JOURNAL OF BONE AND MINERAL RESEARCHVolume 24, Number 4, 2009Published online on December 1, 2008; doi: 10.1359/JBMR.081209� 2009 American Society for Bone and Mineral Research
Vitamin D Status, Parathyroid Function, Bone Turnover, and BMD inPostmenopausal Women With Osteoporosis: Global Perspective
Natalia O Kuchuk,1 Natasja M van Schoor,2 Saskia M Pluijm,3 Arkadi Chines,4 and Paul Lips1,2
ABSTRACT: Poor vitamin D status is common in the elderly and is associated with bone loss and fractures.The aim was to assess worldwide vitamin D status in postmenopausal women with osteoporosis according tolatitude and economic status, in relation to parathyroid function, bone turnover markers, and BMD. Thestudy was performed in 7441 postmenopausal women from 29 countries participating in a clinical trial onbazedoxifene (selective estrogen receptor modulator), with BMD T-score at the femoral neck or lumbarspine � 22.5 or one to five mild or moderate vertebral fractures. Serum 25(OH)D, PTH, alkaline phos-phatase (ALP), bone turnover markers osteocalcin (OC) and C-terminal cross-linked telopeptides of type Icollagen (CTX), and BMD of the lumbar spine, total hip, femoral neck, and trochanter were measured. Themean serum 25(OH)D level was 61.2 ± 22.4 nM. The prevalence of 25(OH)D <25, 25–50, 50–75, and >75 nMwas 5.9%, 29.4%, 43.5%, and 21.2%, respectively, in winter and 3.0%, 22.2%, 47.2%, and 27.5% in summer.Worldwide, a negative correlation between 25(OH)D and latitude was observed. With increasing 25(OH)Dcategories of <25, 25–50, 50–75, and >75 nM, mean PTH, OC, and CTX were decreasing (p < 0.001), whereasBMD of all sites was increasing (p < 0.001). A threshold in the positive relationship between 25(OH)D anddifferent BMD parameters was visible at a 25(OH)D level of 50 nM. Our study showed a high prevalence oflow 25(OH)D in postmenopausal women with osteoporosis worldwide. Along with latitude, affluence seemsto be an important factor for serum 25(OH)D level, especially in Europe, where it is strongly correlated withlatitude.J Bone Miner Res 2009;24:693–701. Published online on December 1, 2008; doi: 10.1359/JBMR.081209
Key words: vitamin D, PTH, bone turnover, BMD, latitude
INTRODUCTION
VITAMIN D DEFICIENCY is common in elderly people andin patients with osteoporosis.(1) It causes secondary
hyperparathyroidism, high bone turnover, bone loss, min-eralization defects, and fractures. Other consequences in-clude myopathy and falls.(2,3) Low vitamin D status mayplay role in diabetes mellitus,(4) cancers, multiple sclerosis,and other autoimmune diseases,(5) and was associated withpoorer physical performance,(6) falls and fractures,(3) and agreater risk of nursing home admission(7) in older men andwomen.
Vitamin D3 is synthesized in human skin after the pho-toisomerization of 7-dehydrocholesterol (7DHC) to pre-vitamin D3, under the influence of UV B (UVB) radiation(wavelength, 280–315 nm). The major factors influencingthis process are either environmental (latitude, season,time of day, ozone and clouds, reflectivity of the surface) orpersonal (skin type, age, clothing, use of sunscreen).(8) Oily
fish also contains vitamin D3, and margarine, milk, somebreads, and yogurts, at least in the United States, are for-tified either with vitamin D3 or with vitamin D2.(9) Withhigher latitudes, there is an increase in the length of the‘‘vitamin D winter,’’ when no previtamin D3 is produced inthe skin: for example, it lasts from November throughFebruary at latitude 428 (Boston, MA, USA) and fromOctober through March at 528 (Edmonton, Canada).(10)
Vitamin D is metabolized in the liver to 25-hydroxyvitaminD [25(OH)D], and the measurement of circulating level of25(OH)D is used to determine vitamin D status. Althoughthe vitamin D–replete and –deficient states have been de-fined,(2,11) there is still no consensus on a cut-off value forthe definition of low 25(OH)D status or a definition forsuccessful repletion of vitamin D. Approximately 80 nM of25(OH)D has been recently suggested to be sufficient.(12)
There is also growing evidence from the international lit-erature about high prevalence of unrecognized vitamin Ddeficiency worldwide in different age groups.(13–22) Sur-prisingly, the levels of 25(OH)D are often higher in theUnited States, Canada, and Scandinavia(23–25) than in thecountries located at lower latitudes. These internationaldifferences are partially explained by different sunshine
1Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands; 2EMGO Institute, VU UniversityMedical Center, Amsterdam, The Netherlands; 3Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands;4Wyeth Research, Philadelphia, Pennsylvania, USA.
