한국임상약학회지제 24 권제 2 호 Kor. J. Clin. Pharm., Vol. 24, No. 2. 2014 Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy Available online at http://www.kccp.or.kr pissn: 1226-6051 골다공증및골감소증치료제의치료효과비교연구 김희선 1 손민지 2 방준석 3 손의동 1 * 1 중앙대학교약학대학, 2 서울대학교약학대학, 3 숙명여자대학교임상약학대학원 (2014 년 3 월 3 일접수 2014 년 6 월 2 일수정 2014 년 6 월 5 일승인 ) Comparative Study of Anti-osteoporotic Agents in Postmenopausal Women Hee Sun Kim 1, Minji Sohn 2, Joon Seok Bang 3, and Uy Dong Sohn 1 * 1 College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea 2 College of Pharmacy, Seoul National University, Seoul 110-799, Korea 3 Graduate School of Clinical Pharmacy, Sookmyung Women's University, Seoul 140-742, Korea (Received March 3, 2014 Revised June 2, 2014 Accepted June 5, 2014) Purpose: The aim of this study was to compare retrospectively the efficacy of anti-osteoporotic agents (RAL-Raloxifene 60 mg, ALD-weekly alendronate 70 mg, RSD-weekly risedronate 35 mg, AVD3-weekly alendronate 70 mg/vitamin D 3 2800IU, IBD-quarterly IV ibandronate 3 mg/3 ml, ZLD-yearly IV zoledronate 5 mg/100 ml) in postmenopausal patients with osteoporosis or osteopenia. Method: This study retrospectively reviewed medical record and compared the lumbar spine BMD percentage changes of each medicine group one year later from the baseline. 209 patients (27, 50, 60, 30, 35, and 7 patients in RAL, ALD, RSD, AVD3, IBD, and ZLD groups, respectively) are within the inclusion criteria for the study. Results: From baseline to month 12, lumbar spine BMD increased significantly larger with bisphosphonate groups, compared to SERM (p < 0.05). In all bisphosphonate groups, the lumbar spine BMD were increased significantly from baseline. Of the bisphosphonates, the changes from baseline in BMD of IV bisphosphonates were more larger than those of oral bisphosphonates, and yearly, quarterly bisphosphonates yielded significantly greater BMD gains, compared with weekly bisphosphonate groups (p < 0.05). In addition, patients receiving 70 mg weekly alendronate+vitamin D3 had greater gains in BMD than alendronate Single preparation (p < 0.05). Conclusion: Bisphosphonates yielded significantly greater BMD gains than SERM. Of the bisphosphonates, the changes from baseline in BMD of yearly, quarterly IV bisphosphonates yielded significantly greater BMD gains, compared with weekly oral bisphosphonate groups. In addition, vitamin D3 plays an significant role in BMD gains. Key words - Osteoporosis, Osteopenia, SERM, Bisphosphonate, Raloxifene, Alendronate 골다공증은골강도의약화로사소한충격에도골절의위험이증가하게되는골격계질환으로질환으로정의된다. 