Review ORAL BIOLOGY RESEARCH 2014; 38(1): 1-8 비스포스포네이트관련악골골괴사 : 문헌고찰 오지수ㆍ김수관 * ㆍ유재식ㆍ김지원ㆍ김은식ㆍ임경섭ㆍ김철만 조선대학교치의학전문대학원구강악안면외과학교실 Bisphosphonate-related ost

Review ORAL BIOLOGY RESEARCH 2014; 38(1): 1-8 비스포스포네이트관련악골골괴사 : 문헌고찰 오지수ㆍ김수관 * ㆍ유재식ㆍ김지원ㆍ김은식ㆍ임경섭ㆍ김철만 조선대학교치의학전문대학원구강악안면외과학교실 Bisphosphonate-related osteonecrosis of the jaws: A literature review Ji-Su Oh, Su-Gwan Kim*, Jae-Seek You, Ji-Won Kim, Eun-Sik Kim, Kyung-Seop Lim, Cheol-Man Kim Department of Oral and Maxillofacial Surgery, School of Dentistry, Chosun University, Gwangju, Korea ABSTRACT The aim of the present study was to review bisphosphonate osteonecrosis of the jaws (BRONJ). Bisphosphonate, pathophysiology, risk factors, staging, clinical manifestation, treatments, and prevention of BRONJ were investigated through a literature search. Bisphosphonates are a group of drugs that treat diseases related to bone resorption such as Paget s disease, osteoporosis, and osseous metastases. BRONJ is defined as exposure and necrosis of bone in the oral cavity for at least 8 weeks in patients receiving bisphosphonate and with no history of radiotherapy of the jaws. Many articles have reported risk factors associated with BRONJ such as systemic diseases, oral infection, poor oral hygiene, and intraoral trauma. The objectives of BRONJ treatment are to minimize necrosis and relieve symptoms. Many treatments are suggested from conservative treatment to radical intervention, but this remains controversial. BRONJ remains a difficult condition to treat although many studies are being carried out. Key Words: Jaw, Necrosis, Oral surgery, Osteomyelitis 서 론 Bisphosphonate osteonecrosis of the jaws (BRONJ) 는방사 선치료를받은기왕력이없고, bisphosphonate 를과거에복용 하였거나현재복용중이면서, 악골에 8 주이상골의노출이 있는경우를말한다 [1]. Bisphosphonate 관련골괴사는이도 (auditory canal) 에발생한증례보고가있지만 [2], 이것은매우 드문경우로다른골보다대부분악골에발생한다. 이는악골 의높은골개조율 (remodeling) 과다른골에비해서세균침입 Received Feb 06, 2014; Revised version received Feb 18, 2014 Accepted Feb 18, 2014 Corresponding author: Su-Gwan Kim Department of Oral and Maxillofacial Surgery, College of Dentistry, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 501-759, Korea Tel: 82-62-220-3815, Fax: 82-62-228-7316 E-mail: sgckim@chosun.ac.kr 이쉽게가능하다는이유로추정되지만아직명확한이유가밝혀지지않았다 [3]. 또한상악골에비해하악골에빈번히발생하는데이는혈액공급의차이, 피질골과해면골의비율차이, 상악골과하악골의발생학적차이로추정된다 [4]. BRONJ는다른병과달리최근에높은발병률을보이면서아직원인과치료법에대한연구가미흡한실정으로현재도많은연구가이루어지고있다. 따라서본연구에서는최근에발표된문헌의고찰을통해 bisphosphonate 와 BRONJ에대해논의해보고자한다. 고찰 Bisphosphonates Bisphosphonate는 Paget s disease, 다발성골수종 (multiple myeloma), 암의골전이, 골다공증 (osteoporosis) 과같은골의흡수와관련된질병의치료를위해개발된약물이다 This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1

