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1 대한내분비학회지 : 제 24권제 3 호 2009 증 례 /jkes Phenytoin 복용과관련된다발성골절과저칼슘혈증을동반한골연화증 1 예 아주대학교의과대학내분비대사내과학교실, 영상의학과교실 1, 신경과학교실 2, 정형외과학교실 3 김은경 이민석 정윤석 곽규성 1 홍지만 2 원예연 3 A Case of Osteomalacia with Multiple Fractures and Hypocalcemia Associated with Phenytoin Therapy Eun-Kyung Kim, Min-Suk Lee, Yoon-Sok Chung, Kyu-Sung Kwack 1, Ji-Man Hong 2, Ye-Yeon Won 3 Department of Endocrinology and Metabolism, Department of Radiology 1, Department of Neurology 2, Department of Orthopedic Surgery 3, Ajou University School of Medicine ABSTRACT Many studies have shown that patients taking antiepileptic drugs are at an increased risk for metabolic bone disease and low bone mineral density. Traditionally, this has been attributed to alterations in vitamin D metabolism by antiepileptic drugs which induce hepatic microsomal cytochrome P450 enzyme. However, there appear to be multiple mechanisms for antiepileptic drug-induced bone loss including lack of physical activity, reduced sunlight exposure, increased propensity for falling, and fractures associated with seizures or loss of consciousness. We experienced a case of antiepileptic drug-induced osteomalacia in a 63-year-old woman who had been on phenytoin for 8 years and was admitted with hypocalcemic seizures and multiple pathological fractures. This patient also had other risk factors for osteomalacia including reduced sunlight exposure, prolonged immobilization, and decreased dietary vitamin D intake. We discontinued phenytoin, and started calcium and vitamin D replacement. The patient s serum calcium and vitamin D level were normalized after treatment. Metabolic bone disease including osteomalacia should be considered in patients who are taking antiepileptic drugs especially those who are exposed to other risk factors. (J Korean Endocr Soc 24:212~216, 2009) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: antiepileptic drugs, osteomalacia, phenytoin 서론 1) 골연화증은새로형성된유골 (osteoid) 의무기질화장애로인해발생하는대사성골질환으로비타민 D나인산염의결핍또는대사장애, 원발성무기질화장애등이그원인이다 [1]. 이중비타민 D의작용감소로인한골연화증은일광노출의부족이나비타민 D의식이섭취의부족, 흡수장애, 대사증가또는간질환등으로인해발생한다. 특히일부접수일자 : 2009년 3월 30일통과일자 : 2009년 6월 11일책임저자 : 정윤석, 아주대학교의과대학내분비대사내과학교실 항경련제가간의 microsomal enzyme의유도체로작용하여비타민 D의이화작용을촉진시킴으로써골연화증등의골대사질환의발생및골절의위험도를증가시키는것으로알려져있다 [2,3]. Valmadrid 등은장기간항경련제를복용중인환자의약 50% 가경미한골감소부터심한골질환에이환되어있다고보고한바있다 [4]. 항경련제로인한골연화증의발생빈도는대상환자의종류에따라 7~50% 로매우다양하게보고되고있다 [5]. 특히이러한환자들중에는신체활동이제한된경우가많고일광노출이부족하여골다공증및골절등의발생이더빈번한것으로알려져있다. 그러나아직까지이러한항경련제의골대사와관련된부작용에대한인식은많이부족한상태이다. 저자들은 phenytoin을장기간

