Journal of Breast Cancer ISSN J Breast Cancer 2007; March 10 (1): ORIGINAL ARTICLE Letrozole 사용후발생한골손실에있어서 Zoledronic Acid 의역할 송병주ㆍ차선욱

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1 Journal of Breast Cancer ISSN J Breast Cancer 27; March 1 (1): 43-5 ORIGINAL ARTICLE Letrozole 사용후발생한골손실에있어서 Zoledronic Acid 의역할 송병주ㆍ차선욱ㆍ배자성ㆍ서영진ㆍ박우찬ㆍ김한성 1 ㆍ오세정ㆍ김정수ㆍ정상설 가톨릭대학교의과대학강남성모병원외과유방센터, 인제대학교의과대학일산백병원 1 병리학교실 Role of Zoledronic Acid on Bone Loss by Letrozole Byung Joo Song, Seon Wook Cha, Ja Seong Bae, Young Jin Seo, Woo Chan Park, Han-Seong Kim 1, Se Jung Oh, Jeong Soo Kim, Sang Seol Jung Breast Center, KangNam St. Mary s Hospital, Departments of Surgery, College of Medicine, The Catholic University of Korea, Seoul; 1 Department of Pathology, Ilsan Paik Hospital, College of Medicine, Inje University, Goyang, Korea Purpose: The aromatase inhibitors cause bone loss by estrogen depletion. Zoledronic acid (ZA) can prevent bone mineral density (BMD) loss associated with the use of aromatase inhibitors. Accordingly interest has arisen in measuring surrogate markers of bone resorption to monitor the response of treatment of BMD loss in place of a radiologic assessment. This study was designed to determine whether ZA would prevent bone loss that is known to occur with letrozole and identified surrogate markers of bone resorption in an animal model. Methods: In ovariectomized or sham-operated rat, we administrated ZA and letrozole to 5 different groups including: a sham operation control group (), a group in which an ovariectomy was performed followed by saline administration (), an ovariectomy with ZA treatment group (), an ovariectomy with letrozole treatment group () and an ovariectomy with ZA and letrozole combined treatment group (L). The levels of serum osteocalcin, serum bone alkaline phosphatase (BALP), serum calcium and urine N-telopeptide (NTX) and BMD were estimated and compared at the same periods for each group. The distinct microscopic findings of proximal tibia at week sixteen were also compared. Results: Significantly reduced levels of urine NTX and significantly increased BMD were measured in the group. In the group no difference was seen in in BMD in comparison to the group. However, a significant increase in BMD was measured in the L group. Urine NTX levels were measured and found to be lower in the group and significantly lower in the L group. Serum osteocalcin levels were similar to each other for each group. Levels of serum calcium and BALP were significantly lower in the L group than in the group. Conclusion: The combination treatment with ZA and letrozole is effective in the inhibition of bone resorption and in the preservation of BMD. Measurement of serum osteocalcin, urine NTX, and BMD, levels are recommended as surrogate markers for determining the response for the treatment of bone loss. (J Breast Cancer 27;1:43-5) Key Words : Aromatase inhibitor, Bisphosphonate, Bone loss, Breast cancer, N-telopeptide 중심단어 : 골손실, Bisphosphonate, 아로마타제억제제, N-telopeptide, 유방암 서 론 책임저자 : 정상설 서울시서초구반포동 55, 가톨릭대학교의과대학강남성모병원외과유방센터 Tel: , Fax: ssjung@catholic.ac.kr 접수일 : 26 년 11 월 17 일게제승인일 : 27 년 2 월 5 일 * 본연구과제는 24 년한국유방건강재단연구비보조를받음. 에스트로겐수용체가양성인유방암환자에서타목시펜의 5년사용은내분비보조요법의표준으로자리잡아왔다. 그러나내분비요법으로 3세대아로마타제억제제 (letrozole, anastrozole, exemestane) 의사용이무병생존율이연장되는좋은치료효과를보여, 타목시펜을아로마타제억제제로전환하거나대치하거 43

