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1 Korean J Fam Pract. 2014;4:61-69 비스테로이드항염증제의복용과골절의위험도 : 관찰연구들에대한체계적문헌고찰과메타분석 Original Article 조한상, 조정수, 윤형호, 서예성, 엄춘식 * 한림대학교의과대학춘천성심병원교실 Use of Nonsteroidal Anti-inflammatory Drugs and Risk of Fracture: A Systematic Review and Meta-Analysis of Observational Studies Han-Sang Jo, Jung-Soo Cho, Hyoung-Ho Yoon, Ye-Seong Seo, Chun-Sick Eom* Department of Family Medicine, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea Background: Previous studies have reported inconsistent findings regarding the relationship between nonsteroidal antiinflammatory drug use and risk of fracture. We investigated this association using a meta-analysis of observational studies. Methods: We searched MEDLINE (PubMed), EMBASE, Cochrane Library from inception through February 2012 using common key words. We included case-control, nested case-control and cohort studies. Two evaluators independently reviewed and selected articles. To assess the quality of the studies, the Newcastle-Ottawa Quality Assessment Scale was used. Results: Of 7,281 articles, meeting our initial inclusion criteria, 4 case-control studies and 3 cohort studies were included in the final analysis. The pooled odds ratio for any fracture was 1.35 (95% confidence interval, 1.20 to 1.51) with the use of nonsteroidal anti-inflammatory drugs when compared with non-use. Conclusion: We found possible evidence linking use of nonsteroidal anti-inflammatory drugs to an increased risk of fracture. Common use of nonsteroidal anti-inflammatory drugs with the potential risk of fracture is of great importance to public health. Clinicians should consider carefully their decision to prescribe nonsteroidal anti-inflammatory drugs for patients already have an elevated risk of fracture. Keywords: NSAIDs; Fractures, Bone; Risk assessment; Meta-Analysis 서론 Received: August 28, 2012, Accepted: February 21, 2014 *Corresponding Author: Chun-Sick Eom Tel: , Fax: imhsjo@gmail.com Korean Journal of Family Practice Copyright 2014 by The Korean Academy of Family Medicine 진통제또는소염제중한가지종류인비스테로이드항염증제는관절염및골절환자들의통증완화및연조직부위손상의치료등에다양하게쓰인다. 1) 그러나이런폭넓은처방에도불구하고비스테로이드항염증제의복용이골절의발생위험도에영향을줄수있는지에대한논란이있다. 2,3) 현재비스테로이드항염증제의소비량은세계적으로증가추세를보 Vol. 4, No. 1 Mar

2 Han-Sang Jo, et al: Use of NSAIDs and Risk of Fx.: A Systematic Review and Meta-Analysis of Observational Studies 이고있으며, 4) 이로인해골절발생률의증가를초래하게된다면보건학적으로중요한문제가될수있다. 이와관련된동물실험및역학연구의결과들은일관된경향을보이진않는다. 기존연구들에서는비스테로이드항염증제의복용은골밀도를증가시키는효과가있으며, 5-7) 이를통해잠재적으로골절발생의위험도를낮출것이라가정하였으나, 결과적으로는연관성을찾지못했거나, 5) 다른부위는영향이없었고고관절골절의경우에만위험도를낮춘다고분석했다. 8,9) 그러나비스테로이드항염증제의복용빈도와골절발생빈도간에비례적인연관성을제시한역학연구들이이후에나왔다. 2,10) 이렇게비스테로이드항염증제의복용과골절위험도에관한여러편의원저들이발표되어왔지만, 무작위대조군임상연구 (randomized controlled clinical trial) 나기존연구에대한메타분석은없어서인과관계를논하기에는한계가있다. 따라서본연구는비스테로이드항염증제의복용과골절위험도간의관계를평가한관찰연구들을메타분석하면서체계적으로고찰하고자한다. 방법 1. 