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1 임상노인의학회지 : 제 9 권제 2 호 Korean J Clin Geri 2008;9(2): 남성골다공증의특징과치료 황선욱 가톨릭대학교의과대학가정의학교실 Characteristics and Treatment of Osteoporosis in Men Sun-Wook Hwang, M.D. Department of Family Medicine, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea 서 론 골다공증으로고통받는남성의수는정확히알려져있지않다. 그리고골밀도검사와골절위험의관계도여성처럼많은연구가되어있지않다. 1) 그러나나이에따라남성도여성과마찬가지로골절위험이증가하는데여성에비하면급격한골절위험이 10년정도늦게나타난다. 2) Schuitt 등 3) 은 55세이상의남성에서골밀도와고관절골절, 비척추골절의상관관계를조사하였는데여성과비슷하다고하였다. 척추골절률은 55 59세사이에는여성과비슷하지만그이후에는여성보다는상대적으로골절률이낮아져 75세에는남성의 13.6%, 여성의 29.3% 가척추골절을가진다. 4) 그리고 Chang 등 5) 은약 50% 의고관절골절이 80세이전에발생하며미국, 북유럽에서는약 20 25% 의고관절골절이남성에서발생한다고하였으며 6) 50세이상의 20 25% 정도가골다공증과관련된골절을겪고있다고하였다. 7) 중요한사실은고관절골절에의한이환율과사망률은남성이여성보다높고 75세이후고관절골절에의한치명률은 20.7% 로여성의 7.5% 에비하여훨씬높다는사실이다. 그리고 1990년에는남성고관절골절발생자수가 50만명이었던것이 2025년에는 116만명으로증가할것으로예측되고있다. 8) 척추골절도과거에는남성에비하여여성이 10배많았는데최근에는여성의절반수준으로높게나타나고있다. 9) 그리고예기치못한척추골절은특히 50 60대의남성에서더흔하며반면손목골절은남성에게흔하지않고나이에따라증가하지않는다. 10,11) 본 론 1. 병태생리, 원인 남성은성선기능저하증이나전립선암등특별한경우를제외하고는여성과같이성호르몬손실이적기때문에중년에는골소실이천천히진행된다. 남성은폐경처럼갑작스런성선기능의중지가나타나지않지 교신저자 : 황선욱, 경기도의정부시금오동 65-1, , 가톨릭대학교의정부성모병원가정의학과 Tel: , Fax: , hw97med@hanmail.net

2 임상노인의학회지제 9 권제 2 호 2008 만서서히연령과관련된골소실이나타난다. 이는남성호르몬의감소에따른 Sex Hormone Binding Globulin (SHBG) 의증가와관련이있다. 역학적연구에서 SHBG의증가가골소실에영향을미치며골절위험을증가시키는것으로나타났다. 12) 그외에도 aromatase 효소활동의감소를통해서 testosterone으로부터 estradiol 의생성의감소도남성골다공증의병태생리에부가적인역할을담당한다. 13) Salmenda 등 14) 은혈청 estradiol 농도가낮은남성은높은남성에비해매년 1% 이상씩골밀도소실이일어난다고보고하였다. 따라서 estrogen 감소는남녀골다공증모두에있어서중요한역할을한다. 이시기남성의골소실은해면골얇아짐 (trabecular thining) 15,16) 으로특징지울수있는데이는해면골천공 (trabecular perforation) 보다적은척추골소실을유발한다. 해면골천공 (trabecular perforation) 은폐경여성에서골교체상태 (bone turnover state) 가높게나타나는것을의미한다. 그리고남성에게골밀도보호기능을나타내는다른요인은남성이여성보다최대골량 (peak bone mass) 이 10 12% 높게도달하며해면골 (trabecular bone) 의두께와양은비슷하지만피질골 (cortical bone) 이더두껍고골 (bone) 이더크다. 17) 이차성골다공증의 3가지주요요인은알콜남용, 스테로이드과용 ( 쿠싱증후군, 만성스테로이드치료등 ), 성선기능저하증 (hypogonadism) 이다. 이런원인들이약 40 50% 를차지한다 ) 다른원인으로갑상선기능항진증, 위장관질환, 만성폐쇄성폐질환, 파킨슨병같은신경근육질환, 당뇨, 다발성골수종또는다른악성질환들, 약물 ( 항경련제, 고용량항암요법, 고혈압약물, SSRI) 등이있다 (Table 1) ) 그밖에여성과마찬가지로흡연, 운동부족, 마른체격, 낮은칼슘섭취, 비타민 D 부족, 단백질부족, 골절가족력, 골절병력, 저체중, 악력 (grip strength) 의감소등과같은위험요인이존재할때골절을촉진시킨다. 24,25) Table 1. Secondary cause of osteoporosis in men Secondary osteoporosis Alcoholism Hormonal disorders Hypogonadism Cushing's syndrome Hyperthyroism Hyperparathyroism (1 o and 2 o ) Gastrointestinal disorder Malabsorption syndromes Inflammatory bowel disease, gluten entheropathy Primary biliary cirrhosis Post gastrectomy Hypercalciuria Chronic obstructive pulmonary disease Transplantation osteoporosis Neuromuscular disorder Systemic illnesses Rheumatoid arthritis Multiple myeloma Other malignancies Mastocytosis Medication/drug-related Gllucocorticoids Anticonvulsants Thyroid hormone Chemotherapeutics

3 황선욱 : 남성골다공증의특징과치료 유전학적인요인도중요한역할을한다. 26) 일란성이란성쌍둥이의비교에서보면 80% 의골밀도변화가유전과연관이있다. 27) 그리고역학적연구에서는부모의골절병력이중요한골다공증위험요인이라고나타났다. 그러나정확한관련유전자는아직밝혀지지않았다 ) 2. 진단일반적으로남성에서는골밀도 (BMD) 를잘측정하지않지만키가작아지거나척추후만증, 골절, 증상이있는요통이남성골다공증의처음나타나는특징이므로검사가필요하다. 31,32) 골다공증은보통 DXA 기계로측정하는데주로 L1-L4, 고관절 (hip), 특히대퇴경부, 전체대퇴골 (total femur) 을측정한다. Z score는환자의골밀도를비슷한연령대와비교한것이며 T score는정상젊은이의이상적인최대골량 (peak bone mass) 과비교한것이다. 측정한부위중가장낮은 T 점수가개인의골밀도를나타낸다. 33) International society for clinical densitometry에서는골밀도가 2.5 이하인경우남성골다공증으로진단한다. 34) International society for clinical densitometry에서발표한 DXA의적응증은 70세이상의남성, 골절경향을가진사람, 골감소증이나골다공증으로약물치료를받는사람, 골다공증약물치료를고려중인사람, 치료효과를보기위해낮은골밀도치료를받고있는사람, 골밀도가낮으나현재치료를받고있지않은사람등이다. 35) DXA 검사에서이상이발견되거나비외상성골절 (fragility fracture) 이있는사람은조혈기관계통 (hematopoietic system)( 다발성골수종등 ), 내분비질환 ( 갑상선기능항진증, 부갑상선기능항진증등 ), 영양결핍소견 (vitamin D 감소등 ), 신장기능등을검사해야한다. 처음검사로는 CBC, 혈청소변, 칼슘, ALP, 신기능, 간기능, 25-hydroxyvitamin D, I-PTH, TSH 등을측정한다. 추가적으로총 testosterone과 estradiol level 도남성에게측정하는것이좋다. 낮은 estradiol이골다공증을일으킬수있으나아직특별히받아들여지는치료법은없다 (Table 2). 36,37) Testosterone level은나이에따라감소하지만병적인범위로까지는잘떨어지지않는다. 따라서 testosterone 보충요법은전립선암과심장병위험을증가시킬수있으므로성선기능저하증, 우울증, 기력저하, 근육량감소등호르몬감소에의한증상이뚜렷할때를제외하고는잘사용하지않는다. Table 2. Laboratory evaluation for osteoporosis in men Initial screening* Complete blood cell count Calcium Phosphorus Alkaline phosphatase Kidney and liver function test Vitamin D (25-hydroxyvitamin D) Thyroid-stimulating hormone level Total testosterone Additional tests Serum protein Electrophoresis to screen for multiple myloma 24-hour urine collection to rule out hypocalciuria or hypercalciuria Estradiol level Parathyroid hormone for hyperparathyroidism *Recommended to determine cause in men diagnosed with osteoporosis. Consider further testing when initial screening dose not yield a definitive cause. If level is low,it is likely to be contributing to osteoposis,but no treatment is available

4 임상노인의학회지제 9 권제 2 호 2008 골형성률 (bone formation rate) 은 bone specific ALP, osteocalcin 등으로측정한다. 골흡수 (bone resorption) 증가의표지자 (marker) 는콜라겐분해물질 (collagen breakdown products) 로측정하며소변에서의 pyridinoline, deoxypyridinoline, N-telopeptide crosslinked collagen type1과혈청 C-telopeptide crosslinked collagen type1으로측정할수있다. 현재치료제로골흡수억제제가많이사용됨으로 N-telopeptide crosslinked collagen type1과 C-telopeptide crosslinked collagen type1이가장흔히사용하는표지자이다. 높은골교체에의한골다공증 (high turnover osteoporosis) 에서는파골세포 (osteoclast) 에의한골흡수가증가되어골모세포 (osteoblast) 가이를따라오지못하게된다. 이것은콜라겐분해물질 (collagen breakdown products) 증가로알수있다. 역으로말하면골모세포에의한골형성 (osteoblastic bone formation) 의실패로인해발생하는낮은골교체에의한골다공증 (low turnover osteoporosis) 에서는 N-telopeptide crosslinked collagen type1이정상이거나낮을수있다. 그리고골형성표지자는특히억제되어있다. 38) 3. 치료최근의후향성코호트연구에따르면 65세이상의남성골다공증환자중에 7.1% 그리고척추, 고관절골절환자의 16% 가골다공증약물치료를받고있는것으로나타났다. 39) 남성에게도골다공증의예방법은여성과유사하다. National Institute of Health and Food and Nutrition Board에서권장하는음식칼슘섭취는 1,200 1,500 mg이며 40) 비타민 D 섭취량은 IU/day은되어야하며 70이상의남성은 IU 섭취가권장된다. 적절한운동도반드시필요하다. 그러나남성골다공증환자에게약물치료는주로고위험도의골절을가진경우에추천된다. 남성골다공증에도 bisphosphonate를주된치료로사용하는데 41) bisphosphonate는 pyrophosphonate의유사체로화학적으로분해되지않으며뼈에강력하게결합하며뼈의파골세포에의한골흡수 (osteoclastic resorption) 를막는역할을한다. Alendronate, risedronate, ibandronate 등은지금까지광범위한연구가시행되었으며골밀도증가와골절률을 50% 정도향상시키는것으로나타났다. 42) 이런약들은매우높은산성이어서소화불량을야기할수있다. Alendronate와 risedronate는매일복용또는일주에한번복용할수있으며 ibandronate는 1개월에 1회복용, 또는 3개월마다주사가가능하다. 처음에는주로여성을주대상으로치료효과를평가해왔으나최근에는남성에게도효과가있다고입증되고있으며 43) 특정부위의골절예방에대한입증은어렵지만특히척추골절에대해서는남성에게도똑같은효과가있다고보고되고있다. 그러나시간이지남에따라 bisphosphonate는골교체 (bone turnover) 를감소시키며동물실험에서높은농도에서골의강도 (bone strength) 와탄성 (resilience) 이감소하였다. 일부연구에서는장기간사용하면횡력에의한골절 (transverse stress fracture) 을가져올수있다고하였으며이런사람들은조직검사를하면매우낮은골교체 (turnover) 를보였다. 따라서 bisphosphonate는효과는뛰어나지만골교체표지자 (bone turnover marker) 를반드시추적하여매우억제되어있다면 bisphosphonate를끊고 N-telopeptide crosslinked collagen type 1 등이치료수준 (therapeutic level) 으로돌아올때까지기다려야한다. 44) 메타분석에서남성에서 alendronate 치료는낮은골밀도나골절이있는경우척추골절위험을효과적으로감소시켰으나비척추골절에대한효과는불충분하였으며 45) 일주한번투여한 (70 mg) 경우와매일투여한경우 (10 mg) 에서효과는비슷하였다. 46) Risedronate 역시골밀도를증가시키고척추골절률을감소시킨다. 47) 그리고최근에미국뿐아니라국내에서도남성골다공증치료제로승인되었다. Alendronate와 risedronate는또한남성에서스테로이드과용, 성선기능저하증, 이식등과같이이차성골다공증이원인인경우에도효과가있었다 ) 그리고여러나라에서스테로이드로인한남성골다공증치료에승인되었다. 53) Etidronate 2주씩 3개월간격으로치료하는방법도

5 황선욱 : 남성골다공증의특징과치료 Table 3. Treatment of osteoporosis, with grades of evidence, in men Drug Dosage Grade* Contraindications and side effects Nutrients, total daily intake (diet+supplements) Calcium 1,500 mg C Contraindications: hypercalciuria hypercalcemia Vitamin D 3 (cholecalciferol) 800 IU A Bisphosphonate therapy Alendronate 70 mg/week A Contraindications: renal failure or Risedronate 35 mg/week (glomerular filtration rate<30 ml/min), history of allergy to bisphosphonate exposure. 400 mg/d for Side effects: usually limited to GI intolerance. or Cyclic etidronate 14d per 90-d cycle Anabolic therapy: teriparatide 20 ug/d D Contraindications: skeletal malignancy, subcutaneously history of radio therapy of for 18 month the skeleton, Paget s disease, hypercalcemia Side effects: nausea, headaches, muscle cramps *Grades of evidence, from the 2002 osteoporosis canada guidelines. For treatment of idiopathic osteoporosis,or for treatment and prevention of glucocorticoid osteoporosis. For prevention (not treatment) of glucocorticoid osteoporosis. Although the randomized controlled trials (RCTs) that involved men were not powered to detect reductions in fracture incidence, the pivotal RCT (evidence grade A),which involved postmenopausal women with severe osteoporosis,resulted in significant reductions in both vertebral and nonvertebral fracture. 또한스테로이드에의한남성골다공증을예방하는데에효과적이었다 (Table 3). 54) 최근에 human recombinant PTH (1-34)-teriparatide가높은골절위험을가진남성환자에게효과적인것으로나타났다 ( 일차성또는이차성골다공증, 성선기능저하에의한골다공증 ). 그러나약물비용, 복잡한투약일정, 잠재적인위험성등이사용하는데있어서제한요인이다 ) Teriparatide를매일 20 μg 피하로사용하면골 (bone) 에동화효과 (anabolic effect) 를나타내며요추골밀도와골형성표지자 (bone formation marker) 를빠르게증가시킨다. 여러연구에의하면 2년간척추골밀도가 13% 증가하였으며고관절골밀도도유사하게증가하였다 ) 지금까지연구대상자수가작고소규모연구라서 PTH의남성골절률감소에대해서는확실한자료는없지만관찰연구에서 teriparatide가중등도에서중증의척추골절의위험을감소시키는것으로나타났다. 64) Teriparatide와 bisphosphonate를함께사용한경우남성에서도여성과마찬가지로단독사용한경우보다이득을보지못하였다 ) PTH 적응증으로는 bisphosphonate를사용하는데도골밀도가감소되고골절이발생되고골교체상태가낮게유지될때사용할수있다. 69) 성선기능저하증인남성에서 testosterone 보충요법이골밀도를증가시키는것으로나타났으나골절률을낮추는지는알려져있지않다. 70,71) 일부연구에따르면남성호르몬이감소된남성에서낮은용량의 testosterone 치료는요추에이득을나타냈으나대퇴경부에는큰이득을보이지않았다. 72) 치료방법으로는일반적으로피하요법이근주요법보다는골밀도에좋은효과를보였다. SERM (selective estrogen receptor modulator) 제제인 raloxifene은전립선암에대해서억제효과가있으며 73), 척추골밀도를증가시키고척추골절률을감소시키는것으로나타났으며적은여성화효과를가져서최근에남성에도적용되고있다. 74)

6 임상노인의학회지제 9 권제 2 호 명의노인에서 6개월간 raloxifene (60 mg/day) 으로치료한연구에서 raloxifen을혈청 estradiol level이 96 pmol/l 이하인남성에투여했을경우골흡수표지자인소변의 cross-linked N-telopeptide of type I collagen (NTX) 가감소하였으며반면이 estrogen level 이상인경우골흡수가증가하였다. 이것은 raloxifen을높은용량으로 120 mg/day 6주간중년성선기능정상인남성에적용했을때 estradiol level이 pmol/l 이하인경우골전환표지자가상당히감소한결과와비슷한것이다. 따라서남성에서 raloxifene 치료는혈청 estradiol level이낮은경우에골대사에좋은효과를나타낸다. 75) 결 론 남성골다공증은현재증가추세에있으며노인인구에서특히많이발생하고골절이동반될경우심각한고통을수반하게된다. 따라서적절한진단을통해조기에발견하고치료한다면골다공증에의한합병증을예방할수있다. 최근에새로운약제들이개발되고있으며남성골다공증에도많이적용되고있기때문에앞으로더좋은치료방법과결과가나올것으로기대되고있어적극적인관심을가지고진단과치료를해야할것이다. 참고문헌 1. Melton LJ III, Khosla S, Achenbach SJ, O'Connor MK, O'Fallon WM, Riggs BL. Effects of body size and skeletal site on the estimated prevalence of osteoporosis in women and men. Osteoporos Int 2000;11: Melton LJ. Epidemiology of fractures. In: Riggs BL, Melton LJ, editors. Osteoporosis: etiology, diagnosis and management. 2nd ed. Philadelphia: Lippincott-Raven Publishers; p Schuitt SC, van der Klift M, Weel AE, de Laet CE, Burger H, Seeman E, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2004;34: Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, et al. Improvement in spine bone density and reduction in risk of vertebral factures during treatment with antiresorptive drugs. Am J Med 2002;112: Chang KP, Center JR, Nguyen TV, Eisman JA. Incidence of hip and other osteoporotic fractures in elderly men and women: Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 2004;19: Cooper C, Campion G, Melton LJ 3rd. Hip fractures in the elderly: A world-wide projection. Osteoporos Int 1992;2: Melton LJ 3rd, Atkinson EJ, O'Connor MK, O'Fallon WM, Riggs BL. Bone density and fracture risk in men. J Bone Miner Res 1998;13: Seeman E. Osteoporosis in men. Am J Med 1993;30:S Cooper C, Atkinson EJ, O'FalIon WM, Melton LJ 3rd. Incidence of clinically diagnosed vertebral fractures: A population-based study in Rochester, Minnesota J Bone Miner Res 1992;7: Kanis JA, Pitt FA. Epidemiology of osteoporosis. Bone 1992;13:S7-S Alffram PA, Bauer CGH. Epidemiology of fractures of the forearm. J Bone Joint Surg Am 1962;44: Goderie-Plomp HW, Van der Klift M, De Ronde W, Hofman A, de Jong FH, Pols HA. Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: The Rotterdam study. J Clin Endocrinol Metab 2004;89: Van Pottelbergh I, Gomaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab 2003;88: Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC. Sex steroids and bone mass in older men: Positive associations with serum estrogens and negative associations with androgens. J Clin Invest 1997;100:

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9 황선욱 : 남성골다공증의특징과치료 69. Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, et al. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone. J Bone Joint Surg Am 2005;87: Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997;82: Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000;85: Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, et al. Pamidronate to prevent bone loss during androgen deprivation therapy for prostate cancer. N Engl J Med 2001;345: Anderson FH, Francis RM, Peaston RT, Wastell HJ. Androgen supplementation in eugonadal men with osteoporosis: Effects of six months' treatment on markers of bone formation and resorption. J Bone Miner Res 1997;12: Maricic M, Adachi JD, Sarkar S, Wu W, Wong M, Harper KD. Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 2002;162: Doran PM, Riggs BL, Atkinson EJ, Khosla S. Effects of raloxifene, a selective estrogen receptor modultor, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res 2001;16:

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