Bisphosphonate-related osteonecrosis of the jaws (Table 1)[5]. Bisphosphonate 는현재 3 세대까지개발되었는 데, etidronate 나 clodronate 와같은 1 세대 bisphosphonate 는 nitrogen 을포함하고있지않다. Pamidronate 와같은 2 세대 bisphosphonate 는말단에단백질기 (amino-terminal group) 를가진곁사슬 (side chain) 을가지고있으며, 1 세대보다 10 배에서 100 배큰역가 (potency) 를보인다. Risedronate 나 zoledronate 와같은 3 세대 bisphosphonate 는매우강력한역가 를가지고있는데, zoledronate 의경우 pamidronate 보다 100 배, etidronate 보다 10,000 배의효능이있다 [6]. 임상에서빈번하 게이용되고있는 alendronate (Fosamax) 의경우 etidronate 보 다 500 배, risedronate (Actonel) 는 etidronate 보다 1,000 배의역 가를가진다 [7]. 또한 bisphosphonate 의반감기는 alendronate 가 12 년이상, zoledronate 가 10 년이상으로다른약물에비해 서매우긴반감기를가지고있다 [8]. Bisphosphonate 의투여방법은경구투여와정맥투여로나눌 수있는데, 경구투여의경우 1% 만이위장관으로흡수되며, 정 맥투여는 50% 이상의흡수율을보이므로다발성골수종이나 암과관련된경우정맥투여, 골다공증과관련된경우경구투 여를하는것이일반적이다 [9]. Bisphosphonates 는신장및위 궤양과같은위장관의부작용을가지고있으나가장심한부 작용은악골의괴사이다 [10]. Pathophysiology 조직학적으로 bisphosphonate 를투여한환자의골은저세 포성 (hypocellular), 과광화 (hypermineralized) 된특징을가 지고있다. Howship s lacunae 와 reversal lines 이감소되어있 고정맥울혈 (venous congestion) 이있다. 이와반대로방사선 조사를받은골은상대적으로정상적인 Howship s lacunae 와 Table 1. Spectrum of Indications for Bisphosphonate Treatment Indications for bisphosphonate treatment Giant cell tumors of the jaw (previous therapy: intralesional steroid injection, subcutaneous or nasal application of calcitonin) Osteogenesis imperfecta (increased survival of osteoblasts) Chronic osteomyelitis: chronic, recurrent, multifocal, and diffuse sclerosing osteomyelitis Fibrous dysplasia Orthopedic implants (to reduce bone loss after uncemented total hip and knee arthroplasty) Hypercalcemia caused by malignant diseases or bone metastases Osteoporosis Morbus Paget Chronic pain Reprinted from the article of Bittner et al. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:41-7 with permission of the copyright holder [5]. reversal lines을가지고있으며, 골의혈관화도감소한다고하였다 [7,11]. 이와는대조적으로 BRONJ가 비스포스포네이트관련악골골수염 으로불릴만큼악골의만성골수염과조직병리학적으로매우유사하다고하였으며, bisphosphonate 의복용에대한정보없이이둘을구별하기힘들다고하였다 [12]. BRONJ의병인론에대해서많은연구가진행되어왔으나, 아직명확하지는않으며현재까지밝혀진병인론은다음과같다 [8,13]. 첫째, bisphosphonate는강력하게파골세포 (osteoclast) 의활동을억제하고파골세포의세포사 (apoptosis) 를유도한다. 또한조골세포의분화와증식을억제한다 [14]. 이로써골의흡수와형성이모두감소하게된다. 두번째, 혈관형성을억제시켜골의혈관분포를감소시키며 [15,16], 상피성장인자 (endothelial growth factor) 의억제시켜 [17] 이는악골에서골개조 (bone remodeling) 와창상치유를방해하게된다. 셋째, bisphosphonate 는수산화인회석 (hydroxyapatite) 에강한결합력을가지고있어장기간영향을미치게된다. 결과적으로골의 turnover는과도하게억제되고치유능력은감소하게된다. 이를바탕으로두가지의가설이제기되었는데, 첫번째는 inside-out theory로파골세포의억제와이로인한골의 turnover의감소, 물리적미세손상으로인한국소감염에의해악골내에서골괴사가일어나고골이노출되게된다는가설이다. 두번째가설은 outside-in 으로구강점막의손상으로인한세균의침착과국소감염이발생하고골개조의감소와함께골의괴사를일으킨다는이론이다 [18]. Bisphosphonate의 BRONJ 발생기전에대해거의모든논문들이골의 turnover 의감소를가장주목하였는데, 최근에 Ristow 등 [19] 은골스캔을통해 bone turnover (BT) 를비교하는연구를통해, 하악골에서 BRONJ의 2/3가발생하지만 BT는오히려대퇴골과비슷하며, BT의 over-suppression 이 BRONJ 발생에있어독점적인원인이아니라고하였다. 이밖에치은의점막세포에직접적인독성야기 [20], 미생물에의한감염, 면역과관련된가설등이보고되고있다 [21,22]. Wang 과 Stern [23] 은백서의조골세포에서 resedronate가골형성단백질과같은단백질의코딩유전자를포함하여세포분화와세포사와관련된유전자를활성화시킨다고보고하였다. 국소감염과감염에의한 ph의변화와관련해서, 감염에의한산성화는골에서 bisphosphonate 의 release와활성화를촉진시킨다고하였다 [24]. 또한산성의환경에서는 nitrogen bisphosphonate 가강력한세포독성을보인다고하였다 [25]. 최근에는 bisphosphonate가 DNA 메틸화 (methylation) 를변화시키고, 이는세포외기질 (extracellular matrix) 의조직화및염증반응에영향을미쳐 BRONJ와같은부작용이발생할수있다는연구가발표되었다 [26]. 2

