 50 μm (b, c).

Figure 8. (a) Intraoral photographs at 1 year postoperatively (August 2018). (b) Removable partial denture.

Close modal

MRONJ treatment

The #14 implant was removed prior to sequestrectomy to increase mobility. Clarithromycin, 200 mg (Clarith tablets 200; Taisho Pharmaceutical Co, Ltd) was prescribed for 14 days twice a day because right maxillary sinusitis occurred simultaneously with ONJ progression, although the patient's nasal symptoms and thickening of the sinus mucosa were alleviated. Because of the spreading bone necrosis, including the removed #14 implant, sequestrectomy of the area was planned.

The patient was informed that resection might worsen the MRONJ, but it was necessary to remove the infection site early, while continuing the osteoporosis treatment. She agreed to the proposed measures. Hence, the alendronate sodium hydrate, which she had been taking continuously for about 4 years (since 2013 after thyroid surgery), was changed to raloxifene hydrochloride (Evista, 60 mg tablets; Eli Lilly) once a day in May 2017. It was discontinued once before the sequestrectomy surgery 4 months later. Serum calcium levels remained constant within the standard range (8.2–8.7 mg/dL) throughout these drug changes. In contrast, control of her type 1 diabetes had gradually worsened since 2014 when she had started using insulin injections (Humalog injection, 100 units/mL) via insulin pump therapy. There had been no complications (eg, retinopathy, neuropathy), and her HbA1c level at the preoperative examination was 8.4%.

A plan was made to remove the insulin pump device during the operation because acute attacks are manageable by intravenous injection. Clarithromycin was given twice a day for 9 days as antimicrobial prophylaxis.

Sequestrectomy and maxillary sinus lavage were performed under general anesthesia in September 2017. The area to undergo sequestrectomy was determined from preoperative CT images. The bone resection area included only sites where bleeding could be confirmed intraoperatively. The wound was completely closed using a mucoperiosteal flap because vertical bone resorption had extended to the bottom of the maxillary sinus.

The postoperative course was considered good, and the stitches were removed 1 week postoperatively with no observed recurrence of inflammatory symptoms. Oral administration of raloxifene hydrochloride (Evista, 60 mg tablets, once a day) was resumed postoperatively. To date (October 2019), there have been no findings to support relapse of the MRONJ. The treatment course and the patient's condition were classified as good, and there have been no unpleasant events for a year after the sequestrectomy. A removable partial denture has been adopted, and gradual progress has ensued (Figure 8).

Since the concept of osseointegration (wherein titanium is directly connected to bone tissue) has been accepted,12  dental implants have made great progress and have become beneficial to oral health. Because of their structure, however, implants also pose the risk of allowing bacterial invasion into internal tissues, such as connective and alveolar bone tissue, wherever implants exist in the oral epithelium. Peri-implantitis is a nonspecific, suppurative inflammation in the peri-implant tissue due to an oral bacterial infection. Clinical symptoms are characterized by pus drainage, peri-implant tissue bleeding, and alveolar bone resorption. If the infection becomes severe, the implant must be removed, thereby impairing the patient's quality of life.11  There are many unknowns about peri-implantitis despite its having an onset mechanism and clinical symptoms similar to those of periodontitis, which is mainly caused by plaque infection.

BPs are bone resorption inhibitors. Once deposited in bone, BPs are specifically taken in by osteoclasts, and later released into the serum in an acidic environment. Bone resorption and remodeling are suppressed, leading to apoptosis by the osteoclasts, which contain BPs.13  Although the pathophysiological pathogenesis mechanism of MRONJ that develops characteristically in the jawbone has not been clarified, the involvement of inflammation and infection has been discussed, as have changes in the bone remodeling response, excessive bone resorption, inhibition of angiogenesis, continuous minor trauma, immunodeficiency, vitamin D deficiency, and the toxicity of BP to soft tissue.1,14,15  Because the peri-implant environment is considered prone to chronic inflammatory conditions, it is speculated that peri-implant MRONJ is more likely to develop because the immune function is weaker than when natural teeth are in place, and a strong occlusal force tends to act.

