11-01김용식

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1 대한고관절학회지제 21 권제 1 호 Vol. 21, No. 1, March, 2009 원 저 혈액질환환자에서대퇴골두무혈성괴사의위험인자 김용식 윤영필 1 임영욱 김동엽 2 권순용 2 가톨릭대학교의과대학강남성모병원정형외과, 대전선병원정형외과 1, 가톨릭대학교의과대학성모병원정형외과 2 목적 : 혈액질환환자를대상으로대퇴골두무혈성괴사가발생한군과발생하지않은군을비교분석하여대퇴골두무혈성괴사와연관된위험인자를밝혀보고자한다. 대상및방법 : 1994년 1월 1일부터 2007년 5월 31일까지혈액종양내과에서입원치료한혈액질환환자를대상으로대퇴골두무혈성괴사가발생한군 (54명) 과발생하지않은군 (54명) 을대상으로골수이식의종류, 이식편대숙주질환, 전신방사선조사, 스테로이드사용량등을위험요소로분석하였다. 결과 : 복합회귀분석에서위험요소중총스테로이드사용량 1.5 g/bmi 이상인경우유의한위험인자로분석되었다. 골수이식의시행여부와전신방사선조사여부는두군에서통계적으로유의하지않은결과를보였다. 골수이식을시행한경우에복합회귀분석에서이식편대숙주질환의발생유무와동종이식의시행여부를조사해보았을때통계적으로유의하지않은결과를보였다. 결론 : 혈액질환환자에서 1.5g/BMI 이상의스테로이드를사용한경우는대퇴골두무혈성괴사의가능성이높으므로주의깊은추시가필요하다. 색인단어 : 대퇴골두무혈성괴사, 혈액질환, 스테로이드 서 1980 년대이후로혈액질환에대한치료로골수이식및항암치료는효과적인치료수단이다. 골수이식의경우, 그이전에는혈액질환의말기에시도하는치료수단이었으나현재에는젊은혈액질환환자에게서질환의초기에시행되고있으며그생존율또한향상되고있다 22,23). 이에따라혈액질환치료를받은환자들이여러가지치료의부작용으로인하여후기합병증에이환될위험도가증가되었다 1,10,20). 그중에정형외과영역에서가장대표적인것이뼈의무혈성괴사증이며대퇴골두에서가장흔하게발생한다 4,6,16). 무혈성괴사증의병인은아직정확하게밝혀지지않았다 3,11,14). 하지만이과정은대부분은진행성이고 3~5 년이 투고일 : 2008년 9월 27일 1차수정일 : 2008년 10월 27일 2차수정일 : 2008년 11월 6일 3차수정일 : 2008년 11월 13일게재확정일 : 2009년 2월 16일 통신저자 : 권순용서울특별시영등포구여의도동 62 가톨릭대학교의과대학성모병원정형외과 TEL: FAX: sykwon@catholic.ac.kr 론 내에관절의파괴를동반한다. 그러므로이런환자의경우에는대부분수술적치료가필요하게된다 2). 대퇴골두무혈성괴사는비교적늦게발견되어여러연구기관에서전향적또는후향적연구를통해위험인자에대한연구는되어왔으나우리나라에서는실제발표된자료가없다. 이연구의목적은대퇴골두무혈성괴사로진행될가능성이높은고위험군을미리예측하여조기진단에도움을주기위하여본원혈액질환환자를대상으로대퇴골두무혈성괴사의위험요인을후향적으로분석하고자한다. 대상및방법 1994 년 1 월 1 일부터 2007 년 5 월 31 일까지본원혈액종양내과에입원치료한혈액질환환자를대상으로현재까지추시가가능한대퇴골두무혈성괴사가발생한군 (54 명 ) 과발생하지않은혈액질환군을대조군으로위험인자를비교분석하였다. 대조군은대퇴골두무혈성괴사가발생한군과비슷한질병이환기간 ( 이환기간이 6 개월이내의차이 ) 을가지고있고질환구성이비슷한혈액환자에서 54 명을추출하였다. 질환군과대조군중에서골수이식을시행한환자를다시분류하여그위험인자를비교 67

2 김용식 윤영필 임영욱 김동엽 권순용 분석하였다. 대퇴골두무혈성괴사의진단은환자의임상증상및 X-ray 상이상소견이있는경우, x-ray 상이상이없는경우에 MRI 상 T2 영상에서이중선증후가나타나는것으로하였다. 여러문헌에서위험인자로인정되는골수이식여부, 전신방사선조사여부, steroid 사용량을분석하였고골수이식을시행한환자에서는골수이식의종류, 이식편대숙주질환의발생유무를위험요소로단변량분석하였다 7,12,13,15,19,21,25,26). 골수이식은골수이식자가골수이식인지동종골수이식인지로, 이식편대숙주질환의발생유무, 전신방사선조사여부, 양군에서혈액질환이진단된시점에서대퇴골두무혈성괴사가발생한시점까지의 steroid 의누적용량의계산하였으며, 대퇴골두무혈성괴사가발생하지않은군에서는대퇴골두무혈성괴사가발생한군의평균발생기간을적용하였고, hydrocortisone 으로표준정량화하였다. 골수전처치로사용한항암약제및이식편대숙주질환을예방하기위한전처치는질환에따라차이가나고재생불량성빈혈의경우치료목적으로사용하므로이는 위험요인분석에서제외시켰다. 모든자료는입원및외래의무기록을참조하였고, SPSS 11.5 version 프로그램을이용하여단순로지스틱회귀분석 (simple logistic regression) 과복합로지스틱회귀분석 (multivariant logistic regression) 을시행하였다. p-value 가 0.05 미만인경우를통계적으로유의한것으로판단하였다. 결 대퇴골두무혈성괴사가발생한경우는총 54 명이었으며평균연령은 33.2 세 ( 범위, 19~60 세 ) 였다. 남자는 32 명여자는 22 명이었고혈액질환진단후합병증으로인하여대퇴골두무혈성괴사로진단된기간은평균 36.8 개월 ( 범위, 5~92 개월 ) 이었으며, 골수이식후대퇴골두무혈성괴사로진단된기간은평균 26.5 개월 ( 범위, 10~78 개월 ) 이었다. 총 54 명 104 례의대퇴골두무혈성괴사가발생하였고 ARCO stage I 은 1 예, stage II 는 25 예, stage III 이상은 과 Table 1. Patients with ONFH & Without ONFH Characteristics with ONFH (n=54) without ONFH (n=54) Age 33.22± ±15.3 Gender (Male : Female) 32 : : 22 Dx.