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1 Osteoporosis Vol. 9 No. 1 April 2011 pp Review Article 비스포스포네이트연관악골괴사 (BRONJ) 의치과적견해 아주대학교의과대학치과학교실 이정근 Dental Considerations of the Bisphosphonate-related Osteonecrosis of the Jaw Jeong Keun Lee Department of Dentistry, Ajou University School of Medicine Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a disease entity which is rare, but is a serious side effect of bisphosphonate therapy. Several professional associations have published position papers on BRONJ; in 2009, the Korean position statement was reported as a collaborative effect between the Korean Endocrine Society, Korean Society of Bone Metabolism, Korean Society of Osteoporosis, and Korean Association of Oral and Maxillofacial Surgeons. Diagnostic criteria and treatment strategies for BRONJ are now being established through a thorough investigation and cooperation amongst numerous specialties. Still obscure, it is suggested that the pathogenesis of BRONJ is due to the inhibition of farnesyl pyrophosphate synthase of the osteoclastic mevalonate pathway, thus disturbing the cytoskeletal motility for the fusion of mononuclear cells into a multinucleated giant cell or the establishment of a ruffled border. Eventually, such changes will be followed by inactivation and apoptosis of osteoclasts, leading to decreased bone resorption. The incidence of BRONJ is known to be as low as 0.01~0.001% of the entire population, but BRONJ is as high as 1 in 300 in the case of dental intervention of patients on bisphosphonate therapy. It is important for clinicians to remember in requesting a dental consultation for a patient on bisphosphonate therapy that oral cavity has a special environment for wound healing. Routine minor trauma caused by foreignbodies, such as hard food, is compensated by an appropriate wound healing mechanism involving rapid bone turnover due to the rich vascular supply of the oral mucosa. Bisphosphonate will disturb this normal wound healing as a consequence of decreased bone turnover. It should also be kept in mind that the disturbed wound healing is further complicated by the presence of normal microflora in the oral cavity and by the unique anatomic condition of the thin oral mucosa covering the the mandible, most mobile skeleton in the head and neck area. The potency of the bisphosphonates (intravenous bisphosphonate), local factors, such as local dental intervention (especially dental extraction), and systemic factors, such