1-3) 골강도는골량 (quantity) 과골질 (quality) 에의해결정되는데골량은주로골밀도 (Bone Mineral Density, BMD) 와골질에의해결정되며, 골질은구조, 골교체율, 무기질화, 미세손상축적등으로구성된다. 4,5) 골다공증은폐경 ( 제1형 ) 이나노화 ( 제2형 ) 로인한일차성 ( 혹은원발성 ) 골다공증과특정질병이나수술, 약물복용에의해최대골량형성에장애가있거나골소실이증가하여발생하 Correspondence to : Uy Dong Sohn Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea Tel: +82-2-820-5614, Fax: +82-2-826-8756 E-mail: udsohn@cau.ac.kr 는이차성 ( 혹은속발성 ) 골다공증으로나눌수있는데이중가장흔한제1형과제2형골다공증은거의같은시기에진행되므로정확히분류하기어렵다. 4,6) 골다공증은골절이발생하기전까지는거의자각증상이없기때문에주로건강검진에서발견되거나다른진료과정에서밝혀지는특징이있으며현재는주로골밀도를측정하여골다공증을진단하고있다. 7) 골밀도측정방법은측정부위나방법이다양한여러중류의골밀도측정기가사용되고있으나이중에너지방사선흡수법 (dual energy X-ray absorptiometry, DEXA) 이가장적합한표준기종으로인정되고있다. 8,9) 골밀도는나이, 성별, 종족간의정상평균값을비교하여해석하는데흔히사용되는 T-score는 ( 환자의측정값- 젊은집단의평균값 )/ 표준편차 로골절에대한절대적인위험도를 98
폐경기여성에서골다공증및골감소증치료제의효과비교연구 99 나타내기위해골량이가장높은젊은연령층의골밀도와비교한값이다. 세계보건기구 (World Health Organization, WHO) 에서는이 T-score 를기준으로 -1.0 이상이정상, -1.0 에서 -2.5 사이를골감소증 (osteopenia), -2.5 이하를골다공증으로구분하고있다. 10) 평균수명의연장으로우리나라평균수명이늘어났고급속히고령사회로접어든시점에서노년기건강에대한관심은점점늘어나고그와함께보건의료비의상승또한문제가되고있다. 11) 2004년노인보건의료실태를보면 65세이상노인중만성질환을가진노인이약 90.9%, 2개이상복합질환을가진노인도 73% 이상을차지하여대부분의노인의만성질환에이환되었음을알수있다. 12) 그러나, 여러만성질환중에서도골다공증과같은질환은사망에직접적인원인이되지않는다는생각으로인해그중요성에대한인식이낮고그에대한관심과인지도가매우낮은질환이다. 미국의경우 1,000만명이골다공증으로, 1.400만명이골다공증위험군으로추정되고있으며골다공증성골절로인한사망은연간 37,500건으로, 골다골증관련질환으로인해 1995년기준연간 138억달러가소비되고있어큰사회경제적문제로대두되고있다. 13) 국내에서는 60세이상여성의골다공증유병률이 50% 이상으로추정되고있으나지금까지보고된골다공증유병률에관한연구가연령, 교육수준, 조사지역등연구대상의특성차이등으로인하여보고된내용에차이를보이고있다. 14) 사회경제적부담절감및건강증진을위하여향후보다체계적이고정확한유병률조사와원인규명과함께및적극적예방및치료관리가필요한시점이다. 현재골다공증의치료및예방에사용되고있는약제는골흡수억제제인 Estrogens, 선택적에스트로겐수용체조절제 (selective estrogen receptor modulator, SERM), bisphosphonates, calcitonin이있으며유일한골합성제제인부갑상선호르몬이있다. 4,15-16) Estrogens은 FDA에서승인된전신적호르몬요법의일차적인적응증은열성홍조와같은혈관운동성증상및질위축을동반하는폐경증상의경우와폐경후골다공증및노인성골다공증의중요한원인중하나가에스트로겐결핍으로서폐경기여성에게골다공증을예방할목적으로시행할수있다. 17) 자궁이없는여성의경우에스트로겐단독요법 (estrogen therapy, ET) 을자궁을가진여성의경우에는자궁내막증식을막기위하여에스트로겐- 프로게스테론병합요법 (estrogen- progesteron therapy, EPT) 을시행하는것이일반적이다. 4) WHI(World Health Initiative) 의연구결과 EPT의경우유방암, 뇌졸중, 관상동맥질환, 혈전색전증의증가위험이있으며 ET의경우뇌졸중과정맥혈전증이의미있게증가하므로폐경증상을치료하기위해호르몬요법을사용할경우가능하면짧은기간동안적은용량을사용하며골다공증 예방목적으로사용할경우위험과이점을고려함과동시에다른약제의사용을고려할것을권고하였다. 17,18) SERM은비스테로이드성제제로표적조직의에스트로겐수용체와결합하여신체의조직에따라선택적으로에스트로겐과유사한작용을하거나혹은에스트로겐에대한길항작용을나타내는약제로 raloxifene만이유일하게폐경여성의골다공증의예방및치료제로사용되고있다. 18) Bisphosphonate 제제는파골세포의활동을억제하고수명을단축시킴으로써골흡수를억제하는효과를가진다. 여러연구에서 Bisphosphonate 제제는보든폐경여성에서용량의존적으로척추및골반골밀도를의미있게증가시키는것으로나타났으며현재골다공증치료제로가장먼저선택하는표준치료제이다. 18) 골다공증치료제로국내에서승인된 bisphosphonate 제제는 pamidronate, alendronate, risedronate, ibandronate, zoledronate가있다. 