they are also used to treat multiple myeloma , bone metastases , and calcium disorders 2 .
these patients reportedly often develop bisphosphonaterelated osteonecrosis of the jaw ( bronj ) that is caused by subsequent dental surgery 3 , 4 . in general
, it is thought that nitrogencontaining bisphosphonates are much high risk of osteonecrosis than nitrogen notcontaining bisphosphonates .
thus , medications for cancer , such as zoledronate ( zometa ) , are thought to have much high risk of osteonecrosis than medications for osteoporosis , such as alendronate ( bonalon ) 5 .
besides bisphosphonates , other antiresorptive agents such as denosumab and antiangiogenic medications also cause osteonecrosis 6 .
thus , the american association of oral and maxillofacial surgeons position paper published in 2014 and the committee recommended changing the nomenclature of bronj to the term  medicationrelated osteonecrosis of the jaw  ( mronj ) to accommodate the growing number of jaw osteonecrosis cases associated with other antiresorptive and antiangiogenic therapies 7 . according to the position paper , there are three categories of risk factors for mronj : ( 1 ) medicationrelated risk factors ( e.g. , bisphosphonate use ) , ( 2 ) local factors ( e.g. , dental surgery ) , and ( 3 ) demographic and systemic factors and other medication factors . in this case report , the patient developed mronj and died of sepsis , although he received shortterm oral bisphosphonate therapy and had not received any dental surgical treatment because he was completely edentulous .
however , he had many systemic factors such as diabetes , cirrhosis , and steroid use for interstitial pneumonia .
the presence of multiple systemic factors can be a very high risk for mronj , even though there are few medicationrelated factors and local factors 8 , 9 , 10 .
the patient was a 59yearold man with a history of smoking and drinking , insulin use for diabetes , cirrhosis associated with chronic hepatitis c , steroid use for interstitial pneumonia , sepsis , and spinal disk herniation .
this study was conducted according to the guidelines of hiroshima city hiroshima citizens hospital , and a written informed consent was obtained from this patient .
white blood cell count ( wbc ) was 7800/l and creactive protein ( crp ) level was 15.523
he was treated with intravenous steroids ( i.e. , methylprednisolone sodium succinate 1000 mg / day for 3 days , prednisolone sodium succinate 20 mg twice daily for 4 days , and methylprednisolone sodium succinate 1000 mg / day for 3 days ) . this regimen was followed by oral steroids ( i.e. , prednisolone 60 mg / day for 2 months ) . to prevent steroidinduced osteoporosis , he was treated with oral bisphosphonate ( i.e. , alendronate 35 mg / week for 7 weeks ) .
however , the administration of these drugs was stopped because of a right buccal space infection .
the patient had severe swelling from the right buccal area to the infraorbital region , hypesthesia , and tenderness , but no spontaneous pain ( fig .
there were ulcerations and exposed bone on the alveolar part of the right incisor and molar ( fig .
computer tomography ( ct ) scanning with a radiocontrast agent showed swelling in the right buccal area , but showed no mandibular bone resorption ( fig .
2b ) . magnetic resonance imaging ( mri ) demonstrated an abnormal signal ( e.g. , low signal on t1weighted [ t1w1 ] mri and high signal on t2weighted [ t2w1 ] mri ) in the bone marrow of the right mandibular angle ( fig .
based on these results , the patient was diagnosed as having right mandibular cellulitis , sepsis , and disseminated intravascular coagulation ( dic ) .
we administered intravenous antibiotic treatment and irrigated part of the exposed bone with povidone  iodine every weekday . at 3 days after the first visit , sequestrectomy and drainage
therefore , we changed the antibiotics from meropenem hydrate ( meropen ; sumitomo dainippon pharma co. , ltd . ,
osaka , japan ) alone to meropenem hydrate and ampicillin / sulbactam ( unasyn s ; pfizer inc .
one month after the first visit , swelling from right buccal area had nearly disappeared ( fig .
4b ) . exposed bone remained on the alveolar portion of the right mandibular molar and pus discharge was present ( fig .
antibioticresistant bacteria ( grampositive bacilli ) were detected at that time ( table 1 ) .
therefore , we changed the antibiotics to sitafloxacin ( gracevit ; daiichi sankyo , tokyo , japan ) ( fig .
3 ) . seven weeks after the first visit , his condition had taken a turn for the worse .
, he died of multiorgan failure . finally , we diagnosed this patient as mronj .
his multiple systematic factors and mronj caused lethal sepsis because it fulfilled the diagnostic criteria : previous treatment with bisphosphonate , exposed bone in the maxillofacial region that has persisted for 8 weeks and no history of radiation therapy to the jaws .
( b ) bisphosphonaterelated exposed necrotic bone in the right posterior mandibular ( during drainage ) .
( a ) no bone resorption is present on the right part of the mandibula in orthopantomogram analysis .