as patient age (old age), have statistical significance for all BRONJ risk factors. Although the recognition of BRONJ by clinicians has been inadequate until now, the growing body of evidence is unveiling the detailed aspects of BRONJ. Continued investigation and extensive cooperation of related specialties will elucidate the nature of the disease, thus enhancing the quality of life of patients on bisphosphonate therapy. Key Words: BRONJ, Bisphosphonate, Osteonecrosis, Jaw, Dental consideration Received: Junuary 12, 2010 Revised: Junuary 14, 2010 Accepted: Junuary 22, 2010 Corresponding Author: Jeong Keun Lee, Department of Dentistry, School of Medicine, Ajou University, San 5 Woncheon-dong, Yeongtong-gu, Suwon, Gyeonggi, , Korea Tel: , Fax: , arcady@ajou.ac.kr 18

2 Jeong Keun Lee:Dental Considerations of the BRONJ 파젯씨병 (Paget s disease) 의치료에에티드로네이트 (etidronate) 를처음사용하면서 1960년대부터비스포스포네이트 (bisphosphonate) 는치료제로서의가치가인식되기시작했다. 1 비스포스포네이트를골다공증의치료제로사용하기시작한것은불과 10여년전의일로 1994년미국식품의약국 (Food and Drug Administration; FDA) 의승인을얻어골다공증, 골감소증과당질코르티코이드유발성골다공증등의치료제로사용되었다. 2 이후 2003년 Marx 3 가처음으로장기간의비스포스포네이트치료를받은환자에서발치후발생한악골괴사증례를보고한이후유사증례들의보고가계속되고있어, 이를통칭비스포스포네이트연관악골 ( 턱뼈 ) 괴사 (Bisphosphonaterelated osteonecrosis of the jaw; BRONJ) 로정의하고있다. BRONJ는비스포스포네이트를투여받은환자에서구강내소수술후발생한악골괴사로아직발병원인과치료방법이명확히밝혀지지않았지만 2003년이후점차증가하고있는합병증이다. 그럼에도불구하고일반인은물론비스포스포네이트를처방하는의사나 BRONJ를임상현장에서최초로목격하는치과의사조차도 BRONJ에관한인식이충분하지않은것이사실이다. 4 미국국립골다공증재단 (National Osteoporosis Foundation) 에따르면 2010년에는골다공증환자가미국내에서약 1,200만명에이를것으로예측하고있는바, 5 국내에서의경향또한이와크게다르지않을것으로예측되며, 앞으로임상에서 BRONJ에노출되는임상의들의숫자도점점증가할것이다. 본논문은이와같은추세에서비스포스포네이트와관련깊은임상의들의 BRONJ에대한인식을제고하기위하여기획되었다. BRONJ의역학파젯씨병에전맥주사로처음사용한이후 1 종양관련고칼슘혈증에대한치료 6 를비롯하여골다공증예방및치료목적으로하는비스포스포네이트의투약은근래에매우흔한일이되었지만 2 BRONJ에익숙한임상의들이아직은많지않기때문에 BRONJ의진정한발생빈도를알아내는일은쉬운일이아니다. 이와더불어 BRONJ의발생률을추정하기어렵 게만드는요인은다양하다. 비스포스포네이트와관련없이발생되는골괴사자체의발생빈도가알려져있지않고, 비스포스포네이트의투여형태에따라 BRONJ의발생빈도가달라진다는점등이다. 7-9 그럼에도불구하고미국골대사학회특별조사위원회의보고서 (Task Force Report of American Society for Bone and Mineral Research; ASBMR) 에서전반적인 BRONJ의발생률이 10,000명당한명에서 100,000명당한명꼴로조사되었다고발표한바있다. 10 비록높은발생률은아니지만임상에서미리예견하기어려운합병증이기때문에비스포스포네이트투약결정과정에서이에관해환자에게미리설명하고동의를구해야하며병의진행에관하여임상의스스로가숙지하고있어야한다. BRONJ의임상진단비스포스포네이트투여와관련되어흔히피로, 감기유사증상, 빈혈, 위장관계증상등이나타난다. 11 하지만이러한비특이적인증상만으로는비스포스포네이트사용에문제점을인식하지못하다가, 악골괴사가처음보고된 2003년이후구강악안면외과의사를중심으로한꾸준한문제제기에접하게된다. 이후비스포스포네이트합병증으로악골괴사에관한보고가축적되자미국구강악안면외과학회 (American Association of Oral and Maxillofacial Surgeons; AAOMS) 에서는 2007년 BRONJ에관한공식견해서 (Position Paper) 를공표하여이에대한인지도를높이고자하는노력에착수하게된다. 12 시간이흐를수록쌓이는임상자료들로인하여공식견해서는 2009년도에개정되었으며 13 지금도 BRONJ에대한파악은계속정교해지고있다. 미국과거의유사한시기에비스포스포네이트에의한악골괴사증례를경험한호주에서도 Australian and New Zealand Bone Mineral Society, Osteoporosis Australia, Medical Oncology Group of Australia 및 Australian Dental Society의명의로공식견해서를발행한바있고, 14 우리나라에서도본학회를비롯하여대한내분비학회, 대한골대사학회, 대한구강악안면외과학회에서공동주관이되어난상토론을거친후 19