2 - 김은경외 5 인 : Phenytoin 복용과관련된다발성골절과저칼슘혈증을동반한골연화증 1 예 - 복용한환자에서다발성골절과저칼슘혈증을동반한골연화증 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 박 O O, 63세여자주소 : 경련및의식저하현병력 : 환자는 8년전좌측중대뇌동맥영역의경색진단을받고신경과에서입원치료받은후거동이불편하여거의집에서만지내며 8년전부터현재까지항경련제 (phenytoin, Phenytoin R 300 mg/day) 를복용중이었다. 환자는내원 18개월전특별한외상없이좌측원위경비골의골절이발생하였으며, 내원 1달전에는누워있는상태에서자세변동하다가우측원위대퇴골체의골절이발생하였으나전신적상태가좋지않아수술적치료를하지못하고보존적치료만시행받았다. 내원 15일전설사를주소로내원하여 7일동안입원치료후퇴원하였고이후에도설사는간헐적으로있었다고하며퇴원 7일째경련이후의식저하를주소로응급실을내원하여신경과진료를받던중심한저칼슘혈증이있어내분비내과로의뢰되었다. 과거력 : 35년전고혈압, 15년전당뇨병을진단받고약물치료중이었으며내원 5년전급성신우신염으로인한패혈증, 내원 1년전폐렴으로입원치료받은병력이있었다. 가족력 : 특이소견없었다. 개인력 : 음주및흡연의개인력은없었다. 신체진찰소견 : 내원당시환자의생체징후는혈압 96/61 mmhg, 맥박 92회 / 분, 호흡 24회 / 분, 체온 36.3 C이었고신장 153 cm, 체중 40.7 kg로마른체형이었다. 환자는만성병색의급성악화소견을보였고전반적으로기운이없었다. 의식은기면상태이었으나경련발작은멈춘상황이었고동공의크기는양안이같았으며동공반사도정상이었다. 경부진찰시갑상선은촉지되지않았다. 심장및폐청진에서특이소견은없었으며복부진찰시간, 비장종대나종물은촉지되지않았고복수도관찰되지않았다. 상하지의운동능력은정확히평가할수없었으며감각능력및심건부반사는정상이었다. 검사실소견 : 내원당시시행한말초혈액검사에서백혈구 11,900/mm 3, 혈색소 8.7 g/dl, 혈소판 471,000/mm 3 이었고, 혈청생화학검사는혈액요소질소 20.3 mg/dl, 크레아티닌 1.2 mg/dl, 총단백 5.9 g/dl, 알부민 2.8 g/dl, 알칼리인산분해효소 607 IU/L ( 참고치 20~120), 알라닌아미노전이효소 9 IU/L, 아스파르트산아미노전이효소 18 IU/L였다. 칼슘 3.6 mg/dl ( 참고치 : 8.4~10.2), 이온화칼슘 2.1 mg/dl ( 참고치 : 4.2~5.4), 인 2.5 mg/dl ( 참고치 : 2.7~4.5) 로모두감소되어있었으며, 25(OH)D 4.8 ng/ml ( 참고치 : 9~38) 로감소되어있었고, intact PTH 258 pg/ml ( 참고치 : 10~60) 로 증가되어있었다. 혈청 osteocalcin ng/ml ( 참고치 : 12.9~55.9), 소변검사에서 N-telopetide는 96 nmbce /mm Cr ( 참고치 : 17~103) 였다. 영상검사 : 흉부 X선검사에서전반적으로심한골감소와다발성늑골골절및이로인한흉곽의변형소견이관찰되었다. 척추 X선검사역시심한골감소소견이관찰되었고흉추 (T6,12) 및요추 (L1) 의압박골절을보였다. 대퇴부 X 선검사에서는심한골피질의두께감소 (thinning of cortex) 와우측원위부대퇴골체골절이관찰되었다 (Fig. 1). 좌측에서도대퇴골경부골절과원위부경비골골절이확인되었다. 수부및족부 X선검사에서도심한골감소소견이보였다. 골스캔에서는여러골절부위의섭취증가를보였으며 (Fig. 2), 골밀도검사 (DXA, Prodigy, GE Lunar) 에서요추부의 T 값 -6.3, Z값 -4.2로심한골감소가관찰되었다 (Fig. 3). 뇌자기공명영상에서좌측중대뇌동맥영역및우측대뇌기저핵부위의오래된경색이관찰되었으나이전검사와변화가없었으며급성병변은관찰되지않았다. 치료및경과 : 환자는내원당시경련은멈춘상태였으나경련발작재발을방지하기위해응급실내원직후 phenytoin 을정주하였으며칼슘수치가감소되어있음을확인하고글루콘산칼슘을지속적으로정맥주사하였다. 내원후 12시간째부터의식상태가호전되었으며경련발작의원인감별을위해신경과에서신경학적검사, 뇌영상검사와뇌파검사를시행하였으나특별한이상소견이보이지않아저칼슘혈증에의한경련발작및의식저하로추정하였고이에대한평가및치료를위하여내분비내과로전과되었다. 환자의병력및내원초기시행한검사소견으로미루어항경련제와관련된골연화증으로진단하고칼슘및비타민 Fig. 1. Plain radiography revealed thinning of cortices and fracture of right distal femoral shaft with cast application state