Ji-Su Oh et al. 최근에 Kwon 등 [12] 은골다공증치료를위해 bisphosphonate 를복용한환자를대상으로 BRONJ 와만성골수염을 비교하였으며, 골스캔결과 hot spot 을보여이는조골세포의 활성과혈액관류의증가를의미한다고하였다. 또한, 골의노 출, 광범위한골파괴, 인접조직의침범을제외하고만성골수 염과유사하여 BRONJ 는 frozen 병소가아니라고하였다. Risk factors BRONJ 발생의위험요소는크게 bisphosphonate 투여관 련요소, 전신적요소, 국소적요소로나눌수있다 (Table 2) [22,27]. Bisphosphonate 의타입이나, 용량, 투여방법, 투여기 간, 노출빈도에따라 BRONJ 의발생이좌우된다 [28]. 이중 bisphosphonate 의타입이가장중요한요소로서 3 세대 nitrogen bisphosphonate 의경우 non-nitrogen bisphosphonate 보다강 력한위험요소로작용한다 [22]. 세균의침착과관련해서특이 한 amino-terminal domain 이있는데 nitrogen bisphosphonate 는이 domain 에상호작용이가능해서 actinomyces 와같은세 균침착이증가되고 BRONJ 에서골괴사를촉진시킬수있다 [6]. Bisphosphonate 의투여경로에따라약효의발현이다르게 나타나며, 6-12 개월정맥투여는 3-5 년의경구투여와약효가 같다 [8,13,29]. Bisphosphonate 의정맥주사시 12 개월, 경구투 여시 36 개월이상을복용할경우 BRONJ 의발생가능성이높 으며 [27], 정맥주사가경구투여보다 BRONJ 의높은위험요소 로작용한다 [22]. 전신적요소는 BRONJ 발생에큰영향을미 치지는않지만, 다발성골수종환자에서발생한 BRONJ 에서는 cytochrome P540-2C gene (CYP2C8) 의유전변이가보고되기 도했다 [30]. 국소적요인은구강위생, 환자의구내상태, 수술 등과같은구강내외상이며, 이중 BRONJ 는국소적염증과매 우깊은연관이있다고보고되고있다 [22,31]. Table 2. Risk Factors Associated with Osteonecrosis Systemic factors Concurrent medication Local risk factors Age Systemic disease (renal failure, anaemia, obesity, diabetes) Smoking Immunosuppressants Chemotherapy agents Bisphosphonate related risk factors Bisphosphonate potency Duration of treatment Dentoalveolar surgery Oral infection (periodontal and dental abscesses) Poor oral hygiene Intraoral trauma Reproduced from the article of Patel et al. Br J Oral Maxillofac Surg 2011;49:251-7 with permission of the copyright holder [27]. Staging and manifestation BRONJ 의병기는병기 0 에서부터병기 3 까지골의노출여 부, 염증여부, 환자의증상, 진행정도에따라미국구강외과학 회 (American Association of Oral and Maxillofacial Surgeons) 에서 2009 년에제시한가이드라인을기준으로하며 (Table 3), 병기에따라치료프로토콜이다르다 [28]. 노출된골의존재 가병기에매우중요한요소로이병기에는누공이존재하는 병기 3 에해당하는환자에서도골의노출이없는경우병기 0 으로진단되는모순이있다 [4]. Bagan 등 [32] 은 2012 년에발 표한논문에서 126 명중 6 명은하악골의병적골절, 구강외누 공, 상악동저의골용해가존재하나괴사된골의노출이없어 현재사용하고있는 BRONJ 의병기 [28] 에포함할수없다는 점을지적하면서, exposed and necrotic bone 을 exposed and necrotic bone or an oral fistula without exposed bone 으로변 경할것을제시하였다. 임상증상은환자의대부분이골의노출을보이며, 노출된골 은보통거칠고단단한표면을갖는다 [33]. 동통은환자에따라 다양한정도로나타나고, 연조직부종, 염증, 농양의형성 [33] 이 나누공등의감염증상을동반하기도하며, 심한경우악골의 병적골절이나신경의손상도가능하다. 특히, 상악에발병한경 우상악동염 [34] 이나상악동혹은비강으로의개통을동반할 수있다 (Table 4)[8,22,35]. 또한, 골괴사와함께구강점막의궤양 이발생할수있는데이는 bisphosphonate 의부작용중하나인 위장관궤양과유사하게직접적인점막의손상이다 [20]. BRONJ 는방사선학적으로다음과같은특징을갖는다 : 소 주골 (trabecular bone) 의두께와무기질함량의변화에서부터 microlacunae 의형성, 피질골침식, 골경화 (osteosclerosis), 부 Table 3. Staging for BRONJ [28] Stage 0 Stage 1 Stage 2 Stage 3 No clinical evidence of necrotic bone, but non-specific clinical findings and symptoms Exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection Exposed and necrotic bone in patients with pain and clinical evidence of infection Exposed and necrotic bone in patients with pain, infection, and one or more of the following: Exposed necrotic bone extending beyond the region of alveolar bone (ie, inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) Pathologic fracture Extraoral fistula Oral antral/oral nasal communication Osteolysis extending to the inferior border of the mandible or sinus floor BRONJ: bisphosphonate osteonecrosis of the jaws. 3

