Osteoporosis Vol. 10 No. 2 August 2012 pp. 76-81 Case Report 유전자재조합인간부갑상선호르몬 (1-34) 으로회복된비스포스포네이트연관악골괴사증례 연세대학교의과대학내과학교실 1, 연세대학교치과대학구강악안면외과학교실 2 이수진 1 허지혜 1 김원진 1 김경민 1 차인호 2 이유미 1 A Case of Intractable Bisphosphonate-Related Osteonecrosis of the Jaw Treated with Teriparatide Sujin Lee 1, Ji Hye Huh 1, Won Jin Kim 1, Kyoung Min Kim 1, In-Ho Cha 2, Yumie Rhee 1 1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 2 Department of Oral and Maxillofacial Surgery, College of Dentistry, Yonsei University, Seoul, Korea Bisphosphonates are the most widely used medications for treating high bone turnover osteoporosis, Paget`s disease of bone, multiple myeloma and metastatic carcinomas, etc. However, a destructive complication of bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur. The treatments of BRONJ are challenging and the currently recommended managements for BRONJ are still controversial. Our case demonstrated that teriparatide can be a treatment of choice for intractable BRONJ, which had not been cured for 2 years even with the proper surgical treatment and withdrawal of bisphosphonates. Key Words: Bisphosphonate, Bisphosphonate-related osteonecrosis of the jaw (BRONJ), Teriparatide 비스포스포네이트는골다공증치료제로가장많이투약되는약물로강력하게골흡수를감소시켜골량이증가된다. 이는파골세포의활성도를억제시킬뿐아니라환자에서골전이로인한고칼슘혈증에도치료제로사용되고있다. 하지만 2003년 Mark 등이 1 비스포스포네이트를사용한환자에서발생한비스포스포네이트관련악골괴사 (Bisphosphonaterelated osteonecrosis of the jaw; BRONJ) 를처음보고한후, 유사증례들이증가하고있다. 이를적절히치료하는방법에대한논의가필요한상태이다. Received: April 30, 2012 Revised: August 20, 2012 Accepted: August 24, 2012 Corresponding Author: Yumie Rhee, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, Korea Tel: +82-2-2228-1973, Fax: +82-2-392-5548 E-mail: YUMIE@yuhs.ac BRONJ는악골에방사선치료를받지않았으며, 비스포스포네이트를과거에복용하였거나, 현재복용하고있는환자에서악골부위에뼈가노출되어있으면서적절한치료에도불구하고 8주이상치료되지않는경우에진단할수있다. 2 드물지만치명적인이합병증에대해수술을통한외과적처치, 부갑상선호르몬을이용한약물요법등여러방법들이제시되어왔으나장기간의예후및치료결과를보장하는처치법은아직정립되지않았다. 이에본저자들은 BRONJ 발생후비스포스포네이트의중단및적절한치료에도불구하고 2년이상호전되지않는환자를유전자재조합인간부갑상선호르몬 (1-34) 으로치료하여호전된경과및이후다시비스포스포네이트재개속에서도문제가없어이를보고하는바이다. 76
Sujin Lee, et al:a Case of Intractable Bisphosphonate-Related Osteonecrosis of the Jaw Treated with Teriparatide 증례 72세여자환자로좌측하악구치부통증을주소로 2008년 4월구강악안면외과에내원하였다. 과거력상 8년전고혈압과고지혈증진단받고항고혈압제와항고지혈증약제를투약중이었고, 7년전에는오른쪽대퇴부골절로내부고정술 (internal fixation) 을받았으며, 3년전흉추 12번및요추 1번압박골절및골다공증을진단받고, 1주일에한번씩 35 mg의리제드로네이트를 3년간경구복용중이었다. 그외특이병력없었으며가족력도특이사항없었다. 내원당시시행한이학적검사상급성병색보였고, 좌측하악에통증및부종이있었으며, 고름이관찰되었다. 이후항생제복용및치주소파술을시행하였으나염증호전되지않고상처가 8주이상지속되었으며, 당시시행했던단층컴퓨터촬영스캔에서좌측하악체부분에주위와경계가불명확한불규칙한경화가관찰되었고 (Fig. 1A), 방사선투과병 변 (radiolucent lesion) (Fig. 1B) 이관찰되었다. 이환자는 3년이상비스포스포네이트를복용한과거력및상기증상으로 BRONJ 진단받고, 2008년 5월 28 일괴사된뼈조직을제거하는부골적출술 (sequestrectomy) 을시행받았다. 부골적출술시시행했던조직검사결과에서골괴사및만성비특이적염증소견 (bone necrosis and chronic nonspecific inflammation) 을보였다. 이후틀니제작하여지내던중 2010년 10 월틀니부분잇몸부종및통증으로고름이생겨발치하였으나, 발치한부위에서출혈이지속되고골생성이되지않아내분비내과에의뢰되었다. 2008년 BRONJ 진단받았을당시 b-crosslaps (CTx) 0.221 ng/ml ( 정상치 1.008) 이었으며, 2010년내분비내과로의뢰되었을당시혈청칼슘 8.7 mg/dl ( 정상치 8.5-10.5), 인산 2.9 mg/dl ( 정상치 2.5-4.5), 혈청총단백 7.1 g/dl ( 정상치 6.0-8.0), 알부민 4.3 g/dl ( 정상치 3.3-5.3), 혈액요소질소 16.0 mg/dl ( 정상치 5.0-25), 크레아티닌 0.82 mg/dl ( 정상 A B Fig. 1. (A) Initial CT scan, transverse view. Low attenuated intrabony lesion and destructive bony change of left mandibular body area. (B) Panoramic radiograph. A osteolytic lesion in the edentulous ridge of left mandibular body on initial examination. Fig. 2. Medication history. 77
Osteoporosis Vol. 10 No. 2 August 2012 pp. 76-81 치 0.5-7.5), alkaline phophatase 48 IU/L, ( 정상치 38-115), AST 21 IU/L ( 정상치 13-34), ALT 17 IU/L ( 정상치 5-46), 총콜레스테롤 211 mg/dl ( 정상치 100-220) 였다. 골대사표지자 b-ctx는 0.333 ng/ml ( 정상치 1.008), Osteocalcin 22.67 ng/ml ( 정상치 15-46), PTH 20.61 pg/ml ( 정상치 15-65), 25-OH- Vitamin D 28.56 ng/ml ( 정상치 9-37.6) 였으며 24시간소변칼슘량은 335.1 mg/hr ( 정상치 70-180) 이었다. 내분비내과에의뢰된후이중에너지방사선흡수법 (DEXA) 으로시행한골밀도결과 L1-L4의 T- score가 -2.7, 경부대퇴골에서의 T-score는 -3.6, 전체대퇴골에서의 T-score는 -2.4로골다공증소견이었다. BRONJ 호전이없었고, 골절에대한위험도가높았기때문에테리파라타이드를하루에 20 ug씩피 하주사로 2010년 12월에투여하기시작하여 6개월동안투약했다 (Fig. 2). 5개월후혈청 b-ctx 및 osteocalcin이각각처음에비해 227%, 249% 증가하였고 (Fig. 3), 파노라마방사선촬영술 (panoramic radiography) (Fig. 4) 에서하악골에골생성이일어난것을확인할수있었으며, 임상적으로도잇몸병변이호전된것을확인하였다. 테리파라타이드중단이후, 증가된골량의유지목적으로졸레드로네이트 5 mg을정맥투여하였으며, 이후에도지속적으로부작용발생없이 (Fig. 4) 외래에서추적관찰중이며, 2012년 3월시행한골밀도측정결과 L1-L4의 T-score는 -2.2, 경부대퇴골 T-score -3.4로 2010년에비해서각각 18%, 5% 씩증가되었으며, 전체대퇴골은 T-score -2.4로변화없었다. Fig. 3. Serum CTX and osteocalcin levels were elevated after teriparatide therapy. A B C Fig. 4. Panoramic radiographs. (A) At the point of starting the teriparatide. (B) 8 months after teriparatide. (C) 6 months after restarting bisphosphonate. 78
Sujin Lee, et al:a Case of Intractable Bisphosphonate-Related Osteonecrosis of the Jaw Treated with Teriparatide 고찰비스포스포네이트는파골세포의활성을낮추어골흡수를줄이며, 이에따라골모세포의활성도가감소되어골의재형성 (bone remodeling) 을억제시키는약제로, 골다공증예방및치료목적으로가장많이쓰이고있는약제다. 최근들어이약제와관련된악골괴사 (BRONJ) 가발생하는경우가보고되고있다. 1,2 가장널리쓰이는알렌드로네이트로인한골괴사발생률은 0.01~0.04% 로보고되었고, 2 본증례의환자가복용하고있었던경구리제드로네이트로인한골괴사도보고된바있다. 3 비스포스포네이트관련악골괴사는고령, 여성, 발치과거력이있는환자에서발생빈도가높으며, 4 상악골보다는하악골에많이발생하며, 특히후방부설측에호발하는것으로알려져있는데이는다른부위에비해점막이얇고혈관분포가좋지못하고, 뼈돌출이현저하여위험에노출되어있을뿐아니라, 비스포스포네이트에의하여나타나는골재형성억제효과도강하기때문이다. BRONJ의치료에대해서는아직도논란의여지가많지만, BRONJ의정도에따라 2 항생제및구강세척과같은보존적치료와외과적처치를할수있다. 보존적, 외과적처치외에도부갑상선호르몬 5-7 혹은고압산소요법을 8 부가적으로시도할수있다. 부갑상선호르몬제로사용되는테리파라타이드는 부갑상선호르몬 N말단의 34 아미노산을포함하고있는합성호르몬으로조골모세포를자극하여파골모세포의활성을간접적으로증가시켜골의재형성속도, 피질골의두께및해면골의연결성을증가시킨다. 9,10 실제로척추골절과거력이있는 1,637명의폐경후여성에게부갑상선호르몬을투여했을때척추및대퇴부등전체골밀도를증가시켰으며, 골절위험도가 65% 감소되고, 8개월동안투여해서척추골밀도가 10% 정도증가하는것을보고한바있다. 11,12 BRONJ 치료시비스포스포네이트제제를중단하는것만으로도치료의효과가나타날수있으나, 13 치과적수술로해결되지않는 BRONJ를테리파라타이드투여로치유한증례가있으며, 국내에서도보고된증례가있다 (Table 1). 6,14 본환자에서도보존적치료, 외과적처치및비스포스포네이트제제를중단하였음에도불구하고 2년이지나도골형성이되지않고, 염증이해결되지않아테리파라타이드를부가적으로 6개월동안 1일 1회 20 mcg을피하지방에투여하였다. BRONJ에대한치료로서 15 테리파라타이드의치료용량및유지기간에대해서는잘알려져있지않다. 16 테리파라타이드는투약중단시증가한골량이감소하게되기때문에투약후골량유지를위한조치가있어야한다. Rhee et al. 17 등이실험한결과에서테리파라타이드를투여하다가중단한경우증가 Table 1. Cases of BRONJ treated with teriparatides in Korea Author and year Patients Sex/Age Bisphosphonate BP Duration (years) Teriparatide duration (months) Dental treatment BRONJ site (Kwon et al. 2011) M/88 Risedronate 5 1 Marginal resection Mandible F/74 Alendronate 8 3 Marginal resection Mandible F/80 Alendronate 3 2 Segmental resection Mandible F/76 Alendronate 3 1 Decortication and curettage Mandible Risedronate Ibandronate F/79 Alendronate 5 2 Surgical debridement, sequestrectomy Mandible M/68 Alendronate 4 3 Spontaneous regression Maxilla (Song et al. 2008) F/74 Alendronate 5 6 Debridement and curretage Mandible 79
Osteoporosis Vol. 10 No. 2 August 2012 pp. 76-81 했던골밀도가감소하게되는데, 이를비스포스포네이트를이어서사용한경우예전치료의골량및골밀도에대한효과를유지한결과를보고한바있으며다른연구에서도실제로테리파라타이드를중단하고 2년반이후에척추골밀도가 2~3% 감소하는것을보고하였다. 이환자는테리파라타이드를투여하기전에비록비스포스포네이트를사용하였지만 FRAX R (Fracture Risk Assessment Tool) 를이용하여계산한고관절골절및대퇴부골다공증성골절에대한 10년발생률이각각 19%, 11% 로골절위험도가높은환자였으며, 골다공증에대한지속적인치료가필요한상태였기때문에, 테리파라타이드중단시발생하는골밀도감소를막기위해졸레드로네이트 5 mg 1회를정맥투여하였다. 18 테리파라타이드투여후 15개월되는시점에서골밀도를재평가하였고, FRAX R 로계산한골절위험도는각각 17%, 9.1% 로감소한것을확인할수있었다. 본증례는비스포스포네이트를사용해야하는심한골다공증환자에서발생한 BRONJ 합병증으로복용하고있던비스포스포네이트를중단하고, 수술적치료에도불구하고치유되지않았던환자에서테리파라타이드를단기간사용하여골재형성을증가시켜골병변이회복된이후비스포스포네이트재투여하였으나합병증이발생하지않고경과관찰중인환자에대한보고이다. 결론악골괴사는드물지만, 골다공증치료제로사용하는비스포스포네이트의복용으로생기는심각한합병증의하나이다. 치과에서수술적치료및약물중단했음에도잘치유되지않았던비스포스포네이트관련악골괴사가유전자재조합인간부갑상선호르몬 (1-34) 투여로치유되었고, 이후비스포네이트를재시작하였으나합병증없는환자를경험하였기에보고하는바이다. 참고문헌 1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61: 1115-7. 2. Ruggiero SL, Mehrotra B. Bisphosphonate-related osteonecrosis of the jaw: diagnosis, prevention, and management. Annu Rev Med 2009;60:85-96. 3. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34. 4. 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 Korean Soc Osteoporos 2010;8:73-81. 5. Harper RP, Fung E. Resolution of bisphosphonateassociated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhpth(1-34)]. J Oral Maxillofac Surg 2007;65:573-80. 6. Kwon YD, Lee DW, Choi BJ, Lee JW, Kim DY. Short-term teriparatide therapy as an adjunctive modality for bisphosphonate-related osteonecrosis of the jaws. Osteoporos Int 2012 Jan 5. [Epub ahead of print] 7. Lee JJ, Cheng SJ, Jeng JH, Chiang CP, Lau HP, Kok SH. Successful treatment of advanced bisphosphonaterelated osteonecrosis of the mandible with adjunctive teriparatide therapy. Head Neck 2011;33:1366-71. 8. Freiberger JJ. Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009;67:96-106. 9. Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 2003;18:1932-41. 10. Grey A. Teriparatide for bone loss in the jaw. N Engl J Med 2010;363:2458-9. 11. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathy- 80
Sujin Lee, et al:a Case of Intractable Bisphosphonate-Related Osteonecrosis of the Jaw Treated with Teriparatide roid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. 12. Black DM, Bouxsein ML, Palermo L, McGowan JA, Newitt DC, Rosen E, et al. Randomized trial of once-weekly parathyroid hormone (1-84) on bone mineral density and remodeling. J Clin Endocrinol Metab 2008;93:2166-72. 13. Choi SW, Kim SR, Lee KB, Nam KW, Seo KB, Nam U, et al. Osteonecrosis of the Jaw in a Patient with Osteoporosis Treated with Oral Bisphosphonates. J Korean Orthop Assoc 2010;45:151-4. 14. Song K-E, Min Y-K, Lee J-K, Lee KB, Joo HJ, Kwack K-S, et al. A probable case of oral bisphosphonateassociated osteonecrosis of the jaw and recovery with parathyroid hormone treatment. Current Therapeutic Research 2008;69:356-62. 15. de Souza Faloni AP, Queiroz TP, Comelli Lia RC, Cerri PS, Margonar R, Rastelli AN, et al. Accurate approach in the treatment of oral bisphosphonaterelated jaw osteonecrosis. J Craniofac Surg 2011; 22:2185-90. 16. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65:415-23. 17. Rhee Y, Won YY, Baek MH, Lim SK. Maintenance of increased bone mass after recombinant human parathyroid hormone (1-84) with sequential zoledronate treatment in ovariectomized rats. J Bone Miner Res 2004;19:931-7. 18. Kurland ES, Heller SL, Diamond B, McMahon DJ, Cosman F, Bilezikian JP. The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human parathyroid hormone(1-34)]. Osteoporos Int 2004; 15:992-7. 81