Risk factors for developing MRONJ are generally linked to the following factors: drugs; local and/or systemic factors; and genetic factors. Drug-related MRONJ often occurs in patients medicated with oral alendronate as a bone resorption inhibitor for hypercalcemia and osteoporosis associated with hyperparathyroidism. Alendronate, a second-generation BP, contains nitrogen and is estimated to be 10–1000 times more active than first-generation BPs. The third-generation zoledronate is even more potent at inhibiting bone resorption.16  Generally, BP injection used as cancer treatment has high absorption efficiency. Thus, at high doses, the risk of osteonecrosis of the jaw is estimated to be greater with an injected BP than when it is given orally. The number of osteoporosis patients in Japan, a super-aging society, has risen to 1,280,000, and oral BP users will likely increase as well.17  In the future, we must pay attention to any further increase in MRONJ patients who are taking an oral BP given its current lower incidence.

Regarding the administration period of oral BPs, the risk of developing MRONJ has previously increased from 3 years to 4 years, as reported in a recent position paper.1  A previous study of 13 000 people using long-term oral BPs reported that BRONJ prevalence was 0.1% but, when calculated over a 4-year period, the incidence increased to 0.21%.18  In our patient, MRONJ developed 4 years after starting an oral BP, implying that the cumulative use of BPs over a long period might have had an effect.

Local factors leading to MRONJ include invasive dental treatment, such as tooth extraction and implant surgery. It is difficult to regard implant surgery as a local factor in the present case, however, because the implant treatment was completed several years before the patient started taking the oral BP. It was previously reported that the incidence of MRONJ was low after implant surgery on healthy jawbone.19  Likewise, inflammatory lesions appearing as apical and marginal periodontitis has been proposed to have a greater effect on MRONJ development than the surgical invasion of tooth extraction in recent years.20  In our patient, the implant treatment was performed after we confirmed clinical improvement of periodontal tissue in response to the initial periodontal treatment. Although the patient was constantly undergoing maintenance treatment, peri-implantitis developed in the #14–#16 area during the 8 years after maintenance began. Active surgical therapy was not performed to alleviate peri-implant inflammation despite recognizing bleeding in ∼6-mm pockets and redness of the peri-implant tissue due to the patient having taken oral BPs at that time. Fortunately, clinical improvement was obtained by cleaning out the removed superstructure and non-surgical therapy. Frequent maintenance was planned with the patient's grateful approval.

Histopathological examination revealed bacterial accumulations in the sequestrum, but we did not identify the bacterial genus and species. A wide variety of oral bacterial infections have been reported due to the bacterial flora of peri-implantitis.21 Coriobacterium, the major genus of actinomycetes, is one of the bacterial species specific to peri-implantitis. Some studies have detected actinomycetes in MRONJ lesions,22  suggesting that similar bacterial species may be involved in the development of both peri-implantitis and MRONJ. As for MRONJ having a relatively low incidence despite the increase in BP users, it may be because of the differences in the bacterial infections in the oral cavity.

Although the present patient does not suffer from bruxism, it has been noted that implants at the most distal location are subjected to excessive bite force, thus implying that the inflammatory response may worsen due to excessive occlusal force acting on peri-implant tissues, which could be harmful as a modifier after endogenous infection of dental plaque. In our case, the symptoms of peri-implant inflammation were identified in the #16 implant located at the most distal point, suggesting that it might be related to an occlusal load.

Considering the aforementioned suppositions, it was hypothesized that certain factors in MRONJ development contribute to chronic inflammation, and, subsequently, that occlusal force activated remodeling of the bone tissue. Thus, it became easy to accumulate BP in the local environment.