Bisphosphonate-related osteonecrosis of the jaws Table 4. The Signs and Symptoms [8] Typical Atipycal Pain Soft tissue swelling Infection Exposed necrotic bone Recurrent abscesses Fistula Non-healing mucosal ulcers Changes in the health of periodontal tissues Loose teeth Unexplained soft tissue infection Mucosal perforation Table 5. Management Strategies for BRONJ Strategy Conservative treatment Non-surgical treatment Surgical management Local intervention Radical intervention Adjunctive measures Treatment Mouthwash and analgesia Antibiotics and antifungals No surgical flap Surgical flap Marginal resection Segmental resection Hyperbaric oxygen Parathyroid hormone Platelet-rich plasma LASER Ozone Reproduced from the article of McLeod et al. Br J Oral Maxillofac Surg 2011;49:335-42 with permission of the copyright holder [38]. BRONJ: bisphosphonate osteonecrosis of the jaws. Fig. 1. Necrotic bone exposure with pus discharge on anterior mandible. Fig. 2. Complete healing without bone exposure after sequestrectomy. 골 (sequestra) 의형성, 골막의골증식, lamina dura의증가, 하치조신경관의축소 [33,36,37]. 또한, bisphosphonate 를투여받는환자에서는발치시방사선사진에서발치와의형태가오래지속되는특징이있다 [5]. Treatment BRONJ의치료법은보존적치료에서악골절제술등의외과적치료까지매우다양하게소개되고있고 (Table 5)[38], 아직까지정립된치료법이없다. Lerman 등 [18] 은 97명을대상으로한최근의연구에서항생제투여및비수술적부골적출술 (sequestrectomy) 의보존적치료를통해 12개월동안 71%- 80% 의호전을보였음을보고하면서, BRONJ는재발과치유의정도가매우다양하고, 예후를예측하기힘들기때문에보존적인치료를추천하였다. 반대로 debridement와항생제투여로는치료가불가능한증례가있어부골적출술 (Figs. 1, 2) 이나악골절제술과같은외과적수술이 BRONJ의치료에효과적이라고하였다 [39]. Pichardo 와 van Merkesteyn [40] 은약 97.5% 가발치, 보철등치과치료와관련이있다고보고하면서, 이는 BRONJ가치아나치조골에서발생하는것을의미하며따라서골수염의치료처럼외과적수술을추천하였다. 그러나, BRONJ는골수염과달리 debridement와같은외과적수술에대한예후가환자마다차이가크며, 안정된예후를보장할수없다. 또한괴사되지않은골과의경계가매우불분명하고, 괴사된골을완전히제거하기어렵다. 따라서항생제의투여와국소소독제의사용이필요하다 [28,41]. 이에 2013년에 Assaf 등 [42] 은 Visually Enhanced Lesion Scope (VELscope ) 이 BRONJ 수술시에괴사된골의경계를감지하는데유용하게이용될수있다고하였다 [39]. 외과적수술시에는수술의경계를설정하고, 감염의재발을막으며, 안정된창상의폐쇄가중요하다 [8]. 또한, 악성종양으로 bisphosphonate 를투여받고있는환자에서는 BRONJ와골내악성종양의전이양상이유사하기때문에반드시조직학적검사가필요하다 [33]. 병리적골절이나하악하연까지침범한경우하악골의절제가필요할수있는데, 재건용플레이트 4

Ji-Su Oh et al. 를이용하거나혈관화골이식을이용할수있으며, 아직혈관 화골이식이재건용플레이트보다우수하다는증거는없다. 또한절제부위의골치유와이식된골에서의 BRONJ 재발은 아직연구가이루어지지않고있다 [5]. 외과적수술이필요할경우 bisphosphonate 의투여중지기 간에대해대부분은치료전 3-6 개월을추천하였고, 치료후 조직이완전히치유될때까지 bisphosphonate 의투여를중 지하도록하였다 [27,28,37,43]. 이와달리다른연구에서는 bisphosphonate 의일시적으로투여를중단하는것은 BRONJ 의진행에영향을미치지않아의미가없다고하였다 [44]. Bisphosphonate 의투여여부에대해서는효과와부작 용에대한평가가필요하다. BRONJ 와같은심각한부작 용에도불구하고심한증상을동반한암의골전이의경우 bisphosphonate 의투여로인한장점이더크기때문이다. 다양한치료법에대한연구가계속진행되고있다. 외과 적수술후 platelet-rich plasma [45] 나 plasma rich in growth factors [46] 를이용한술식도성공적인결과를보고하고있 다. 고압산소요법 (hyperbaric oxygen therapy) 의경우골의 turnover rate 를증가시킴으로써 BRONJ 를치료하는개념으 로, 치료결과에대한차이가커서아직 BRONJ 의치료에적 용하기에는더많은연구가필요하다 [8,47]. 