$대한내분비학회지 : 제 24 권제 3 호 2009 Fig. 2. Increased uptakes in right distal femur, left proximal femur and distal tibia (arrows) were observed in whole body bone scan suggesting recent or unhealed fractures.$ Bone mineral densitometry revealed severely decreased bone mineral density of lumbar (L1~4) vertebrae. D를투여하도록하였다.

Bone mineral densitometry revealed severely decreased bone mineral density of lumbar (L1~4) vertebrae. D를투여하도록하였다.

3 대한내분비학회지 : 제 24 권제 3 호 2009 Fig. 2. Increased uptakes in right distal femur, left proximal femur and distal tibia (arrows) were observed in whole body bone scan suggesting recent or unhealed fractures. Multiple focal increased uptake in both ribs showing multiple rib fractures and metabolic bone diseases. 고 찰 Fig. 3. Bone mineral densitometry revealed severely decreased bone mineral density of lumbar (L1~4) vertebrae. D를투여하도록하였다. 또한신경과와협의하여기존에복용하던 phenytoin 대신 levetricetam (Keppra R 2 g/day) 과 oxcarbazepine (Tripleptal R 600 mg daily) 으로변경하여복용하도록하였고입원이후경련은발생하지않았다. 내원 3일째혈청이온화칼슘수치가 4.3 mg/dl로정상수준까지회복되었다. 이후칼슘 1.8 g과 cholecalciferol 1,200 IU (Cal-D-Vita R ) 및 calcifediol 40 μg (Caldiol R ) 을경구투여하였으며치료 3개월후혈청이온화칼슘수치가 4.5 mg/dl로정상화되었고비타민 D 역시 35.4 ng/ml로정상수준까지회복되었다. 항경련제와관련된골대사질환은이미 1967년 Schimid[2] 에의해처음보고되었으며이후많은연구들을통해서항경련제의복용이골밀도의감소및골절위험도의증가와관련성이있음이알려져왔다. 그러나항경련제를복용하는환자군들의특성때문에단면조사연구가대부분이었으며최근에와서야몇몇추적연구들이이루어졌다. Sato 등 [6] 이 40명의항경련제복용군과 40명의정상대조군을대상으로연구한바에의하면항경련제복용군이정상대조군에비해제2 중수골에서평균 13% 의골밀도감소가있으며혈청칼슘과 25(OH)D가저하되며 1,25(OH) 2D와 intact PTH 가증가됨을관찰하였다. 또한 Andress 등 [7] 은항경련제를복용중인 103명의환자들을대상으로 2년동안추적관찰을시행하였고이들에서대퇴경부의골밀도가연간평균 1.8% 감소함을보고하였다. 이에따라골절위험도역시증가하는데 Cummings 등 [8] 은항경련제복용자는대퇴부골절의위험도가 2.8배증가함을발표하였고 van Staa 등 [9] 은 6개월이상항경련제를복용할경우골절의비교위험도가 2.1로부신피질호르몬 ( 비교위험도 : 1.3~1.6) 을포함한다른어떤약제보다도높음을보고하였다. Phenytoin, carbamazepine, phenobarbital과같은항경련제가골대사질환을유발하는주된기전은 cytochrome p450 enzyme (CYP450) 의유도체로작용하여비타민 D의이화작용을증가시키고비타민 D의혈청농도가낮아져이에따라골감소및골연화증이나타나는것으로알려져있다 [12]. CYP450에의하여비타민 D 이화작용이증가하면혈청 25OH 비타민 D 농도가감소하며혈청칼슘이감소하고알칼리인산분해효소가증가하고부갑상선호르몬농도가증가