( b , c ) right buccal swelling is apparent , but there is no bone resorption of the mandibula , based on computer tomography ( ct ) analysis .
( d , e ) abnormal signal ( i.e. , a low signal on t1weighted imaging [ tiwi ] and a high signal on t2weighted imaging [ t2w1 ] ) of the bone marrow on the right angle part of the mandibula . bacterial identification and microbial sensitivity test the transition in the laboratory test values for the white blood cell count ( wbc ) and the creactive protein ( crp ) level , and the use of several antibiotics for cellulitis and medicationrelated osteonecrosis of the jaws ( mronj ) .
( a ) disappearance of swelling from the right buccal area to the infraorbital region .
( c ) discharge of pus by exposed bone on the alveolar part of the right mandibular molar .
in recently years , there have been many reports on osteonecrosis of the jaw ( onj ) caused by bisphosphonates and by other antiresorptive and antiangiogenic therapies 6 , 11 , 12 .
bisphosphonaterelated osteonecrosis of the jaw  to  medicationrelated osteonecrosis of the jaw  7 .
denosumab , a rank ligand inhibitor , is an antiresorptive agent and used to treat osteoporosis , multiple myeloma , and giant cell tumor 13 .
the manufacturer reports that the frequency of onj with denosumab is nearly the same as the frequency with zoledronic acid treatment 14 .
thus , it may be that the development of onj is associated with the inhibition of bone resorption , rather than the use of a certain type of drug .
however , it is considered that careful attention is required for the use of bisphosphonates in the present case due to the frequent use for the treatment of osteoporosis , osteopenia , and other diseases .
many reports indicate that the incidence of onj is significantly higher with the use of intravenous ( iv ) bisphosphonates such as zoledronic acid ( zometa ; novartis , basel , switzerland ) than by the use of oral bisphosphonate 3 , 15 .
the incidence of onj because of the use oral bisphosphonates was higher in japan than in europe and america 16 .
the period of drug use is also important , and longterm use is considered a high risk for the development of onj . in our patient ,
the period of oral bisphosphonates use was only 7 weeks , but it caused severe symptoms .
it may be that these symptoms were because of his multiple systemic factors . in this case
thus , it is thought that there were another option not to use bisphosphonate for such a highrisk patient or at least before administration we had to perform a risk assessment for mronj enough .
in addition , the presence of comorbid condition such as obesity , alcohol use , and smoking was a risk factor for mronj 9 .
poor oral hygiene and oral infection such as periodontal disease are also risk factors 18 , 19 .
the dentures were possibly contaminated with oral bacteria . in this case , we do not know whether the dentures were illfitting and there were denturerelated traumatic ulcers because he already had ulcerations and exposed bone when we first saw him . however , we think denturerelated traumatic ulcers might have promoted a mronj .
osteonecrosis of the jaw has also been reported in patients with no history of surgery or in edentulous regions of the jaw 20 .
physicians have to be careful with the use of bisphosphonates or other bone resorption inhibitors in patients , regardless of the presence or absence of teeth or surgical history . the most important thing to prevent mronj
it required cooperation among physicians , nurses , dentists , dental hygienists , pharmacists , and other medical staff 7 .
physicians who prescribe bisphosphonates or other bone resorption inhibitors have to provide a detailed explanation to patients of the risk of mronj and consult dentists if a patient has even a small risk factor . to prevent mronj
, dentists and dental hygienists have to explain sufficiently to patients the importance of oral hygiene , and perform oral care and dental treatments before patients use these drugs .
there is a tendency to believe that mronj is caused by longterm bisphosphonate use ( especially intravenous bisphosphonate ) and dental surgery .
we found that multiple systemic factors can be a worse risk factor for mronj because it may cause lethal disease such as sepsis .
physicians have to be careful when administering bisphosphonate , other antiresorptive agents , and antiangiogenic medications for patients with multiple systemic factors , even if the patients seem to have no problems in the oral cavity .
ky : involved in study conception , design , and drafting manuscript ; as : involved in study conception , design , and is the chief doctor for the patient ; fo : is one of the main doctors for the patient and performed data acquisition ; mn : is supervisor and main doctor for the patient ; ks and ey : performed analysis and interpretation of data ; yh : is one of the main doctors for the patient and performed data acquisition ; si : made critical revision for this report ; st : made critical revision and is the corresponding author .
 key clinical messagemedicationrelated osteonecrosis of the jaw ( mronj ) is developed even in the patients who are edentulous and treated with shortterm bisphosphonate therapy and oral administration . 
 it sometimes causes lethal sepsis in patients who have multiple health problems such as diabetes , cirrhosis , steroid use for interstitial pneumonia , sepsis , and spinal disk herniation . 
Introduction
Case Report
Discussion
Conclusion
Conflict of Interest
Authorship