부갑상선호르몬 (parathyroid hormone) 을이용한 BRONJ 의치료도많은연구 에서진행되어왔는데 [48-50], BRONJ 의치료에긍정적인효 과를보고하였으나아직부족한상태이다. Prevention BRONJ 의발생이치과치료와관련되어있는경우가많고, 치료법이확실치않으며예후또한예측이불가능하기때문에 Table 6. The Prevention of BRONJ Where Invasive Dental Treatment Is Required Preoperatively Perioperatively Postoperatively Mouth rinse with 0.12% or 0.2% chlorhexidene Prophylactic antibiotics: amoxicillin 3 g orally 1 hour preoperatively or clindamycin 600 mg orally 1 h preoperatively, if allergic to penicillin Conservative surgical technique Primary closure of soft tissue where possible Chlorhexidene mouth rinse for 2 weeks, or until mucosal healing Postoperative antibiotics for 5 days: penicillin V 250 mg four times a day doxycycline 100 mg every day, or metronidazole 200 mg three times a day, if allergic to penicillin Reproduced from the article of Patel et al. Br J Oral Maxillofac Surg 2011;49:251-7 with permission of the copyright holder [27]. BRONJ: bisphosphonate osteonecrosis of the jaws. BRONJ의예방은무엇보다중요하다. Bisphosphonate를이용한치료를시작하기전에구강에대한평가가먼저이루어져야하며, 환자에게 BRONJ 와관련된정보를충분히제공해야한다. 또한조기진단과치료가 BRONJ의예후와밀접하게연관되어있기때문에 bisphosphonate를투여받는동안에는주기적인검사와구강위생교육을철저히해야한다 [28,34]. 또한, bisphosphonate 를복용하는환자에서침습적치과치료가필요한경우 BRONJ 발생가능성이높아지기때문에이에대한예방이무엇보다중요하다 (Table 6)[27]. 최근의컴퓨터단층촬영 (computed tomography, CT) 을이용한평가에서해면골 CT의밀도 (radiodensity) 는 BRONJ의유무에따라유의한차이를보이기때문에골이노출되기전에 BRONJ의가능성을조기에예측할수있다고보고하였다 [51]. 2014년에 Dayisoylu 등 [52] 은산성상태에서는 bisphosphonate의 release가증가하는반면중탄산나트륨 (sodium bicarbonate) 를이용한알칼리상태는골에서의 bisphosphonate 의침착을감소시키고 alkaline phosphatase 의작용이증가되었다고보고하면서, BRONJ 발생을예방하기위해발치나구강내침습적치료시에알칼리성 rinses나 pastes의국소적사용을추천하였다. 결론 BRONJ의발병률은다발성골수종이나암과관련된정맥으로투여된경우를제외하고매우낮은발병률이보고되었지만, 최근임상에서골다공증과관련된경구투여한환자의 BRONJ 발생을흔히접할수있다. 현재까지많은연구가진행되었음에도불구하고, BRONJ 의발생에대한명확한기전이나치료법이밝혀지지않았고, 환자에따라매우다양한양상을보이며, 예후를예측하기힘들어치료하기매우까다롭다. 이에현재까지의가이드라인을기준으로최대한보존적인요법을시행하고, 치유가되지않는경우외과적수술을시행하며, BRONJ 의발생을최소화할수있는예방법에대한고려가필요하다. 감사의글 This study was supported by research fund from Chosun University, 2012. References 1. Advisory Task Force on Bisphosphonate-Related Osteno- 5

Bisphosphonate-related osteonecrosis of the jaws necrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonaterelated osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369-376, 2007. 2. Kharazmi M, Hallberg P, Persson U, Warfvinge G: Bisphosphonate-associated osteonecrosis of the auditory canal. Br J Oral Maxillofac Surg 51:e285-e287, 2013. 3. Tsurushima H, Kokuryo S, Sakaguchi O, Tanaka J, Tominaga K: Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats. Int J Oral Maxillofac Surg 42:1481-1487, 2013. 4. Mast G, Otto S, Mücke T, Schreyer C, Bissinger O, Kolk A, Wolff KD, Ehrenfeld M, Stürzenbaum SR, Pautke C: Incidence of maxillary sinusitis and oro-antral fistulae in bisphosphonaterelated osteonecrosis of the jaw. J Craniomaxillofac Surg 40:568-571, 2012. 5. Bittner T, Lorbeer N, Reuther T, Böhm H, Kübler AC, Müller- Richter UD; American Association of Oral and Maxillofacial Surgeons: Hemimandibulectomy after bisphosphonate treatment for complex regional pain syndrome: a case report and review on the prevention and treatment of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 113:41-47, 2012. 6. Kos M, Kuebler JF, Luczak K, Engelke W: Bisphosphonaterelated osteonecrosis of the jaws: a review of 34 cases and evaluation of risk. J Craniomaxillofac Surg 38:255-259, 2010. 7. McLeod NM, Davies BJ, Brennan PA: Management of patients at risk of bisphosphonate osteonecrosis in maxillofacial surgery units in the UK. Surgeon 7:18-23, 2009. 