Considering the systemic factors and that MRONJ developed at age 72 years, previous cohort surveys reported an increased risk of onset at age 65 years and older.23  It is surmised that the risk of developing breast cancer and osteoporosis increases with age even if aging is currently not a definitive systemic factor for MRONJ. Whether diabetes is a risk factor for developing MRONJ has not reached a consensus,5,24  although an immunocompromised state due to diabetes has been speculated to be a risk factor for peri-implantitis.25  In the present patient, it was implied that type 1 diabetes affected MRONJ development at the site that had been locally infected. Regarding concomitant drugs, the patient was not medicated on corticosteroids, angiogenesis inhibitors, or immunosuppressants, which have been reported associated with an increased risk for developing MRONJ. However, levothyroxine sodium hydrate to diminish thyroid hormone and ethyl icosapentate for hyperlipidemia were administered.

Genetically, an association of single nucleotide polymorphisms (SNPs) during MRONJ onset has been reported,26  although no further genetic diagnostic tests were performed because none of the relatives of the patients had a history of this disease.

Literature review

The present study searched for articles published until 2019. The databases Medline via PubMed was searched. As a result, from all 67 articles that fit these circumstances, hand search was performed for cases that MRONJ was developed in functioning implants. Five case reports were hit in the past 10 years. Most of the previous patients with peri-implant-related MRONJ who were operated on because of the onset of jawbone necrosis while using BPs had their MRONJ triggered by an implant surgical procedure.27,28  However, as in the present rare case studies, there have been a few reports of patients who developed peri-implant MRONJ after beginning oral BP treatment2933  (Table 1). The results of other studies are shown in Table 2. It is anticipated that many cases involving BP intake that started after implants were already functioning will be reported in the future.

Table 1

Case reports of MRONJ development after BPs treatment in functional implants*†

Case reports of MRONJ development after BPs treatment in functional implants*†
Case reports of MRONJ development after BPs treatment in functional implants*†
Table 2

Other studies of MRONJ development after BPs treatment in functional implants

Other studies of MRONJ development after BPs treatment in functional implants
Other studies of MRONJ development after BPs treatment in functional implants

A recent systematic review showed that a history of oral or intravenous BP use is not an absolute contraindication for dental implant placement, and osseointegration can be achieved even among those patients.36  Another review reported that implant treatment is possible if it can meet 3 criteria: (1) preoperative antibiotics are administered; (2) bone augmentation is avoided; (3) satisfactory oral hygiene is maintained.37 

In this case presentation, it was suggested that MRONJ development was caused by multiple factors attributable to BP accumulation released during a previous bout of local inflammation with persistent peri-implantitis after local infection in an environment where the immune function was depressed by type 1 diabetes. In situations where implant maintenance is prolonged with widespread implant treatment, cases of BP intake for treatment of osteoporosis may increase in the future. The risk of developing peri-implant MRONJ in patients taking BPs should be recognized. Moreover, such patients' implants should be carefully monitored. Similarly, one must keep in mind that the incidence of systemic diseases will increase in our super-aging society. It is therefore suggested that more attention must be paid to local infection control during implant maintenance.

We documented a case of peri-implant MRONJ in a 73-year-old woman. The patient underwent implant removal and sequestrectomy, with no postoperative recurrence. The conditions of this case imply that the local infection around the already osseointegrated implant and type 1 diabetes are factors in MRONJ development. We summarized the case and included a literature review on the pathogenesis of MRONJ.

Abbreviations

Abbreviations
BPs:

bisphosphonates

MRONJ:

medication-related osteonecrosis of the jaw

1. 
Ruggiero
SL,
Dodson
TB,
Fantasia
J,
et al
American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update
.
J Oral Maxillofac Surg
.
2014
;
72
:
1938
1956
.
2. 
Marx
RE.
Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic
.
J Oral Maxillofac Surg
.
2003
;
61
:
1115
1117
.
3. 
Yoneda
T,
Hagino
H,
Sugimoto
T,
et al
Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw
.
J Bone Miner Metab
.
2017
;
35
:
20
.
4. 
Khan
AA,
Morrison
A,
Kendler
DL,
et al
International Task Force on Osteonecrosis of the Jaw. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the International Task Force on ONJ
.
J Clin Densitom
.
2017
;
20
:
8
24
.
5. 
Khan
AA,
Morrison
A,
Hanley
DA,
et al
International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus
.
J Bone Miner Res
.
2015
;
30
:
3
23
.
6. 
Yoneda
T,
Hagino
H,
Sugimoto
T,
et al
Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons
.
J Bone Miner Metab
.
2010
;
28
:
365
383
.
7. 
Holzinger
D,
Seemann
R,
Matoni
N,
Ewers
R,
Millesi
W,
Wutzl
A.
Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws
.
J Oral Maxillofac Surg
.
2014
;
72
:
1937.e1
1937.e8
.
8. 
Matsuo
A,
Hamada
H,
Takahashi
H,
Okamoto
A,
Kaise
H,
Chikazu
D.
Evaluation of dental implants as a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw in breast cancer patients
.
Odontology
.
2016
;
104
:
363
371
.
9. 
Armitage
GC.
Development of a classification system for periodontal diseases and conditions
.
Ann Periodontol
.
1999
;
4
:
1
6
.
10. 
Papapanou
PN,
Sanz
M,
Buduneli
N,
et al
Periodontitis: consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions
.
J Periodontol
.
2018
;
89
:
S173
S182
.
11. 
Berglundh
T,
Armitage
G,
Araujo
MG,
et al
Peri-implant diseases and conditions: consensus report of workgroup 4 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions
.
J Periodontol
.
2018
;
89
(Suppl 1)
:
S313
S318
.
12. 
Brånemark
PI,
Adell
R,
Breine
U,
Hansson
BO,
Lindström
J,
Ohlsson
A.
Intra-osseous anchorage of dental prostheses. I. Experimental studies
.
Scand J Plast Reconstr Surg
.
1969
;
3
:
81
100
.
13. 
Roelofs
AJ,
Thompson
K,
Gordon
S,
Rogers
MJ.
Molecular mechanisms of action of bisphosphonates: current status
.
Clin Cancer Res.
2006
;
12:6222s–6230s.
14. 
Reid
IR,
Bolland
MJ,
Grey
AB.
Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?
Bone
.
2007
;
41
:
318
320
.
15. 
Sonis
ST,
Watkins
BA,
Lyng
GD,
Lerman
MA,
Anderson
KC.
Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients
.
Oral Oncol
.
2009
;
45
:
164
172
.
16. 
Shibahara
T,
Morikawa
T,
Yago
K,
Kishimoto
H,
Imai
Y,
Kurita
K.
National Survey on Bisphosphonate-Related Osteonecrosis of the Jaws in Japan
.
J Oral Maxillofac Surg
.
2018
;
76
:
2105
2112
.
17. 
Yoshimura
N,
Muraki
S,
Oka
H,
et al
Prevalence of knee osteoarthritis, lumbar spondylosis, and osteoporosis in Japanese men and women: the research on osteoarthritis/osteoporosis against disability study
.
J Bone Miner Metab
.
2009
;
27
:
620
628
.
18. 
Lo
JC,
O'Ryan
FS,
Gordon
NP,
et al
Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) Investigators. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure
.
J Oral Maxillofac Surg
.
2010
;
68
:
243
253
.
19. 
Chadha
GK,
Ahmadieh
A,
Kumar
S,
Sedghizadeh
PP.
Osseointegration of dental implants and osteonecrosis of the jaw in patients treated with bisphosphonate therapy: a systematic review
.
J Oral Implantol
.
2013
;
39
:
510
520
.
20. 
Tsao
C,
Darby
I,
Ebeling
PR,
et al
Oral health risk factors for bisphosphonate-associated jaw osteonecrosis
