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1 KMJ Original Article The Association Between Serum GGT Level and Bone Mineral Density in Postmenopausal Women Heung Yeol Kim 1, Eun Hee Kong 2 1 Department of Obstetrics and Gynecology, College of Medicine, Kosin University, Busan, Korea 2 Department of Family Medicine, College of Medicine, Kosin University, Busan, Korea 폐경후여성의혈청 GGT 와골밀도관련성 김흥열 1, 공은희 2 고신대학교의과대학 1 산부인과학교실, 2 가정의학과학교실 Objectives: The aim of this study was to identify the relationship between serum gamma-glutamyltransferase (GGT) and bone mineral density (BMD) in postmenopausal women. Methods: We evaluated 200 postmenopausal women who were visiting a health promotion center at a university hospital from January 2009 to December Their current medical diseases and medication history were collected through medical records. Basic physical examinations and laboratory tests were performed on all subjects. Results: The levels of serum GGT within their normal range were positively correlated with waist circumference (P = 0.01), triglycerides (P <0.001), alkaline phosphatase (P = 0.009), and uric acid (P = 0.01). The serum GGT within their normal range were negatively associated with the femur neck BMD (P = 0.002). In adjusted analysis including age and body mass index, the BMD of the femur neck was more strongly associated with a high-normal serum GGT level among the postmenopausal women as compared with those with a low-normal serum GGT level (P = 0.02). Conclusions: Serum GGT within its normal range is negatively correlated with the BMD in the femur neck among postmenopausal women. It can be useful for selecting a group that is at high risk for the bone fracture regardless of the underlying mechanism. Key Words: Bone mineral density, Gamma-glutamyl transferase, Postmenopause 최근노령인구증가에따라골다공증유병률이증가하고있다. 대사성골질환인골다공증의임상적의의는골절이다. WHO 에서는 10년내골절위험도 (10-year fracture risk) 를산출하는방법을개발하였으며, 위험인자로연령, 성별, 골절병력, 대퇴골경부골밀도, 체질량지수 (body mass index=kg/m 2, 이하 BMI), 경구글루코코르티코이드사용, 이차골다공증 ( 예, 류마티스관절염 ), 부모의대퇴골골절병력, 현재흡연, 1일 3단위이상음주등을포함시켰다. 1 폐경후여성은에스트로겐의골흡수 억제효과가사라져골흡수가증가되고골밀도가낮아져골절위험이증가한다. 또한, 폐경으로체지방분포의변화가생겨인슐린저항과대사증후군위험이증가되며, 2 대사증후군과관련된전신적인염증은골흡수를활성화시켜골밀도를낮춘다. 3 최대골량은일반적으로영양, 내분비계상태, 육체적활동, 성장과정에서의건강등에의해영향을받는다. 4 최근많은전향적연구들에서정상범위내에서높은수치를보인혈청 gamma-glutamyl transferase ( 이하 GGT) Corresponding Author: EunHee Kong, Department of Family Medicine, Kosin University College of Medicine, #34, Amnam-dong, Seo-gu, Busan, , Korea TEL: FAX: eh-kong@kosin.ac.kr Received: October 19, 2012 Revised: December 6, 2012 Accepted: January 2,

2 가비만, 흡연, 신체적비활동성, 높은육류섭취등의건강하지못한행태들과함께관찰되었다. 5-7 건강검진에서흔히이용되는검사항목인혈청 GGT 의골밀도와의관련성에대해서는아직까지직접적으로연구된데이터가거의없는실정이다. 이에저자는폐경후여성에서정상범위내의혈청 GGT수치에따라골밀도가어떻게달라지는가를분석하고자하였다. 연구대상및방법 2009년 1월 1일부터 2011년 12월 31일까지일개대학병원의건강증진센터를방문한폐경후여성을대상으로하였으며골대사에영향을줄수있는내분비질환, 간질환및혈액질환을가진여성들은제외하였다. 또한, 검진전 6개월이내여성호르몬치료를받은경력이있는경우, 흡연, 음주, 스테로이드등골대사에영향을줄수있는약물복용경력이있는경우를제외하고혈청 GGT가정상범위 ( 50 mg/dl: 분석기기에서제시한참고기준 ) 내에있는 200명을대상으로연구를시행하였다. 모든연구대상자들은의무기록을통한후향적방법으로검진받았을당시나이, 키, 몸무게, BMI, 허리둘레, 폐경기간, 분만력, 혈압, 일반혈액검사, 생화학검사, 지질검사, 골밀도를조사하였다. 검진시연구대상자들의체중및신장은자동신체계측기 (Inbody720, BiospaceCopr., Cheonan-si, Republic of Korea) 를이용하여가벼운실내복을착용하고신발을벗고직립자세에서킬로그램과센티미터단위로각각소수점한자리까지측정하였고, BMI는측정된체중과키의값으로구하였다. 허리둘레는대상자가숨을내쉰상태에서마지막늑골의하단과장골능선의상단부위의중간지점에서줄자를이용하여소수점한자리 (0.1 cm) 까지측정하였다. 8 혈압측정은 10분이상안정상태를유 지한후자동혈압측정계 (OMRON T5-M, OMRON Corp., Japan) 로우측상완에서수축기혈압과이완기혈압을측정하였으며, 혈압이 140/90 mmhg 이상측정되었을시에는추가로 10분이상더안정을취한이후재측정하였다. 총콜레스테롤, 고밀도지단백콜레스테롤, 중성지방, 알칼리포스파타제 (alkaline phosphatase, 이하 ALP), GGT, 요산, 칼슘, 인, 고감도 C반응단백질 (High Sensitivity C-Reactive Protein, 이하 Hs-CRP) 등일반혈액검사및생화학검사는 12시간이상공복후전주정맥에서혈액을채취하여측정하였다. 양에너지방사선골밀도측정기 (dual energy x-ray absorptionmetry, DXA 모델 : Discovery- W, Hologic, Boston, USA) 를사용하여요추 (L1~L4) 의평균골밀도와양측대퇴골경부 (femur neck) 의골밀도를측정하였다. 골밀도는 T-점수 ( 최고의골량을가지고있는동일한성인젊은여성의골밀도와대상인의골밀도를비교했을때의차이를표준편차로표시한점수 ) 를사용하여나타내었다. 4분위수 (quartile) 를이용하여연구대상자수를네그룹 (Q1~Q4) 으로범주화하였으며, 정상범위내혈청 GGT 의 4분위절단수치는 12, 15, 23 mg/dl였다. 연구대상자들의일반적인특성은평균과표준편차로나타냈다. 정상범위내혈청 GGT 범주에따른각변수및골밀도차이를분석하기위해일원배치분산분석 (One way ANOVA) 을사용하였다. 나이와 BMI를보정한후, 각각의변수들이골밀도에미치는영향을알아보기위해중다선형회귀분석 (Multiple linear regression analysis) 을시행하였다. 모든통계적분석은윈도우용 SPSS (Version 20, Stanford, CA, USA) 을사용하여처리하였으며유의수준은 0.05 미만으로하였다. 36

3 Serum GGT Level and Bone Mineral Density 결과 대상자들의평균연령은 ± 6.29 세, 평균체질량지수는 ± 3.23 kg/m 2, 평균허리둘레 ± 8.23 cm, 평균혈청 GGT 수치는 ± 9.53 mg/dl 였다. 평균골밀도의 T-점수는대퇴골경부 ± 1.47, 요추 (L1~L4) ± 1.07였다 (Table 1). 정상범위내의혈청 GGT 가높을수록집단에서허리둘레 (P = 0.01), 중성지방 (P < 0.001), ALP (P = 0.009), 요산 (P = 0.01) 은유의하게높았지만, 대퇴골경부골밀도 (P = 0.002) 는유의하게낮았다 (Table 2). Table 1. General characteristics. Characteristics Mean ± SD Age, y ± 6.29 Weight, kg ± 8.12 Height, cm ± 5.28 BMI, kg/m ± 3.23 WC, cm ± 8.23 SBP, mmhg ± DBP, mmhg ± Glucose, mg/dl ± T-C, mg/dl ± HDL-C, mg/dl ± LDL-C, mg/dl ± TG, mg/dl ± ALP, mg/dl ± GGT, mg/dl ± 9.53 Uric acid, mg/dl 4.48 ± 0.91 Calcium, mg/dl 9.35 ± 0.38 Phosphate, mg/dl 3.74 ± 0.56 Hs-CRP, mg/dl 0.17 ± 0.52 F-BMD, T-score (SD) ± 1.47 L-BMD, T-score (SD) ± 1.07 (N=200) BMI: body mass index, WC: waist circumference, SBP: systolic blood pressure, DBP: diastolic blood pressure, T-C: total cholesterol, HDL-C: high density lipoprotein cholesterol, LDL-C: low density lipoprotein cholesterol TG: triglyceride, ALP: alkaline phosphatase, GGT: gamma-glutamyl transferase, Hs-CRP: high sensitivity C-reactive protein, F-BMD: bone mineral density of Femur neck, L-BMD: bone mineral density of Lumbar spine (L1~L4). Table 2. Association with biochemical markers by the quartile of normal serum GGT levels. Quartile of normal serum GGT levels (mg/dl) Q1 (4~12) (N = 50) Q2 (13~15) (N = 50) Q3 (16~23) (N = 50) Q4 (24~50) (N = 50) P-value Age, y ± ± ± ± Weight, kg ± ± ± ± Height, cm ± ± ± ± BMI, kg/m ± ± ± ± WC, cm ± ± ± ± SBP, mmhg ± ± ± ± DBP, mmhg ± ± ± ± Glucose, mg/dl ± ± ± ± T-C, mg/dl ± ± ± ± HDL-C, mg/dl ± ± ± ± LDL-C, mg/dl ± ± ± ± TG, mg/dl ± ± ± ± < ALP, mg/dl ± ± ± ± Uric acid, mg/dl 4.23 ± ± ± ± Calcium, mg/dl 9.31 ± ± ± ± Phosphate, mg/dl 3.67 ± ± ± ± Hs-CRP, mg/dl 0.15 ± ± ± ± F-BMD, T-score (SD) ± ± ± ± L-BMD, T-score (SD) ± ± ± ± Data shown are mean ± SD Note: P-value by one way ANOVA analysis 37

4 대퇴골경부골밀도 T- 점수는나이가어릴수록, 체중이증가할수록, 키가클수록골밀도값이높았다 (P < 0.05) (Table 3). 대퇴골경부골밀도가낮은군에서정상범위 내혈청 GGT 가높았다 (P < 0.001)(Table 3). 나이와체질량지수를보정한후, 대퇴골경부골밀도는정상범위내의혈청 GGT 와유의한관계가있었고 (P = Table 3. Association with biochemical markers by the BMD T-scores of femur neck Bone mineral density of femur neck T-score -1.0 (N = 103) -2.5 < T-score < -1.0 (N = 66) T-score -2.5 (N = 31) P-value Age, y ± ± ± 6.90 < Weight, kg ± ± ± Height, cm ± ± ± BMI, kg/m ± ± ± WC, cm ± ± ± SBP, mmhg ± ± ± DBP, mmhg ± ± ± Glucose, mg/dl ± ± ± T-C, mg/dl ± ± ± HDL-C, mg/dl ± ± ± LDL-C, mg/dl ± ± ± TG, mg/dl ± ± ± ALP, mg/dl ± ± ± GGT, mg/dl ± ± ± 7.54 < Uric acid, mg/dl 4.38 ± ± ± Calcium, mg/dl 9.32 ± ± ± Phosphate, mg/dl 3.71 ± ± ± Hs-CRP, mg/dl 0.22 ± ± ± Data shown are mean ± SD Note: P-value by one way ANOVA analysis Table 4. Multiple linear regression analysis for associated biochemical markers of BMD T-score of femur neck Variables B Standard error Beta P-value WC, cm SBP, mmhg DBP, mmhg Glucose, mg/dl T-C, mg/dl HDL-C, mg/dl LDL-C, mg/dl TG, mg/dl ALP, mg/dl GGT, mg/dl Uric acid, mg/dl Calcium, mg/dl Phosphate, mg/dl Hs-CRP, mg/dl (constant) Note: P-value from multiple linear regression analysis. Adjusted by age and BMI. 38

5 Serum GGT Level and Bone Mineral Density Table 5. Multiple linear regression analysis for associated biochemical markers of BMD T-score of lumbar spine (L1~L4) Variables B Standard error Beta P-value WC, cm SBP, mmhg DBP, mmhg Glucose, mg/dl T-C, mg/dl HDL-C, mg/dl LDL-C, mg/dl TG, mg/dl ALP, mg/dl GGT, mg/dl Uric acid, mg/dl Calcium, mg/dl Phosphate, mg/dl Hs-CRP, mg/dl (constant) Note: P-value from multiple linear regression analysis. Adjusted by age and BMI 0.02) (Table 4), 요추 (L1~L4) 의평균골밀도는혈청 ALP 와유의한관련성이있었다 (P = 0.03) (Table 5). 고찰 본연구결과정상범위내의혈청 GGT 의수치가올라갈수록허리둘레, 중성지방, ALP, 요산이유의하게높았고, 대퇴골경부골밀도는유의하게낮았음을확인할수있었다. 골밀도에대한일원배치분산분석을통해체중이증가할수록대퇴골경부골밀도의 T- 점수가의미있게높았음을본연구에서볼수있었다. 이는 Zhifeng 등 9 의연구결과와일치한다. 이들은연령을보정한후키, 지방량, BMI 가대퇴골경부골밀도와양의상관관계에있음을설명하였다. 연령과폐경에따른골밀도를고려하여보고한것을보면, 폐경후여성의경우체지방량과제지방량이모두골밀도와관련이있으며, 특히지방량이관련성이높은것으로보고하였다. 10 반면, 척추골밀도는총지방량과관련이있고, 11 대퇴부골밀도는체지방량보다제지방량과더연관이있다는보고도있었다. 12 Lee 등 10 은폐경후여성에서연령이대퇴골경부와요추골밀도에서의의있는결정인자로보고하였다. 이는폐경후연령이증가할수록뼈의해부학적구조변화로겉질뼈의외경증가량에 비해내경의증가량이많게되어골밀도가감소하는것으로보고있다. 13 산화스트레스도폐경후골다공증발병에중요한역할을하는것으로보고되고있다 파골세포에서생성된활성산소인과산화물이골흡수에관여하는산화스트레스로골분해가일어나며, 항산화효소는골흡수에관여하는항산화방어기전의표지자이다. 19 Dreher 등 20 은글루타티온과산화효소 (glutathione peroxidase) 소실또는감소가골아세포기능손상을초래하여골다공증이생긴다고하였다. Sontakke 등 21 과 Maggio 등 22 은폐경후골다공증여성의혈장에서글루타티온과산화효소의활성도가유의하게낮았다고보고하였다. Altindag 등 17 도요추와대퇴골경부모두에서산화스트레스지수와골밀도의음의상관성을보고하였으며, 산화스트레스가대퇴골경부보다는요추에더영향을준다고하였다. 산화스트레스에의해항산화물질인글루타티온 (glutathione) 이세포내로이동하면서 GGT 의활성도를증가시킨다 따라서, 산화스트레스를나타내는지표로서혈청 GGT 가골밀도와관련됨을예측해볼수있다. 하지만, 본연구에서정상범위내의혈청 GGT 의수치가올라갈수록대퇴골경부골밀도는유의하게낮게관찰되었으나요추골밀도와는유의한상관성이없었다. 또한, 혈청 39

6 GGT 는간담도계질환, 심장및신장질환, 제2형당뇨병, 비만, 갑상샘기능항진증등의질환이있는경우에그활성도가증가된다. 25 또한, 간의지방량과독립적으로혈청 GGT 활성은내장지방량증가와도관련된다 본연구에서도혈청 GGT 가허리둘레및중성지방과양의상관관계가있음을보여주었다. 하지만, 본연구에서정상범주내의혈청 GGT가어떠한기전으로골밀도와관련되어있는지는연구하지못했다. 그리고, 본연구에서정상범위내의혈청 GGT 의수치가올라갈수록요산이유의하게높았다. 몇몇근거중심연구에서요산증가와간효소중 GGT 와 ALT 활성증가는대사증후군과관련된다고하였다 산화스트레스증가와요산증가의관련성을나타내는한연구에서요산은잠재적인항산화작용을나타내며, 대사질환에서중요한역할을한다고하였다. 30 또한, 공복시요산증가는고중성지방혈증과인슐린저항성과관련된다고하였다 산화스트레스와의관련성이보고되고있는요산과의관계에서도양의상관관계가있음을확인하였다. 33 본연구는일개대학병원의수검자를대상으로한단면연구로서정상범위내의혈청 GGT 와골밀도사이의관계에있어선후관계가명확하지않다. 또한, 나이, 골다공증가족력, 칼슘섭취부족, 신체활동감소, 흡연, 음주등다양한요인들이골밀도에영향을준다. 특히, 폐경후여성에서는이들요인이복합적으로함께작용하여골밀도에영향을주기때문에이들을각각분석하여기전을설명하는것은쉽지않다. 향후이에대한좀더보완된연구가필요하다고생각한다. 골다공증의예방과치료에있어서골절위험도를예측하고골절위험인자를조절하는것은중요하다. 하지만, 폐경후 10 년이내에는정상골밀도를보이는경우가많아골절의위험을예측하는것은쉽지않다. 그러므로, 노령인구의비율이증가되고있는현실에서본연구처럼폐경후여성을대상으로매우간편하고저렴한검사중한가지인혈청 GGT 와골밀도의연관성을연구하는것은의미가있다고생각한다. 결론적으로, 본연구에서는골밀도와혈청 GGT 간의 기전을설명하진못했지만, 단면연구로써폐경후여성을대상으로정상범위내의혈청 GGT 수치에따라대퇴골경부골밀도가달라짐을확인하였다. 이러한결과는향후폐경후여성을대상으로골절위험을예측하는선별검사연구에도움이될수있을것으로기대한다. REFERENCES 1. Kanis JA, Oden A, Johansson H, Borgstrom F, Strom O, McCloskey E. FRAX and its applications to clinical practice. Bone 2009;44: Han M. Metabolic Syndrome Emerging from Menopause. J Korean Soc Menopause 2011;17: Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/rankl/rank system for bone and vascular diseases. JAMA 2004;292: Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin North Am 2005;34: , xi. 5. Lee DH, Blomhoff R, Jacobs DR, Jr. Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res 2004;38: Strasak AM, Rapp K, Brant LJ, Hilbe W, Gregory M, Oberaigner W, et al. Association of gamma-glutamyltransferase and risk of cancer incidence in men: a prospective study. Cancer Res 2008;68: Ryu S, Chang Y, Kim DI, Kim WS, Suh BS. gamma- Glutamyltransferase as a predictor of chronic kidney disease in nonhypertensive and nondiabetic Korean men. Clin Chem 2007;53: Lim J, Kim S, Ke S, Cho B. The Prevalence of Obesity, Abdominal Obesity and Metabolic Syndrome among Elderly in General Population. Korean J Fam Med 2011;32: Sheng Z, Xu K, Ou Y, Dai R, Luo X, Liu S, et al. Relationship of body composition with prevalence of osteoporosis in central south Chinese postmenopausal women. Clin Endocrinol (Oxf) 2011;74: Lee JY, Jeong KA, Cha YJ, Kim HY. The Relationship between Body Composition, Serum Lipid Profile and Bone Mineral Density in Korean Women. Osteoporosis 2009;7: Douchi T, Yamamoto S, Oki T, Maruta K, Kuwahata R, Nagata Y. Relationship between body fat distribution and bone mineral density in premenopausal Japanese women. Obstet Gynecol 40

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