4) Calcitonin은파골세포의수용체에결합하여골흡수를저하시키는작용을하는데현재합성연어 calcitonin이주로사용되고있으며주사제와비강흡입제가있다. 골다공증의예방이아닌치료목적으로승인되어있으며다른골다공증에비해치료효과가약하기때문에 bisphosphonate 제제나 raloxifene 등을사용할수없는폐경여성에게사용할수있으며진통효과가있어최근발생한골절로인한통증에효과적으로사용할수있다. 4,16-18) 유일한골합성제제인부갑상선호르몬은조골세포를직접자극하여골형성을촉진하여지속적으로골밀도를상승시키며 teriparatide( 재조합인간 PTH 1-34) 가치료제로승인되어있다. 부갑상선호르몬은골다공증에대한긍정적인효과가있으나용량및치료기간에대한연구가아직충분치않고보험비급여로고가이라현재골절이동반된심한골다공증환자한정되어사용되고있다. 4,18) 본연구에서는폐경후골다공증또는골감소증으로진단되어골다공증약제를투여받은환자중에서빈용되는 6 가지연구대상의약제를선정하여투여전과투여 1년후의골밀도변화를중심으로후향적으로비교함으로써계열별, 투여경로별, 투여주기별, VD3 복합여부에따른효과를비교분석하고자하였다. 연구방법 연구대상및자료수집본연구는 2007년 1월부터 2008년 12월까지 C대학부속병원에서다음의골다공증치료제를투여받은폐경후골다공증및골감소증환자를대상으로조사하였다. 연구대상약물은 SERM 계열의 raloxifene, bisphosphonate 계열의 alendronate, risedronate, ibandronate, zoledronate 와 alendronate와 Vit. D 3 복합제를대상으로하였다 (Table 1). 연구대상자는척추골밀도측정시 T-score 가 -1.0 미만의
100 Kor. J. Clin. Pharm., Vol. 24, No. 2, 2014 Table 1. Study medications. Group Ingredient & Strength Dosing frequency Route of administration Category RAL Raloxifene 60 mg 7D PO SERM ALD Alendronate 70 mg 7D PO BIS RSD Risedronate 35 mg 7D PO BIS AVD3 Alendronate 70 mg + Cholecalciferol 2800 IU 7D PO BIS IBD Ibandronate 3 mg/3 ml 3M Inj. BIS ZLD Zoledronate 5 mg/100 ml 1Y Inj. BIS 7D (once weekly); 3M (once every 3 months); 1Y (once yearly); PO (oral administration); Inj. (injection); SERM (selective estrogen receptor modulator); BIS (bisphosphonate) 골감소증혹은골다공증을가진폐경여성으로대상약제중한가지를 1년이상복용한경우에한하며투여 1년후골밀도를측정하지않은환자, 골밀도나골교체율에영향을줄수있는갑상선기능항진증, 부갑상선기능항진증, 만성신부전증, 소화흡수장애, 조절되지않은당뇨병등의질환을가진환자, 개인의의료자료가불충분한환자는연구대상에서제외하였다. 본연구에필요한자료는환자의의무기록자료를토대로환자의나이, 신장, 체중, 투여전및투여 1년후골밀도 (Tscore, g/cm 2 ) 를후향적으로조사하였다. 골밀도의측정치는이중에너지방사선흡수법으로측정한결과를사용하였고, 폐경후여성의경우척추의골밀도가대퇴골에비해골다공증의빈도가높게측정되며골대사의변화를예민하게반영하므로척추의골밀도변화를조사하였으며, L 5 는골밀도의편차가너무심하여 ISCD (International Society for Clinical Densitometry) 권고안인요추 1~4번 (L 1 -L 4 ) 평균치를기준으로조사하였다. 19,20) 평가방법각연구대상약물의복용 1년후의골밀도변화율을기준으로투여경로별, 투여주기별, 계열별, Vit.D 3 복합여부의 관점에서비교하였다. 통계처리치료시작전각군의기저치특성비교에는일원분산분석 (one-way ANOVA) 를사용하였고각각의군에있어치료제의효과여부를검증하기위해치료전후의 T-score 와골밀도수치로대응표본 T 검정 (paired t-test) 를실시하였다. 각치료제의효과비교는독립표본 T-검정 (independent sample t-test) 과공분산분석 (analysis of covariance), 일원분산분석 (one-way ANOVA) 및 Kruskal-Wallis test를사용하였다. 통계학적분석은 Statistical Package for the Social Science (SPSS) version 12.0 program을사용하였으며, 분석된통계결과는평균 ± 표준편차로표기하였다. 각각의통계분석에서 p-value가 0.05 미만인경우를통계학적으로유의한차이가있다고판정하였다. 