Dr Lips has received research funding from Wyeth, Merck,Procter and Gamble, and Sanofi-Aventis. Dr Chines owns stock inWyeth and is a Wyeth employee. All other authors state that theyhave no conflicts of interest.
693
exposure, skin pigmentation, air pollution, skin covering,and vitamin D intake with diet,(26) as well as supplementuse and fortification policies.(27) The use of different assaysfor the measurement of 25(OH)D also impairs the com-parison between countries.(28)
The aim of this study was to describe 25(OH)D statusaccording to season in postmenopausal women with osteo-porosis, in different countries with different economic statusall over the world using a central laboratory facility, and toinvestigate the relationship between 25(OH)D status andparathyroid function, bone turnover markers, and BMD.
MATERIALS AND METHODS
Study population
For this study, baseline data were used from the FractureIncidence Reduction and Safety of Bazedoxifene AcetateCompared with Placebo and Raloxifene in OsteoporoticPostmenopausal Women Clinical Trial. Bazedoxifene isone of the selective estrogen receptor modulators(SERMs).
The total study population of this multicenter trial con-sisted of 7491 postmenopausal women. For this study,baseline data were available from 7455 women, 50–85 yr ofage (mean, 66.4 ± 6.7 yr), from 29 countries on six conti-nents (North America, South America, Europe, Asia,Africa, Australia).
All women who participated in this trial were at least 2 yrpostmenopausal and had either osteoporosis according toWHO criteria (BMD T-score at the lumbar spine or fem-oral neck was < –2.5) or one to five mild or moderateasymptomatic vertebral fractures with a T-score > 23.5.Women with a history of diseases that may affect bonemetabolism other than osteoporosis, severe prevalentvertebral fractures, postmenopausal symptoms requiringtreatment, known history or suspected cancer of the breast,malignancy within the last 10 yr, history of venous throm-boembolic events, active renal lithiasis, endocrine disor-ders requiring treatment (except well-controlled diabetesmellitus type 2 or hypothyroidism), and untreated malab-sorption disorders were excluded. Patients with the use ofthe following drugs within 6 mo before screening were alsoexcluded: systemic corticosteroids, systemic estriol > 2 mg/d, topical estrogen more often than three times a week,progestogens, androgens, calcitonin, bisphosphonates,PTH, SERMs, cholecalciferol (>50,000 IU/wk), and anti-seizure drugs. In addition, the following subjects were ex-cluded from this study based on laboratory measurements:high serum 25(OH)D (n = 2), high serum C-terminal cross-linked telopeptides of type I collagen (CTX; n = 1), lowserum calcium (n = 2), high serum calcium (n = 8), and lowserum phosphorus (n = 1), leaving 7441 women with knownlevels of serum 25(OH)D. From these women, 87.3% (n =6495) were white, 6.5% (n = 482) were black, 4.6% (n =346) were Hispanic, 1.3% (n = 100) were Asian, and 0.3%(n = 18) had other ethnicities.
The protocol was approved by the ethical review board ateach center, and written informed consent was obtained fromall participants in accordance with the Declaration of Helsinki.