2 44 Byung Joo Song, et al. 나또는연장하는치료방법이자리를잡아가고있다.(1) 폐경후여성에서는에스트로겐부족으로골손실이증가되고있는데, 폐경후유방암여성에서내분비요법은이러한골손실의변화를더심각하게만든다. 이러한변화를종양치료에의한골손실 (cancer-treatment-induced bone loss, CTIBL) 이라고한다. 아로마타제억제제는혈중내에스트로겐을고갈시키므로 CTIBL은타목시펜보다아로마타제억제제를사용할때더심하게골손실이나타나골절의위험성이증가한다.(1-5) CTILB는골절의위험성과골다공증과전이관련병적골절같은골격-관련사건 (Skeletal-related events, SRE) 을증가시키므로, 이에따른의료비용의지출은 SRE 가없을때비해상당히증가한다.(6, 7) 따라서아로마타제억제제사용으로나타나는 CTILB로인한골손실에의한골절의예방과 SRE 를줄이기위해새로운치료전략이필요하다. 이를위해사용할수있는약제가 bisphosphonate이다. ASCO (American Society of Clinical Oncology) 의권고안을보면아로마타제억제제로인한골손실은예방할수있고치료할수있으며, 골전이와관련없이골밀도를유지하기위해모든유방암환자에서 bisphosphonate (pamidronate 또는 ZA) 를사용하여이득을얻을수있다고한다.(3, 8) Bisphosphonate는파골흡수 (osteoclastic resorption) 을억제하는중요한약제로골다공증과골전이가있을때사용한다.(9) 경구용 bisphosphonate는폐경후여성의골다공증치료를위해사용되어골밀도를증가시켜골절을줄일수가있었다. 간편하게투여하고강력하고효과적인주사용제제로가장최근에개발된 3세대 bisphosphonate인 ZA 는기존 1세대 etidronate에비하여 배의효과를보이고, 작용기전으로는근본적으로파골세포생성 (Osteoclastogenesis) 을억제하고, 파골세포의세포사를조장하여골표면의미세환경을변화시켜직접혹은간접적으로골흡수를억제한다.(1, 11) 또한암세포에직접작용하여골표면으로부착과성장을억제하는항암효과가있다는보고가최근전임상적연구에서발표되었다.(12-14) 아로마타제억제제사용후에나타나는골절은삶의질을저하시킬뿐만아니라의료비용의지출도증가하게된다. 따라서아로마타제억제제사용과함께골손실의예방을위한전략이필요하다. Bisphosphonate는파골세포 (osteoclast) 의억제제로골다공증이나골전이치료에사용되고있어, 골손실의예방을위한전략에 bisphosphonate를사용할수있다.(9, 14) 골대사를평가하기위한다양한생화학적예측인자 (Surrogate marker) 에대한관심이많아지고있어, 골손실의치료에대한반응정도를정확하게평가할수있는생화학적표지자의선택이중요하다. 이에해당하는생화학적표지자에는혈청 osteocalcin, 혈청 bone alkaline phosphatase (BALP), 뇨중칼슘, hydroxyproline, 혈청및뇨중콜라젠분해산물로 pyridinoline (PYD), deoxypyridinoline (DPD), 제 I형콜라젠의 N-Telopeptide (NTX) 와 C-Telopeptide (CTX) 이있으며,(15-17) 뇨중에서 NTX 와 CTX 가골흡수를예측하는가장정확하고예민한인자라고하고있다.(18) 이에저자들은 bisphosphonate (ZA) 와아로마타제억제제 (letrozole) 를함께사용하여골손실을줄일수있는지확인하고, 이때골손실의치료정도를적절하게평가할수있는생화학적표지자를알아보고자하였다. 이러한결과는임상적으로아로마타제억제제사용시발생할수있는골손실을줄이기위해 zoledronic acid를함께사용할수있다는치료의근거가될수있다. 방법 1. 연구대상본연구에사용한동물들은가톨릭대학교의과대학실험동물연구실동물실험위원회에승인을얻어사용하였다. 가톨릭대학교의과대학실험동물연구실에서분양받은 45 마리의성숙한암컷흰쥐 (Sprague-Dawley, 체중 g) 를대상으로환경조절된 ( 온도 22±4, 습도 65±5%, 조명 6: A.M.-6: P.M.) 실험동물사육실에서 Stainless steel wire cage에한마리씩분리사육하였으며, 실험군은임의로배치하였다. 모든식이와탈이온수는자유섭취방법으로하였으며실험에사용된모든기구는무기질오염방지를위해.4% EDTA (Ethylene diamine tetracetic acid) 로씻은후탈이온수로세척하여사용하였다. 2. 양측난소절제술총 45 마리의성숙한암컷흰쥐중 4 마리를대상으로양측난소절제술을시행하였다. 펜토탈소디움 (thiopental sodium, 중외제약 ) 25 mg/kg 를복강내주입하여전신마취시킨후, 양측배복부의털을삭모하였다. 복와위에서 1% Betadine solution 으로수술부위를소독하여무균조작하에수술을시행하였다. 한쪽측배부하방에약 1.5 cm 가량피부절개후근육, 복막까지차례로절개하여복강내로진입하였다. 난소를노출시킨후, 3호견사로결찰하였다. 난소를절제한후절개창은복막, 근육, 피부순으로봉합하였다. 반대측난소도같은방법으로절제하였다. 나머지 5 마리는같은방법으로수술하되, 복벽을절개하여복강내로진입한후난소는절제하지않고다시봉합하는가장수술 (sham operation) 을시행하였으며, 이군을대조군 () 으로하였다. 3. 약물투여및실험군모든실험동물은매주 1회체중을측정하고체중의변화에따라