3 Osteoporosis Vol. 9 No. 1 April 2011 pp Korean Position Statement를공표하기에이른다. 15 진단지침에근거한 BRONJ의진단기준은다음의 3가지를모두만족하여야한다. 1 악골부위에뼈가노출되어있으면서적절한치료에도불구하고치유되지않고 8주이상지속되는경우 2 비스포스포네이트를과거에복용하였거나, 현재복용하고있는경우 3 턱부위에방사선치료를받은과거력이없는경우위의진단기준은현재진행형인작업가설로아직완성된것은아니지만현재로서가장완벽하다고본다. AAOMS에서 2007년도에발표된공식견해서에서는병의진행에따라병기를 1기에서 3기로구분하다가 2009년도에개정된내용에서는다음의비특이적증상들을포함하는 0기가추가되었다. 16 0기 : 뼈는괴사되어있지않지만동통, 치아동요, 점막부종, 발적, 궤양등비특이적증상을호소 1기 : 괴사된뼈가노출되어있지만증상및감염의증거없음 2기 : 괴사된뼈가노출되어있으면서동통및감염의증거있음 3기 : 2기의소견과함께, 다음중한가지이상 동반한경우 1 병적골절동반 2 구강외누공을형성 3 괴사된뼈의노출부위가치조골 ( 잇몸뼈 ) 을넘어침범 4 구강과비강으로누공 (fistula) 또는개통 (communication) 을형성 5 하악골 ( 아래턱뼈 ) 아래로골용해가진행된경우 BRONJ의검사실소견폐경기후골다공증치료효과및투약에대한환자의순응도 (compliance) 확인을위하여사용되는골회전표지자 (bone turnover marker) 중제1형교원질카르복시종단펩티드교차연결 (type I collagen C-telopeptide crosslink; CTX) 은현재골다공증환자의 BRONJ 예측인자로서의활용가능성이제기된상태이다. CTX는제1형교원질아미노종단펩티드교차연결 (type I collagen N-telopeptide crosslink; NTX) 과함께골흡수평가에사용되는제I형교원질종단펩티드 (telopeptide) 중하나이다. I형교원질카르복실기종단의 α-1 사슬은증령 (aging) 과더불어펩티드사슬재배열 (β- Fig. 1. Structure of type 1 collagen revealing CTX. Structure of type 1 collagen molecules linked by pyridinoline or deoxypyridinoline cross-links (pyridinoline [PYD] or deoxypyridinoline [DPD]). The N- and C-telopeptide cross-links of type 1 collagen (NTX and CTX) are released by proteases during osteoclastic bone resorption. 20

4 Jeong Keun Lee:Dental Considerations of the BRONJ isomerization) 을일으키는데, CTX는이때생성되는사슬간연결로, 골흡수가일어날때교원질의카르복실기종단부에서유리되기때문에일찌감치파골세포활동의표지자로서활용되어왔다 (Fig. 1). 17 현재혈청 CTX (sctx) 는 EKAHD-β-GGR 아미노산서열에대한항체를이용한 ELISA를이용하여검출하고있는데 18 골흡수억제효과및골흡수능에 NTX보다민감해서 BRONJ의예측인자로서흔히사용된다. Marx는 CTX 측정치가 100 pg/ml보다낮으면고위험군, 100 pg/ml 에서 150 pg/ml 사이이면중등도의위험군, 그리고 150 pg/ml 이상이면저위험군으로구분했다. 20 하지만이수치는실험적증거에의한기준이아니며증거에의거한기준치를확립하는과정은아직진행되고있는상태이다. 따라서 CTX를해석할때비스포스포네이트를투여받고있는환자가현재 BRONJ로부터안전한지의여부가아니라앞으로 BRONJ로이행될가능성이얼마나높은지에관한위험구역측정 (risk zone determination) 에불과하다는점을명심해야한다. 21 연구결과, 비스포스포네이트를 1개월간휴약하는경우 (bisphosphonate holiday) CTX 측정치가 25 pg/ml 정도증가하는것으로나타났다. 