-ONFH (Months) 36.8 (±18.6) - BMT-ONFH (Months) 26.5 (n=32)0 - BMT Autogenic Allogenic Total TBI GVHD Underlying Disease AML ALL CML AA MDS ITP Total Steroid 19.4 g 9.6 g 890 mg/bmi 430 mg/bmi 0~0.50 g/bmi ~1.00 g/bmi ~1.50 g/bmi g/bmi ONFH: Osteonecrosis of Femoral Head; BMT: Bone Marrow Transplantation; TBI: Total Body Irradiation; GVHD: Graft Versus host Disease; AML: Acute Myeloid Leukemia; ALL: Acute Lymphoblastic Leukemia; CML: Chronic Myeloid Leukemia; AA: Aplastic Anemia; MDS: Myelodysplastic Syndrome; ITP: Idiopathic Thrombocytopenic Purpura; BMI: Body Mass Index 68

3 혈액질환환자에서대퇴골두무혈성괴사의위험인자 78 예로나타났고인공고관절치환술은 40 예에서시행되었다. 양쪽모두를침범한경우는 54 명중 36 명으로대부분양쪽고관절을침범하였다. 대퇴골두무혈성괴사가발생한군의질환별구성은 AML 11 명, ALL 8 명, CML 9 명, 재생불량성빈혈 17 명, 골수이형성증후군 (MDS) 3 명, 특발성혈소판감소증 (ITP) 6 명이었다. 대퇴골두무혈성괴사가발생한군에서는 32 예 ( 자가골수이식 3 예, 동종골수이식 29 예 ) 에서, 대조군에서는 22 예 ( 자가골수이식 7 예, 동종골수이식 15 예 ) 에서골수이식이이루어졌고그중전신방사선조사는대퇴골두무혈성괴사가발생한군에서는 22 예, 대조군에서는 15 예에서시행되었다. 이식편대숙주질환은대퇴골두무혈성괴사가발생한군에서 20 예가발생했고대조군 에서는 7 예가발생하였다. 혈액질환진단시점에서대퇴골두무혈성괴사가발생한시점까지의 steroid 누적용량은 19.4 g (890 mg/bmi) 이었고, 대조군에서진단후 34 개월동안사용한용량은 9.6 g (430 mg/bmi) 이었다 (Table 1, Fig. 1). 이상의결과를위험인자각각에대해단순및복합회귀분석을하였으며스테로이드 1.5g/BMI 이상사용한환자에서통계학적유의한차이를보였다 (Table 2, 3). 골수이식을시행한환자중에서도각각의위험인자에대하여복합회귀분석을시행하였으며동종골수이식을시행한경우와이식편대숙주질환이있는경우에모두에서통계학적으로유의한차이를보이지않았다 (Table 4). 스테로이드 1.5 g/bmi 이상사용한집단이통계학적으 Fig. 1. Total steroid dosage & frequency in steroid dosage interval in patient with ONFH & without ONFH. Table 2. Risk Factors as Assessed by Simple Logistic Regression Variable Baseline Compared Odds Ratio 95%CI P value TBI X O ~ BMT X O ~ Total <0.5 g/bmi 0.5~1.0 g/bmi ~ Steroid 1.0~1.5 g/bmi ~ >1.5 g/bmi ~ Table 3. Risk Factors as Assessed by Multiple Logistic Regression Variable Baseline Compared Odds ratio 95%CI P value BMT X O ~ Total <0.5 g/bmi 0.5~1.0 g/bmi ~ Steroid 1.0~1.5 g/bmi ~ >1.5 g/bmi ~ * 69

4 김용식 윤영필 임영욱 김동엽 권순용 로유의한위험요소였으며 9.17 배의위험도 (95% 신뢰구간 1.04~80.71) 를나타내었다. 골수이식을시행한환자중에서는동종골수이식의여부와이식편대숙주질환유무는복합회귀분석에서통계학적으로유의하지않았으며이는두군의작은개체수에기인하는것으로생각된다. 고 혈액질환은환자의사망율이매우높았기때문에약물치료또는골수이식후발생한대퇴골두무혈성괴사는근래까지크게관심을갖지않았던문제로최근골수이식과항암약물의발달로생존율이급격히높아지면서후기합병증인대퇴골두무혈성괴사는사회복귀에장해요소로부각되고있다 1). Atkinson 등 2) 은친족내동종골수이식후 2 년이상생존한 50 명의환자중 5 명 (10%) 이대퇴골두무혈성괴사가발생했으며이들모두이식편대숙주질환에이환되어있었다고보고하였다. 이들은이식편대 찰 숙주질환을치료하기위해사용된 steroid 가원인인자로보고하였다. Enright 등 5) 은 4.4% (642 명의환자중 28 명 ) 의무혈성괴사발생율을보고하였는데, 고령과 steroid 치료가필요한이식편대숙주질환을위험요인으로제시하였다. 또한 Socie 등 18) 은혈액질환환자중 3.7% (27/727 명 ) 의대퇴골두무혈성괴사발생과연관된원인으로남성, 16 세이상의연령, steroid 치료가필요한급성이식편대숙주질환을보고하였다. 이외에보고된무혈성괴사와위험요소들을요약하였다 (Table 5). 본연구에서는스테로이드 1.5 g/bmi 이상사용한군에서만통계적으로유의하게나타났다. 골수이식을시행한환자중에서는동종골수이식의여부와이식편대숙주질환유무는단순회귀분석에서는통계학적으로유의한결과를보였지만다변량분석으로복합로지스틱회귀분석을시행하였으나통계적으로유의하게나타난위험요인은없었다. 