.
J Oral Maxillofac Surg
.
2013
;
71
:
1360
1366
.
21. 
Shiba
T,
Watanabe
T,
Kachi
H,
et al
Distinct interacting core taxa in co-occurrence networks enable discrimination of polymicrobial oral diseases with similar symptoms
.
Sci Rep
.
2016
;
6
:
30997
.
22. 
De Ceulaer
J,
Tacconelli
E,
Vandecasteele
SJ.
Actinomyces osteomyelitis in bisphosphonate-related osteonecrosis of the jaw (BRONJ): the missing link?
Eur J Clin Microbiol Infect Dis
.
2014
;
33
:
1873
1880
.
23. 
Yamazaki
T,
Yamori
M,
Ishizaki
T,
et al
Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study
.
J Oral Maxillofac Surg
.
2012
;
41
:
1397
1403
.
24. 
Saad
F,
Brown
JE,
Van Poznak
C,
et al
Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases
.
Ann Oncol
.
2012
;
23
:
1341
1347
.
25. 
Klokkevold
PR,
Han
TJ.
How do smoking, diabetes, and periodontitis affect outcomes of implant treatment?
Int J Oral Maxillofac Implants
.
2007
;
22
:
173
205
.
26. 
Nicoletti
P,
Cartsos
VM,
Palaska
PK,
Shen
Y,
Floratos
A,
Zavras
AI.
Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: the role of RBMS3
.
Oncologist
.
2012
;
17
:
279
287
.
27. 
Bedogni
A,
Bettini
G,
Totola
A,
Saia
G,
Nocini
PF.
Oral bisphosphonate-associated osteonecrosis of the jaw after implant surgery: a case report and literature review
.
J Oral Maxillofac Surg
.
2010
;
68
:
1662
1666
.
28. 
Zushi
Y,
Takaoka
K,
Tamaoka
J,
Ueta
M,
Noguchi
K,
Kishimoto
H.
Treatment with teriparatide for advanced bisphosphonate-related osteonecrosis of the jaw around dental implants: a case report
.
Int J Implant Dent
.
2017
;
3
:
11
.
29. 
Shirota
T,
Nakamura
A,
Matsui
Y,
Hatori
M,
Nakamura
M,
Shintani
S.
Bisphosphonate-related osteonecrosis of the jaw around dental implants in the maxilla: report of a case
.
Clin Oral Implants Res
.
2009
;
20
:
1402
1408
.
30. 
Junquera
L,
Gallego
L,
Pelaz
A.
Multiple myeloma and bisphosphonate-related osteonecrosis of the mandible associated with dental implants
.
Case Rep Dent
.
2011
;
2011
:
568246
.
31. 
Yuan
K,
Chen
KC,
Chan
YJ,
Tsai
CC,
Chen
HH,
Shih
CC.
Dental implant failure associated with bacterial infection and long-term bisphosphonate usage: a case report
.
Implant Dent
.
2012
;
21
:
3
7
.
32. 
Marín-Fernández
AB,
García Medina
B,
Aguilar-Salvatierra
A,
Jiménez-Burkhardt
A,
Gómez-Moreno
G.
Jaw osteonecrosis management around a dental implant inserted 2 years before starting treatment with zoledronic acid
.
J Clin Exp Dent
.
2015
;
7
:
e444
e446
.
33. 
Favia
G,
Tempesta
A,
Limongelli
L,
Crincoli
V,
Piattelli
A,
Maiorano
E.
Metastatic Breast Cancer in Medication-Related Osteonecrosis Around Mandibular Implants
.
Am J Case Rep
.
2015
;
16
:
621
626
.
34. 
López-Cedrún
JL,
Sanromán
JF,
García
A,
et al
Oral bisphosphonate-related osteonecrosis of the jaws in dental implant patients: a case series
.
Br J Oral Maxillofac Surg
.
2013
;
51
:
874
879
.
35. 
Escobedo
MF,
Cobo
JL,
Junquera
S,
Milla
J,
Olay
S,
Junquera
LM.
Medication-related osteonecrosis of the jaw; implant presence-triggered osteonecrosis: case series and literature review
.
J Stomatol Oral Maxillofac Surg.
(In press).
36. 
Chadha
GK,
Ahmadieh
A,
Kumar
S,
Sedghizadeh
PP.
Osseointegration of dental implants and osteonecrosis of the jaw in patients treated with bisphosphonate therapy: a systematic review
.
J Oral Implantol
.
2013
;
39
:
510
520
.
37. 
Walter
C,
Al-Nawas
B,
Wolff
T,
Schiegnitz
E,
Grötz
KA.
Dental implants in patients treated with antiresorptive medication:- a systematic literature review
.
Int J Implant Dent
.
2016
;
2
:
9
.