4 - 김은경외 5 인 : Phenytoin 복용과관련된다발성골절과저칼슘혈증을동반한골연화증 1 예 - 한다. 그러나최근에는 CYP450 system과관계없는항경련제인 valproic acid 역시골감소를일으키는것으로나타났으며 [11], Weinstein 등 [10] 은항경련제를복용한환자군과정상대조군을비교해볼때혈청 25(OH)D 와 1,25(OH) 2D의농도가정상이면서도칼슘이감소되고골감소증이발생한다고보고하여이러한 유도체가설 (inducer theory) 외에다른기전들도골연화증의발생에관여할것으로사료된다 [11]. 한편항경련제를복용하는환자들의특성을고려하여볼때일광노출이나육체적활동량이일반인에비해적고칼슘과비타민 D의식이섭취가충분하지못할가능성이높아이역시골감소및골연화증을악화시키는요인과관련이있을것으로생각되고있다. 실제로 Gough 등 [13] 은항경련제의복용여부와관련없이장기간입원환자의경우에비타민 D가감소된것을관찰하여장기간의입원상태자체로만으로도골대사질환의위험요소가될수있다고하였다. 또한항경련제를복용하더라도정상생활을영위하면서외래치료를받는환자에서는그렇지않은환자에비해임상적으로유의한골대사질환의빈도가크게감소하는것으로나타나장기간의입원으로여러위험인자에노출되면골대사질환의위험도가크게증가된다고하였다 [14]. Valmadrid 등 [4] 이조사한바에의하면미국신경과의사의 28%, 소아신경과의사의 41% 만이항경련제복용환자에서정기적으로골대사질환에관한검사를시행하며예방적으로비타민 D나칼슘제재를투여하는경우는더적은것으로나타났다. 국내상황역시비슷하여항경련제관련골대사질환에대한인식은아직낮은편이며이와관련하여몇몇연구들이보고된바있으나아직미흡한실정이다 [15,16]. 앞서언급된바와같이여러요인이항경련제와관련된골대사질환에작용하며그기전이불분명하여이에대한감시및치료원칙역시아직확실히정해진것은없다. Heller 등 [17] 은항경련제를장기복용하는모든환자들에게기저혈청칼슘및인, 골밀도검사를하도록권고하였고이상소견이발견되는경우 25(OH)D 및 intact PTH 등정밀검사를시행하도록권고하였다. 또한예방및치료와관련하여 barbiturate, phenytoin, carbamazepine을복용중인모든환자에서칼슘과비타민 D를복용하도록권고하였으나최근 valproic acid도골대사질환을일으킬수있는것으로나타나이들역시포함될수있겠다. Drezner[18] 는보다구체적으로골대사질환에아직이환되지않은경우 2,000 IU, 골감소증이나골다공증인경우 2,000~4,000 IU, 골연화증의경우에는이보다더많은양의비타민 D를복용하여야한다고하였다. 또한비타민 D 투여와함께장기간입원또는신체활동의제한으로일광노출이부족한환자들에게자외선치료가도움이된다는연구들이있으나아직까지정확한방법및효과는확립되지않은상태이다 [19,20]. 본증례의경우환자가 8년전뇌경색을진단받고당시 경련발작소견이있어이후 phenytoin을복용하던중전신쇠약으로인해거동이불편한상태로거의집에서누워만지냈으며영양상태또한좋지못하였다. 환자는내원 15일전설사를주소로내원하여당시에도저칼슘혈증을보여약 1주일간칼슘및비타민 D (Dicamax R 1T: calcium 500 mg, cholecalciferol 1,000 IU) 를복용하였으나입원당시심각한저칼슘혈증, 고인산혈증, intact PTH의증가소견을보였다. 이는설사로인해약제의흡수가저하되어저칼슘혈증이악화되었고경련발작으로까지이어진것으로생각된다. 본증례의경우단순한골다공증이아니라혈청알칼리인산분해효소가증가하였고 25(OH)D 농도가매우낮았으며영상검사에서골피질의두께감소와비전형적인부위의다발성골절등의소견을보여골연화증으로진단할수있었다. 원인으로서 phenytoin 복용, 일광노출부족, 영양불량등이종합적으로작용한것으로추정되었다. 요약항경련제는매우빈번히사용되는약물이나이와관련된합병증인골대사질환에대한인식은아직부족한상태이다. 항경련제관련골대사질환은 cytochrome P450 enzyme 유도에의한비타민 D의이화작용증가외에도다양한요인들이관여하는것으로알려져있다. 저자들은장기간 phenytoin을복용하던환자에서저칼슘혈증으로인한경련및다발성골절을동반한골연화증을경험하였기에문헌고찰과함께보고하는바이다. 참고문헌 1. Frame B, Parfitt AM: Osteomalacia: current concepts. Ann Intern Med 89: , Schmid F: Osteopathien bei antiepileptischer Dauerbehandlung. Fortschr Med 85: , Kruse R: Osteopathies in antiepileptic long-term therapy (preliminary report). Monatsschr Kinderheilkd 116: , Valmadrid C, Voorhees C, Litt B, Schneyer CR: Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol 58: , Hoikka V, Savolainen K, Alhava EM, Sivenius J, Karjalainen P, Parvianinen M: Anticonvulsant osteomalacia in epileptic outpatients. Ann Clin Res 14: , Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, Maeda H, Satoh K: Decreased bone mass