3 Role of Zoledronic Acid on Bone Loss by Letrozole 45 약물의용량을측정하였다. Zoledronic acid (Zometa, Norvatis pharma, AG) 는 3. g/kg 를주 1회생리식염수에용해하여 16 주간피하주사하였다. Letrozole (Femara, Norvatis pharma, AG) 는 2 mg/kg를매일탈이온수에용해하여 16 주간경구투여하였다. 난소절제실험군은투여약물의종류와방법에따라다음과같이 4군으로구분하여각각 1 마리씩임의로배치하였다. 제 1군 (): 가장수술 (sham operation) 군. 제 2군 (): 난소절제흰쥐에생리식염수를주 1 회 16 주간피하주사. ( 위약군 ) 제 3군 (): 난소절제흰쥐에 ZA 3. g/kg 를주 1회 16 주간피하주사. 제 4군 (): 난소절제흰쥐에 letrozole 2 mg/kg를매일 16 주간경구투여. 제 5군 (L): 난소절제흰쥐에 ZA 3. g/kg 를주 1회 16 주간피하주사하며 letrozole 2 mg/kg를매일 16 주간경구투여. 4. 결과분석 1) 대퇴골골밀도측정 Small animal total body option 을가지고있는 dual energy X-ray absorptiometry (DEXA: Lunar DPX-L, USA) 를이용하여수술전, 수술후8주, 수술후16주에각각세차례측정하였으며, 골밀도의단위는 g/cm 2 이었다. 2) 혈청생화학표지자측정흰쥐안와후방의모세혈관에서정맥혈을채취하여혈청 osteocalcin은 osteocalcin RIA kit (Biosource T-IRMA, RUE de co. Europe, USA) 를사용하여면역방사계수측정법에따라측정하였다. 혈청칼슘은항응고제가처리되어있지않은튜브에채혈한후 3, rpm에서 2분간원심분리하여얻은혈청을측정시액 (Sigma chem. co. USA) 과분광광도계 (Spectronic 61, Milton roy co. USA) 를사용하여분석하였다. 혈청 BALP의측정은 p-nitrophenylphosphate를기질로하여 ALP의발색정도를보는 Bessey-Lowry법에의해측정한 TALP 중 BALP 의 N-acetylglucosamine과 wheat germ agglutinin이결합하여침전하는성질을이용하여 Behr와 Barnert의방법에따라측정하였다.(19, 2) 3) 뇨생화학표지자측정흰쥐를 4: P.M-8: A.M ( 다음날 ) 까지각각격리하면서시험관에 24 시간소변을채취하였다. 뇨중칼슘은측정시액 (Sigma chem. co. USA) 과분과광도계 (Spectronic 61, ilton roy c. USA) 를이용하여측정하였다. 뇨중 NTX 의함량은 NTX ELISA kit (TEOMARK Ostex international, Inc. USA) 를이용하여면역방사계수측정법에따라측정하여, 뇨크레아티닌값에대한상대값으로보정하여계산하였다 (nm bone collagen equivalents (BCE)/nM creatinine). 4) 조직학적검사 조직검사를위한골표본의제작은흰쥐를희생한후경골근위부를이용하였다. 경골을채취하여부착되어있는연부조직을전부제거한후 1% 중성포르말린용액에고정하였다. 무기질의탈석회화를위해 1% nitric acid에 6시간이상침적하였다. 탈수과정과파라핀포매후경골근위부에서조직절편을만들어 Hematoxylin & Eosin 염색한후슬라이드를만들어광학현미경으로골수주 (bone trabeculae) 와세포의형태를관찰하여비교하였다. 5) 통계분석 동일시점에서각군의실험결과를비교하기위해측정치를 Mean±SD 으로표시하였고, Student s t-test와 ANOVA test를사용하여 p 값이.5 이하인경우를유의한차이로간주하였다. 1. 체중의변화 결 난소절제수술 16 주후각각 군이 49.6%, 군이 49.5%, 군이 47.2%, L군이 42.1% 로평균 47.1% 의체중증가를 Body weight (gram) L 과 8 16 Fig 1. The changes of body weight in each group at the same periods. This graph shows change of body weight before operation, 8 weeks and 16 weeks after operation. In each group the body weight is increase significantly at 16 weeks after ovariectomy (p<.5).