연구결과 대상환자의특성연구대상약제를투여받은환자는총 1157명 (RAL군 162 명, ALD군 206명, RSD군 397명, AVD3 199명, IBD군 152 Table 2. Baseline characteristics of the study subjects. Characteristics RAL (n=27) ALD (n=50) RSD (n=60) AVD3 (n=30) IBD (n=35) ZLD (n=7) F (p-value) Age (yr) 62.1±6.8 64.4±7.2 64.7±8.6 65.9±6.9 63.1±7.7 61.7±3.0 1.074 Range 52~77 51~80 43~86 48~78 46~80 58~65 (0.376) BMI (kg/m 2 ) 23.7±3.1 23.5±2.8 23.2±3.5 23.6±3.0 23.9±2.6 22.8±3.8 Lumbar spine T-score Lumbar spine BMD (g/cm 2 ) -2.09±0.71-2.05±0.67-2.32±0.66-2.20±0.63-2.09±043-2.25±0.66 0.85±0.09 0.84±0.08 0.81±0.08 0.84±0.08 0.84±0.07 0.84±0.08 0.303 (0.911) 1.269 (0.279) 1.074 (0.376) RAL (raloxifene 60 mg); ALD (alendronate 70 mg); RSD (risedronate 35 mg); AVD3 (alendronate 70 mg + cholecalciferol 2800 IU); IBD (ibandronate 3 mg/3 ml); ZLD (zoledronate 5 mg/100 ml); BMI (body mass index, kg/m 2 ); BMD (bone mineral density); Values are expressed as Mean±SD
폐경기여성에서골다공증및골감소증치료제의효과비교연구 101 명, ZLD군 41명 ) 이었고이중약물투여전척추골밀도 T- score가 -1.0 이상인경우, 폐경여성이아닌경우, 대상약제를 1년이상투여하지않은경우, 투여 1년후골밀도를재측정하지않은경우, 골밀도나골교체율에영향을줄수있는갑상선기능항진증, 부갑상선기능항진증, 만성신부전증, 소화흡수장애, 조절되지않은당뇨병등의질환을가지고있는환자, 자료가불충분한환자를제외한총 209명을연구대상 (RAL군 27명, ALD군 50명, RSD군 60명, AVD3 30명, IBD군 35명, ZLD군 7명 ) 으로하였다. 치료시작전각군의기저치특성을비교하기위해일원분산분석 (one-way ANOVA) 을수행한결과 RAL군, ALD군, RSD군, AVD3 군, IBD군, ZLD군의순으로각각의평균연령은 62.1세, 64.4세, 64.7세, 65.9세, 63.1 세, 61.7세이며 Body Mass Index(kg/m 2 ) 는각각 23.7, 23.5, 23.2, 23.6, 23.9, 22.8, Baseline Lumbar spine T-score 는 -2.09, -2.05, -2.32, -2.20, -2.09, -2.25, Baseline 요추골밀도 (g/cm 2 ) 는 0.851, 0.843, 0.814, 0.836, 0.835, 0.840으로각각의기저치들이비슷한분포를보였고유의수준에서각군간의차이가없었다 (Table 2). 각치료제별약효분석각각의연구대상치료제가투여전과비교하여투여 1년후에효과를나타내는지를검증하기위해각군에대해투여전후의 T-score 와골밀도수치를가지고대응표본 T-검정 (paired t-test) 를실시하였다. 투여전과투여후차가척추 T-score 에있어서는 RAL군, ALD군, RSD군, AVD3군, IBD군, ZLD군의순으로각각 -0.16±0.38, -0.21±0.19, -0.30±0.25, -0.37±0.37, -0.36±0.30, Table 3. Comparison between before and after the antiosteoporotic medications. Medication Differences T p-value RAL ALD RSD AVD3 IBD T-score -0.16±0.38-2.207 0.036 BMD -0.02±0.05-2.162 0.040 T-score -0.21±0.19-8.169 0.000 BMD -0.03±0.02-8.128 0.000 T-score -0.30±0.25-9.193 0.000 BMD -0.04±0.03-9.299 0.000 T-score -0.37±0.37-5.514 0.000 BMD -0.04±0.04-5.508 0.000 T-score -0.36±0.30-7.088 0.000 BMD -0.05±0.04-7.372 0.000 T-score -0.41±0.15-2.813 0.031 ZLD BMD -0.05±0.02-2.985 0.024 RAL (raloxifene 60 mg); ALD (alendronate 70 mg); RSD (risedronate 35 mg); AVD3 (alendronate 70 mg+cholecalciferol 2800 IU); IBD (ibandronate 3 mg/3 ml); ZLD (zoledronate 5 mg/100 ml); BMD (bone mineral density, g/cm 2 ); Values are expressed as Mean±SD Fig. 1. BMD change among anti-osteoporotic medications. BMD (bone mineral density, g/cm 2 ); RAL (raloxifene 60 mg); ALD (alendronate 70 mg); RSD (risedronate 35 mg); ALD+VD3 (alendronate 70 mg+cholecalciferol 2800 IU); IBD (ibandronate 3 mg/3 ml); ZLD (zoledronate 5 mg/100 ml) -0.41±0.15로유의한차이를보였고척추골밀도 (g/cm 2 ) 에있어서투여전과후의차는각군의순으로 -0.019±0.045, -0.026±0.022, -0.036±0.030, -0.044±0.044, -0.045±0.036, -0.051±0.017로 p-값이각각유의수준 0.05보다작게나타나각각의치료제는투여전보다투여후에 T-score 및골밀도에있어서유의한증가를보였다. 또한치료제별로약효에차이가있는지를검정하기위해골밀도변화율에대해 n수가크지않은경우를고려하여비모수검정으로써 Kruskal-Wallis test를시행한결과유의확률 0.044로각치료제의약효가다르다고할수있다 (Table 3)(Fig. 1). 계열별효과비교경구투여약제중 SERM계열의 RAL군과 bisphosphonate 계열의 ALD군, RSD군, IBD군, ZLD군약물의효과를비교하기약물투여 1년후의기저치에대한골밀도변화율의차이를비교하였다. 두계열간골밀도변화율을독립표본 Table 4. Comparison between anti-osteoporotic medication categories. Category n Change rate of BMD T p-value SERM 27 2.33±5.06-2.370 0.019 BIS 152 4.35±3.89 BMD (bone mineral density, g/cm 2 ); SERM (selective estrogen receptor modulator); BIS (bisphosphonate); Values are expressed as Mean±SD
102 Kor. J. Clin. Pharm., Vol. 24, No. 2, 2014 T 검정으로비교하였을때각계열평균은 SERM 계열이 2.325±5.058, bisphosphonate 계열이 4.437±3.894로통계적으로유의한차이를보였다 (Table 4). 또한기저치골밀도의차이에따른영향을고려하여투여전골밀도를공변량으로공분산분석을실시한결과또한공변량변동에따른유의확률은 0.002로기저치골밀도가골밀도변화에영향을주며이요인을제거한순수한골밀도 Table 6. Comparison of BMD changes between routes of administration. Routes of administration n Change of BMD T p-value Oral 110 3.89±3.48-2.404 0.017 Injection 42 5.56±4.65 BMD (bone mineral density, g/cm 2 ); Values are expressed as Mean±SD Table 5. Comparison of effectiveness among each antiosteoporotic medications to BMD changes. Source Type III SS DF MS F p-value a) Modified model 245.479 b) 2 122.740 7.708 0.001 Intercept 271.053 1 271.053 17.022 0.000 BMD before treatment 151.733 1 151.733 9.529 0.002 Series 72.165 1 72.165 4.532 0.035 Error 2802.611 176 15.924 - - Sum 5972.121 179 - - - Corrected Sum 3048.090 178 - - - BMD (bone mineral density, g/cm 2 ); Type III SS (Type III sums of squares, Type III SS are each adjusted for all other effects in the model, regardless of order. The Type III tests are the ones that the text calls the Tests for Individual Coefficients and describes. The p- values and F statistics for these tests are found in the box labeled Type III Sum of Squares on the output); DF (degrees of freedom); MS (mean square, The difference between the observed score and the average score for Sum of squares divided by the degrees of freedom) a) Calculated with the significance level is 0.05 b) R 2 =0.081 (adjusted R 2 =0.070) 변화율에대한유의확률은 0.035로두계열간에통계적으로유의한차이가나타났다 (Table 5)(Fig. 2). 투여경로별비교 Bisphosphonate계열의약제중경구로투여하는약제 (ALD 군, RSD군 ) 와주사로투여하는약제 (IBD군, ZLD군 ) 의및효과를비교하기위해약물투여 1년후의기저치에대한골밀도변화율의차이를비교하였다. 두비교군간의골밀도변화율을독립표본 T 검정 (independent sample t-test) 으로비교하였을때각각의평균은경구제가 3.885±3.479 주사제가 5.557±4.645로통계적으로유 의한차이를보였다 (Table 6). 또한기저치골밀도의차이에따른영향을고려하여투여전골밀도를공변량으로공분산분석을실시한결과또한공변량변동에따른유의확률은 0.003로기저치골밀도가골밀도변화에영향을주며이요인을제거한순수한골밀도변화율에대한유의확률은 0.010로두계열간에통계적으로유의한차이가있음을확인할수있었다 (Table 7). 투여주기별비교 Bisphosphonate계열의약제중투여주기별로매일투여하는약제 (ALD군, RSD군 ) 1D군과 3개월에한번투여하는약제 (IBD군) 3M군과 1년에한번투여하는약제 (ZLD군) Table 7. Comparison of effectiveness between the routes of administration to BMD changes. Source Type III SS DF MS F p-value a) Modified model 210.922 b) 2 105.461 7.561 0.001 Intercept 276.243 1 276.243 19.806 0.000 BMD before treatment Routes of administration 125.972 1 125.972 9.032 0.003 95.082 1 95.082 6.817 0.010 Error 2078.215 149 13.948 - - Sum 5161.009 152 - - - Corrected Sum 2289.136 151 - - - Fig. 2. The scatter plot of BMD changes before and after anti-osteoporotic medications. BMD (bone mineral density, g/cm 2 ); Type III SS (Type III sums of squares); DF (degrees of freedom); MS (mean square) a) Calculated with the significance level is 0.05 b) R 2 =0.092 (adjusted R 2 =0.080)
폐경기여성에서골다공증및골감소증치료제의효과비교연구 103 Table 8. Comparison of BMD changes among dosing frequencies. Dosing frequency n Change of BMD T p-value 1D 137 3.58±3.87 3M 35 5.36±4.37-2.404 0.017 1Y 7 6.56±6.15 BMD (bone mineral density, g/cm 2 ); 1D (once daily); 3M (once every 3 months); 1Y (once yearly); Values are expressed as Mean±SD 1Y군으로나누어각각의효과를비교하기위해약물투여 1 년후의기저치에대한골밀도변화율의차이를비교하였다. 각비교군의골밀도변화율을일원분산분석 (one-way ANOVA) 비교하였을때각각의평균은 1D군이 3.578±3.870 3M군이 5.357±4.370 1Y군이 6.556±6.148로통계적으로유의한차이를보였다 (Table 8). 기저치골밀도의차이에따른영향을고려하여투여전골밀도를공변량으로공분산분석을실시한결과또한공변량변동에따른유의확률은 0.001로기저치골밀도가골밀도변화에영향을주며이요인을제거한순수한골밀도변화율에대한유의확률은 0.012로각비교군간에통계적으로유의한차이가있음을확인할수있었다 (Table 9). VD3 복합여부에따른비교경구투여약제중 alendronate 단일제제인 ALD군과 alendronate에 VD3가복합되어진 AVD3 군과의효과를비교하기위해약물투여 1년후의기저치에대한골밀도변화율의차이를비교하였다. 두비교군간의골밀도변화율을독립표본 t-검정으로비교하였을때각각의평균은단일제가 3.142±2.861 복합제가 5.558±5.499로통계적으로유의한차이를보였다 (Table 10). Table 9. Comparison of effectiveness among dosing frequencies to BMD changes. Source Type III SS DF MS F p-value a) Modified model 314.490 b) 3 104.830 6.711 0.000 Intercept 392.243 1 392.243 25.111 0.000 BMD before treatment 180.176 1 180.176 11.535 0.001 Dosing frequencies 141.176 2 70.588 4.519 0.012 Error 2733.600 175 15.621 - - Sum 5972.121 179 - - - Corrected Sum 3048.090 178 - - - BMD (bone mineral density, g/cm 2 ); Type