The women were enrolled between December 2001 andSeptember 2003 at 206 centers in 29 countries (23 in thenorthern and 6 in the southern hemisphere; a list of centersis available on request). Fasting blood samples wereobtained at baseline, and after centrifugation, the serumsamples were kept frozen until determination. Serum25(OH)D was measured at the Covance Central Labora-tory by the DiaSorin 25(OH)D assay with an interassay CVbetween 8.2% and 11.0%. Serum PTH concentrations weremeasured using the DiaSorin N-tact PTH SP immunor-adiometric assay (IRMA), with an interassay CV of 3.4–4.9%. The alkaline phosphatase (ALP) and serum calciumassays were performed on the Roche Hitachi analyzers,with an interassay CV of 2.5–5.2% for ALP and 1.4–1.5%for calcium. The phosphorus, creatinine, and albuminassays were performed on the Roche Modular analyzer,with an interassay CV of 1.6–1.8%, 1.7–2.3%, and 2.3–2.6% for phosphorus, creatinine, and albumin, respec-tively. All assays on bone markers were performed in aspecialized centralized laboratory (Synarc, Lyon, France)under the direction of Dr Patrick Garnero. Serum totalosteocalcin (OC) and CTX were measured by automatedanalyser (Elecsys; Roche Diagnostics) with an interassayCV <7.2% for OC and <5.7% for CTX.
Seasons were defined as follows: summer, April–September; winter, October–March in the northern hemi-sphere and the reverse in the southern hemisphere. Foreach of the 206 centers, latitude was searched in a databaseof geographic coordinate information (http://www.tageo.com/index.htm and http://www.geonames.org). The dataon vitamin D were presented per country according togeographical regions. For each country, gross domesticproduct per capita (GDP) was searched for 2003 in TheWorld Economic Outlook (WEO) Database April 2003(World Economic And Financial Surveys, InternationalMonetary Fund, http://www.imf.org/external/pubs/ft/-weo/2003/01/data/index.htm). GDP was expressed in cur-rent U.S. dollars (USD) per person. Data were derived byfirst converting GDP in local currencies to USD and di-viding GDP by the total population in 2003. GDP was usedas an indicator of affluence in different countries.
BMD of lumbar spine and hip (total hip, femoral neck, andtrochanter; in g/cm2), were measured by DXA on Hologic,Lunar, or Norland densitometers and standardized.(29)
Statistical analysis
SPSS 12.0 was used to perform statistical analyses.ANOVA was used to assess the seasonal differences inserum 25(OH)D in different countries and geographicalregions. ANOVA was also used to assess differences inserum PTH, bone turnover markers, and BMD accordingto different cut-points for serum 25(OH)D (i.e., <25, 25–50,50–75, and >75 nM). Pearson’s correlation coefficientswere calculated between serum 25(OH)D, latitude, andGDP and BMD, according to season. Partial correlationwas performed with the calculation of Pearson’s correlationcoefficient to study the relationship between vitamin D andlatitude controlling for GDP. Locally weighted regressionsmoothing (LOESS) plots were performed in STATA tostudy the relationship between 25(OH)D, PTH, and BMD.
694 KUCHUK ET AL.
Potential confounders included age, BMI, serum creati-nine, and season. First, unadjusted analyses were per-formed. Subsequently, potential confounders were addedto the models.
RESULTS
The mean serum 25(OH)D level in 7441 postmenopau-sal women was 61.2 ± 22.4 nM. There was a significantseasonal difference in mean serum 25(OH)D, with higherlevels in the summer than in the winter for most countriesand geographical regions. Table 1 presents these data to-gether with the percentages of women in different serum25(OH)D level groups (<25, 25–50, 50–75, and >75 nM) perseason in different countries. The prevalence of serum25(OH)D level <25 nM was higher in winter for all regions,with the highest prevalence in south and southeasternEurope, both for winter (up to 34.4% for Romania and28.2% for Croatia) and for summer (10.9% for Croatia and10.5% for Romania).
Figure 1 shows the significant negative correlation be-tween 25(OH)D and latitude worldwide. As expected, thiscorrelation was stronger in winter (r = 20.36, p < 0.001without controlling, and rc = –0.40, p < 0.001 with con-trolling for GDP per capita) than in summer (r = 20.09, p <0.001 and rc = –0.13, p < 0.001, respectively). Conversely, inEurope, a significant positive correlation was observedbetween 25(OH)D and latitude (r = 0.21, p < 0.001). Weexamined this finding more closely, trying to explain it withavailable data. Although GDP per capita in 2003 wasstrongly correlated with latitude when Europe was taken asa whole (r = 0.51, p < 0.001), it differs substantially betweenEuropean countries. Figure 2 shows mean values of25(OH)D, latitude, and GDP per country and differencesbetween them. In the group of countries with GDP >10.000 USD, the distribution of GDP was strongly corre-lated with latitude (r = 0.75, p < 0.001). The positive cor-relation between 25(OH)D and latitude in these countries(r = 0.13, p < 0.001) almost disappeared and became non-significant (rc = 0.01, p = 0.626) when controlling for GDP.In the countries with GDP < 10.000 USD (Eastern Euro-pean economies), the correlation between GDP and lati-tude was less strong (r = 0.17, p < 0.001), and the positivecorrelation between 25(OH)D and latitude (r = 0.17, p <0.001) remained significant when controlling for GDP (rc =0.14, p < 0.001). The positive correlation between GDP and25(OH)D, however, stayed significant for both groups ofcountries after controlling for latitude (rc = 0.10, p < 0.001and rc = 0.18, p < 0.001 for the groups of countries withGDP <10.000 USD and >10.000 USD, respectively).
Table 2 shows the mean values of bone markers andBMD measurements in different 25(OH)D groups. Ingroups with increasing mean 25(OH)D of <25, 25–50, 50–75, and >75 nM, mean PTH was 4.5 ± 1.5, 4.1 ± 1.5, 3.7 ±1.2, and 3.5 ± 1.2 pM, respectively (by ANCOVA, p <0.001). Also, the other parameters of bone turnover, suchas serum levels of OC (bone formation) and CTX (boneresorption), were significantly lower in the highest serum25(OH)D group (except for ALP, a marker of bone for-
mation, which did not significantly change). All BMDvalues were significantly higher in the highest serum25(OH)D group.
The relationship between 25(OH)D and some bone pa-rameters is presented in Fig. 3. LOESS plots, corrected forage, BMI, serum creatinine, and season, show the meanvalues of serum PTH and BMD for each value of serum25(OH)D. In the inverse relationship between serum PTHand 25(OH)D, there was a steep decrease of PTH up to 50nM and a more slow decrease between 50 and 100 nM. Thisrelationship between PTH and 25(OH)D showed no pla-teau with serum 25(OH)D up to 100 nM. Although onlysignificant for BMD of hip trochanter, the LOESS plot ofthe relationship between 25(OH)D and BMD parametersseemed to show a threshold around the 25(OH)D value of50 nM. A similar shape of LOESS plot was observed forBMD of femoral neck (data not shown).
DISCUSSION
This study allows one to compare serum 25(OH)D andPTH levels in postmenopausal women with osteoporosisthroughout the world. A central laboratory facility wasused to perform the measurements in 7441 women whowere enrolled in one double-blind, randomized, controlledclinical trial, thereby eliminating the variation in assay andmethods between the laboratories in different countries.
We found considerable differences in vitamin D statusin different countries depending on season and latitude(Table 1), with high prevalence of serum 25(OH)D < 25and 25–50 nM in many countries. The results are consistentwith the previous global study with similar design, in whichthe highest prevalence of vitamin D deficiency [25(OH)D< 25 nM] was observed in countries of central and southernEurope.(23) In our study, more countries of southeasternEurope were represented, all of them with high prevalenceof low serum 25(OH)D, especially in winter.
Worldwide, serum 25(OH)D was negatively correlatedwith latitude, a finding that we expected. For Europe,however, this correlation was paradoxically positive, as wasalso seen in other studies.(23–25) Thus, although the syn-thesis of vitamin D in the skin is known to be the mostimportant source of vitamin D, there are more factors thanlatitude and sun exposure that determine the serum25(OH)D level. The use of multivitamins, which is knownto be associated with higher income, is common among theelderly in the United States and in Europe and was foundto be 50–60%.(30,31) Dietary intake of vitamin D–rich food(oily fish like salmon, mackerel, herring, and sardines,which are considered to be the best sources) is also im-portant to consider. The traditional use of cod liver oil orother supplements was up to 60% in a study from Ice-land.(32) In a Danish study on the use of dietary supple-ments in 3707 women and 942 men, it was found that, in theage group of 60–65 yr, 78% of women and 60% of menwere using some kind of supplement, whereas 18% ofwomen and 14% of men also used fish oils.(33) In a Nor-wegian study on 37,226 women 41–55 yr of age, cod liver oilsupplements were taken by 44.7%.(34)
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In our study, GDP as a marker of affluence is positivelycorrelated with 25(OH)D in Europe, also after correctionfor latitude. Therefore, in a group of European countrieswith GDP > 10.000 USD, in which GDP is strongly cor-related with latitude (r = 0.75; p < 0.001), we expected tofind a negative correlation between latitude and 25(OH)Dafter controlling for GDP. However, the positive correla-tion between latitude and 25(OH)D in these countriesdisappeared and became nonsignificant. We do not havedata on income of participating women, neither on theirdiet, use of multivitamins, or holidays in sunny countries,which could all affect their serum 25(OH)D level. A lowprevalence of low serum 25(OH)D in northern Americaand northern Europe was found before,(24,25) but as far aswe know, the investigators did not try to explain this by
differences in affluence between the countries. The indi-cators of poor income (lowest levels of income, food stampuse, food insufficiency) are known to be associated withlower dietary intakes among homebound older adults,(35)
and high prevalence of diets with the lowest quartile in atleast two of four musculoskeletal nutrients (vitamin D,calcium, magnesium, and phosphorus).(36) Therefore, itwould be interesting to assess the relationship betweenincome level per person, the diet, fortification policy, theuse of supplements, and holidays in sunny destinations, andto study the share of each factor that has influence on therelation between latitude and serum 25(OH)D.
In our study, in the inverse relationship between serumPTH and 25(OH)D, no plateau was observed at serum25(OH)D up to 100 nM. Above that level, there seems to
FIG. 1. Relationship between latitude andserum 25(OH)D worldwide. (A) Winter. (B)Summer.
VITAMIN D, BONE MARKERS, AND BMD 697
be a plateau; but because 95% of our subjects have serum25(OH)D <100 nM and the CIs >100 nM are wide, noconclusions can be drawn for serum 25(OH)D levels >100nM. The results of a study on 25(OH)D, PTH, and calciumintake suggested that vitamin D sufficiency can maintainlow serum PTH values even when the calcium intake levelis <800 mg/d, whereas a high calcium intake (>1200 mg/d)is not sufficient to maintain low serum PTH, as long asvitamin D status is insufficient.(32) Interestingly, that studyindicated that the variation of the relationship between25(OH)D and PTH might be dependent on calcium intake,
as well as different serum 25(OH)D levels needed for theinflection point of serum PTH. In fact, some studies find aninflection point in the relationship between serum25(OH)D and serum PTH, whereas other do not. Thesedifferent outcomes could be caused by different statisticaltechniques. For example, if a regression model is used, itsuggests a negative relationship without a plateau. Whenlocally weighted regression smoothing is used to show theshape of the relationship, some studies find a plateau athigher serum 25(OH)D levels. In our study, a plateauseems visible after serum 25(OH)D of 100–120 nM, but the
FIG. 2. Relationship between latitude, se-rum 25(OH)D, and gross domestic productper capita (GDP) in USD in Europe. (A)Latitude and serum 25(OH)D. (B) Latitudeand GDP. (C) Serum 25(OH)D and GDP.
TABLE 2. MEAN VALUES (±SD) OF SERUM PTH, BONE TURNOVER MARKERS, AND BMD FOR DIFFERENT GROUPS ARRANGED
ACCORDING TO SERUM 25(OH)D OF <25, 25–50, 50–75, AND >75 NM
Parameter
Serum 25(OH)D (nM)
p byANCOVA*
<25 nM(n = 334)
25–50 nM(n = 1922)
50–75 nM(n = 3374)
>75 nM(n = 1811)
25(OH)D (nM) 19.2 ± 3.9 38.8 ± 7.0 62.6 ± 7.5 90.2 ± 12.8 <0.001
PTH (pM) 4.5 ± 1.5 4.1 ± 1.5 3.7 ± 1.2 3.5 ± 1.2 <0.001
ALP (U/liter) 81.1 ± 22.1 80.9 ± 22.4 81.9 ± 22.2 82.8 ± 22.3 0.081
OC (ng/ml) 34.1 ± 13.4 33.5 ± 13.1 31.7 ± 12.3 30.8 ± 13.2 <0.001
CTX (ng/ml) 0.56 ± 0.26 0.55 ± 0.23 0.52 ± 0.23 0.52 ± 0.25 <0.001
BMD of lumbar spine (g/cm2) 0.828 ± 0.13 0.846 ± 0.13 0.847 ± 0.13 0.856 ± 0.14 <0.01
BMD of total hip (g/cm2) 0.790 ± 0.11 0.800 ± 0.12 0.803 ± 0.12 0.813 ± 0.12 0.001
BMD of femoral neck (g/cm2) 0.700 ± 0.12 0.710 ± 0.13 0.720 ± 0.13 0.729 ± 0.13 <0.001
BMD of femoral trochanter (g/cm2) 0.608 ± 0.11 0.628 ± 0.11 0.635 ± 0.11 0.643 ± 0.12 <0.001
For conversion of 25(OH)D from nM to ng/ml, divide by 2.496; for conversion of PTH from pM to pg/ml, multiply by 11.1.
* Corrected for confounders (age, BMI, serum creatinine, season).
698 KUCHUK ET AL.
CI above this level becomes wide, because there are notmany subjects with such high serum 25(OH)D levels.
In contrast with another study,(34) PTH did not show anysignificant relationship with creatinine in our study, aftercontrolling for weight, height, or both (data not shown), inthe total group as well as in a group of respondents with25(OH)D < 50 nM.
A recent review of the literature that reported a thresholdfor the relation between serum 25(OH)D and PTH foundthat most estimates were clustered between 40 and 50 nM or70 and 80 nM. The same review found that, in the studies witha mean 25(OH)D of >50 nM, calcium intake did not affectPTH, but in studies with a mean 25(OH)D of <50 nM, dietarycalcium was inversely related to PTH.(37) In an Americanstudy on vitamin D and calcium supplementation, whichevaluated the effect of increasing 25(OH)D levels >25 nMwith vitamin D therapy on blood concentrations of serumPTH, PTH levels did not substantially decline in subjectswho had a starting blood level of 25(OH)D of at least 50nM,(38) which is consistent with our observation.
In our study, a significant positive correlation was foundbetween 25(OH)D and BMD of the femoral trochanter.Furthermore, mean values of BMD at all measured sites
(lumbar spine, total hip, femoral neck, and femoral tro-chanter) were higher in groups with higher serum 25(OH)Dlevel (Table 2). These absolute differences in mean BMDbetween the different vitamin D groups might be small, butat the population level, these differences could mean asubstantial reduction in fracture risk. Hip fractures werefound to be strongly related to reduced BMD in all regionsof the proximal femur, with a risk ratio of 2.5–2.7 for hipfracture (95% CI, 1.9–3.6) with each SD decrease of BMDat any site of the proximal femur, after adjustment forage.(39) Therefore, a decrease in BMD of the femoral neckfrom 0.729 to 0.700 g/cm2 (0.25 of SD) in our data mayincrease the RR for hip fracture by >50%. Indeed, the pro-tective effect of vitamin D on fractures was found in severalstudies.(14,40) In addition, a positive association between25(OH)D and BMD was established in The National Healthand Nutrition Examination Survey III (NHANES III) in13,432 subjects including whites, Hispanics, and blacks.(41)
There are different views on the optimal level of serum25(OH)D. For the prevention of rickets, a serum 25(OH)Dlevel >25 nM seems to be sufficient. For prevention of boneloss and other outcomes, the optimal level of serum25(OH)D probably is >50 nM.(42,43) However, in a recentreview on the estimation of optimal serum concentrationsof 25(OH)D for multiple health outcomes, the most ad-vantageous serum concentration of 25(OH)D was found tobe >75 nM for outcomes including BMD, lower extremityfunction, risk of falls, fractures, and colorectal cancer.(44)
The percentage of postmenopausal women with osteopo-rosis with serum 25(OH)D <75 nM in the winter ap-proaches 90–100% in Europe and 80% in Canada and theUnited States. Even in Brazil, the country with the best25(OH)D status in our study, the percentage of womenwith 25(OH)D levels of >75 nM is only 34.3% in winter and43% in summer. Accepting the cut-off value of 75 nMwould implicate that almost 80% of postmenopausalwomen with osteoporosis worldwide should be treated forhypovitaminosis D in winter and up to 75% in summerbecause of levels <75 nM. To achieve these levels, a highsupplementation dose might be needed. If the requiredlevel of serum 25(OH)D is 50 nM,(2,11) 35% of postmen-opausal women with osteoporosis worldwide should betreated for hypovitaminosis D in winter and up to 25% insummer, and this would be easier to achieve.
The strength of our study is in the central laboratoryfacility for all measurements from 206 centers in 29 coun-tries, eliminating the variation between laboratories. An-other strong point is the significant relationship betweenserum 25(OH)D and BMD at all measured sites (Table 2).A limitation is that the women participating in a clinicaltrial usually differ from the general population. Therefore,the results can not be generalized to all postmenopausalwomen with osteoporosis. Because it is well known thatsubjects who are participating in clinical trials usually aremore conscious about their health, the estimation of a highprevalence of vitamin D deficiency in the general popula-tion is conservative. Another limitation is a small samplesize for some countries.
Our study showed a high prevalence of low serum25(OH)D in women with postmenopausal osteoporosis all
FIG. 3. Relationship of serum 25(OH)D with PTH and BMD.(A) With PTH, p < 0.001. (B) With BMD of hip trochanter* (p =0.01; dotted line represents 95% CI). *Similar shape was observedfor the BMD of the femoral neck (p = 0.19; data not shown).
VITAMIN D, BONE MARKERS, AND BMD 699
over the world. These results confirm that hypovitaminosisD is a worldwide problem that needs to be addressed.(18,45–
47) Vitamin D deficiency has such important health impli-cations that measurement of serum 25(OH)D was pro-posed to be part of a routine physical examination forchildren and adults of all ages.(47) The U.S. economicburden caused by vitamin D insufficiency from inadequateexposure to solar UVB irradiance, diet, and supplementswas estimated at 40–56 billion USD in 2004, whereas theeconomic burden for excess UV irradiance was estimatedat 6–7 billion USD.(48) Besides sunshine exposure, vitaminD status can be improved by increasing dietary intake (e.g.,by oily fish and cod liver oil, food fortification, and vitaminD supplements).
ACKNOWLEDGMENTS
We are grateful to Caspar Looman for statistical support.
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Address reprint requests to:P Lips, MD, PhD
VU University Medical CenterDepartment of Endocrinology
PO Box 7057
1007 MB Amsterdam, The NetherlandsE-mail: [email protected]
Received in original form June 8, 2008; revised form November 3,2008; accepted November 25, 2008.
VITAMIN D, BONE MARKERS, AND BMD 701