문헌검색 2012년 2월까지를최종검색시점으로하였으며, 출판된논문의언어는제한을두지않았다. MEDLINE (1966년 2012 년 2월 ), EMBASE (1980년 2012년 2월 ), Cochrane Library (1998 년 2012년 2월 ) 데이터베이스를이용하여검색을시행했다. Medline과 EMBASE 그리고 Cochrane Library 검색을위한중심단어들은다음과같다. #1. NSAIDs OR nonsteroidal anti-inflammatory drugs OR non-steroidal OR aceclofenac OR celecoxib OR diclofenac OR ibuprofen OR indomethacin OR ketoprofen OR meloxicam OR naproxen #2. fracture OR fracture risk OR bone health OR osteoporosis OR osteopenia OR bone metabolism OR bone mineral density OR BMD #3. #1 AND #2 2. 연구선택우리는병원또는지역사회의성인인구를대상으로하는비스테로이드항염증제의복용과골절위험도에관한무작위대조군임상연구와환자-대조군연구, 코호트연구를선택하려고하였으며, 두명의저자들이독립적으로검색후얻어진연구들중, 포함기준을만족하는연구들을선택했으나, 결정 이일치하지않는연구가있을때에는두저자간의토론과합의를통해서조정했고, 합의불가시 3번째저자가중재후최종선택을했다. 비스테로이드항염증제의종류에는비선택적항염증제와 COX-2 선택적항염증제등이있으나특별한제한없이모든형태의약물종류를포함했다. 그러나아세트아미노펜 (acetaminophen) 의경우는소염작용이포함되지않으므로종에속하지않는것으로간주하여제외했다. 3. 자료추출및질평가연구설계, 대상자수와특성, 복용한비스테로이드항염증제의종류및기간, 추적관찰기간, 결과변수, 보정한혼란변수의보정된자료를추출했다. 관찰연구의질평가도구인 Newcastle-Ottawa Quality Assessment Scale (NOS) 의환자-대조군과코호트연구를위한체크리스트 11) 를이용했다. 전반적인평가는 0 9점사이의점수를매겨시행했으며최종분석에는 6 8점사이의논문들을포함시키기로했다. 최종분석에선택된 7편논문들의평균점수는 7점이었다. 4. 주분석및부집단분석연구기간복용한비스테로이드성항염증제와골절의위험도를분석했고, 유사한성격을가진 1) 연구설계 ( 환자-대조군, 코호트연구 ), 2) 골절확인방법 ( 저자보고, 데이터베이스보고 ) 을기준으로부집단을나누어분석했다. 5. 통계분석연구들은각각 odds ratios (OR), relative risks (RR) 로결과를 95% 의신뢰구간 (confidence interval, CI) 과같이제시했다. 우리는연구대상의발생률이연간 5% 미만으로드물게생기는점을고려하여, OR가 RR에근접한다는가정하에연구들에서보고한수치들의형태에관계없이통합하여분석했다. 연구들간결과들의이질성여부를검토하기위해연구들간의총변이도의백분율을측정하는 Higgins I 2 를시행했다. 12) Forest plot을통해결과들을표로요약했고, 최종분석에포함된연구들의출판편향여부를확인하기위해 Begg s funnel plot 을작성했으며 Egger s test를시행했다. 연구결과들을분석하기위해통계프로그램인 Stata SE ver (Stata Co., College Station, TX, USA) 를사용했다. 결과 전자검색으로검색된총 7,281 개의초록을조사하여주 62 Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

3 조한상외 : 비스테로이드항염증제의복용과골절의위험도 : 관찰연구들에대한체계적문헌고찰과메타분석 제와연관된 43개의연구를선택했고이중 13개의연구를선정해서전문을조사했으며, 그결과비스테로이드항염증제복용과골절위험도의관계를연구한환자-대조군연구 4편 (Etmian 등, 1) Vestergaard 등, 2) Rashiq와 Logan, 8) van Staa 등 10) ) 과코호트연구 3편 (Bauer 등, 5) Vestergaard 등, 13) van Staa 등 14) ) 이포함기준을만족해서메타분석대상논문으로골라분석을시행했다 (Figure 1). 환자-대조군연구중 Etmian 등 1) 에선 15,792명의환자군과 47,289명의대조군을, Vestergaard 등 2) 의경우 59,690명의환자군과 142,274명의대조군을, Rashiq와 Logan 8) 는 102명의환자군과 204명의대조군을, van Staa 등 10) 에서는 32,209명의환자군과 21,013명의대조군을포함했다. 코호트연구중 Bauer 등 5) 에서는전체 7,786명의코호트중에서비척추성골절이발생한 893건을분석했고, Vestergaard 등 13) 에서는골절력이있는대상들중, 321명의비스테로이드항염증제복용군과, 골절발생직전부터 10년간복용력이없는 1,695명의대조군을포함하였으며, van Staa 등 14) 에서는비척추성골절과관련된 incidental 비스테로이드항염증제 users가 2,882명, regular 비스테로이드항염증제 users는 10,505명그리고 5,793명의약물비복용군을포함하였다 (Table 1). 선택된연구들은영국에서 3편, 덴마크에서 2편, 그리고미국과캐나다에서각각 1편씩이시행되었으며, 1986년부터 2012년사이에출간되었다. NOS 체크리스트에의한질평가결과 7편연구모두최종평가는 6 8점으로연구들간의질에는큰차이가관찰되지않았다 (Tables 2, 3). 선정된 7편의연구중환자-대조군연구 1편에서 8) 비스테로이드항염증제의복용이골절위험도를낮춘다고분석했다. 그리고코호트연구 1편에서는 5) 비스테로이드항염증제의복용이골절위험도와연관성을드러내지않는다고보았다. 나머지 3편의환자-대조군연구들과 1,2,10) 2편의코호트연구들에서는 13,14) 비스테로이드항염증제의복용이골절위험도를높인다고판단했다. 