이는변수에대한개체수가작아서나타나는것으로생각되고좀더많은환자를대상으로시행한다면 Table 4. Risk Factors as Assessed by Multiple Logistic Regression after BMT Variable Baseline Compared Odds Ratio 95%CI P value BMT Autogenic Allogenic ~ GVHD X O ~ Table 5. Risk Factors Reported by Major Studies on AVN Authors No. of Follow-up AVN Prevalence Assessment of Associations SCT Type Patients Period (yrs) (%) Corticosteroid Role Found with AVN Atkinson et al Allotransplant 5/50 (10). nr agvhd, cgvhd (1987) Enright et al Allotransplant 28/624 (4.4) Multivariate Age, Disease Type, Allo-SCT, (1990) Analysis TBI, cgvhd, Alloreactivity Wagener et al Autotransplant 0/260 t test Age, Male Gender, agvhd (1991) Allotransplant 8/33 (24). Socié et al Autotransplant 0/100 Multivariate Age, Initial Diagnosis, TBI, (1994) Allotransplant 27/727 (3.7) Analysis agvhd, cgvhd Socié et al Allotransplant 0077/4388 (17.5) Multivariate Allo-SCT (93%) vs Auto-SCT (7%), (1994) analysis TBI, agvhd, cgvhd Fink et al Allotransplant/ 87/1939 (5). Logistic Regression Age, GVHD (1998) Autotransplant Wiesmann et al nr r Allotransplant 17/272 (6.3) nr Allo-SCT, Male Gender, (1998) Lower BMD at Femoral Neck Ebeling et al Allotransplant 4/52 (7.7) t test (1998) Stern et al.(2001) Autotransplant 0/310 nr.. Allotransplant 10/104 (9.6) Corticosteroid Treatment Torii et al.(2001) 0100 Nr Allotransplant 19/100 (19) t test Younger age, Cumulative Steroid dose, Pulse i.v. MPD Therapy, cgvhd ANV: Avascular Necrosis; SCT: Stem Cell Transplant; agvhd,cgvhd:;actue/chronic Graft vs Host Disease; nr:data not Reported; TBI: Total Body Irradiation; BMD: Bone Mineral Density ;MPD; Methyprednisolone 70

5 혈액질환환자에서대퇴골두무혈성괴사의위험인자 보정될수있을것으로사료된다. 무혈성괴사와관련된위험요인들의정확한병태는아직밝혀져있지않다. 그러나, 지방대사의조정장애, 약물에기인한혈관벽의손상과혈관염이가능성있는병인으로알려져있다. 지방대사는 steroid 와성선저하 (gonadal insufficiency) 에변화되고이러한변화는골수이식후장기간지속된다 24). 골수이식후혈관염은자가면역질환적인성격을가지고있고만성이식편대숙주질환과연관되어있다 8). 어떠한체내기관도증가된자가항체없이이후기합병증에이환될수있다. 실제로무혈성괴사는전신성홍반성낭창과같은자가면역질환환자뿐만아니라특히골수이식후면역조절장애상태에있는환자에서자주발생한다 9,17). 그러나오랫동안고용량의 steroid 를사용해온퇴행성신경질환, 만성폐질환환자와같은비염증성질환에서는잘발생하지않는다 25). 만성이식편대숙주질환환자는고용량의 steroid 를장기간사용하므로본연구에서는 steroid 의효과와이식편대숙주질환의효과는구별할수가없었다. 결 복합회귀분석에서 1.5 g/bmi 이상의 steroid 사용량의경우통계적으로매우유의한위험요인으로분석되었다. 이러한위험요인에대한지식은장기간생존자에게있어서심각한장애가되는, 비교적자주발생하는후기합병증인대퇴골두무혈성괴사의조기진단을가능하게할수있을것으로생각되고조기치료및추시함으로써본인의고관절을보존할수있을것으로생각된다. 론 REFERENCES 01) Andrykowski MA, Altmaier EM, Barnett RL, et al.: The quality of life in adult survivors of allogeneic bone marrow transplantation: Correlates and comparision with matched renal transplant recipients. Transplantation, 50: , ) Atkinson K, Cohen M, Biggs J: Avascular necrosis of the femoral head secondary to corticosteroid therapy for graft-versus-host disease after marrow transplantation: effective therapy with hip arthroplasty. Bone Marrow Transplant, 2: , ) Cruess, RL: Osteonecrosis of bone: current concepts as to etiology and pathogenesis. Clinics in Orthopedics, 208: 30-39, ) Ebeling PR, Thomas DM, Erbans B, Hopper JL, Szer J, Grigg A: Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation. J Bone Miner Res, 14: , ) Enright H, Haake R, Weisdorf D: Avascular necrosis of bone: a common serious complication of allogenic bone marrow transplantation. Am J Med, 89: , ) Fink JC, Leisenring WM, Sullivan KM, Sherrard DJ, Weiss NS: Avascular necrosis of following bone marrow transplantation: a case-control study. Bone, 22: 67-71, ) Felson DT, Anderson JJ: Across-study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone. Lancet, I: , ) Glucksberg H, Storb R, Fefer A, et al.: Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA matched sibling donors. Transplatation, 18: , ) Grotz W, Breitenfeldt K, Cybulla M: Immunosuppression and skeletal disorders. Transplant Proc, 33: , ) Kolb HJ, Bender-Gotze C: Late complications after allogenic bone marrow transplantation for leukemia. Bone Marrow Transplant, 6: 61-72, ) Mankin HJ: Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med, 326: , ) Marsh JC, Zomas A, Hows JM, Chapple M, Gordon- Smith EC: Avascular necrosis after treatment of aplastic anemia with antilymphocyte globulin and high-dose methylprednisolone. Br J Heamatol, 84: , ) Marymont JV, Kaufman EE: Osteonecrosis of bone associated with combination chemotherapy without corticosteroids. Clin Orthop Relat Res, 204: , ) Mont MA, Hungerford DS: Non traumatic avascular necrosis of the femoral head. J Bone Joint Surg, 77-A: , ) Mori A, Hashino S, Kobayashi S, et al.: Avascular necrosis in the femoral head secondary to bone marrow infarction in patient with graft-versus-host disease after unrelated bone marrow transplantation. Ann Hematol, 80: , ) Russel JA, Blahey WB, Stuart TA, Edwards G, Card RT: Avascular necrosis of bone in bone marrow transplant patients. Med Pediatr Oncol, 17: , ) Sato K, Satomi S, Oguma S, et al.: Relationship between aseptic necrosis of femoral head bone and immunosuppression therapy, especially CsA administration. Nippon Geka Gakkai Zasshi, 94: , ) Socie G, Cahn JY, Carmelo J, et al.: Avascular necrosis of bone after allogenic bone marrow transplantation: analysis of risk factor for 4388 patients by the Societe Francaise de Greffe de Moelle(SFGM). Br J Haematol, 97: , ) Socie G, Selimi F, Sedel L, et al.: Avascular necrosis of bone after allogenic bone marrow transplantation: clinical findings, incidence and risk factors. Br J Haematol, 86: , ) Stern JM, Sullivan KM, Ott SM, et al.: Bone density loss after allogenic hematopoietic stem cell transplantation: a prospective study. Biol Blood Marrow 71

6 김용식 윤영필 임영욱 김동엽 권순용 Transplant, 7: , ) Torii Y, Hasegawa Y, Kubo T, et al.: Osteonecrosis of the femoral head after allogenic bone marrow transplantation. Clin Orthop Relat Res, 382: , ) Thomas ED: Frontiers on bone marrow transplantation.: fetal hematopoiesis. Blood Cell, 17: , ) Thomas ED, Buckner CD, Banaji M, et al.: One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood, 49: , ) Vande Berg BC, Malghem J, Lecouvet FE, et al.: Fat conversion of femoral marrow in glucocorticoid-treated patients: a cross-sectional and longitudinal study with magnetic resonance imaging. Arthritis Rheum, 42: , ) Vreden SG, Hermus AR, van Liessum PA, Pieters GF, Smals AG and Kloppenborg PW: Aseptic bone necrosis in patients on glucocosteroid replacement therapy. Neth J Med, 39: , ) Wiesmann A, Pereira P, Bohm P, Faul C, Kanz L and Einsele H: Avascular necrosis of bone following allogenic stem cell transplantation: MR screening and therapeutic options. Bone Marrow Transplant, 22: , ABSTRACT Risk Factors for Osteonecrosis of the Femoral Head in Patients with Heamatologic diseases Yong-Sik Kim, M.D., Young-Phil Yune, M.D. 1, Young-Wook Lim, M.D., Dong-Yeob Kim, M.D. 2, Soon-Yong Kwon, M.D. 2 Department of Orthopedic Surgery, Kangnam St. Mary s Hospital, The Catholic University, Seoul, Korea Department of Orthopedic Surgery, Sun General Hospital, Daejeon, Korea 1 Department of Orthopedic Surgery, St. Mary s Hospital, The Catholic University, Seoul, Korea 2 Purpose: We aimed to clarify the risk factors associated with the development of ONFH by comparing patients with hematologic diseases and osteonecrosis of the femur head (ONFH) to those patients without ONFH and who have hematologic diseases Materials and Methods: The study population was limited to the patients admitted to our Hematology-Oncology department from 1 January 1994 to 31 May The patients were divided into 2 groups (those with ONFH, 54 patients and those without ONFH, 54 patients) and the risk factors for ONFH were evaluated by a comparative analysis. We analyzed the effect of a history of bone marrow transplantation (BMT), graft-versus-host disease (GVHD), total body radiation (TBI) and the amount of steroid used as the risk factors for ONFH. Results: On the multiple logistic regression analysis, a total steroid use of >1.5 g/bmi was statistically identified as a significant risk factor for ONFH. The history of BMT and TBI were not statistically correlated with the development of ONFH. Among the patients with BMT, allogenic BMT and a history of GVHD were not statistically correlated with the development of ONFH on the multiple logistic regression analysis. Conclusion: Patients with hematologic diseases and who have used steroid >1.5g/BMI should carefully observed because they are more likely to develop ONFH. Key Words: Osteonecrosis of femoral head (ONFH), Hematologic disease, Steroid 72

한국성인에서초기황반변성질환과 연관된위험요인연구

한국성인에서초기황반변성질환과 연관된위험요인연구 한국성인에서초기황반변성질환과 연관된위험요인연구 - - i - - i - - ii - - iii - - iv - χ - v - - vi - - 1 - - 2 - - 3 - - 4 - 그림 1. 연구대상자선정도표 - 5 - - 6 - - 7 - - 8 - 그림 2. 연구의틀 χ - 9 - - 10 - - 11 -