8. Lu SY, Liang CC, Lin LH: Retrospective analysis of 27 cases of bisphosphonate-related osteonecrosis of the jaw treated surgically or nonsurgically. J Dent Sci 2013 [Epub ahead of print]. 9. Ezra A, Golomb G: Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev 42:175-195, 2000. 10. Coleman RE: Risks and benefits of bisphosphonates. Br J Cancer 98:1736-1740, 2008. 11. Hellstein JW, Marek CL: Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682-689, 2005. 12. Kwon TG, Choi SY, Ahn BC, An CH: Comparison of chronic osteomyelitis versus bisphosphonate-related osteonecrosis of the jaws in female patients without malignant bone disease. J Oral Maxillofac Surg Med Pathol 25:214-220, 2013. 13. Russell RG, Croucher PI, Rogers MJ: Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos Int 9:S66-S80, 1999. 14. Shimizu E, Tamasi J, Partridge NC: Alendronate affects osteoblast functions by crosstalk through EphrinB1-EphB. J Dent Res 91:268-274, 2012. 15. Favia G, Pilolli GP, Maiorano E: Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone 45:406-413, 2009. 16. Scavelli C, Di Pietro G, Cirulli T, Coluccia M, Boccarelli A, Giannini T, Mangialardi G, Bertieri R, Coluccia AM, Ribatti D, Dammacco F, Vacca A: Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. Mol Cancer Ther 6:3256-3262, 2007. 17. Marx RE, Sawatari Y, Fortin M, Broumand V: Bisphosphonateinduced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567-1575, 2005. 18. Lerman MA, Xie W, Treister NS, Richardson PG, Weller EA, Woo SB: Conservative management of bisphosphonate-related osteonecrosis of the jaws: staging and treatment outcomes. Oral Oncol 49:977-983, 2013. 19. Ristow O, Gerngrob C, Schwaiger M, Hohlweg-Majert B, Kehl V, Jansen H, Hahnefeld L, Otto S, Pautke C: Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonaterelated osteonecrosis? J Oral Maxillofac Surg 2013 [Epub ahead of print]. 20. McLeod NM, Brennan PA, Ruggiero SL: Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. Surgeon 10:36-42, 2012. 21. Reid IR, Bolland MJ, Grey AB: Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41:318-320, 2007. 22. Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum S, Pautke C: Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg 40:303-309, 2012. 23. Wang J, Stern PH: Dose-dependent differential effects of risedronate on gene expression in osteoblasts. Biochem Pharmacol 81:1036-1042, 2011. 24. Otto S, Hafner S, Mast G, Tischer T, Volkmer E, Schieker M, Stürzenbaum SR, von Tresckow E, Kolk A, Ehrenfeld M, Pautke C: Bisphosphonate-related osteonecrosis of the jaw: is ph the missing part in the pathogenesis puzzle? J Oral Maxillofac Surg 68:1158-1161, 2010. 25. Otto S, Pautke C, Opelz C, Westphal I, Drosse I, Schwager J, Bauss F, Ehrenfeld M, Schieker M: Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofac Surg 68:2837-2845, 2010. 26. Polidoro S, Broccoletti R, Campanella G, Di Gaetano C, Menegatti E, Scoletta M, Lerda E, Matullo G, Vineis P, Berardi D, Scully C, Arduino PG: Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw. Mutat Res 757:104-113, 2013. 27. Patel V, McLeod NM, Rogers SN, Brennan PA: Bisphosphonate osteonecrosis of the jaw--a literature review of UK policies versus international policies on bisphosphonates, risk factors 6