총 7편의연구를종합한비스테로이드항염증제의복용에대한골절위험도의 OR은 1.35 (95% CI, 1.20 to 1.51), 이질성에대한 I 2 =94.1% 였다 (Figure 2). 연구간의이질성원인을조사하기위해유사한성격, 즉연구설계, 골절확인방식들을기준으로 2가지부집단을나누어분석했다. 연구설계에따라환자대조군연구들의 OR 은 1.36 (95% CI, 1.18 to 1.56), I 2 =96.9%, 코호트연구들의 OR은 1.30 (95% CI, 1.01 to 1.68), I 2 =53.2% 였다. 저자보고 (self-report) 연구들의 5,8) OR은 0.80 (95% CI, 0.55 to 1.16) 그리고 I 2 =22.7% 로유의하지않았고, 데이터베이스보고연구들의 1,2,10,13,14) OR은 1.41 (95% CI, 1.25 to 1.58), I 2 =95.6% 로유의했다. Begg s Funnel plot에서는뚜렷한비대칭이관찰되지않았고, Egger s test에서비스테로이드항염증제의복용과골절위험도의관계에대한 Figure 1. Flow diagram of selection of studies for inclusion in meta-analysis. Vol. 4, No. 1 Mar

4 Han-Sang Jo, et al: Use of NSAIDs and Risk of Fx.: A Systematic Review and Meta-Analysis of Observational Studies Table1. Characteristics of studies included in the final analysis (n=7) Country; study design or Author (year) Study years Agent and comparison Outcome and ascertainment Adjustment variables setting Rashiq and Logan 8) (1986) UK; HCC; university hospital, Nottingham; aged Agent: NSAIDs, GI drugs, diuretics, cardiovascular drugs, steroids, hypotensive drugs, hypnotics, psychotropic agents, analgesics, antibiotics; comparison: last use 12 mo ago vs. nonuse Outcome: hip fracture Ascertainment: radiologically confirmed diagnosis Age, gender, by the time before fracture, any drug, GI drugs, diuretics, other cardiovascular drugs, hypotensive drugs, hyponotics, NSAIDs, psychotropic agents, analgesics, steroids, antibiotics, drugs not elsewhere classified Bauer et al. 5) (1996) USA; Cohort; white women aged Agent: NSAIDs, aspirin; comparison: last use 12 mo ago vs. nonuse Outcome: hip fracture, all nonspine fracture Ascertainment: radiologically confirmed diagnosis Age, women, weight, current estrogen and corticosteroid use (%), back pain, self reported rheumatoid and osteoarthritis, history of gastric surgery and osteoporosis, bone mineral density Van Staa et UK; Cohort; GPRD; Agent: NSAIDs; comparison: regular Outcome: nonvertebral, forearm, Age, number of women, follow-up (duration), back pain, RA, falls al. 14) mean age: 54 (3 or more NSAIDs use 10 y ago) hip, vertebral fracture year before, hormone replacement therapy, a baseline history of (2000) use vs. nonuse, regular use vs. incidental (1 or 2 NSAIDs use) use Ascertainment: insurance code fracture (nonvertebral, vertebral) using ICD-9 system Van Staa et UK; NCC; GPRD; Agent: NSAIDs, hypnotics/ Outcome: any fracture Age, number of women, history of anemia, dementia, al. 10) mean age: 50 anxiolytics, antidepressants, anti- Ascertainment: insurance code cerebrovascular disease, chronic obstructive pulmonary disease, (2002) Parkinson, antiarrhythmic drugs; using ICD-9 system comparison: last use 6 mo ago vs. nonuse recent use of oral corticosteroids, anti-convulsants, NSAIDs, antiarrythmics, hypnotics/anxiolytics, antidepressants, or anti- Parkinson drugs Vestergaard et al. 2) (2006) Denmark; PCC; the National Hospital Discharge Register; age<40, 40 59, and 60 years 2000 Agent: NSAIDs, acetaminophen, ASA; comparison: recency of use (last use <1 y ago vs. >1 y ago), cumulated and daily dose (<20 DDD; DDD; and 75 DDD) Outcome: any fracture, hip, forearm, spine fracture Ascertainment: hospital admission with a diagnosis of fracture (the Danish version of ICD-10 system) Age, men, annual income (DKR), living with someone, working, no comorbidity, previous fracture, number of bed days in hospital in 1999, contacts to general practitioner or specialists in 1999, alcoholism, RA, OA, antiepileptic drugs, sedatives, anxiolytics, and hypnotics, neuroleptics, antidepressants, ever use of any corticosteroid, morphine and morphine agonists, codeine, dextropropoxyphene, tramadol, migraine drugs, acetaminophen combinations of codeine+asa, any type of NSAID or ASA, aceclofenac, celecoxib, diclofenac, diflunisal, etodolac, flurofen, ibuprofen, indomethacin, ketoprofen, lornoxicam, meloxicam, nabumeton, naproxen, phenylbutazon, piroxicam, rofecoxib, sulindac, tenoxicam, tiaprofen, tolfenam (Continued to the next) 64 Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

5 조한상외 : 비스테로이드항염증제의복용과골절의위험도 : 관찰연구들에대한체계적문헌고찰과메타분석 Table1. Continued Country; study design or Author (year) Study years Agent and comparison Outcome and ascertainment Adjustment variable setting Etmian et al. 1) (2009) Canada; PCC; comprehensive administrative claims and pharmacy data repository: aged Agent: NSAIDs, COX-2 inhibitors; comparison: current use (last use 3 mo ago) vs. past use Outcome: any fracture, hip, spine or forearm fracture Ascertainment: hospital admission with a diagnosis of Fracture (ICD system) Age, sex, ethnicity, medical co-morbidity, sociodemographic and medical diagnoses known to affect fracture risk Vestergaard et al. 13) (2012) Denmark; Cohort; Danish Osteoporosis Prevention Study; Danish Caucasian women aged Agent: NSAIDs, ASA, opioids, paracetamol; comparison: exposed/non-exposed during 10 years of follow-up but before time of fracture Outcome: any fracture Ascertainment: radiologically confirmed diagnosis Age, women, month form last menstrual bleeding, weight, height, waist, urine hydroxyproline and creatinine, alkaline phosphatase, schober s measure, fasting plasma glucose, FSH, serum creatine and estradiol, osteocalcin, BMD, daily intake of calcium and vitamin D, family history of a fracture, prior fracture, current smoking HCC: hospital based case-control, NSAIDs: nonsteroidal anti-inflammatory drugs, GI drugs: gastrointestinal drugs, GPRD: the General Practice Research Database, ICD: International Classification of Diseases, RA: rheumatoid arthritis, NCC: nested case-control, PCC: population based case-control, DDD: defined daily dosages, OA: osteoarthritis, ASA: acetylsalicylic acid, FSH: follicle stimulating hormone, BMD: bone mineral density. Table 2. Methodological quality of case-control studies included in the final analysis, based on the Newcastle-Ottawa Scale (n=4) Selection Comparability Exposure Case-control studies Adequate definition of cases Representativeness of cases Selection of controls Definition of controls Control for important factor or additional factor Ascertainment of exposure (blinding) Same method of ascertainment for subjects Non-response Total score (0 9) rate Rashiq and Logan 8) (1986) Van Staa et al. 10) (2000) Vestergaard et al. 2) (2006) Etmian et al. 1) (2009) Vol. 4, No. 1 Mar

6 Han-Sang Jo, et al: Use of NSAIDs and Risk of Fx.: A Systematic Review and Meta-Analysis of Observational Studies Table 3. Methodological quality of cohort studies included in the final analysis, based on the Newcastle-Ottawa Scale (n=3) Selection Comparability Outcome Total score (0 9) Adequacy of follow-up of cohorts Follow-up long enough for outcomes to occur Assessment of outcome Control for important factor of additional factor Outcome of interest not present at start of study Ascertainment of exposure Selection of the nonexposed cohort Representativeness of the exposed cohort Cohort and nested case-control studies (n=3) Bauer et al. 5) (1996) Van Staa et al. 14) (2000) Vestergaard et al. 13) (2012) P-value가 0.694로유의하지않으므로포함된연구들사이의출판편향은없었다 (Figure 3). 고찰 비스테로이드항염증제는골절의유발위험성과관련하여다양한방식으로영향을끼칠수있다. 프로스타글란딘 (prostaglandin, 특히 prostaglandin E 2 ) 은 cyclic 3 5 adenosine monophosphate의강력한길항제이며골흡수와골형성을자극함으로써골회전 (bone turnover) 을높이는데중요한역할을할수있다 ) 이런효과들은프로스타글란딘이파골세포와조골세포의전구세포들에영향을미쳐서이들의증식및분화에영향을주기때문인것으로보인다. 15) 본연구를통해우리는성인들에서비스테로이드항염증제의복용이골절위험도를높이는개연성이있음을알수있었다. 부집단을나누어분석을시행한결과, 연구설계에관한부집단분석의경우환자-대조군연구들과코호트연구들에서모두골절위험도를높이는것으로나왔고, 특히환자-대조군연구들의 OR가코호트연구들의 OR보다더높게나왔다. 일반적으로는증거수준 (evidence-level) 측면에서코호트연구가환자-대조군연구보다높은경향을보이지만, 분석대상인환자-대조군연구들은 Rashiq와 Logan 8) 을제외하고는환자군과대조군이대규모로설정되어있고, OR의 95% CI 구간의폭도좁았으며, marginal한분포를보이고있어서, 코호트연구들보다위험도가높게나오는것으로보인다. 다음으로골절확인방식에대한부집단분석에서는, 보통저자보고보다데이터베이스를통한보고를더신뢰하는데, 저자보고연구들인경우의 OR보다데이터베이스를통한보고인연구들의 OR가더높은위험도를보였다는점에서, 비스테로이드항염증제복용이골절발생률을높일수있는개연성을강화한다고본다. 그리고부집단분석에포함되지는못했지만, 비스테로이드항염증제종류중에서일부 (ibuprofen, diclofenac, naproxen) 만골절위험도를높인다는보고들에 2,19) 대해서는이후에도추가적인연구가필요해보인다. 자세의균형을조절하는기전에변화가있을시사고가나기쉽고이로인해골절위험도가증가할수있는데, 2) ibuprofen이나 piroxicam과같은약제를복용시어지럼증을부작용으로보고한경우와, 19) rofecoxib (11%), naproxen (12%) 복용군이대조군 (5%) 에비해어지럼증을더흔하게호소한다고밝힌논문도있다. 20) 각각의연구에서보정된혼란변수들로는, 나이와성별이모든연구들에공통적으로있고, 비스테로이드항염증제외에병용한약물들에대한평가는일부의연구들에만 2,5,8,10) 있 66 Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

7 조한상외 : 비스테로이드항염증제의복용과골절의위험도 : 관찰연구들에대한체계적문헌고찰과메타분석 Figure 2. Risk of overall fracture risk among those who received nonsteroidal anti-inflammatory drugs in observation al studies. Figure 3. Begg s funnel plots and Egger s test for identifying publication bias (P=0.694) in a meta-analysis of case-control and cohort studies (n=7). OR: odds ratio. 었다. 연구의질평가항목에선평균 7점으로, 연구자체가최소요구사항들을만족한상태이며, 부적절하거나충족기준에미달해서결론이바뀔상황은아니라고본다. 본연구에는몇가지제한점들이있다. 첫째, 남 / 여모두가포함된연구들에 1,4,8,10,13) 비해한쪽성별 ( 여성 ) 만대상으로하여이를보정한연구들은 5,14) 성별발생률차이를고려할때, 선택비뚤림의가능성이있다. 둘째, 연구의대상이유럽과북미의백인들로주로한정되면서, 황인종과흑인종에대한연구는포함되지않았다. 각인종별로 CYP2C8-CYP2C9 haplotypes 에상당한차이가있으며, 21) 비스테로이드항염증제의대부분은 CYP2C9의 substrates이고일부는 CYP2C8 polymorphisms 에의해약물역동 (pharmacokinetics) 과부작용의위험도에차이가있을수있다는논문을 22) 통해미루어볼때인종간차이가줄수있는영향에대해서도추가적인연구가필요하다고 본다. 셋째, Bauer 등 5) 과 Rashiq와 Logan 8) 의관찰기간은타연구들에비해그기간이약 1 3년으로짧아비스테로이드항염증제복용으로인한골절발생의영향을관찰하기에충분한기간이아닐수있다. 넷째, 골절발생건수는다른연구들이 Bauer 등 5) 과 Rashiq와 Logan 8) 의연구에비해많았기때문에무작위오류발생가능성이적을것이다. 다섯째, 각연구들에서는비스테로이드항염증제의복용량을평가하기위해서연구기간해당약물을처방받은경력이있는지를살폈거나, 해당약물의처방개수별로분류하거나, 규칙적으로복용하였는지또는간헐적으로복용하였는지여부를구별하거나, 연구시점에비스테로이드항염증제를복용중인지과거에복용여부가있었는지를파악하거나, World Health Organization Collaborating Center for Drug Statistics Methodology ( whocc.no/atcddd/) 에근거하여누적복용량을 defined daily dosages (DDDs) 로환산하는등다양한종류의기준들을포함하고있다. 총 7편의연구들중에서 2편의연구들만이 2,13) 비스테로이드항염증제복용량을계량할수있는누적복용량 (DDDs) 을분석에이용했다. 여섯째, 골밀도저하가골절의발생률을높이는중요한요인임에도불구하고비스테로이드항염증제의복용으로인한골절의위험성을평가하는데있어서, Bauer 등 5) 과 Vestergaard 등 13) 의연구를제외하고는환자들의기저골밀도의영향을보정하지않았다. 다른연구에서 COX-2 선택적비스테로이드항염증제와아스피린의병용이전신의골밀도를높여서상대적으로골절위험도를줄인다는보고가 7) 있었는데, 앞으로시행될관련연구에서는분석시기저골밀도의영향에대한고려가포함되어야한다. 일곱번째 년대 2편의 5,8) 연구는비스테로이드항염증제복용이골절발생의위험도를낮춘다고분석했지만, 2000년이후발표된 5편의 1,2,10,13,14) 대규모연구에서는위험도를높인다고판단했다. 근래의연구일수록비스테로이드항염증제복용을 Vol. 4, No. 1 Mar

8 Han-Sang Jo, et al: Use of NSAIDs and Risk of Fx.: A Systematic Review and Meta-Analysis of Observational Studies 골절의위험요소로인식하고있으며, 연속된연구결과들에일관성이있기때문에결론을내릴수있다고본다. 결론적으로비스테로이드항염증제의복용은골절발생위험도를높이므로, 향후의사들이골절발생위험군에속하는환자들에게비스테로이드항염증제를처방시더주의를기울여야할필요가있다. 요약 연구배경 : 기존의관찰연구들에서는비스테로이드항염증제복용이골절의발생위험도에영향을줄수있는가에대한논란을지속해왔다. 본연구는비스테로이드항염증제복용과골절발생의위험도간의관계를평가한관찰연구들에대해서체계적인문헌고찰과메타분석을시행하였다. 방법 : MEDLINE (PubMed), EMBASE, Cochrane Library 데이터베이스를이용해 2012년 2월까지의자료를검색하였다. 두명의저자가자료추출양식을사용하여연구설계, 대상자수와특성, 복용한비스테로이드항염증제의종류와기간, 추적관찰기간, 결과변수와, 혼란변수를보정한자료를추출하였다. 연구의질을평가하기위해서 Newcastle-Ottawa Scale을이용하였다. 출판비뚤림존재여부를평가하기위해서 Begg s funnel plot을이용하여평가하였다. 결과 : 총환자-대조군연구 4편과코호트연구 3편이선택되었다. 전체비스테로이드항염증제복용에대한교차비는 1.35 (95% 신뢰구간, ) 였다. 결론 : 본메타분석결과비스테로이드항염증제복용은골절발생위험도를높이는것으로보인다. 따라서향후의사들이골절발생위험군에속하는환자들에게비스테로이드항염증제를처방할시에더주의를기울여야한다. 중심단어 : 비스테로이드항염증제 ; 골절의위험도 ; 메타분석 REFERENCES 1. Etmian ME, Lix LM, Metge CJ, Prior HJ, Leslie WD. Non-steroidal anti-inflammatory drugs are associated with osteoporotic fractures: a population-based analysis. Calcif Tissue Int 2009;85: Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 2006;79: Vestergaard P, Rejnmark L, Mosekilde L. Increased mortality in patients with a hip fracture-effect of pre-morbid conditions and post-fracture complications. Osteoporos Int 2007;18: Samad MK. Consumption patterns of non-steroidal antiinflammatory drugs by the community without prescription in Dhaka city. Bangladesh J Pharmacol 2009;4: Bauer DC, Orwoll ES, Fox KM, Vogt TM, Lane NE, Hochberg MC, et al. Aspirin and NSAID use in older women: effect on bone mineral density and fracture risk. Study of Osteoporotic Fractures Research Group. J Bone Miner Res 1996;11: Morton DJ, Barrett-Connor EL, Schneider DL. Nonsteroidal anti-inflammatory drugs and bone mineral density in older women: the Rancho Bernardo study. J Bone Miner Res 1998;13: Carbone LD, Tylavsky FA, Cauley JA, Harris TB, Lang TF, Bauer DC, et al. Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: impact of cyclooxygenase selectivity. J Bone Miner Res 2003;18: Rashiq S, Logan RF. Role of drugs in fractures of the femoral neck. Br Med J (Clin Res Ed) 1986;292: Taggart HM. Do drugs affect the risk of hip fracture in elderly women? J Am Geriatr Soc 1988;36: Van Staa TP, Leufkens HG, Cooper C. Utility of medical and drug history in fracture risk prediction among men and women. Bone 2002;31: Wells GA, Shea B, O Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [Internet]. Ottawa (ON): Ottawa Hospital Research Institute; 2011 [cited 2012 Feb 22]. Available from: clinical_epidemiology/oxford.asp. 12. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21: Vestergaard P, Hermann P, Jensen JE, Eiken P, Mosekilde L. Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporos Int 2012;23: Van Staa TP, Leufkens HG, Cooper C. Use of nonsteroidal antiinflammatory drugs and risk of fractures. Bone 2000;27: Kawaguchi H, Pilbeam CC, Harrison JR, Raisz LG. The role of prostaglandins in the regulation of bone metabolism. Clin Orthop Relat Res 1995;(313): Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

9 조한상외 : 비스테로이드항염증제의복용과골절의위험도 : 관찰연구들에대한체계적문헌고찰과메타분석 16. Raisz LG. Physiologic and pathologic roles of prostaglandins and other eicosanoids in bone metabolism. J Nutr 1995;125(7 Suppl):2024S-7S. 17. R aisz LG. Prostaglandins and bone: physiology and pathophysiology. Osteoarthritis Cartilage 1999;7: Raisz LG. Potential impact of selective cyclooxygenase-2 inhibitors on bone metabolism in health and disease. Am J Med 2001;110 Suppl 3A:43S-5S. 19. Shearn MA. Nonsteroidal anti-inflammatory agents: nonopiate analgesics: drugs used in gout. In: Katzung BG, editor. Basic and clinical pharmacology. Norwalk (CT): Appleton & Lange; p Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003;289: Speed WC, Kang SP, Tuck DP, Harris LN, Kidd KK. Global variation in CYP2C8-CYP2C9 functional haplotypes. Pharmacogenomics J 2009;9: Daily EB, Aquilante CL. Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics 2009; 10: Vol. 4, No. 1 Mar

Treatment and Role of Hormaonal Replaement Therapy

Treatment and Role of Hormaonal Replaement Therapy Treatment and Role of Hormone Replacement Therapy Chung-Ang University Hospital Chee Jeong Kim 7.2 5.3 6.4 5.6 7.3 5.5 1 1 2 3 4 10 11 7 34 49 122 123 1.0 - - 10. 2001 1998 1998 Improvement of postmenopausal