PHARMACOTHERAPEUTICS J Korean Med Assoc 2017 April; 60(4):330-335 pissn 1975-8456 / eissn 2093-5951 https://doi.org/10.5124/jkma.2017.60.4.330 비타민 D 의보충요법 이재혁 서남대학교의과대학명지병원내분비내과 Pharmacologic supplementation of vitamin D Jae Hyuk Lee, MD Division of Endocrinology, Department of Internal Medicine, Myongji Hospital, Seonam University College of Medicine, Goyang, Korea Vitamin D deficiency is common among Koreans and worldwide, leading both physicians and patients to become interested in whether vitamin D supplementation is needed. However, current levels of supplementation with vitamin D are insufficient, especially among aging Koreans. The musculoskeletal effects of vitamin D supplementation have been established, and its extraskeletal effects also have drawn particular interest. Nonetheless, more studies are needed to assess its extraskeletal effects with regard to cardiovascular disease, cancer, and diabetes, as well as its adverse effects. Serum 25-hydroxyvitamin D levels greater than 20 ng/ml are generally appropriate for preventing osteoporosis, while serum 25-hydroxyvitamin D levels greater than 30 ng/ml are probably helpful for the management of osteoporosis and the prevention of fractures and falls. The recommended dietary vitamin D intake is at least 800 IU per day, which appears to reduce the risk of fractures. Key Words: Vitamin D; Osteoporosis; Fracture; Mortality; Cardiovascular diseases 서론 최근들어비타민 D 에대한관심이커지고있는데, 이러한 관심은우리나라뿐만아니라전세계적으로비타민 D 의측정 이보편화되어비타민 D 상태를정확히측정할수있게되면 서비타민 D 가부족하다는많은연구가발표되었기때문이 다. 비타민 D 는무기질및골대사에중요한역할을하며, 이 의결핍이구루병, 골연화증및골다공증등대사성골질환 의발생과밀접한관련이있다는것이알려지게되었다. 최 근의연구들에서는비타민 D 의다양한기능, 즉세포의증식 Received: March 10, 2017 Accepted: March 21, 2017 Corresponding author: Jae Hyuk Lee E-mail: jaehyugy93@naver.com Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 과분화, 근육및면역체계에서의역할등이관심의대상이되고있으며, 비타민D 결핍또는부족이심혈관계질환, 당뇨병, 암, 감염성질환, 자가면역질환등과관련이있음이보고되고있다 (Figure 1) [1]. 최근들어비타민D의상태가정상이하인상태, 즉비타민 D 부족상태라는것이있고, 이런경우명백한증상이나타나지는않지만여러가지문제를일으킬수있다는사실이밝혀졌다. 하지만현대에들어많은사람들이도시에서생활하고대부분의시간을실내에서보내면서피부의비타민D 합성을위한충분한햇빛을쬐지못하고있다. 따라서비타민D 부족은현대사회의중요한건강문제로대두되었다. 비타민 D 역학 적정비타민D 농도와관련하여발표된여러연구에서비타민D 농도가증가함에따라골밀도가증가하고낙상이감 330 대한의사협회지
Lee JH Pharmacologic supplementation of vitamin D Circulation 1,25[OH]2 Vit D DBP Nucleus Vitamin D target cell 혈청 25(OH)D 농도는 20대에가장낮은수치를보였으며, 20대부터증가하여 60대에가장높았고이후다시감소하는양상을보였다. 비타민D 부족의위험인자로는 20-40대의젊은나이, 봄과겨울의계절적요인, 도시거주, 실내에서일하 VDR RXR VDR (DNA) * Co-activators/repressors RNA polymerase Protein for Ca absorption +/- Gene transcription 는직업등으로나타났다 [4]. 비타민 D 의보충 비타민 D 부족에대한많은연구가있는반면에비타민 D Figure 1. Cell signaling and the regulation of protein expression by vitamin D. Active vitamin D (1,25[OH] 2 Vit D), which is synthesized by kidney cells and secreted into the blood vessels, combines with vitamin D-binding protein (DBP) in the blood, and then move into the cells which are the target cells of vitamin D. Within the cytosol, vitamin D receptor protein (VDR) can recognize this vitamin D-DBP complexand once vitamin D-DBP complex is detached, then vitamin D combines at this time with VDR to get into the nucleus. Within thenucleus, vitamin D-VDR-retinoid X receptor (RXR) complex combines with a particular vitamin D-dependent DNA elements and regulates the vitamin Ddependentgene expression (transcription). Reproduced from Shin MY, et al. J Nutr Health 2016;49:1-7, according to the Creative Commons license [1]. 소하는것으로보고된바있다. 미국의국민건강영양조사인 National Health and Nutrition Examination Survey 자료 의분석에서는 1988-1994 년에비해서 2001-2004 년의혈 청 25-hydroxyvitamin D (25(OH)D) 가감소한것이보고되 었다. 또한혈청 25(OH)D 의농도가 10 ng/ml 미만인비타 민 D 결핍의유병률은 2% 에서 6% 로증가하였으며, 30 ng/ml 이상인경우는 45% 에서 23% 로감소하였다 [2]. 우리나라의비타민 D 부족역시매우흔한것으로나타났다. 우리나라국민건강영양조사자료를바탕으로비타민 D 농도와 골밀도를분석한연구에서는 25(OH)D 농도 20-30 ng/ml 이상을적정비타민 D 농도로보고하고있다 [3]. 다만, 골다 공증을치료하거나골절예방을위해서는 25(OH)D 농도를 30 ng/ml 이상으로유지시키는것이바람직할것으로보 인다. 2008 년국민건강영양조사자료를바탕으로한연 구결과에서평균혈청 25(OH)D 농도는남성에서 21.2± 7.5 ng/ml, 여성에서 18.2±7.1 ng/ml 였다. 남성의 47.3%, 여성의 64.5% 에서 25(OH)D 농도가 20 ng/ml 미만으로부 족하였으며, 25(OH)D 농도가 30 ng/ml 이상으로충분한경 우는남성의 13.2%, 여성의 6.7% 밖에되지않았다. 또한 보충요법의효과여부에대한연구는일관성이없고, 비타민 D 종류와용량, 칼슘과동반투여여부에따라다양한결과가보고되고있다. 비타민D를충분히얻기위한방법으로햇빛쬐기, 음식을통한섭취, 비타민D 보충제복용등이있다. 햇빛의경우여름철에전신에 10-15분정도햇빛을쬐면비타민D 15,000-20,000 IU가합성되는것으로알려져있으며, 얼굴, 손, 팔등신체의일부만노출한경우에도 1000 IU 정도는생성되는것으로알려져있다. 하지만, 여름이외의계절의경우햇빛이약해피부의비타민D 합성이어려울수있으며, 특히피부색이어둡거나노인의경우피부에서의비타민D 합성은더욱어렵다. 비타민D를함유한음식으로생선, 육류, 버섯, 계란등이알려져있으나많은양이포함되어있지않다. 서양의경우유제품, 쥬스, 시리얼등서양인이즐겨먹는음식에비타민D를강화시키고있으나우리나라의경우비타민D 강화음식섭취가적어서음식을통한비타민 D 보충은어려운실정이다. 하지만, 비타민과호르몬의특성을동시에가지고있는비타민D가뼈건강을촉진시키는작용이외에, 근래에와서는만성질병을예방할수있는다양한생리적기능이있다는연구결과들이많이보고되고있다 (Figure 2) [1]. 비타민 D 의근골격계효과 골밀도에대한비타민D의영향은비타민D 단독투여는위약과차이가없으며 [5], 칼슘을같이투여한경우효과적이다 [6]. 비타민 D 의보충요법 331
J Korean Med Assoc 2017 April; 60(4):330-335 Vitamin D VDR RNA POL Ⅱ 1,25 (OH)2D 5' 3' 25-hydroxylase RXR liver Target gene VDRE 25(OH)D 1a-hydroxylase (CYP27B1) 24-hydroxylase (CYP24A1) 1, 24, 25 (OH)3D Classical role *Calcium uptake *PTH synthesis renal phosphate/calcium *Osteoblast/osteaclast differentiation & function Non- classical role *Anticancer antiproliferative regulation of apoptosis and angiogenesis *Anti-bacterial *Antigen presentation *Anti-inflammatory 기저 25(OH)D의농도가 25 ng/ml 이하로낮았던대상자들에게는비타민D 보충이둔부근력의유의한호전을보였다 [13]. 