1. Risk factors for vitamin D inadequacy among women with osteoporosis : an international epidemiological study 2. The prevalence of vitamin D inadequacy amongst women with osteoporosis : an international epidemiological investigation 1. Int J Clin Pract, August 2006, 60, 8, 1013–1019 ; R. RIZZOLI, J. A. EISMAN, J. NORQUIST, O. LJUNGGREN, G. KRISHNARAJAH, S-K LIM, J. CHANDLER 2. Journal of Internal Medicine 2006; 260: 245–254 ; P. LIPS1, D. HOSKING, K. LIPPUNER, J. M. NORQUIST, L. WEHREN, G. MAALOUF,S. RAGI-EIS & J. CHANDLER FM R1 최정국

INTRODUCTION Vitamin D plays a major role in bone health Vitamin D Sourse - diet (fatty fish, fish oils, fortified dairy products) - cutaneous synthesis by sunlight Skin synthesis - UV 290~315nm : stimulate conversion of 7-dehydrocholesterol to previtamin D - season, time of day, duration of exposure, use of sunscreens, skin pigmentation, latitude - decreases with advancing age

INTRODUCTION In Liver Previtamin D  25(OH)D (25-hydroxyvitamin D) ; major circulating form In Kidney 25(OH)D  1,25-dihydroxy vitamin D ; active form PTH regulates production of 1,25-dihydroxyvitamin D ; calcium homeostasis Severe deficiency of vitamin D  osteomalacia, rickets Chronic inadequacy of vitamin D  secondary hyperparathyroidism ; increased bone turnover, bone loss, risk of fragility fracture adequate serum vitamin D level - important to general skeletal health - important for optimal response to Tx of postmenopausal osteoporosis

INTRODUCTION Primary objective of this study - distribution of vitamin D level from geographical areas at various latitude - estimated the prevalence of vitamin D inadequacy - association between serum 25(OH)D and serum intact PTH - analyses and discussion of risk factors for vitamin D inadequacy Adequate vitamin D level - minimum 25(OH)D level : 75 nmol/l (30 ng/ml)

METHODS Both study Methods were simular Review at Journal 1. Study Design and Participants a cross sectional study Region : Northern, Central, Southern Europe, Middle East, Latin America, Pacific Rim, Asia Country latitude : varied from north to south of the equator (64N–38S) Participants : 1 clinic visitor for medical care 2 database of those attending the clinic Two periods: period I (May 2004 to October 2004) period II (November 2004 to March 2005)

METHODS Eligibility criteria - female gender - postmenopausal for at least 2 years (absence of menses, natural or surgical) Definition of osteoporosis - BMD ; T-score < 2.5 at any site - written documentation of diagnosed osteoporosis in the medical chart - low trauma, non-pathological fragility fracture of the hip, spine, wrist, humerus or clavicle after age 45 - current or previous treatment for osteoporosis with any approved osteoporosis medication

METHODS Information Collected Data were collected at a single clinic visit - height, weight, past medical history, current and prior medication - dietary and supplemental vitamin D intake - weekly sun exposure - general health - education by doctor about the importance of vitamin D single blood sample of 10–30 ml was collected - serum 25(OH)D and serum intact PTH serum 25(OH)D level : measured by the Nichols Advantage competitive binding chemiluminescence immunoassay Blood samples were analysed in one Lab

METHODS Statistical Analysis vitamin D inadequacy defined as serum 25(OH)D levels <75 nmol/l (30ng/mL) Summer - northern hemisphere : May 2004~October 2004 (enrolment period I) Winter - northern hemisphere : November 2004~March 2005 (enrolment period II) southern hemisphere, it was the reverse Equatorial regions (Thailand, Malaysia, Mexico and Brazil) - not assigned seasons Logistic regression model SAS Version 8.1

RESULTS Between May 2004 and March 2005 at 55 sites 55 sites grouped into five regions - Europe (Sweden, United Kingdom, Germany, Netherlands, France, Switzerland, Hungary, Spain) - the Middle East (Turkey and Lebanon) - Asia (South Korea, Japan, Thailand and Malaysia) - Latin America (Mexico, Brazil and Chile) - Pacific Rim (Australia) A total of 2606 women participated - serum 25(OH)D levels were available for 2589 (99.3%) - women ranged in age from 41 ~ 96 yrs, with a mean age of 67.1 yrs - Over half the women were white

RESULTS most of the participants (63%) reported good to excellent health T-score < -2.5 : 2210 (85.4%) Treatment Hx of osteoporosis : 2010 (77.6%) - bisphosphonate, raloxifene, calcitonin, HRT or N-terminal PTH - with or without vitamin D supplementation Vitamin D and/or calcium : 461 (17.8%) untreated : 579 (22.4%)

RESULTS serum 25(OH)D level : 17.5 ~ nmol/l (7 to 243 ng/ml) Mean serum level : 67 nmol/l and SE = 0.8 (26.8 ng/ml and SE = 0.3) Largest value ; nmol/l (243 ng/ml), next value ; 300 nmol/l (120 ng/ ml) Mean values for serum 25(OH)D by country and region

RESULTS In 11 non-equatorial countries, a slight to modest increase in the prevalence of vitamin D inadequacy was observed during winter No significant difference between summer VS winter Difference exist between ‘non-equatorial’ VS ‘equatorial’

RESULTS Journal 2. Table 3

RESULTS All the above factors remained significantly associated with vitamin D inadequacy (except education level, sun exposure, skin tone)

RESULTS multivariate analyses were similar to univariate analysis

RESULTS Journal 2. Fig. 3 Mean serum intact PTH by serum 25(OH)D subgroup

DISCUSSION serum 25(OH)D levels < 75 nmol/l : 64% None of the regions had average serum 25(OH)D level >75 nmol/l Latitude : independent with Vit D inadequacy - other factor than latitude potential risk factors identified in this study - race - high BMI - living in non-equatorial regions - vitamin D supplementation <400 IU daily - poor general health - absence of discussion with a doctor - low education level - low sun exposure, skin reactivity - absence of travel to sunny areas in the past month

DISCUSSION BMI - strongly associated with vitamin D inadequacy - may relates to diminished sun exposure or decreased bioavailability of vitamin D winter season was not significantly associated with vitamin D inadequacy in the non-equatorial countries Dietary intake questionnaire - adapted for each country to include commonly consumed vitamin D- rich foods (fish) - But fish consumption was relatively low in this study & only number was recorded (no quantity) clothing and cultural habits - may strongly influence the effect of sun exposure in some countries

DISCUSSION Limitation Sample women : seeking routine health care - may not be generalisable to all postmenopausal women - more conscious about their health Some race and latitude differences are collinear - difficult to determine which factor may be primary and secondary - However, did not alter overall high prevalence commercial assays (Nichols Advantage) - have been criticised for incorrect - compare with gold standard HPLC : 25(OH)D3 – overestimate 25-(OH)D2 – underestimate - However, results were almost identical

DISCUSSION Important and clinically relevant conclusion - although ample sunlight, vitamin D inadequacy is common with 64% - modifiable risk factors high BMI, inadequate vitamin D supplementation, limited education, low sun exposure