III SS (Type III sums of squares); DF (degrees of freedom); MS (mean square) a) Calculated with the significance level is 0.05 b) R 2 =0.103 (adjusted R 2 =0.088) Table 10. Comparison of BMD changes in terms of vitamin D contents. Vitamin D n Change of BMD T p-value No (ALD only) 50 3.14±2.86-2.585 0.012 Yes (AVD3) 30 5.56±5.50 BMD (bone mineral density, g/cm 2 ); ALD (alendronate 70 mg); AVD3 (alendronate 70 mg + Cholecalciferol 2800 IU) Table 11. Comparison of effectiveness between medication in terms of vitamin D contents to BMD changes. Source Type III SS DF MS F p-value a) Modified model 334.867 b) 2 167.434 12.243 0.000 Intercept 346.561 1 346.561 25.342 0.000 BMD before treatment 225.390 1 225.390 16.481 0.000 Vit. D contents 96.026 1 96.026 7.022 0.010 Error 1053.005 77 13.675 - - Sum 2698.910 80 - - - Corrected Sum 1387.872 79 - - - BMD (bone mineral density, g/cm 2 ); Type III SS (Type III sums of squares); DF (degrees of freedom); MS (mean square) a) Calculated with the significance level is 0.05 b) R 2 =0.241 (adjusted R 2 =0.222) 또한기저치골밀도의차이에따른영향을고려하여투여전골밀도를공변량으로공분산분석을실시한결과또한공변량변동에따른유의확률은 0.000로기저치골밀도가골밀도변화에영향을주며이요인을제거한순수한골밀도변화율에대한유의확률은 0.010로두계열간에통계적으로유의한차이가있음을확인할수있었다 (Table 11). 고 평균수명의연장으로노인인구는증가하고있으며우리나라도 2020년에는노인인구비율이전체인구의 15% 에달할것으로예상되고있다. 13) 이러한고령인구의증가로만성질환또한늘어나고있으며그중하나인골다공증의경우그자체로는증상이없어골절이발생하였거나검사를받고나서야확인되는경우가대부분이다. 21) 이러한점에서골다공증은예방부터치료까지체계적인관리치료법이요구된다. 골다공증의치료를위한약제의경우다양한기전과제형으로지속적으로연구개발되고있는데본연구에서는골다공증및골감소증으로진단된폐경여성을중심으로그중최근많이사용되고있는골다공증치료제인 SERM과 bisphosphonates를중심으로계열별, 투여경로및투여주기등 찰
104 Kor. J. Clin. Pharm., Vol. 24, No. 2, 2014 에따라골밀도변화에미치는영향을비교하여그효과를비교해보고자하였다. 비교연구결과, bisphosphonates계열약물이 SERM과비교하였을때좀더높은골밀도변화를보였으며 bisphosphonates계열중에서는경구투여약제보다는주사제가, 투여주기가긴약물이, 비타민 D가복합된제제가좀더높은골밀도변화를나타냈다. 골다공증효과적인치료에있어서는충분한칼슘공급과규칙적운동, 금연및절주등의일상생활에서의노력과더불어약물치료를병행하여할것이며치료제의선택에있어서는효과및이상반응, 복약순응도가고려하여결정하여야할것이다. 16,22) 본연구는치료의중단및정기적검사미실시등으로각군별로충분한연구대상수의선정에제한이있었고후향적평가라는면에서환자의복약순응도, 동반질환및병용약제에대한충분한검토, 골밀도를제외한다른요인에대한평가의어려움으로골밀도검사만으로효과를분석한측면에서한계점이있었다. 향후골다공증의예방및효율적치료관리를위해골다공증에대한객관적인유병률조사를통한현황파악, 골다공증약제의보험급여기준에대한재검토및골다공증의장기적인예방책및효과적치료법에대한계속적인연구가필요하다고생각된다. 결 본연구는폐경후골다공증또는골감소증으로진단되어골다공증약제를투여받은환자중에서빈용되는 6가지약제인 SERM계열의 raloxifene, bisphosphonate 계열의 alendronate, risedronate, ibandronate, zoledronate와 alendronate 및 VD3 복합제를대상으로하여약제투여전골밀도를기준으로투여 1년후의골밀도변화율을 209명환자를대상으로후향적으로비교분석한연구로서 SERM계열보다는 bisphosphonate 계열에서좀더높은골밀도변화율을나타내며 bisphosphonate 계열중에는경구제제에비해주사제가, 투여주기가길수록, 단일제제보다는 VD3가복합된제제에서통계적으로유의하게더높은골밀도변화율을나타냈다. 론 참고문헌 1. NIH Consensus Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285: 785-95. 2. Vestergaard P. Anti-resorptive therapy for the prevention of postmenopausal osteoporosis: when should treatment begin? Treat Endocrinol 2005; 4(5): 263-77. 3. Tosteson AN, Burge RT, Marshall DA, et al. Therapies for Treatment of Osteoporosis in US Women: Cost-effectiveness and Budget Impact Considerations. Am J Manag Care 2008; 14(9): 605-15. 4. Physician's Guideline for Osteoporosis. Korean Society for Bone and Mineral Research. 2007 5. Rakel & Bope. Conn's Current Therapy 2008; 60th ed.: Chapter 149 6. Study of an Osteoporosis Management Program in Korea. Korean Health Promotion Foundation & Ministry of Health and Welfare. 2007 7. Small RE. Uses and Limitations of Bone Mineral Density Measurements in the Management of Osteoporosis. Med Gen Med 2005; 7(2): 3. 8. Lenchik L, Leib ES, Hamdy RC, et al. Executive summary International Society for Clinical Densitometry position development conference. J Clin Densitom 2002; 5: S1-3. 9. Nancy E. Lane. Epidemiology, etiology, and diagnosis of osteoporosis, American Journal of Obstetrics and Gynecology 2006; 194: 3-11. 10. Lash RW, Nicholson JM, Velez L, et al. Diagnosis and Management of Osteoporosis. Prim Care 2009; 36(1): 181-98. 11. Analysis of the health care situation in Korea. Korea Ministry of Health and Welfare, 2008 12. Chung KH, Oh YH, Seok JE, et al. Study the needs of the elderly living conditions and welfare of Korean society in 2004 (Policy Report No. 2005-03 of Korea Institute for Health and Social Affairs, 2005; 1-192). 13. Choi JY, Han SH, Shin AS, et al. Prevalence and Risk Factors of Osteoporosis and Osteopenia in Korean Women: Cross-sectional Study. J Menopausal Med 2008; 14(1): 35-49 14. Prevalence of osteoporosis research, to be conducted at the national level. Centers for Disease Control Press Release 2008 15. Yoon SH, Kim JG. Current treatment of postmenopausal osteoporosis. Korean J Obstet Gynecol 2005; 48(4): 844-56. 16. Lewiecki EM. Prevention and treatment of postmenopausal osteoporosis. Obstet Gynecol Clin North Am 2008; 35(2): 301-15. 17. Clinician's Guide to Prevention and Treatment of Osteoporosis National Osteoporosis Foundation. 2008, p19-26. 18. Kang BM. Comparison of Anti-osteoporotic Medications and Alternatives. Obstet Gynecol Sci 2006; 49(12): 2459-73. 19. Hamdy RC, Petak SM, Lenchik L. Which central dual X- ray absorptiometry skeletal sites and regions of interest should be used to determine the diagnosis of osteoporosis?
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