4 46 Byung Joo Song, et al. 보여통계적으로유의한체중증가율을보였다 (p<.5) (Fig 1). Bone density (g/cm 3 ) L 8 16 Fig 2. The changes of bone mineral density, femur in each group at the same periods: before operation, 8 weeks and 16 weeks after operation. 2. 대퇴골골밀도의변화난소절제수술 16주후 군이 13.% 의증가를, 군이 1.5 % 의증가를보였고, 군은 31.3% 의증가를, L군은 35.% 의증가를보였다 (p<.5). 그중 Zoledronic acid를투여한군에서유의하게높은골밀도증가율을보였다 (p<.5) (Fig 2). 3. 혈청 osteocalcin 함량의변화난소절제수술 16주후수술전에비하여 군이약 18.1% 의감소를, L군은약 9.2 % 의감소를, 군이약 1.7% 의감소를보였으나, 각각의실험군사이에큰차이는없었다 (Fig 3A). 4. 혈청과뇨중칼슘농도의변화각각의난소절제실험군은수술전과수술 16 주후혈청칼슘농도에큰변화를보이지않았으며정상범위를유지하였다. 상대적으로 L 군이다른실험군에비하여혈청칼슘농도가의의있게감소하는경향을보였으며, 뇨중칼슘농도는상대적으로 군과 L 군에서다른실험군에비하여뇨중칼슘농도가증가 Serum osteocalcin (ng/ml) L Serum calcium (mg/dl) L A 8 16 B Urine calcium (mg/dl) L Serum BALP (IU/L) L 8 16 C 8 16 D Fig 3. The changes of the concentration of serum biochemical markers, such as osteocalcin (A), serum calcium (B), urine calcium (C), BALP (D) in each group at the same periods: before operation, 8 weeks and 16 weeks after operation.

Role of Zoledronic Acid on Bone Loss by Letrozole 47 하는경향을보이지않았다 (Fig 3B, C). 5. 혈청 BALP 수치의변화 난소절제수술 16 주후수술전에비하여 군이약 3.5% 의증가를, 군이 13.4% 의증가를보였다. 반면에 군은약 19.1% 의감소를, L군은약 3.

9% 의 14 12 1 8 6 4 2 L 8 16 Fig 4. The changes of the concentration of urine biochemical marker, NTX in each group at the same periods: before operation, 8 weeks and 16 weeks after operation.

조직학적변화난소절제수술 16 주후실험군은모두경골근위부의해면골 (Cancellous bone) 소실이나타났다. 그러나 군과 L 군은다른실험군에비하여골손실이적으며, 골수주 (bone trabeculae) 의증가가있음을보이고있어, Zoledronic acid를투여한군이상대적으로골흡수가적게나타남을확인할수있었다 (Fig 5).

저자들은양측난소절제술을시행하여임의로골다공증모델을만들어위약과 ZA 를각각단독으로투여한군을비교하였다. 위약군에비하여 ZA 를단독으로투여한군에서유의하게골흡수가적게이루어져골흡수예방에치료효과가있음을확인하였다.

The distinct pathologic findings of proximal tibia in each group: (A), (B), (C), (D) and L (E) at 16 weeks after operation (H&E stain, 1).

5 Role of Zoledronic Acid on Bone Loss by Letrozole 47 하는경향을보이지않았다 (Fig 3B, C). 5. 혈청 BALP 수치의변화 난소절제수술 16 주후수술전에비하여 군이약 3.5% 의증가를, 군이 13.4% 의증가를보였다. 반면에 군은약 19.1% 의감소를, L군은약 3.5% 의감소를보여 Zoledronic acid를투여한군이다른실험군에비하여상대적으로혈청 BALP 수치가감소하고있음을알수있으나통계적으로유의하지는않았다 (Fig 3D). 6. 뇨중 NTX 수치의변화 Urine NTX (nm BCE/mM Cr) 난소절제수술 16 주후수술전에비하여 군이약 19.9% 의 L 8 16 Fig 4. The changes of the concentration of urine biochemical marker, NTX in each group at the same periods: before operation, 8 weeks and 16 weeks after operation. 현저한증가를, 군이약 55.9% 의증가를보였다. 반면 군이약 6.6% 의감소를, L군은약 16.5% 의감소를보여 Zoledronic acid를투여한군이다른실험군에비하여상대적으로골흡수가적게나타남을확인할수있었다 (p<.5) (Fig 4). 7. 조직학적변화난소절제수술 16 주후실험군은모두경골근위부의해면골 (Cancellous bone) 소실이나타났다. 그러나 군과 L 군은다른실험군에비하여골손실이적으며, 골수주 (bone trabeculae) 의증가가있음을보이고있어, Zoledronic acid를투여한군이상대적으로골흡수가적게나타남을확인할수있었다 (Fig 5). 고찰아로마타제억제제 (letrozole) 를사용하였을때나타나는골손실을줄이기위해 ZA를함께사용하여이를예방할수있는지를확인하기위해난소를절제한백서를이용하여골다공증모델을만들어실험을하였다. Reid 등 (21) 은 351 명의폐경후여성에서 1년간 ZA 를투여한결과위약군에비해골밀도와골흡수표지자의증가가있었음을확인하였다. 저자들은양측난소절제술을시행하여임의로골다공증모델을만들어위약과 ZA 를각각단독으로투여한군을비교하였다. 위약군에비하여 ZA 를단독으로투여한군에서유의하게골흡수가적게이루어져골흡수예방에치료효과가있음을확인하였다. 또, 저자들은위약군과 letrozole 을단독으로투여한군및 ZA 와 letrozole을병합하여투여한군을추가로비교한결과, letrozole을단독으로투여한군과위약군간골흡수정도에는큰차이가없었으나, ZA 와 letrozole을병합하 A B C D E Fig 5. The distinct pathologic findings of proximal tibia in each group: (A), (B), (C), (D) and L (E) at 16 weeks after operation (H&E stain, 1). The distinct histologic findings of proximal tibia in each group at 16 weeks after operation. (A) and (B): control and saline infusion group show silmilar thickness of bony trabeculae. (C): Zoledronic acid infusion group reveals thikended bony trabeculae compared to and. (D): Letrozole group shows thining of bony trabeculae. Some trabeculae reveals thinned and tappered ends (left lower corner). L (E): Both Letrozole and Zodedronic acid infusion group reveal markedly thickened bony trabeculae (H&E stain, 1).

6 48 Byung Joo Song, et al. 여투여한군에서현저하게골흡수가적게이루어지는것을볼수있었고, 이는 ZA 를단독으로투여한군에서의치료결과보다더좋은성적이었다. 이런결과는조기유방암을가진폐경후여성에서내분비보조요법으로 letrozole을사용하였을때 ZA 가 CTIBL을예방할수있다는임상시험 (Z-FAST와 ZO-FAST) 과결과가일치하는것이다.(22-24) Bisphosphonate로골손실을치료한후치료반응정도를평가하기위해효과나비용면에서유용하지않은방사선검사보다는혈청이나소변에서생화학적예측인자 (Surrogate marker) 를측정하여평가를하려는관심이많아지고있다. 생화학적예측인자로골형성지표인혈청 osteocalcin, 혈청 BALP와골흡수지표로뇨중칼슘, 뇨중 hydroxyproline, 혈청및뇨중콜라젠분해산물로 PYD, DPD, 제 I형콜라젠의 NTX와 CTX이있다.(15-17) 생화학적표지자중혈청 osteoclacin은 Bone Gla ( -carboxyglutamic acid)-protein으로알려져있다. 뼈구조에서 Hydroxyapetite 및칼슘과단단하게결합되어있고, 골대사에서골흡수가증가하는경우이차적으로골모세포의활동이증가하면서, 골모세포에서그합성이증가되는것으로보고되고있다.(25, 26) 골밀도감소에따른골모세포의감소와파골세포의활성도를예민하게감지할수있는것으로알려져있으나, 정상적으로골형성이이루어지는성장기에는그역할에한계가있다. 저자들의실험에서혈청 osteocalcin의함량은난소절제수술 8주후다른실험군에비하여 ZA 를단독으로투여한군에서현저히증가하였으나, 난소절제수술 16 주후각각의실험군사이에큰차이가없었다. 이는난소절제수술후급격한골소실에대한골모세포의활성이활발하게이루어지다가, 시간이경과함에따라골다공증이충분히이루어진후에는골모세포의활성이감소하면서나타난것으로보인다. 혈청내의칼슘대사는부갑상선호르몬, 비타민 D, calcitonin의상호조절로대부분의생리적변화에도불구하고항상성을유지하므로, 실험요인을변화시켜도정상범위내에있는것으로보고되고있다.(27) 본실험에서역시혈청칼슘농도는가장수술대조군을포함한모든실험군에서정상범위내에있었고, 이에골흡수의예측인자로는유용하지않다고할수있다. 또한 Zoladex를사용한군의소변에서칼슘의분지가줄어드는것을알수있었다. BALP는혈중 ALP의약 5% 정도만뼈에서유리되므로, BALP에만특이적으로작용하는효소를이용함으로써 BALP 수치를측정하여골형성지표로이용할수있다.(28, 29) 본실험에서도 군과 L 군이 BALP의감소를보여주고있어 ZA 투여군이 BALP의수치가상대적으로낮음을알수있었으나통계적유의성은없었다. 최근골흡수의지표로주목을받고있는 NTX 는파골세포가안정된제 I형콜라젠으로구성된뼈기질을분해할때소변으로 배설되는콜라젠분해산물인 Pyridinoline의한형태이다.(18) Woitge 등 (3) 이보고한바에의하면건강한대조군에비하여골다공증환자군에서현저하게혈중및뇨중 NTX 수치가증가하였으며, 진행성유방암의골전이가있는환자군역시대조군에비하여유의하게혈중및뇨중NTX 수치가증가하였다. 혈중 NTX 수치의변화는뇨중 NTX 수치의변화와마찬가지로골흡수정도를반영하였다.(16) 저자들의실험에서도가장수술대조군이나 ZA 를단독으로혹은병합으로투여한실험군에비하여위약군에서유의하게뇨중 NTX 수치가증가하였고, 이를통하여뇨중 NTX 가골흡수의예측인자로의의가있음을확인하였다 (p<.5). 또한실험군의골밀도검사결과를보면 ZA 를투여한군에유의하게증가되어있는것을볼수가있었다. 결론본실험을통해저자들은 ZA 가골밀도증가와골흡수억제에효과적임을입증하였으며, 이러한결과를볼때아로마타제억제제로인한골손실의감소를예방하기위해 ZA 를사용할수있다는실험적근거로볼수있다. 따라서실제임상에서아로마타제억제제와 ZA 를함께사용하여좋은효과가있을것으로기대된다. 골손실의치료정도를평가하기위한골흡수의예측인자로혈청 osteocalcin과뇨중 NTX가생화학적표지자로의의있었으며, 골밀도측정역시유용함을확인하였다. 참고문헌 1. Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with earlystage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 23;98: Mackey JR, Joy AA. Skeletal health in postmenopausal survivors of early breast cancer. Int J Cancer 25;114: Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 24. J Clin Oncol 25;23: Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast

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8 5 Byung Joo Song, et al. 29. Dresner-Pollak R, Mayer M, Hochner-Celiniker D. The decrease in serum bone-specific alkaline phosphatase predicts bone mineral density response to hormone replacement therapy in early postmenopausal women. Calcif Tissue Int 2;66: Woitge HW, Pecherstorfer M, Li Y, Keck AV, Horn E, Ziegler R, et al. Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res 1999;14:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R