5 대한내분비학회지 : 제 24 권제 3 호 2009 and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 57: , Andress DL, Ozuna J, Tirschwell D, Grande L, Johnson M, Jacobson AF, Spain W: Antiepileptic drug-induced bone loss in young male patients who have seizures. Arch Neurol 59: , Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM: Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332: , van Staa TP, Leufkens HG, Cooper C: Utility of medical and drug history in fracture risk prediction among men and women. Bone 31: , Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB: Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 58: , Babayigit A, Dirik E, Bober E, Cakmakci H: Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 35: , Fitzpatrick LA: Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav 5:S3-S15, Gough H, Bissesar A, Goggin T, Higgins D, Baker M, Crowley M, Callaghan N: Factors associated with the biochemical changes in vitamin D and calcium metabolism in institutionalized patients with epilepsy. Ir J Med Sci 155: , Fogelman I, Gray JM, Gardner MD, Beastall GH, McIntosh WB, Allam BF, Boyce BF, Boyle IT, Lawson DH: Do anticonvulsant drugs commonly induce osteomalacia? Scott Med J 27: , Cho YW, Lee IK, Hur SH: Adverse effects of antiepileptic drugs on bone mineral density in women with epilepsy. J Korean Endocr Soc 17: , Suh YS, Kim YG, Lee JH, Yoo KH, Lee JW, Tockgo YC: The effect of long-term phenobarbital administration on the bone mineral density of children. J Korean Pediatr Soc 37: , Heller HJ, Sakhaee K: Anticonvulsant-induced bone disease: a plea for monitoring and treatment. Arch Neurol 58: , Drezner MK: Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav 5:S41-S47, Toss G, Andersson R, Diffey BL, Fall PA, Larkö O, Larsson L: Oral vitamin D and ultraviolet radiation for the prevention of vitamin D deficiency in the elderly. Acta Med Scand 212: , Williams C, Netzloff M, Folkerts L, Vargas A, Garnica A, Frias J: Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. South Med J 77: ,

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract