대한골다공증학회지 : 제 8 권제 2 호 pp.96~22, 2 원저 골감소증및골다공증을동반한폐경후여성에서경구칼시페디올의효과 아주대학교의과대학내분비대사내과학교실, 산업의학교실, 예방의학교실 2 김태호 김수정 이순영 2 정윤석 The Effects of Oral Calcifediol in Postmenopausal Women with Osteopenia and Osteoporosis Tae Ho Kim, Soo Jeong Kim, Soon Young Lee 2, Yoon-Sok Chung Department of Endocrinology and Metabolism, Department of Occupational and Environmental Medicine, Department of Preventive Medicine and Public Health 2, Ajou University School of Medicine, Suwon, Korea Objectives: The purpose of this study was to evaluate the effects of oral 25(OH)D on vitamin D related bone metabolic factors and adverse events in Korean postmenopausal women with osteopenia and osteoporosis. Methods: A total 6 women from outpatient Department of Endocrinology and Metabolism were enrolled in this study. A phase IV clinical trial was conducted in which a randomized double-blind, placebocontrolled study with calcifediol (Caldiol R, 2μg daily; Medica Korea Co., Ltd., South Korea) or placebo for 8 weeks. Serum 25-hydroxyvitamin D and parathyroid hormone levels were measured at, 4, and 8 weeks and adverse events were monitored. Results: In the calcifediol group, the serum 25-hydroxyvitamin D levels were>75 nmol/l in 9.3% of the subjects at 8 weeks, and significantly higher compared with the placebo group (2.±32. vs. 3.5±2. nmol/l; P<.). Although the serum PTH level was significantly decreased after 8 weeks in the calcifediol group (P<.), there was no significance when compared with the placebo group (2.±7.7 vs. 25.6±2.7 pg/ml; P=.234). There was no drug-related adverse event. Conclusion: Oral calcifediol improved serum 25-hydroxyvitamin D status without drug-related adverse events in Korean postmenopausal women with osteopenia and osteoporosis. Key Words: Serum 25-hydroxyvitamin D, Serum PTH Received: January 3, 2 Revised: April, 2 Accepted: April 2, 2 Corresponding Author: Yoon-Sok Chung, Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchun-dong Yeongtong-gu, Suwon 443-72, Korea Tel: +82-3-29-527, Fax: +82-3-29-4497 E-mail: yschung@ajou.ac.kr * 본연구는 메디카코리아의지원으로수행되었음. * 본연구의초록은 29 년 2 월대한골다공증학회추계학술대회에서포스터로발표하였음. 골다공증에있어서비타민 D의부족은흔하며심각한문제이다. 폐경후여성및노인에서흔히발생하는비타민 D의부족은이차적으로부갑상선호르몬의분비를증가시켜골흡수를촉진함으로써골감소증및골다공증을악화시키고, 근력을약화시키며낙상의위험을증가시켜결과적으로골절발생을증가시킨다 2,3. 최근의여러연구들에서는전세계적으로뿐만아니라한국인에서도비타민 D 결핍이심 - 96 -
폐경후여성에서경구칼시페디올의효과 각함이보고되었다 4,5. 인체내비타민 D의부족한정도는혈중 25-hydroxyvitamin D 농도가가장잘반영하는것으로알려져있다 6-8. 최근의여러논의들에서노인과폐경후여성에서의골절의위험도를낮추기위해서혈중 25-hydroxyvitamin D 농도를 75 nmol/l 이상으로유지할것을권고하고있다 9. 부족한비타민 D의보충을위한여러종류의비타민 D 제제와그대사물들이개발되어있으나, 대부분의경우비타민 D와칼슘의복합제제형태로출시되어있으며, 이로인해칼슘의가장흔한부작용인소화불량, 변비등의위장장애등이있을수있으며, 철분제나갑상선호르몬제등과같은여러약제들의흡수에영향을미치기도한다. 따라서이러한제한점들을해결하기위하여골다공증환자의치료에비타민 D 단독함유제의사용을고려할필요가있다. Vieth 등은비타민 D 3 보다칼시페디올 (Calcifediol) 이더효과적이고안정적으로혈중 25-hydroxyvitamin D 농도를증가시킴을보고하였으며, 소규모의임상시험에서는건강한폐경후여성에서칼시페디올을복용하였을때, 비타민 D 3 보다더빠르고, 안정적인혈중 25-hydroxyvitamin D 농도의상승소견을보였음을보고하였으나 2, 아직한국인을대상으로경구 25 (OH)D를단독으로사용한연구는없다. 이에본연구에서는골감소증및골다공증을가진한국인폐경후여성들을대상으로경구칼시페디올을투여한후, 비타민 D 관련골대사지표와부작용을평가하고자하였다. 대상및방법. 대상 28년 월부터 29년 2월까지 개대학병원내분비대사내과외래를방문한폐경후여성들중 DXA (Dual energy X-ray Absorptiometry, 이중에너지방사선흡수법 ) 로측정한요추또는대퇴골밀도가 T-score -. 이하로골감소증및골다공증을진단받은환자를대상으로하였다. 최근 3개월이내에비스포스포네이트, 여성호르몬제, SERM, 그리고부갑상선호르몬등의골다공증치료약제를투약한자, 비타민 D가포함된약제를투약한자, 이차성골다 공증환자, 간경화환자, 신부전환자는제외하였으며, 단순칼슘단독제제를복용하고있는경우는포함하였다. 모든대상환자들은임상시험의목적및내용등을설명받은뒤동의서를작성하였으며, 아주대학교병원의학연구윤리심의위원회에서승인을받았다. 총 65명의환자들이시험에참여하였으며, 6명이시험을완료하였다. 2. 연구방법본연구는 4상임상시험으로대상자들은실험군과대조군으로무작위배정되었으며, 실험군은경구 25-hydroxyvitamin D인 calcifediol (Caldiol R, 2μg daily; Medica Korea Co., Ltd., South Korea) 을, 대조군은위약을 일 회용법으로 8주간복용하였다. 임상시험전연령, 신장, 체중, 폐경후기간, 골절과거력, 골절이나골다공증의가족력을확인하였으며, 척추 ( 흉추및요추 ) 의측면 X선촬영과척추와대퇴골의골밀도를측정하였다. 임상시험시작시, 4주, 8주째혈중 25-hydroxyvitamin D, 부갑상선호르몬, 칼슘, 인, 알부민, 총알칼리성포스파타제, 소변내칼슘, 크레아티닌을측정하였다. Primary end point는혈중 25- hydroxyvitamin D였고, secondary end point는혈중부갑상선호르몬, 소변내칼슘-크레아티닌비였다. 혈중 25-hydroxyvitamin D는미국 DiaSorin회사의 25(OH) vitamin D 25I RIA kit를이용하여방사면역법으로측정하였으며, coefficiency of variation은 8.2 ~.% 였다. 혈중부갑상선호르몬은프랑스의 CIS bio international 회사의 ELISA intact PTH IRMA kit를이용하여방사면역법으로측정하였으며, coefficiency of variation은 2.~7.5% 였다. 혈중 25-hydroxyvitamin D는 conventional unit인 ng/ml에서 2.496을곱하여 SI unit인 nmol/l로변경계산하였다. 3. 통계처리수집된자료는평균과표준편차또는백분율로제시하였으며, 기저치 (baseline) 에서같은실험군내의차이, 그리고실험군과대조군두군간의차이는독립표본 t검정 (t-test) 과카이제곱검정 (X 2 -test) 을통해비교하였다. 4주, 8주후의혈중 25-hydroxyvitamin D, 부갑상선호르몬, 칼슘대사인자등의비교에는 - 97 -
대한골다공증학회지 : 제 8 권제 2 호 Table. Clinical characteristics at baseline (mean±sd or %) Characteristics Caldiol (n=3) Placebo (n=29) Age (years) Time since menopause (years) Height (cm) Weight (kg) Past history of fracture or osteoporosis (any site) Family history of fracture or osteoporosis BMD at the L-L4 (g/cm 2 ) T-score L-L4 BMD at the total femur (g/cm 2 ) T-score total femur BMD at the femur neck (g/cm 2 ) T-score femur neck BMD at femur trochanter (g/cm 2 ) T-score femur trochanter BMD at femur wards (g/cm 2 ) T-score femur wards Serum calcium (mg/dl) Serum phosphorous (mg/dl) Serum 25(OH)D (nmol/l) Intact PTH (pg/ml) 58.32±6.79.6±7.4 55.2±4.59 57.43±5.96 25.8% 6.45%.96±.9 -.52±.89.842±.78 -.3±.6.783±.78 -.26±.63.648±.72 -.84±.67.578±.75 -.98±.64 9.39±.36 3.54±.5 34.84±2.3 26.28±2.43 57.86±5.24 7.74±5.46 55.74±5.77 59.39±8.7 3.79% 3.79%.937±.92 -.66±.72.855±. -.87±.92.799±.94 -.3±.75.666±.3 -.7±.95.64±. -.79±.86 9.42±.37 3.52±.55 28.3±.29 28.5±3.97 P-value for t-test or x 2 -test.77.95.694.3.245.344.389.59.62.436.459.27.437.55.47.347.747.94.3.65 반복측정분산분석 (repeated measures ANOVA) 을이용하였다. 모든통계분석은 SPSS 7.을사용하였으며, P<.5인경우를통계적으로유의하다고판단하였다. 결 과. 임상시험대상자들의특징 칼시페디올군과위약군양군에서연령, 폐경기간, 골절력, 요추와대퇴골의골밀도, 혈청칼슘, 혈청인, 그리고부갑상선호르몬수치의유의한차이는보이지않았으나, 혈중 25-hydroxyvitamin D 농도는칼시페디올군에서위약군보다유의하게높았다 (Table ). 2. 혈중 25-hydroxyvitamin D 일차유효성평가항목인혈중 25-hydroxyvitamin D 농도는비록기저치에두군간에유의한평균값의차이가있었으나, 8주간의치료기간이경과함에따라칼시페디올군에서위약군보다차이가훨씬두 Fig.. Changes in the serum 25(OH)D during 8 weeks of treatment 드러졌으며, 이는통계적으로유의한 P값 (P<.) 을나타내었고, 기저치를보정하였을때에도유의한차이를나타내었다 (Fig. ). 두군모두에서기저혈중 25-hydroxyvitamin D농도가 75 nmol/l 이상인대상은없었으며, 칼시페디올군에서 4주째의평균혈중 25-hydroxyvitamin D 농도는 85.32±26.68 nmol/l였으며, 2명 (64.5%) 이 75 nmol/l 이상에도달하였고, 8주째의평균혈중 25- hydroxyvitamin D 농도는 2.5±3.99 nmol/l였으며 - 98 -
폐경후여성에서경구칼시페디올의효과 Table 2. Changes in the serum and urine parameters during 8 weeks of treatment Variables Caldiol R (n=3) Placebo (n=29) P-value* Week 4 8 4 8 Serum calcium (mg/dl) Serum phosphorus (mg/dl) Serum alkaline phosphatase (U/L) Corrected serum calcium (mg/dl) Urine calcium (mg/dl) Urine phosphorus (mg/dl) Urine calcium-creatinine ratio 9.39±.36 3.54±.5 72.97±2.22 9.2±.37 2.55±5.76 5.62±27.87 4.±8.3 9.46±.35 3.72±.49 75.7±9.3 9.5±.34 3.86±5.8 57.58±33.68 4.2±7.36 9.46±.43 3.62±.49 75.7±8.77 9.6±.36 4.32±5.73 5.48±29.33 5.96±6.29 9.42±.37 3.52±.55 82.4±3.34 9.4±.35 2.57±7.39 54.5±23.79.7±6.29 9.37±.34 3.42±.48 8.79±26.92 8.99±.28 2.92±8.53 48.2±27.25.88±7.6 9.43±.3 3.47±.44 8.93±23.4 9.2±.25 4.7±.8 5.45±3.25 2.44±7.95 interaction effect.468.74.246.7.838.273.62 Table 3. Adverse events Fig. 2. Changes in the serum PTH during 8 weeks of treatment 28명 (9.3%) 이 75 nmol/l 이상에도달하였다. 위약군에서는혈중 25-hydroxyvitamin D 농도가 75 nmol/l 이상에도달한사람이없었다. 3. 혈중부갑상선호르몬과요중칼슘-크레아티닌비각그룹의연구시작시점과 8주후의혈중부갑상선호르몬수치를비교해보았을때, 칼시페디올군에서는통계적으로유의한감소를보였으나 (P<.) 위약군에서는그렇지않았다 (P=.79). 그렇지만혈중부갑상선호르몬에서시간의지남에따른전체적인두그룹간의통계적으로유의한차이는보이지않았다 (P=.234) (Fig. 2). 요중칼슘-크레아티닌비에서도시간의지남에따른두그룹간의통계적으로유의한차이는없었다 (P=.62) (Table 2). 4. 안정성칼시페디올군은 6명 (9.4%) 에서, 위약군은 2명 Total number (%) Asthma* Back pain* Edema, weight gain* Proctorrhagia* Right knee joint pain* Gastrointestinal disorder Knee pain* Tingling sensation* Caldiol R (n=3) 6 (9.4) Placebo (n=29) 2 (6.9) *not related with medication, less likely related with medication (6.9%) 에서부작용이있었으나, 칼시페디올약제와관련이있는부작용은없었다 (Table 3). 고 비타민 D의부족과결핍은비타민 D의섭취와합성의감소, 신장에서의 25 (OH)D의수산화감소가주요원인이다 3.,25 (OH) 2 D 3 의농도는이차적인부갑상선기능의항진정도에영향을받기때문에임상적으로혈중 25-hydroxyvitamin D 농도가비타민 D의부족한정도를가장잘반영하는것으로알려져있다 6-8. 인체내비타민 D 부족에대해서합의된기준은아직없다. 비타민 D의부족에대한진단을위해 Lips 등은비타민 D의부족을경증 (25-hydroxyvitamin 찰 - 99 -
대한골다공증학회지 : 제 8 권제 2 호 D 25~5 nmol/l), 중등증 (25-hydroxyvitamin D 7.5~ 25 nmol/l), 중증 (25-hydroxyvitamin D 7.5 nmol/l) 의 3단계로분류하는 staging system을제안하였으며, 각단계에서의부갑상선호르몬은각각 5%, 5~3%, 3% 이상증가로정의하고, 단순히부족에이르지않는것이아니라건강유지의관점에서혈중 25-hydroxyvitamin D의농도를 75 nmol/l 이상유지할것을권고하였다 4. Chapuy 등도역시혈중 25-hydroxyvitamin D 농도가 75 nmol/l 이하에서부갑상선호르몬이증가되어있다고보고하였다 3. 부갑상선호르몬이높아지면서골교체율은증가하기시작한다. Bischoff- Ferrari 등은메타분석을통해혈중 25-hydroxyvitamin D 의농도를 75 nmol/l 이상으로유지하였을때에노인들에서고관절골절 (26%) 과비척추골절 (23%) 의예방을보고하였으며, 이메타분석에이용된모든연구에서혈중 25-hydroxyvitamin D와골절예방효과의의미있는상관관계를보였다 5. 대규모조사인 NHANES III에서도혈중 25-hydroxyvitamin D의농도가 75~ nmol/l일때, 6세이상에서고관절골밀도와하지기능이가장좋았다 6,7. Vieth는부갑상선호르몬을억제하고적절한칼슘흡수를위한혈중 25-hydroxyvitamin D의농도를 75~6 nmol/l로제안하였으며, 22 nmol/l 이상일때, 혈중및뇨중칼슘농도의상승을보이는위험단계로제안하였다 8,9. 비타민 D 부족의치료를위해많은종류의비타민 D와그대사물들이있으며, 비타민 D 제제로가장많이사용되고있는것은 ergocalciferol과 cholecalciferol이다. 많은연구에서 cholecalciferol이혈중 25-hydroxyvitamin D 농도의상승에더효과적이었으며 2-22, 단독제제보다는칼슘과의혼합제제로사용되고있다. 비타민 D 대사물인 calcifediol (25(OH)D) 과 calcitriol (,25(OH) 2 D 3 ) 도비타민 D 부족에사용할수있다. 25(OH)D는간에서의 25-수산화를필요로하지않으므로, 간질환이있는환자에게유용하게사용될수있으며 23, 체내에서빠르게작용하며반감기도 2~3주로비타민 D 3 의 3~4주보다더짧다.,25 (OH) 2D 3 는체내에서,25(OH) 2D 3 를합성하지못하는만성신부전환자나제형비타민 D 의존성구루병환자에서유용하지만, 빠른작용시간과반감기가 6시간밖에되지않아고칼슘혈증등의부 작용에주의하여야한다. Vieth는 25 (OH)D을복용하였을때, 비타민 D 3 보다 4배이상의혈중 25-hydroxyvitamin D의상승을보이고, 복용용량이증가할수록혈중 25-hydroxyvitamin D가선형관계로증가함을보여주었다. 반면비타민 D 3 는복용용량이증가할수록혈중 25-hydroxyvitamin D의증가는둔화되었다. 같은용량의경구 25(OH)D과비타민 D3를비교한 Jetter 등의연구에의하면폐경후여성에서경구 25(OH)D가 2배이상혈중 25-hydroxyvitamin D 농도를상승시키고, 75 nmol/l에도달하는시간도 4배이상빠름을보여주었다 2. 지금까지한국인골감소증환자를대상으로경구 25 (OH)D만을복용시킨연구는없었다. 박등의 Cal-D-Vita (cholecalciferol 4 IU+elemental calcium 6 mg) 를한국인에게서 년간복용하였던연구에서는 년후평균혈중 25-hydroxyvitamin D의농도가 45% 정도증가하였으나, 75 nmol/l에는미치지못한결과를보여주었으며, cholecalciferol 용량의증량필요성을제시하였다 24. 이외의여러연구들에서적절한혈중 25-hydroxyvitamin D 농도의유지를위해매일 7~, IU 이상의비타민 D를취할것을권고하였다,25,26. 본연구에서는단독비타민 D 보충제제로서경구 25 (OH)D 제제의유용성을확인하고자하였으며, 2 ug의칼시페디올을매일 8주간복용하였을때, 3배정도의혈중 25-hydroxyvitamin D 농도의상승을보여주었으며, 이는 Vieth의연구와비슷한결과이다. 많은연구에서혈중 25-hydroxyvitamin D의농도가상승함에따라부갑상선호르몬이감소함을보고하였다. 본연구에서는경구 25 (OH)D을복용한군에서임상시험시작시점과비교하여 4주, 8주째부갑상선호르몬의통계적으로유의한감소를보였으나, 위약군과비교하였을때에는두그룹사이의의미있는차이는보이지않았다. 경향은보였으나대상환자의숫자가적고 8주라는비교적짧은기간으로인해통계적유의성을보이지않은것으로사료된다. 요중칼슘-크레아티닌비는두그룹간의통계적으로유의한차이는보이지않았다. 칼시페디올을투여함으로서부작용으로발생할수있는고칼슘뇨증이유의하지는않은것으로확인되었다. 본연구의제한점으로는첫째 8주라는비교적짧은 - 2 -
폐경후여성에서경구칼시페디올의효과 기간의연구였다는점, 둘째칼슘 + 비타민D 복합제또는비타민 D 3 복용군과직접적인비교를하지못했다는점, 셋째비타민 D의음식섭취및태양광선노출에따른변화에대해통제를하지못하였던점이다. 본연구를통해저자들은골감소증및골다공증을가진폐경후여성들에서경구 25 (OH)D의복용이혈중 25-hydroxyvitamin D의적절한농도에의도달및유지에효과적이며, 약물과관련된부작용이없음을볼수있었다. 경구 25 (OH)D 제제가비타민 D 부족환자에서부작용없이효과적으로사용될수있을것으로기대된다. 국문초록목적 : 골감소증및골다공증을가진한국의폐경후여성들을대상으로경구 25(OH)D 제제를투여한후, 비타민 D 관련골대사지표와부작용을평가하고자하였다. 방법 : 개대학병원내분비대사내과외래에서모집된 6명의여성을대상으로하였다. 대상자를두그룹으로임의로배정하여실험군은경구칼시페디올 ( 칼디올 R, 2 μg; 메디카코리아 ) 을, 대조군은위약을 일 회용법으로 8주간복용한후혈중 25-hydroxyvitamin D와부갑상선호르몬수치, 부작용여부를추적관찰하였다. 결과 : 칼시페디올군에서는 8주뒤 9.3% 에서혈중 25-hydroxyvitamin D 농도가 75 nmol/l 이상에도달하였으며, 위약군과비교하였을때유의한차이를나타냈다 (2.±32. vs. 3.5±2. nmol/l; P<.). 실험군에서 8주뒤혈중부갑상선호르몬수치의의미있는감소를보였으나 (P<.), 위약군과비교하였을때에는통계적으로유의한차이를보이지않았다 (2.±7.7 vs. 25.6±2.7 pg/ml; P=.234). 약제와관련된부작용은없었다. 결론 : 골감소증또는골다공증을동반한한국인폐경후여성에게경구칼시페디올을매일 2 ug, 8주간투여하였을때, 약제와연관된부작용없이혈중 25- hydroxyvitamin D 농도의유의한증가를볼수있었다. 중심단어 : 혈중 25-hydroxyvitamin D, 부갑상선호르몬 참고문헌. Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA 25;294: 2336-4. 2. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al. Effect of Vitamin D on falls: a meta-analysis. JAMA 24;29:999-26. 3. Visser M, Deeg DJ, Lips P. Longitudinal Aging Study Amsterdam. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): The Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 23;88:5766-72. 4. Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, et al. Prevalence of vitamin D inadequacy among postmenopausal North American Women receiving osteoporosis therapy. J Clin Endocrinol Metab 25;9:325-24. 5. Rhee YM, Lee HJ, Kim YM, Lee SH, Ahn CW, Cha BS, et al. The Status of the Serum 25- hydroxyvitamin D Level in Korean Postmenopausal Women and Its Effect on Bone Metabolism. J Korean Soc Osteoporos 23;:22-3. 6. McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med 992;93():69-77. 7. Tsai KS, Heath H 3rd, Kumar R, Riggs BL. Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis. J Clin Invest 984;73(6):668-72. 8. Krall EA, Sahyoun N, Tannenbaum S, Dallal GE, Dawson-Hughes B. Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women. N Engl J Med 989;32(26):777-83. 9. Dawson-Hughes B, Heaney RP, Holick MF, Lips - 2 -
대한골다공증학회지 : 제 8 권제 2 호 P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 25;6(7):73-6.. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: Serum levels after graded oral dosing in healthy men. Osteoporos Int 998;8:222-3.. Vieth R. The pharmacology of vitamin D, includeing fortification strategies. In: Feldman D, Wesley PJ. Glorieux FH. Vitamin D, 2nd ed. Elsevier Inc.; 25. p. 995-5. 2. Jetter A, Egli A, Dawson-Hughes B, Henschkowski J, Staehelin H, Stoecklin E, et al. Plasma Pharmacokinet-ics: Comparision between Oral Supplementation Regimens with 25 (OH)D and Vitamin D 3. J Bone Miner Res 24 (Suppl ). Available at http://www.asbmr.org/meetings/annual Meeting/AbstractDetail.aspx?aid=b2959d-e5-4e 9a-bfec-9f494bb7f. 3. Chapuy MC, Chapuy P, Meunier PJ. Calcium and vitamin D supplements: effects on calcium metabolism in elderly people. Am J Clin Nutr 987; 46:324-8. 4. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: Consequences for bone loss and fractures and therapeutic implication. Endocr Rev 2;22:477-5. 5. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 25;293(8):2257-64. 6. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson- Hughes B. Positive association between 25-hydroxy vitamin d levels and bone mineral density: a population-based study of younger and older adults. Am J Med 24;6(9):634-9. 7. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW, et al. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged>or=6 y. Am J Clin Nutr 24; 8(3):752-8. 8. Vieth, R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr 26; 36:7-22. 9. Vieth, R. What is the optimal vitamin D status for health? Prog Biophys Mol Biol 26;92:26-32. 2. Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 998;68:854-8. 2. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 24;89:5387-9. 22. Romagnoli E, Mascia ML, Cipriani C, Fassino V, Mazzei F, D'Erasmo E, et al. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab 28;93:35-2. 23. Basha B, Rao DS, Han ZH, Parfitt AM. Osteomalacia due to vitamin D depletion: a neglected consequence of intestinal malabsorption. Am J Med 2;8:296-3. 24. Park TJ, Jo YE, Choi YJ, Kim YK, Ahn SM, Jung SH, et al. The Effects of Oral Vitamin D Supplement in Vitamin D Inadequacy. J Korean Soc Osteoporos 25;3:2-5. 25. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 22;2:659-62. 26. Dawson-Hughes B. Impact of vitamin D and calcium on bone and mineral metabolism in older adults. In: Holick MF, edotor. Biologic effects of light 2. Kluwer Academic Publishers, Boston, MA, 22;75-83. - 22 -