Ji-Su Oh et al. and prevention. Br J Oral Maxillofac Surg 49:251-257, 2011. 28. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B; American Association of Oral and Maxillofacial Surgeons: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. J Oral Maxillofac Surg 67(5 Suppl):2-12, 2009. 29. Ficarra G, Beninati F: Bisphosphonate - related osteonecrosis of the jaws: the point of view of the oral pathologist. Clin Cases Miner Bone Metab 4:53-57, 2007. 30. Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, Santamaria C, Rosiñol L, de la Rubia J, Hernandez MT, Garcia-Navarro I, Lahuerta JJ, González M, San Miguel JF: Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 112:2709-2712, 2008. 31. Lesclous P, Abi Najm S, Carrel JP, Baroukh B, Lombardi T, Willi JP, Rizzoli R, Saffar JL, Samson J: Bisphosphonateassociated osteonecrosis of the jaw: a key role of inflammation? Bone 45:843-852, 2009. 32. Bagan JV, Hens-Aumente E, Leopoldo-Rodado M, Poveda- Roda R, Bagan L. Bisphosphonate-related osteonecrosis of the jaws: study of the staging system in a series of clinical cases. Oral Oncol 48:753-757, 2012. 33. Gander T, Obwegeser JA, Zemann W, Grätz KW, Jacobsen C: Malignancy mimicking bisphosphonate-associated osteonecrosis of the jaw: a case series and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 117:32-36, 2014. 34. Maurer P, Sandulescu T, Kriwalsky MS, Rashad A, Hollstein S, Stricker I, Hölzle F, Kunkel M: Bisphosphonate-related osteonecrosis of the maxilla and sinusitis maxillaris. Int J Oral Maxillofac Surg 40:285-291, 2011. 35. Otto S, Abu-Id MH, Fedele S, Warnke PH, Becker ST, Kolk A, Mücke T, Mast G, Köhnke R, Volkmer E, Haasters F, Lieger O, Iizuka T, Porter S, Campisi G, Colella G, Ploder O, Neff A, Wiltfang J, Ehrenfeld M, Kreusch T, Wolff KD, Stürzenbaum SR, Schieker M, Pautke C: Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: not just a sporadic coincidence--a multi-centre study. J Craniomaxillofac Surg 39:272-277, 2011. 36. Bianchi SD, Scoletta M, Cassione FB, Migliaretti G, Mozzati M: Computerized tomographic findings in bisphosphonateassociated osteonecrosis of the jaw in patients with cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:249-258, 2007. 37. Ogura M, Saitoh T, Miyamoto S, Tamura H, Tonogi M, Yamane G, Tanaka Y: Surgical intervention of osteonecrosis of the jaws associated with bisphosphonate therapy: report of two cases. Asian J Oral Maxillofac Surg 22:148-153, 2010. 38. McLeod NM, Patel V, Kusanale A, Rogers SN, Brennan PA: Bisphosphonate osteonecrosis of the jaw: a literature review of UK policies versus international policies on the management of bisphosphonate osteonecrosis of the jaw. Br J Oral Maxillofac Surg 49:335-342, 2011. 39. Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67(5 Suppl):85-95, 2009. 