20,21 이러한결과는비스포스포네이트투여중단후적절한치과치료시기를가늠하는데좋은척도가될수있다. Table 1. OClassification of bisphosphonates according to R2 side chains and relative potency of each drug Agent R1 side chain R2 side chain Relative potency Etidronate -OH -CH 3 1 Clodronate -CI -CI 10 Tiludronate -H -S CI 10 Pamidronate -OH -CH 2CH 2NH Neridronate -OH -(CH 2) 5NH Opadronate -OH -(CH 2) 2N(CH 3) Alendronate -OH -(CH 2) 3NH Ibandronate -OH CH 3 -CH 2CH 2N< (CH 2) 4CH 3 1,000 Risedronate -OH 2,000 Zolendronate -OH 10,000 a. 비스포스포네이트의약리작용및비스포스포네이트의합병증으로서의 BRONJ b. 비스포스포네이트는파이로인산염 (pyrophosphate) 과유사한 P-C-P 분자구조를가지고있는안정적인합성유사물로 P-C-P 구조의탄소원자에부착되는두개의고리중하나 (R1) 는인산염과함께부착팔 (hook) 로작용하여골결합을결정하는반면나머지한고리 (R2) 가항골흡수성효과정도를결정한다. R2 고리의종류에따라비스포스포네이트의종류가결정되며각세대별로약리적인활성도는약 10,000배까지차이가난다 (Table 1). 22 비스포스포네이트는위장관내에서잘흡수되지않고혈장반감기도수시간에불과하지만골격에서는장기간침착되어존재하는것으로알려져있다. 23 발병원인에대한가설은몇가지가있다. 학계에 Fig. 2. Comparison of ATP (a) and ATP Analogue (b). Noteh the structural difference between the pyrophosphate group in the ATP and bisphosphonate group in the ATP analogue (dashed areas, respectively). 서받아들이고있는가설은비스포스포네이트가파골세포의기능을억제함으로써합병증이발생한다는견해이다. 비스포스포네이트는두번째고리 (R2) 중의질소존재여부에따라단순비스포스포네이트와질소함유비스포스포네이트로구분된다. 즉질 21

5 Osteoporosis Vol. 9 No. 1 April 2011 pp 소존재여부에따라서로다른작용기전에의하여파골세포억제효과를보인다. 질소를함유하고있지않은단순비스포스포네이트의약리작용기전은다음과같이추정되고있다. 파골세포는파골작용을일으키면서세포내이입 (endocytosis) 을통하여골성분을세포내로흡수하는데비스포스포네이트가침착된골을파골세포가탐식할경우가수분해되지않는 ATP 유사체 (analogue) 가파골세포내에축적되어세포자멸사 (apoptosis) 를일으킨다. 이는 ATP 의전구물질인 AMP (adenosine monophosphate) 에파이로인산염 (pyrophosphate) 대신비스포스포네이트가결합하여생기는결과이다 (Fig. 2). 반면질소함유비스포스포네이트는파골세포의세포형태유지, 세포골격배열, 세포막파동 (membrane ruffling), 소포수송 (vesicular trafficking) 등의기능에중요한 역할을담당하는신호전달단백의전사후변형 (posttranslational modification) 과관련깊은메발론산경로 (mevalonate pathway) 를억제함으로써파골세포의세포사멸을야기하는것으로추정하고있다 (Fig 3). 4,24 두종류의비스포스포네이트제제모두파골세포의억제라는공통작용기전을가지는데이를통하여골교체율이낮아지면감염이나골절에노출된뼈의정상적인골재형성을방해함으로써골괴사의원인이된다고본다. 25 추정되는다른작용기전으로비스포스포네이트의혈관형성억제효과에근거하는무혈관괴사가설 26 과광범위한악골내비스포스포네이트축적에의한연조직독성가설 27 이있지만신빙성은낮은편이다. Fig. 3. Overview of the mevalonate pathway. The product of HMG CoA reductase is mevalonate. Inhibition of posttranslational modification (prenylation) & function of osteoclast GTP-binding proteins is postulated to be targeted to the osteoclast farnesyl pyrophosphate synthase. 22

6 Jeong Keun Lee:Dental Considerations of the BRONJ BRONJ의위험요소가장강력한위험요소는비스포스포네이트의효능이다. 효능이강한약제일수록, 투여기간이길수록 BRONJ의발생확률이높아진다. 비스포스포네이트는파젯씨병, 다발성골수종 (multiple myeloma), 전이성골질환 (metastatic bone diseases), 악성질환 (malignant diseases) 의경우고용량을정맥으로투여하는반면, 골다공증의경우저용량의경구투여가일반적이다. 비스포스포네이트를고농도로정맥주사하는경우악골괴사의발생률이 1.8~12% 로보고된반면경구투여의경우 0.01~0.001% 의발생률을보고하고있다. 10,28 반면, 경구투여를하더라도투여기간이 3년을넘으면발생률이증가하기때문에대체로 5년의투여기간이경과한후에는 1년정도의휴약기간이추천된다. 29 악골괴사발생위험요인중전신인자로는고령, 악성종양, 만성신부전, 당뇨병, 항암요법, 스테로이드제등이있고국소인자로는구강내소수술, 잘맞지않는틀니, 돌출된뼈를덮는점막이얇은부위등의해부학적요인, 구강내위생불량, 음주및흡연등의여러요인이있으나, 기존논문에보고된증거에입각하여분석했을때비스포스포네이트정주, 치과치료, 고령등의요소가가장중요한위험요인으로생각된다. 15,30 비스포스포네이트정주, 치과외상, 고령등의환경요인과아울러유전요인분석에서최초로발견해낸유전적요인은 cytochrome P450-2C의유전자인 CYP2C8의단일유전자다변형 (single nucleotide polymorphisms) 이다. 30 이는다발성골수종의치료목적으로비스포스포네이트를정맥주사한증례들에관한분석이었는데이를시점으로다발성골수종외에 BRONJ와관련된다양한질환 7 을대상으로, 환경요인과함께유전적요인에관한고찰도활발히이루어질것으로기대된다. BRONJ의치과적고려사항 BRONJ의위험요소중국소요인에해당하는대부분의요인이치과와관련깊다. 돌출된뼈등의해부학적인요인이나구강내소수술등구강악안면외 과학적요인, 잘맞지않는틀니등치과보철학적인요인모두치과에서다루는치조골 (alveolar bone) 이라는공통점을갖는다. 비스포스포네이트의기대효과가전신적효과임에비하여유난히치조골만국소적으로이와관련된비정상적증상이생기는원인은무엇일까? 기본적으로골조직은골내외의물리적및생화학적환경에반응하여끊임없이골재형성이이어나고있다. 축골 (axial bone) 이나사지골 (extremity bone) 에비하여치조골은악안면조직의풍부한혈류에힘입어골개조가약 10배가량활발하게이루어진다. 31,32 악안면영역에국한해보더라도치조골을위시하여치주인대 (periodontal ligament), 백악질 (cementum), 치은 (gingiva) 의네가지치아주위조직중가장회전 (turnover) 이빠른것이치조골이다. 33 비스포스포네이트의사용으로악골에서유난히원인설명이어려운괴사현상이나타나는이유가여기에있다. 즉, 정상적으로빠른회전율을보이는악골은기본적으로파골세포의활동도그만큼높은상태로, 동일한양의비스포스포네이트에의하여나타나는골재형성억제효과도악골에서는그만큼강조되어나타나게되기때문이다. 정상적으로미생물의서식이일반화되어있는구강내는섭취된음식물등이물에의해작은상처가빈번하게발생될수있는데, 쉽게치유되어야할작은구강내의상처가비스포스포네이트에의해치유가지연되고여기에구강내미생물의감염이겹쳐지면서 BRONJ가발생하기쉬운상태가된다. 이와더불어하악골의설측등점막의피개가얇은부분에 BRONJ의발생빈도가높은점을고려해보면해부학적인요인도기여요인의하나로작용하는것으로여겨진다. 일반적으로 BRONJ의이환율은 10,000~100,000명당한명으로알려져있지만발치를시행한후급격히상승한다. 경구및정주여부에관계없이비스포스포네이트투여군에서발치를시행한경우 BRONJ 의발생률이 300명당한명의꼴로증가되는것이확인된다. 34 비스포스포네이트를투여받고있는환자를치과에의뢰할때 BRONJ의발생가능성에관한지견을의뢰서에반드시포함시켜치과의사의치료계획수립에도움을주도록한다. 골다공증으로비스포스 23

7 Osteoporosis Vol. 9 No. 1 April 2011 pp 포네이트를경구투여하고있는경우에는비교적 BRONJ의발생률이낮지만종양등의이유로고농도의비스포스포네이트를정주하고있는환자에서발치등구강내소수술이불가피할경우병원급의구강악안면외과로이송하기전의뢰서에비스포스포네이트의투여중단시기 (bisphosphonate holiday) 에관한의견교환이필요하다. 최근질소함유비스포스포네이트를질소를함유하지않는일반비스포스포네이트로전환하여투약한경우 BRONJ를감소시킬수있다는증례보고가있는데이점역시참고대상이될수있겠다. 35 향후의과제최초의발견이후많은임상의의축적된경험이현재의 BRONJ 진단및치료기준을세워온초석이되었다. 그러나아직은진행형가설의수준으로 BRONJ에관하여확고히정해진바는없다. 발병원인부터전술한바와같이여러가지가설중가장그럴듯한가설을현재채택하고있을뿐이며 BRONJ에관한지식및경험의축적에따라더욱정교해진가설은언젠가이론으로정립되리라기대해본다. 정교해지는가설의설립과정에임상의들각각의임상경험이모아질때이런노력들이환자들에게보다직접적인혜택으로구체화될수있을것이다. 그리고질병자체의과학적인파악및이에대한대응체계확립과함께꾸준한대국민홍보를통하여환자들로하여금질환에대한인식을높이는작업이이에못지않게중요할것이다. 참고문헌 1. Russel RG. Bisphosphonates. From bench to bedside. Ann NY Acad Sci 2006;1068: Chung YS, Kim EK, Lee MS, Lee JK, Kwon YD, Park YD, et al. Bisphosphonate-Related Osteonecrosis of the Jaw: Clinical Characteristics of Patients in Korea. J Kor Soc Osteoporos 2010;8: Marx RE. Pamidronate (Aredia) and zolendronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61: Park YD, Kim YR, Kim DY, Chung YS, Lee JK, Kim YG, Kwon YD. Awarenwss of Korean dentists on bisphosphonate-related osteonecrosis of the jaws: Preliminary report. J Kor Assoc Oral Maxillofac Surg 2009;35: National Osteoporosis Foundation. America s bone health. Available from: URL: prevalence/index.htm 6. Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 2007; 1117: Pozzi S, Marcheselli R, Sacchi S, Baldini L, Angrilli F, Pennese E, et al. Bisphosphonateassociated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk Lymphoma 2007;48: Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008;23: Dimopoulos MA, Kastritis E, Anagnostopoulos A, Melakopoulos I, Gika D, Moulopoulos LA, et al. Osteonecrosis of the jaw in multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zolendronic acid. Haematologica 2006;91: Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonateassociated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22: Owens G, Jackson R, Lewiecki EM. An integrated 24

8 Jeong Keun Lee:Dental Considerations of the BRONJ approach: bisphosphonate management for the treatment of osteoporosis. Am J Manag Care 2007; 34(Suppl 11):S American Association of Oral and Maxillofacial Surgeons Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65: American Association of Oral and Maxillofacial Surgeons. Position paper on bisphosphonate-related osteonecrosis of the jaw-2009 update. J Oral Maxillofac Surg 2009;67(Suppl 5): Sambrook P, Olver I, Goss A. Bisphosphonates and osteonecrosis of the jaw: Position statement on behalf of the Australian and New Zealand Bone Mineral Society, Osteoporosis Australia, Medical Oncology Group of Australia and the Australian Dental Society. Aust Fam Physician 2006;35: Bisphosphonate related osteonecrosis of the jaw (BRONJ)-Positiion statement of Korea. Korean Endocrine Society, Korean Society of Bone Metabolism, Korean Society of Osteoporosis, Korean Association of Oral and Maxillofacial Surgeons. Available from: URL: kaoms.org/file/ BRONJ_Korea_Position_Statement.pdf. 16. Ruggiero SL. Diagnosis of BRONJ. J Oral Maxillofac Surg 2009;67(Suppl 1): Baim S, Miller PD. Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res 2009;24: Nordic Bioscience Diagnostics. Serum CrossLaps ELISA [package insert]. Nordic Bioscience Diagnostics, Herlev, Denmark; Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS, Lee SL, et al. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int 2000;66: Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonateinduced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65: Kunchur R, Need A, Hughes T, Goss A. Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonateassociated osteonecrosis of the jaws. J Oral Maxillofac Surg 2009;67: Papapoulos SE. Bisphosphonate actions: physical chemistry revisited. Bone 2006;38: Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18: Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it osteonecrosis? J Oral Maxillofac Surg 2006;64: Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 2007;18: Phal PM, Myall RW, Assael LA, Weissman JL. Imaging findings of bisphosphonate-associated osteonecrosis of the jaws. Am J Neuroradiol 2007;28: Reid IR, Bolland MJ, Grey AB. Is bisphosphonateassociated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 2007;41: Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23: Bilezikian JP. Osteonecrosis of the jaw-do bisphosphonates pose a risk? N Engl J Med 2006;355: Sarasquete ME, González M, San Miguel JF, García-Sanz R. Bisphosphonate-related osteone- 25

9 Osteoporosis Vol. 9 No. 1 April 2011 pp crosis: genetic and acquired risk factors. Oral Diseases 2009;15: Jeffcoat MK, Williams RC, Kaplan ML, Goldhaber P. Nuclear medicine techniques for the detection of active alveolar bone loss. Adv Dent Res 1987;1: Ohmae M, Saito S, Morohashi T, Seki K, Qu H, Kanomi R, et al. A clinical and histological evaluation of titanium mini-implants as anchors for orthodontic intrusion in the beagle dog. Am J Orthod Dentofacial Orthop 2001;119: Carranza Jr. FA. The alveolar bone. In: Glickmann s clinical periodontology. 6th ed. Philadelphia, PA: WB Saunders; p Assael LA. Oral bisphophonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg 2009;67 (Suppl 1): Yamaguchi K, Oizumi T, Funayama H, Kawamura H, Sugawara S, Endo Y. Osteonecrosis of the Jawbones in 2 Osteoporosis Patients Treated With Nitrogen-Containing Bisphosphonates: Osteonecrosis Reduction Replacing NBP With Non-NBP (Etidronate) and Rationale. J Oral Maxillofac Surg 2010; 68:

10 Jeong Keun Lee:Dental Considerations of the BRONJ Peer Reviewers' Commentary 비스포스포네이드연관악골괴사 (BRONJ) 는점차증가하고있지만아직발병원인과치료방법이명확히밝혀지지않고있다. 본종설은 BRONJ 의역학, 임상진단법, 검사실소견, 비스포네이트의약리작용, 위험요소, 치과적고려사항을정리하였으며향후과제의제시로독자들에게많은정보를전달하고있다. BRONJ 의가장잘알려진위험요소는효능이강한약제일수록, 투여기간이길수록발생확률이높다는것이다. 정확한가설은아직까지성립이되어있지않지만, 비스포네이트가파골세포의기능을억제함으로써발생한다는가설이학계에서가장유력하게받아들여지고있다. 치과적치료는 BRONJ 의발생을유발할수있는매우연관이높은국소위험요인으로서비스포네이트를투여받고있는환자를치과에의뢰할때는발생가능성에대한지견을의뢰서에포함하여야한다고저자들은주장하고있다. 본종설에서는 BRONJ 를독자들이이해가쉽도록요약하였으며 BRONJ 에관심있는의사들에게많은도움이될것으로생각된다. ( 정리 : 편집위원회 ) 27

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical