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1 대한내과학회지 : 제 92 권제 2 호 In-depth review 스테로이드유발성골다공증 아주대학교의과대학류마티스내과학교실 정주양 서창희 Glucocorticoid-induced Osteoporosis Ju-Yang Jung and Chang-Hee Suh Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea Osteoporosis is a common adverse event among patients on glucocorticoid therapy. Glucocorticoids reduce bone formation and increase cortical porosity in proportion to the dose and duration of glucocorticoid use. While the epidemiology of glucocorticoid-induced osteoporosis has been well characterized, its pathophysiology and effective management remain unclear. Several recommendations for glucocorticoid-induced osteoporosis are used to determine which patients on long-term glucocorticoid treatment to treat and when. The fracture risk can be assessed using dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool algorithm, along with other clinical factors. The management of glucocorticoid-induced osteoporosis includes anti-osteoporotic therapy and measures to prevent bone loss. Bisphosphonates are currently the first choice treatment, with teriparatide and denosumab being alternatives. (Korean J Med 2017;92: ) Keywords: Glucocorticoid; Osteoporosis; Bone mineral density 서론스테로이드는다양한류마티스질환을포함한만성염증성질환에서효과적인항염증제로뿐만아니라, 이식후거부반응을예방하기위한면역억제제로광범위하게사용되고있다 [1]. 만성염증성질환에서 3개월이상의오랜기간동안사용되는스테로이드는다양한부작용을야기하는데, 부종, 피부의변화, 백내장, 녹내장, 인슐린저항성, 고혈압, 감염의위험성증가, 근육병증등이생길수있다 [2]. 스테로이드를복용중인성인은 % 로보고되었으며, 특히골절의위 험이증가되는 60세이상에서사용이 2% 이상으로현저히증가한다고알려져있다 [3]. 스테로이드유발성골다공증 (glucocorticoid-induced osteoporosis) 은가장흔하고위험한스테로이드의부작용이자이차성골다공증의가장흔한원인으로전체골다공증환자의 20% 를차지한다 [2]. 스테로이드로인한골다공증및골절은널리인지되어있으며다양한치료에대한가이드라인들이발표되었다 [2,4-6]. 스테로이드유발성골다공증은의료진의관심에의해서조기평가및치료가가능하고, 이를통하여골절의예방이가능하기때문에합당한평가및조기개입이강조되고있다. Correspondence to Chang-Hee Suh, M.D., Ph.D. Department of Rheumatology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: , Fax: , chsuh@ajou.ac.kr Copyright c 2017 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Ju-Yang Jung, et al. Glucocorticoid-induced osteoporosis - 여기에서는스테로이드유발성골다공증의역학과병리기전에대해알아보고필요한검사및검사의대상, 골절의위험을줄이기위한효과적인예방및치료에대하여알아보고자한다. 역학스테로이드치료는시작하고수주내로골소실이시작되며, 골밀도의저하와골절의위험도는축적된스테로이드의용량과밀접한관계를보인다 [7-9]. 스테로이드의복용을시작하고처음 6개월간골소실이가장높게발생하는데, 평균적으로일년간최대 12% 까지골소실이발생한다 [10]. 골절의위험을증가시키는최소한의스테로이드용량에관해서는이견이많은데, 여러연구의메타분석에서하루 5 mg 이상의프레드니솔론을동등용량복용하면골밀도를감소시키고골절의위험이증가된다고보고되었다 [8]. 또다른연구들에서는하루 5 mg 이하에서도골절의위험이 20% 까지증가하며하루 20 mg 이상에서는 60% 까지증가하였다 [8,11]. 스테로이드를중단하면골절의위험은현저히감소되지만스테로이드복용전으로돌아가지는않는다 [12,13]. 스테로이드유발성골다공증이잘생길수있는위험요인은나이, 낮은체질량지수, 골절의병력, 흡연, 과도한음주, 잦은낙상, 고관절골절의가족력, 글루코코르티코이드수용체유전형, 11베타-하이드록시스테로이드탈수소효소 (11β-hydroxysteroid dehydrogenase)-1의발현, 고용량스테로이드요법, 낮은골밀도와류마티스관절염, 류마티스성다발근통, 염증성장질환, 만성폐질환, 이식등의기저질환이있다 [14]. 류마티스관절염과만성폐쇄성폐질환등과같은많은염 증성질환에서스테로이드의사용과는독립적으로골소실이발생한다. 염증상태를유도하거나유지시키는다양한염증성시토카인들은골형성과골흡수를변화시키기때문이다. 대표적으로류마티스관절염에서주요한염증매개물질인종양괴사인자알파, 인터루킨-1, 6, 11, 17은골흡수를증가시키는 receptor activated nuclear-kappab ligand (RANKL) 의발현을높인다 [15]. 이로인하여류마티스관절염에서골밀도가낮아지고골절이잘생긴다 [16,17]. 그래서류마티스관절염에서저용량스테로이드의사용이병인기전에따른골소실을줄일수도있다는의견이있지만아직이를증명할만한연구결과는없다. 천식과만성폐쇄성폐질환에서흡입용스테로이드가널리사용되고있는데, 대규모코호트를대상으로시행된연구들에서흡입용스테로이드와골절이나골밀도의상관성은상이한결과들이보였다 [18-20]. 만성폐쇄성폐질환환자들을대상으로시행된 16개의 randomized clinical trials (RCT) 결과와 7개의관찰연구를메타분석한결과에서흡입용스테로이드의사용은골절의위험을증가시키는것으로밝혀졌고 (RCT-odds ratio [OR] % confidence interval [CI] , 관찰연구 OR 1.09; 95% CI ), 특히장기간플루티카손이나부데소나이드를사용하는경우용량에비례하여골절의위험이증가되었다 [19]. 하지만저용량의흡입용스테로이드는골절의위험을올리지않았고, 스테로이드의용량에비례해서골절의위험이증가되지만, 스테로이드요법보다천식의중증도가미치는영향이더크다고밝혀졌다 [21]. 병인- 스테로이드가뼈에미치는영향및그기전스테로이드는골형성을감소시키고골흡수를증가시키는 Table 1. Pathogenesis of glucocorticoid-induced osteoporosis Bone metabolism Osteoblast differentiation/proliferation/function Bone formation Osteocyte sclerostin and apoptosis Osteoclast apoptosis bone resorption Bone mass Bone quality Bone strength Muscle Muscle atrophy and weakness Risk of falls Calcium metabolism Intestinal absorption of calcium Renal resorption of calcium Calcium PTH Endocrine system Sex and growth hormone Loss of pulsatile secretion of PTH PTH, parathyroid hormone.

- 대한내과학회지 : 제 92 권제 2 호통권제 675 호 2017 - 것으로알려져있다 (Table 1) [22,23].

3 - 대한내과학회지 : 제 92 권제 2 호통권제 675 호 것으로알려져있다 (Table 1) [22,23]. 스테로이드는골형성에중요한골모세포 (osteoblast) 의활성화를낮춰준다고알려져있으며, 저용량의스테로이드에도골모세포활성화지표인혈청내 I형 N말단프로콜라젠 (N-terminal procollagen), I형 C 말단프로콜라젠, 오스테오칼신 (osteocalcin) 의수치가감소된다 [14,24]. 골형성은 Dikkopf-related protein 1 (DKK-1) 과 sclerostin에의해억제되는데스테로이드에의하여이들의발현이증가된다 [25]. 또한스테로이드는골모세포의전구체가골수에서골모세포대신지방생성과정으로분화되도록유도한다. 그리고골의미세손상을수선하는골세포도사멸시켜골질도감소시킨다. 뿐만아니라, 스테로이드는파골세포의분화에관여하는시토카인의발현은증가시키고파골세포를억제시키는시토카인은감소시켜골흡수를증가시킨다 [15,26,27]. 스테로이드유발성골다공증이시작되면처음에는해면골 (trabecular bone) 이약해져척추뼈골절의위험이증가되고이후피상골 (cortical bone) 이영향을받아대퇴부경부골절의발생가능성도증가된다 [26]. 또한폐경후골다공증과는다른미세구조의이상이더많이발생한다 [28]. 골대사에미치는직접적인작용외에도스테로이드는칼슘의흡수를떨어뜨리고성호르몬과성장호르몬을억제하고부갑상선호르몬의박동성분비를바꾸어골소실을유도한다 [26]. 또한, 스테로이드로인한근육의위축및근력의저하는골밀도를저하시키고낙상의위험도를증가시킨다. 평가및진단어떤대상에게언제스테로이드유발성골다공증을고려하고무슨검사를하고어떤약제를선택해야하는지에대해서는발표된스테로이드유발성골다공증가이드라인들을참고할수있다 [29-31]. 우선검사를시행하기앞서손쉽게활용할수있는방법이골절위험도평가 (Fracture risk assessment tool, FRAX, 이다 (Fig. 1) [32]. 세계보건기구에서개발한 FRAX 는향후 10년간대퇴부와주요골다공증성골절의발생가능성을수치화하여제공한다. 제공된화면에나이, 성별, 흡연력, 스테로이드사용등의변수를입력하면각변수를조합하고골절의위험을수치화하여제시해준다 (Table 2). FRAX 에는스테로이드사용에는복용량이나기간에대한기준이없는데, 일반적으로과거나현재의하루 mg의프레드니솔론동량의스테로이 드복용을기준으로삼는다. 스테로이드의용량에따라 FRAX 계산을교정할수있는데, 프레드니솔론 2.5 mg 이하의저용량의경우골절의발생확률을 20% 낮춰야하고 (0.8), 7.5 mg 이상의고용량일경우 15% 올려야된다 (1.15) [33]. 그러나여기에도스테로이드의복용기간에대한기준은없어서누적용량이다고려되지못하고그외에도낙상의다 Figure 1. Use of the Fracture Risk Assessment Tool (FRAX, [32]. Table 2. Risk factors in the Fracture Risk Assessment Tool (FRAX) Age (40-90 years) Sex Previous fracture Parent fractured a hip Bone mineral density of actual femoral neck Body mass index (weight and height) Glucocorticoids for more than 3 months at a dose of prednisolone 5 mg/day (or equivalent) Rheumatoid arthritis Secondary osteoporosis, type I (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (< 45 years), chronic malnutrition, or malabsorption and chronic liver disease Three or more units/day of alcohol (1 unit = 285 ml beer, 30 ml spirits, or 120 ml wine)

4 - 정주양외 1 인. 스테로이드유발성골다공증 - 른위험요인이나척추기형의존재여부, 골활성화약제의복용여부가계산되지못하는문제점이있다. 또한척추골절의위험이도출되지않는점도주요한결점이다 [7]. 골밀도검사 (bone densitometry) 는골다공증을진단하는데가장중요한검사이고현재로서스테로이드유발성골다공증에서도마찬가지이다. Dual-energy X-ray absorptiometry (DXA) 를통한 T-score 로골밀도를평가하는데, 스테로이드를복용하는환자에서의 DXA를이용한골밀도의측정은폐경후골다공증에서와같이유용하지는않다. 비슷한 T-score 를보이는두군간의골절의발생을비교해보았을때스테로이드를복용하는군에서그렇지않은군에비하여골절위험도가더높다. 스테로이드유발성골다공증에서의골절위험도는부분적으로는골밀도와는별개로골모세포와골세포에스테로이드가미치는직접적인독성효과와밀접한관계가있다 [9]. 골밀도검사의한계가있지만현재로서는스테로이드유발성골다공증환자에서골절의위험을평가하여치료를결정하고약제의반응을평가하는데에는골밀도측정이유용하다. 국제골다공증재단-유럽골대사학회 (IOF-ECTS) 의권고에따르면, 스테로이드를 3개월이상복용하는폐경기여성과 50세이상의남성은반드시골절위험도평가로골절의위험성을평가해야한다 [29]. 만약이전에골절병력이있거나 70세이상이거나하루 7.5 mg 이상의스테로이드를복용한다면치료를고려하라고권고한다. 폐경전여성과 50세이하의남성의경우는이전의골절병력이없다면임상적으로 판단하고, 스테로이드치료를유지하는모든환자들에게발생할수있는위험들에대하여상담하도록권고한다. 스테로이드치료를시작할때골밀도검사와함께비타민 D 결핍이나다른대사질환에대하여확인해야할것이다. 이를위해서기본적인혈액검사와비타민 D 수치, 부갑상선호르몬, 혈청인등을시행할수있다. DXA 나골절위험도평가에서중등도이상의위험을가진경우외측척추방사선검사를통해압박성척추골절을확인할수있다. Trabecular bone score (TBS) 는 DXA의자료에서추출하여기술적분석을통해얻게되는데골미세구조를파악할수있다. TBS가높을수록골미세구조가좋음을의미하며이는골다공증에서향후골절을예측하거나치료의효과를평가하는데유용하다. 스테로이드를유지하는환자들에게서골밀도는정상이지만 TBS는낮아질수있다. 향후스테로이드유발성골다공증에서 TBS가또다른지표로사용될수있을지대규모연구가필요하다. 치료대다수의가이드라인에서폐경후여성과 50세이상의남성을대상으로스테로이드유발성골다공증의치료를고려한다 (Table 3). 폐경전여성에서의골절의발생은매우드물게보고되었고치료에관한증거가약하다. 폐경전여성과젊은나이의남성에게서는이전의골절병력이있거나고용량의스테로이드를유지하는경우고려해볼수있겠다. 미 Table 3. Comparison of guidelines for the management of glucocorticoid-induced osteoporosis Guidelines Glucocorticoid dose threshold BMD threshold American College of Rheumatology National Osteoporosis Foundation Royal College of Physicians of London DVO Guideline (Germany, Austria, Switzerland) 7.5 mg/day for at least 3 months, but any dose and duration in patients at increased risk Based on the FRAX algorithm in addition to declining BMD, higher daily and cumulative dose and intravenous use 5 mg/day for at least 3 months T-score 2.5 T-score 1.0~ 2.5 and 3% of hip/20% of major osteoporotic fracture risk in postmenopausal female or male > 50 years Any oral dose for at least 3 months in T-score 1.5 patients 65 years of age and those with a prior fragility fracture 7.5 mg/day for at least 3 months T-score 1.5 Modified from reference [7]. FRAX, Fracture Risk Assessment Tool; BMD, bone mineral density; DVO, Dachverband Osteologie

5 - The Korean Journal of Medicine: Vol. 92, No. 2, 국류마티스학회에서발표된권고사항을살펴보면, 스테로이드를 3개월이하로복용하는폐경전의가임기여성에서는골다공증치료를피하고 3개월이상복용하고골다공증성골절병력이있는경우폐경전여성에서도스테로이드유발성골다공증을예방하거나치료하기위한약제를시작하라고권하고있다 [30]. 스테로이드치료를시작하거나유지하는경우가능한스테로이드를감량시킬수있는약제를사용하고, 되도록최소한의용량을유지하도록해야한다. 필요할때만복용하거나격일로복용하는등의방법도고려될수있다. 스테로이드유발성골다공증과골절의위험성을알리고, 골밀도를유지하는데도움이되는생활습관을충분히설명하여야한다. 균형잡힌영양분의섭취와규칙적인체중부하운동을권하고, 금연과하루 2잔이상의과도한음주를피하도록교육해야한다. 고령의환자에서는스테로이드로인해근육이약해져낙상의위험이증가되므로이에대한주의도필요하다 [34]. 칼슘과비타민 D 스테로이드유발성골다공증의환자는장내칼슘의흡수가떨어지는데, 칼슘과비타민 D의복합제제는골소실을줄이는데효과적이다 [35]. 모든스테로이드유발성골다공증에대한국제적인치료지침들에는적절한칼슘과비타민 D의보충을권고한다. 일반적으로칼슘의경우하루 1,200 mg 이상을보충제보다는식이로섭취할것이권고된다. 칼슘은산성환경에서더잘흡수되어양성자펌프억제제 (proton pump inhibitor) 를복용중인성인에서는칼슘시트레이트의형태가효과적이다. 비타민 D는부갑상선호르몬을떨어뜨리고근력을유지하여낙상의위험을줄인다 [36]. 메타분석에의하면치료를하지않거나칼슘제만복용하는군에비하여활성비타민 D와같이복용한군에서골밀도상승이크고척추골절의위험이효과적으로감소되었다 [35]. 그러나칼슘과비타민 D는스테로이드유발성골다공증에서골절의위험을독립적으로감소시키지는못하고, 비스포스포네이트만큼골밀도를올리는데효과적이지않으므로칼슘과비타민 D는필요하지만충분하지않다. 또한, 몇몇의연구에서는과도한칼슘제제의사용은고칼슘혈증과요로결석의발생및심혈관질환의위험도증가와관련이있었다 [37]. 비스포스포네이트비스포스포네이트는스테로이드유발성골다공증에서일차치료약제로, 현재알렌드로네이트 (alendronate), 에티드로네이트 (etidronate), 리제드로네이트 (risedronate), 졸레드로네이트 (zoledronate) 가스테로이드유발성골다공증의치료제로미국식품의약국 (Food and Drug Administration, FDA) 의승인을받았고대부분의가이드라인에서권고된다 [14,38-42]. 비스포스포네이트는파골세포의활성도를막아골흡수를줄여골밀도를올리지만, 폐경후골다공증에서만큼치료의효과가뛰어나지않다. 모든비스포스포네이트는경구흡수율이낮아, 공복에한컵이상의물과함께복용하고흡수율을높이기위해 30분이상음식을먹지않는등의복용방법을지켜야한다. 또한부작용으로속쓰림, 식도염이드물지않게발생하며심방세동, 관절통, 근육통등이보고되었다 [43]. 스테로이드유발성골다공증에서비스포스포네이트의사용에관한주요한이슈는가임력을가진폐경전여성에서의사용이다. 엄마로부터태아의비스포스포네이트의노출에대한안전성이입증되지않은상태로, 고위험군이나스테로이드와관련하여골절을경험한경우를제외하고젊은여성과소아에서는비스포스포네이트를피하는것이좋다. 스테로이드유발성골다공증에서비스포스포네이트의장기간사용에관련된또다른우려가있다. 장기간스테로이드의사용에따라골대사가저하되고이론적으로비스포스포네이트가이런상태를더욱악화시키게된다. 이로인해매우드문부작용인턱의골괴사나비정상적인대퇴부골절이생길수있다 [44]. 그러나이러한부작용의발생은매우드물어치료에의한골절의예방효과에비해미약하므로대다수골다공증의치료지침에서비스포스포네이트치료를권장한다. 현재까지알렌드로네이트, 리제드로네이트, 졸레드로네이트가스테로이드유발성골다공증의치료에서승인된약제이며리제드로네이트와졸레드로네이트는스테로이드유발성골다공증의치료뿐만아니라예방으로도승인되었다. 랄록시펜 (Raloxifen) 선택적에스트로겐수용체조절제인랄록시펜은폐경후골다공증에서척추골절의위험을줄인다. 아직까지스테로이드유발성골다공증의치료제로승인된바는없지만, 장기간스테로이드를복용중인폐경후여성환자에게골밀도를올리는효과는입증되었다 [45]. 드문부작용으로부종이나

6 - Ju-Yang Jung, et al. Glucocorticoid-induced osteoporosis - 정맥혈전증이발생할수있으나, 다른약제의사용이불가능할경우고려해볼수있다. 테리파라타이드 (Teriparatide) 스테로이드유발성골다공증에서는골모세포의분화와성숙이감소되어골형성이저하되는데, 테리파라타이드는재조합된부갑상선호르몬제제로, 골모세포전구체의수를증가시키고분화와생존을증가시켜골형성을증가시키는효과를보인다 [46]. 스테로이드유발성골다공증에서테리파라타이드와알렌드로네이트를비교한연구에서척추와대퇴부의골밀도가테리파라타이드군에서더증가되었다 [47,48]. 테리파라타이드는스테로이드유발성골다공증의치료제으로승인을받았으며, 매일 20 μg를피하주사로투여한다. 주요부작용은미약한고칼슘혈증과구역감, 불면이다. 개발단계에서마우스모델에서골육종암이발생하였고이에대한우려가존재하므로 2년이상사용하면안되고, 젊은성인이나소아, 악성골질환환자나방사선치료를받은자에서는피해야할것이다. 데노수맵 (Denosumab) 데노수맵은 RANKL 에대한완전인간형단일클론항체이다. 파골세포의형성과기능에필요한 NF-kappa B의활성화수용체를억제하여파골세포의활성화와골흡수를막는다. 데노수맵는폐경기여성의골다공증에서비척추와대퇴부골절의위험을감소시켰다 [49]. 류마티스관절염을가진골다공증환자에서도스테로이드의복용여부와상관없이골밀도를증가시켰고 [50], 장기간스테로이드를복용하는환자에게서비스포스포네이트에서데노수맵으로교체하자척추골밀도가증가되고골전환수치가감소되는결과를보였다 [51]. 향후스테로이드유발성골다공증에서의사용과관련된연구가더진행될것으로기대된다. 추적관찰스테로이드유발성골다공증으로진단하고치료중이거나스테로이드를장기간유지해야할때골밀도의정기적인측정이필요하다. 그리고만약골다공증의치료중에골밀도가감소되거나 1번이상골절을경험하는경우치료제의변경을고려해야한다 [1]. 스테로이드치료를중단한뒤골절의위험이떨어지면골절의예방치료는중단할수있는데, 일반적으로나이와골밀도, 골절의병력으로평가한다. 결 스테로이드유발성골다공증은약제에의하여생긴부작용으로발생을막을수있으면좋지만, 임상적으로약을줄이거나바꿀수없는경우가많다. 흡입용이나단기간의사용은경구제로장기간유지하는것에비하여안전하다. 스테로이드유발성골다공증은폐경후골다공증과골밀도저하의발생기전과골밀도검사의정확도, 골절의양상등에서차이를보인다. 특히현재유용한 DXA를이용한골밀도측정이스테로이드유발성골다공증을정밀하게대변할수없는상황으로자세한병력과위험요인을함께평가하는것이중요하다. 스테로이드를장기간복용하는환자에게스테로이드유발성골다공증의가능성을인지시키고필요한생활습관을교정하도록상담하고칼슘과비타민 D를보충해야한다. 위험도평가를시행하고골밀도를평가하여합당한예방및치료를시작하는것이추후의골절을예방하는데중요할것이다. 론 중심단어 : 글루코코르티코이드 ; 골다공증 ; 골밀도 REFERENCES 1. Rizzoli R, Biver E. Glucocorticoid-induced osteoporosis: who to treat with what agent? Nat Rev Rheumatol 2015;11: Nawata H, Soen S, Takayanagi R, et al. Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research (2004). J Bone Miner Metab 2005;23: Curtis JR, Saag KG. Prevention and treatment of glucocorticoid-induced osteoporosis. Curr Osteoporos Rep 2007;5: Overman RA, Toliver JC, Yeh JY, Gourlay ML, Deal CL. United States adults meeting 2010 American College of Rheumatology criteria for treatment and prevention of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2014;66: Rizzoli R, Adachi JD, Cooper C, et al. Management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 2012;91: Briot K, Cortet B, Roux C, et al update of recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis. Joint Bone Spine 2014;81: Bultink IE, Baden M, Lems WF. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future

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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