비타민D를하루 700-1,000 IU 보충하면낙상의위험이 19% 감소하였고, 혈청 25(OH)D 농도를 24 ng/ml 이상으로유지한경우는낙상위험도가 17% 감소함을확인하였다 [8]. 하지만낙상예방을위한비타민D 복용의내용을담은국내지침은아직개발되어있지않다. *Anti-hypertensive Figure 2. The nutrient and hormone-like roles of vitamin D. Traditionally, vitamin D is well known as the nutrient which promotes bone health by stimulating Ca absorption by upregulating the protein expression and synthesis for Ca absorption and osteoblast differentiation etc. (as nutrient). In these days, numerous studies show that vitamin D is also having various functions of anticancer through up-regulating the proteins for preventing cancer cell proliferation, anti-cardiovascular and anti-diabetic function, which are not considered only as the nutrient but cell signaling molecule (hormone-like nutrient). 25(OH)D, 25-hydroxyvitamin D; VDR, vitamine D receptor protein; RXR, retinoid X receptor; RNA POL II, RNA polymerase II; VDRE, vitamin D response element. Reproduced from Shin MY, et al. J Nutr Health 2016;49:1-7, according to the Creative Commons license [1]. 골밀도증가의효과는비활성형보다활성형이효과적이었다 [7]. 비타민 D 와골절위험감소는일일 700 IU 이상비타민 D 보충으로혈청농도가충분히올라갈경우골절감소효과 가유의하게나타났다 [6,8,9]. 골절예방을위해서는비타민 D 를칼슘과함께투여해야하는것으로보인다 [6,9]. 2014 National Osteoporosis Foundation 에서는 50 세이상의성 인에서는하루 800-1,000 IU 의비타민 D 를칼슘과함께섭 취할것을권유하고있으며, 비타민 D 결핍의위험이높은노 인의경우혈청농도를측정하여 30 ng/ml 이상을유지할 수있도록비타민 D 를보충할것을권유하고있다 [10]. 일반 성인에서하루 4,000 IU 의비타민 D 보충을넘기지않도록 권고하고있다. 대한골대사학회의 2015 골다공증진단및 치료지침에의하면골절및낙상을예방하기위해서비타민 D 단독투여는효과가없으며, 칼슘과비타민 D 를같이투여 한경우효과적이다 [11]. 50 세이상의인구에서골절예방을 위해서는 1 일 1,200 mg 의칼슘과일일 800 IU 의비타민 D 를권장하였다 [12]. 하지만아직한국인에서골절예방을위 한적절한비타민 D 권장량을연구한결과가없는상태이다. 비타민 D 의비근골격근계효과 비타민 D 의심혈관질환관련성에서 관심을끄는주제는칼슘과심혈관질환 과의관련성이다. 칼슘단독혹은비타 민 D 와같이투여한 Women s Health Initiative 연구를포함하여 3 편의무작위임상시험연구를분 석하였을때심혈관질환특히심근경색의발생위험이증가 하였다 [14]. 또한비타민 D 보충이일반적으로는의미있는 혈압감소효과를보여주지못했으며 [15], 저밀도콜레스테롤 을 3.23 mg/dl 을낮추었지만중성지방과고밀도콜레스테 롤에는영향을미치지않았다 [16]. 항염증효과와내피세포 기능개선에대해서도비타민 D 보충이효과를입증하지못 한것으로볼때 [17], 현재까지의결과로는비타민 D 의보충 이심혈관질환예방에도움을준다는근거는매우미약하다 고할수있다. 비타민 D 는세포성장을조절하는호르몬의역할을하기때 문에암예방효과에대한가능성이제기되고있다. 관찰연구 들을분석한메타분석결과, 비타민 D 섭취가높아지고혈중 25(OH)D 농도가상승하면대장암위험이줄어들었다 [18]. 하지만이후연구들에서칼슘과비타민 D 를보충하였을때 대장암과유방암의발생위험을줄이지못하였다 [19,20]. 따 라서암예방을위해비타민 D 복용을권유하기는어렵다고 할수있다. 332 대한의사협회지
Lee JH Pharmacologic supplementation of vitamin D 췌장의베타세포에는비타민D에대한수용체가있고, 여러실험, 역학연구에서비타민D 결핍은인슐린분비감소와인슐린민감도악화및제2형당뇨병에영향을미친다. 동물실험에서비타민D는췌장에서인슐린분비를증가시키고, 비타민D 결핍시체지방량이증가하여인슐린저항성이악화되고, 역학연구들에서대사증후군의발생이늘어나는경향도보였다 [21]. Nurses Health Study 및메타분석에서비타민D와칼슘을보충하였을때제2형당뇨병발생위험이감소하였다 [22]. 하지만당뇨병발생위험을살펴본무작위임상시험연구에대한메타분석결과는일관적인결과를보여주지못했다 [23]. 따라서현재까지의근거로비타민 D가당뇨병예방에어떠한영향을미칠지에대해서명백한근거는없다고할수있다. 따라서당뇨환자에게비타민D를보충할지여부를결정하기에근거가부족하다고할수있다 [24]. 염증성장질환 [25], 다발성경화증 [26], 천식, 습진등에대한비타민D 효과를다양한연구에서입증하지못했다. 역사적으로도항결핵제가개발되기전결핵감염시햇볕을쪼이면결핵이호전되는것으로알려져왔다. 활동성결핵환자에서건강대조군보다혈중비타민D 농도가낮은것으로관찰되지만 [27], 결핵과감기에대한비타민 D의효과는입증되지못했다 [28,29]. 비타민 D 의약물적보충 우리나라남성의경우하루 160 IU, 여성의경우 104 IU 정도만을음식으로보충하고있는것으로보고되었다. 따라서비타민D 보충제사용이가장현실적이고쉬운방법이될수있다. 우리나라의대한골다공증학회, 대한골대사학회에서는하루 800 IU의비타민D 섭취를권고하고있다. 비타민D 보충의가장좋은방법은매일 800 IU의비타민D를경구로보충하는것이다. 다만, 흡수장애가있는경우, 경구섭취가어려운경우, 약제순응도가낮은경우등에서는비타민D 주사제를고려해볼수있다 [11]. 비타민D 주사제 200,000 IU 의경우근육주사후약 8주경에 25(OH)D 농도를최대 20 ng/ml 증가시키는것으로알려져있다. 다만, 외국의 연구에서비타민D를고용량 (300,000 또는 500,000 IU) 투약후골절이나낙상이증가했다는보고가있으므로주의할필요가있다. 비타민D 농도의경우일반적으로는 25(OH)D 20 ng/ml 이상으로유지하면적절하다고볼수있으며, 골다공증을치료하거나골절예방목적인경우 30 ng/ml 이상을유지하는것이필요하다. 다만, 40-45 ng/ml 이상으로더높이는것에대해서는낙상및골절증가등부정적인결과도있으므로주의할필요가있으며, 추가적인연구결과를지켜봐야할것으로보인다. 비타민 D 독성 비타민D는음식으로인한섭취나자외선노출로얻게될경우과도하더라도독성이거의드물다. 하지만, 약물로비타민D 를과도하게섭취시에소아나성인에서는드물게심각한부작용이나타나는경우도있다. 고칼슘혈증, 신결석뿐만아니라연부조직과혈관의석회화까지보고되고있다. Women s Health Initiative 연구에서도칼슘과비타민D를같이복용시요관결석이증가한다고보고하였으나 [30,31] 비타민D 단독복용시에는그런경향성이보이지않았다. 장기간의비타민D 보충요법이고칼슘혈증과고칼슘뇨증을유발할수있지만, 용량의존적이지않다고보고하였으며, 신결석은증가시키지않는다는보고도있다 [31]. 최근비타민D 와사망률을분석한코호트관찰연구에서는혈청농도 20-24 ng/ml를기준으로심혈관및전체사망률이 J shape curve 를보인다고보고하였다 [32,33]. 하지만전체사망률은비타민D에의해증가하지않고, 오히려감소시킨다고보고한메타분석도보고되었다 [34,35]. 일반적으로비타민D를보충시사망률감소효과는칼슘과같이보충하는지, 보충하는비타민D의종류가무엇인지에따라서달라질수있기때문에아직불확실하다고하겠다. 비타민D 농도와비타민D의독성을유발하는수치의한계에대해서는아직명확한결론이없는상태이지만, European Food Safety Authority 등에서는유아에서는 2,000 IU/day, 성인에서는 4,000 IU/day의용량을최대용량으로권고하고있다. 비타민 D 의보충요법 333
J Korean Med Assoc 2017 April; 60(4):330-335 결론 비타민 D 부족은한국뿐만아니라전세계적인현상이며 보건학적으로중요하다. 적절한양의칼슘과보충시비타민 D 는골절및골다공증예방, 치료에효과적이며, 낙상의감 소를가져올수있다. 다양한장기및질환에서비타민 D 의 역할및효과에대한가능성이제기되고있으나아직명확한 근거가부족한상태이다. 성인에서는 4,000 IU/day 의용량 을최대로하여한국에서는하루 800 IU 의비타민 D 섭취를 권고하고있으며, 가장좋은방법은매일 800 IU 의비타민 D 를경구로보충하는것이다. 찾아보기말 : 비타민 D; 골다공증 ; 골절 ; 사망률 ; 심혈관질환 ORCID Jae Hyuk Lee, http://orcid.org/0000-0001-5453-9480 REFERENCES 1. Shin MY, Kwun IS. Vitamin D: hormone-like nutrient. J Nutr Health 2016;49:1-7. 2. Scragg R, Sowers M, Bell C; Third National Health and Nutrition Examination Survey. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 2004;27:2813-2818. 3. Kim KM, Choi SH, Lim S, Moon JH, Kim JH, Kim SW, Jang HC, Shin CS. Interactions between dietary calcium intake and bone mineral density or bone geometry in a low calcium intake population (KNHANES IV 2008-2010). J Clin Endocrinol Metab 2014;99:2409-2417. 4. Choi HS, Oh HJ, Choi H, Choi WH, Kim JG, Kim KM, Kim KJ, Rhee Y, Lim SK. Vitamin D insufficiency in Korea: a greater threat to younger generation: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008. J Clin Endocrinol Metab 2011;96:643-651. 5. Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P. Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab 1995;80:1052-1058. 6. Cranney A, Horsley T, O Donnell S, Weiler H, Puil L, Ooi D, Atkinson S, Ward L, Moher D, Hanley D, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007; (158):1-235. 7. Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster JY. Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis. Calcif Tissue Int 2005;76:176-186. 8. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692. 9. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155: 827-838. 10. National Osteoporosis Foundation. NOF s clinician s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010. 11. Kim KM, Choi HS, Choi MJ, Chung HY. Calcium and vitamin D supplementations: 2015 position statement of the Korean Society for Bone and Mineral Research. J Bone Metab 2015;22:143-149. 12. Korean Society of Bone Metabolism, Committee for Practice Guidelines. Physician s guide for diagnosis and treatment of osteoporosis. Seoul: Korean Society of Bone Metabolism; 2010. 13. Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL. Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int 2011; 22:859-871. 14. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women s Health Initiative limited access dataset and meta-analysis. BMJ 2011;342:d2040. 15. Wu L, Sun D. Effects of calcium plus vitamin D supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Hum Hypertens 2017 Feb 23 [Epub]. https://doi.org/10.1038/jhh.2017.12. 16. Wang H, Xia N, Yang Y, Peng DQ. Influence of vitamin D supplementation on plasma lipid profiles: a meta-analysis of randomized controlled trials. Lipids Health Dis 2012;11:42. 17. Agbalalah T, Hughes SF, Freeborn EJ, Mushtaq S. Impact of vitamin D supplementation on endothelial and inflammatory markers in adults: a systematic review. J Steroid Biochem Mol Biol 2017 Jan 23 [Epub]. https://doi.org/10.1016/j.jsbmb.2017.01.015. 18. Ma Y, Zhang P, Wang F, Yang J, Liu Z, Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. J Clin Oncol 2011;29:3775-3782. 19. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, Margolis KL, Ockene JK, Phillips L, Pottern L, Prentice RL, Robbins J, Rohan TE, Sarto GE, Sharma S, Stefanick ML, Van Horn L, Wallace RB, Whitlock E, Bassford T, Beresford SA, Black HR, Bonds DE, Brzyski RG, Caan B, Chlebowski RT, Cochrane B, Garland C, Gass 334 대한의사협회지
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