40. Pichardo SE, van Merkesteyn JP: Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin? Oral Surg Oral Med Oral Pathol Oral Radiol 116:287-292, 2013. 41. Ferlito S, Puzzo S, Palermo F, Verzì P: Treatment of bisphosphonate-related osteonecrosis of the jaws: presentation of a protocol and an observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg 50:425-429, 2012. 42. Assaf AT, Zrnc TA, Riecke B, Wikner J, Zustin J, Friedrich RE, Heiland M, Smeets R, Grobe A. Intraoperative efficiency of fluorescence imaging by visually enhanced lesion scope (VELscope ) in patients with bisphosphonate related osteonecrosis of the jaw (BRONJ). J Craniomaxillofac Surg 2013 [Epub ahead of print]. 43. Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Dempster DW, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Al Mardini M, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael RP, Blanas N, Kendler D, Petak S, St-Marie LG, Brown J, Evans AW, Rios L, Compston JE; Canadian Association of Oral and Maxillofacial Surgeons: Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 35:1391-1397, 2008. 44. Gallego L, Junquera L: Consequence of therapy discontinuation in bisphosphonate-associated osteonecrosis of the jaws. Br J Oral Maxillofac Surg 47:67-68, 2009. 45. Curi MM, Cossolin GS, Koga DH, Araújo SR, Feher O, dos Santos MO, Zardetto C: Treatment of avascular osteonecrosis of the mandible in cancer patients with a history of bisphosphonate therapy by combining bone resection and autologous platelet-rich plasma: report of 3 cases. J Oral Maxillofac Surg 65:349-355, 2007. 46. Mozzati M, Gallesio G, Arata V, Pol R, Scoletta M: Plateletrich therapies in the treatment of intravenous bisphosphonaterelated osteonecrosis of the jaw: a report of 32 cases. Oral Oncol 48:469-474, 2012. 47. Freiberger JJ: Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67(5 Suppl):96-106, 2009. 48. Harper RP, Fung E: Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhpth(1-34)]. J Oral Maxillofac Surg 65:573-580, 2007. 49. Song KE, Min YK, Lee JK, Lee KB, Joo HJ, Kwack KS, Chung YS: A probable case of oral bisphosphonate-associated osteonecrosis of the jaw and recovery with parathyroid hormone treatment. Curr Ther Res 69:356-362, 2008. 50. Dayisoylu EH, Şenel FÇ, Üngör C, Tosun E, Çankaya M, Ersöz S, Taskesen F: The effects of adjunctive parathyroid hormone 7

Bisphosphonate-related osteonecrosis of the jaws injection on bisphosphonate-related osteonecrosis of the jaws: an animal study. Int J Oral Maxillofac Surg 117:329-334, 2014. 51. Hamada H, Matsuo A, Koizumi T, Satomi T, Chikazu D: A simple evaluation method for early detection of bisphosphonaterelated osteonecrosis of the mandible using computed tomography. J Craniomaxillofac Surg 2014 [Epub ahead of print]. 52. Dayisoylu EH, Ungör C, Tosun E, Ersöz S, Kadioglu Duman M, Taskesen F, Senel FÇ. Does an alkaline environment prevent the development of bisphosphonate-related osteonecrosis of the jaw? An experimental study in rats. Oral Surg Oral Med Oral Pathol Oral Radiol 117:329-334, 2014. 8