- Email: [email protected]
Racial Difference in Response to Vitamin D Supplementation
O
R
I
G
I
N
A
L
C
O
M
M
U
N
I
C
A
T
I
O
N
5DFLDO'LIIHUHQFHLQ5HVSRQVH WR9LWDPLQ'6XSSOHPHQWDWLRQ 'HQLVH0.UHVHYLF513K'-HQQLIHU('HQWRQ%6&KULVWRSKHU-%XUDQW3K'0XUDOLGKDU3DOODNL0'
Conflict of Interest:$OODXWKRUVOLVWHGKDYHFRQWULEXWHGVXIÀFLHQWO\WRWKH SURMHFWWREHLQFOXGHGDVDXWKRUVDQGDOOWKRVHZKRDUHTXDOLÀHGWREH DXWKRUVDUHOLVWHGLQWKHDXWKRUE\OLQH7RWKHEHVWRIRXUNQRZOHGJHQR FRQÁLFWRILQWHUHVWÀQDQFLDORURWKHUH[LVWV Acknowledgements:7KLVPDQXVFULSWLVWKHUHVXOWRIZRUNVXSSRUWHGE\WKH XVHRIUHVRXUFHVDQGIDFLOLWLHVDWWKH/RXLV6WRNHV&OHYHODQG'HSDUWPHQW RI9HWHUDQV$IIDLUV0HGLFDO&HQWHUVSHFLÀFDOO\WKH*HULDWULF5HVHDUFK (GXFDWLRQDQG&OLQLFDO&HQWHU *5(&& Background:'HÀFLHQF\LQK\GUR[\YLWDPLQ' >2+@' LVFRPPRQ HVSHFLDOO\LQWKHHOGHUO\DQG$IULFDQ$PHULFDQV $$ :KLOH 2+ 'GHÀFLHQF\LVDVVRFLDWHGZLWKPXOWLSOHQHJDWLYHKHDOWKRXWFRPHV FXUUHQWUHFRPPHQGDWLRQVIRUVXSSOHPHQWDWLRQRIWKLVGHÀFLHQF\PD\EH LQVXIÀFLHQW Objective:7RGHWHUPLQHWKHSUHYDOHQFHRI 2+ 'GHÀFLHQF\WKHH[WHQW RIYLWDPLQ'VXSSOHPHQWDWLRQDQGWKHHIIHFWRIVXSSOHPHQWDWLRQRQ 2+ 'OHYHOVLQDQHOGHUO\9HWHUDQSRSXODWLRQ7KHVWXG\DOVRIRFXVHGVSHFLÀFDOO\ RQWKHUROHRIUDFHLQWKHULVNIRU 2+ 'GHÀFLHQF\DQGLQWKHUHVSRQVHWR YLWDPLQ'VXSSOHPHQWDWLRQ Methods:$UHWURVSHFWLYHFKDUWUHYLHZZDVFRQGXFWHGRILQIRUPDWLRQ LQFOXGLQJ 2+ 'VHUXPOHYHOVSUHDQGSRVWVXSSOHPHQWDWLRQUDFHDQG YLWDPLQ'VXSSOHPHQWDWLRQ6XEMHFWVZHUHFRPPXQLW\GZHOOLQJ9HWHUDQV \HDUV IROORZHGE\D9$JHULDWULFFOLQLF$WRWDORIFKDUWVZHUHUHYLHZHG &DXFDVLDQ$$RWKHUXQNQRZQUDFH ,QIRUPDWLRQFROOHFWHG WKURXJKWKHFKDUWUHYLHZZDVDQDO\]HGE\FRPSDULQJWKHPHDQVRI 2+ ' OHYHOVSUHDQGSRVWVXSSOHPHQWDWLRQDFURVVUDFHVDQGDFURVVWLPHV Results:$W%DVHOLQHVXEMHFWV ZHUH 2+ 'GHÀFLHQW QJPO :KLOHRIWKHPZHUHVXSSOHPHQWHGRQO\ RI DFKLHYHG QRUPDO 2+ 'VHUXPOHYHOV$$V Q KDGVLJQLÀFDQWO\ORZHU%DVHOLQH OHYHOVFRPSDUHGWR&DXFDVLDQV Q DQGGLIIHUHQFHVZHUHFRQVLVWHQW DFURVVWLPH)HZHU$$VWKDQ&DXFDVLDQVLQFUHDVHGWRQRUPDO $$ &DXFDVLDQ Conclusions:&RQVHUYDWLYHRUDOYLWDPLQ'VXSSOHPHQWDWLRQLVODUJHO\ LQHIIHFWLYHDWDFKLHYLQJWKHUDSHXWLFVHUXPOHYHOVHVSHFLDOO\IRU$$V)XWXUH UHVHDUFKLVQHHGHGWRIRFXVRQLQGLYLGXDOL]HGVXSSOHPHQWDWLRQVWUDWHJLHV DQGWDUJHWHGULVNIDFWRUVVXFKDVUDFH KEYWORDS: Veterans Q*HULDWULFVQ Race and ethnicity Q Nutrition
Author Affiliations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orresponding Author:'HQLVH0.UHVHYLF513K'*HULDWULF5HVHDUFK (GXFDWLRQDQG&OLQLFDO&HQWHU/RXLV6WRNHV&OHYHODQG9$0HGLFDO&HQWHU& : (XFOLG$YH&OHYHODQG2+'HQLVH.UHVHYLF#YDJRY² ²H[W ²² )D[
INTRODUCTION
V
LWDPLQ ' ' RU ' V\QWKHVLV LV GHSHQGHQW RQ exposure of 7-dehydrocholesterol in the skin to UV-B/ sunlight exposure and also on dietary intake. The liver
1892/12-81(
FRQYHUWVWKHLQDFWLYHIRUPRIYLWDPLQ' 'RU' IURPWKH VNLQDQGGLHWWRK\GUR[\YLWDPLQ' >2+@' RUFDOFLGLRO1 7KHNLGQH\WKHQFRQYHUWV 2+ 'WRWKHELRORJLFDOO\DFWLYH GLK\GUR[\YLWDPLQ' >2+@' RUFDOFLWULRO1 )DFWRUV WKDW FRQWULEXWH WR 2+ ' GH¿FLHQF\ Worldwide, it has been estimated that one billion people KDYH 2+ ' GH¿FLHQF\1–5 /HYHOV RI 2+ ' DUH related to the interaction of multiple factors including UV-B/sunlight exposure,4,6 dietary intake,1,6–7 age,6,8 and body mass.9 While UV-B/sunlight exposure and dietary LQWDNHLQFUHDVH 2+ 'VHUXPOHYHOVDJHGHFUHDVHVWKH activity of 7-dehydrocholesterol in the skin,6,8 and obesity decreases the bioavailability of vitamin D in the body.9 5DFHDQGPHODQLQFRQWHQWVLJQL¿FDQWO\FRQWULEXWHWRWKH ULVNRIEHFRPLQJ 2+ 'GH¿FLHQW$IULFDQ$PHULFDQV $$ KDYH EHHQ IRXQG WR KDYH ORZHU PHDQ VHUXP OHYHOV than Caucasians because of both biological and social factors.10–11 6SHFL¿FDOO\ PHODQLQ LQ GDUNHU VNLQQHG individuals acts as a natural sunscreen to block UV-B rays, reducing vitamin D synthesis.12–14 Additionally, AAs have been found to have lower intake of vitamin D-rich foods or supplements than other races, partly attributed to the prevalence of lactose intolerance in this population.15–16 Recent evidence indicates that AA individuals with low sun exposure need higher vitamin D intake to maintain a healthy vitamin D status as compared to Caucasian individuals.17 These factors contribute to a higher rate of 2+ 'GH¿FLHQF\LQ$$V +HDOWK ULVNV DVVRFLDWHG ZLWK 2+ ' GH¿FLHQF\ Vitamin D regulates calcium and phosphorus absorption DQGKDVEHHQLGHQWL¿HGDVDQLPSRUWDQWIDFWRULQDFKLHYLQJ optimal health.6–7,18–19/RZ 2+ 'OHYHOVFRUUHODWHZLWK low calcium levels and often lead to rickets, osteoporosis, osteomalacia, pain, and fractures.2,20 Recently vitamin ' KDV EHHQ LGHQWL¿HG DV DQ LPPXQRPRGXODWRU DQG LV associated with the prevention of autoimmune diseases, infectious diseases, and cardiovascular diseases.1–2,21 /RZ VHUXP 2+ ' OHYHOV KDYH EHHQ DVVRFLDWHG ZLWK higher risk of cardiovascular mortality, which may help explain the higher rate of cardiovascular deaths in AAs as compared to Caucasians.10/RZVHUXPOHYHOVRI 2+ D have also been associated with increased risks of tuberculosis22 and cancers of the colon and prostate.23–24 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21
6LPLODUO\ 2+ ' GH¿FLHQF\ KDV EHHQ DVVRFLDWHG ZLWK increased levels of C-reactive protein, hypertension, and congestive heart failure.26–27 Emerging evidence supports DQ DVVRFLDWLRQ EHWZHHQ 2+ ' GH¿FLHQF\ DQG WKH progression and all-cause morbidity and mortality related WR+XPDQ,PPXQRGH¿FLHQF\9LUXV +,9 GLVHDVH28–29 &XUUHQWUHFRPPHQGDWLRQVIRUYLWDPLQ'LQWDNH The ,QVWLWXWH RI 0HGLFLQH ,20 XVHV QJP/ WR HVWDEOLVK 'LHWDU\5HIHUHQFH,QWDNHVIRUYLWDPLQ'30 However, this OHYHOLVEDVHGRQO\RQVNHOHWDOKHDOWKEHQH¿WVDQGWKHUHLV growing consensus that at least 32 ng/mL is a more ideal goal with regard to other health outcomes.2–3,29,31 Current UHFRPPHQGDWLRQV IRU YLWDPLQ ' LQWDNH IURP WKH ,20 RI±,8GD\30PD\EHLQVXI¿FLHQWWRDFKLHYH WKHUDSHXWLFOHYHOV QJP/ 1–2,11,13,19,21,32
OBJECTIVE: 7KH SXUSRVH RI WKLV VWXG\ ZDV WR GHWHUPLQH WKH SUHYDOHQFHRI 2+ 'GH¿FLHQF\LQDQROGHUFRPPXQLW\ GZHOOLQJ 9HWHUDQ SRSXODWLRQ SURYLGH LQIRUPDWLRQ RQ the extent of oral vitamin D supplementation for subjects LGHQWL¿HG DV 2+ ' GH¿FLHQW DQG WKH HIIHFW RI WKDW VXSSOHPHQWDWLRQRQVHUXPOHYHOVDQG IRFXVRQWKHUROHRI UDFHLQ 2+ 'GH¿FLHQF\DQGLQWKHUHVSRQVHWRWUHDWPHQW 7KH UHVHDUFKHUV K\SRWKHVL]HG WKDW D PDMRULW\ RI WKHVXEMHFWVZRXOGKDYH 2+ 'OHYHOVOHVVWKDQQJ P/ WKHPDMRULW\RIVXEMHFWVZKRZHUHGH¿FLHQWZRXOG EH VXSSOHPHQWHG DQG ZRXOG VXEVHTXHQWO\ LQFUHDVH WR WKHUDSHXWLFOHYHOV QJP/ DQG $$VXEMHFWVZRXOG KDYH VLJQL¿FDQWO\ ORZHU PHDQ 2+ ' VHUXP OHYHOV
Table 1.6XEMHFW'HPRJUDSKLFVDQG&RPRUELGLWLHV
Subject Demographics Age
Race
*HQGHU 2+ 'VHUXPOHYHO
n=
%
²\UV
²\UV
²\UV
²\UV
\UV
&DXFDVLDQ
$IULFDQ$PHULFDQ $$
2WKHUXQNQRZQ
0DOH
)HPDOH
QJP/
QJP/
QJP/
n=
%
Acute Renal Failure
Arthritis
$VWKPD
&DQFHU0DOLJQDQF\
&RJQLWLYH,PSDLUPHQW
&RURQDU\$UWHU\'LVHDVH
'HSUHVVLRQ
'LDEHWHV
Osteoporosis
6HL]XUH'LVRUGHU
7K\URLG'LVHDVH
Subject Co-morbidities
n = 234
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
92/12-81(19
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21
as compared to Caucasians at baseline and following supplementation.
METHOD: 'HVLJQ DQG 3URFHGXUH A retrospective chart review was conducted between 2008 and 2009 on 234 communitydwelling Veterans cared for in the geriatric clinic of a 0LGZHVWHUQ9HWHUDQV$IIDLUV 9$ 0HGLFDO&HQWHUORFDWHGDW ODWLWXGH12XURXWFRPHVRILQWHUHVWZHUH 2+ 'OHYHOV measured at up to three time periods (Time 1 [Baseline], Time 2 [3 months after Baseline], Time 3 [6 months after %DVHOLQH@ &KDUWV ZHUH UHYLHZHG LI WKHUH ZDV DW OHDVW RQH UHFRUGHG 2+ ' VHUXP OHYHO 7KH GDWH HDFK EORRG OHYHO was drawn was recorded and categorized into season. Seasons were divided into the time periods of December 21st – March 20th ZLQWHU 0DUFKst–June 20th VSULQJ -XQHst– September 20th VXPPHU DQG6HSWHPEHUst – December 20th IDOO 6HDVRQDOLQIRUPDWLRQZDVXVHGDVDSUR[\IRUVXQOLJKW exposure, which was not available due to the retrospective nature of the study. The data collection tool also included information about health status and demographic information for age range, gender, and race. Race was a self-reported category in the patient’s medical record. The design and procedure of this study were approved by the VA facility’s Research and Development Committee and determined H[HPSWIURPUHYLHZE\WKH,QVWLWXWLRQDO5HYLHZ%RDUGGXHWR the retrospective chart review design. 6DPSOH All subjects were patients followed in the *HULDWULF &OLQLF DJHG RU ROGHU ZHUH RU ROGHU 2I WKH 9HWHUDQV ZHUH PDOH 7KH VWXG\ FRQVLVWHG RI &DXFDVLDQ 9HWHUDQV $$9HWHUDQV DQG9HWHUDQVRIRWKHUXQNQRZQ UDFH 6HH 7DEOH IRU D GHVFULSWLRQ RI VXEMHFW demographics, including co-morbidities. $QDO\VHV The statistical software program SPSS 15.0 was used for data analysis. Univariate analyses including GHVFULSWLYHVWDWLVWLFVDQGIUHTXHQFLHVZHUHXVHGWRH[DPLQH all variables. Bivariate tests including independent t-tests, &KLVTXDUHV DQG UHSHDWHG PHDVXUHV $129$V ZHUH used to analyze relationships between variables and to test assumptions. (1RWH 6XI¿FLHQW VDPSOH VL]H ZDV RQO\ available for the Caucasian and AA race categories for purposes of cross-racial analysis.
RESULTS: )RU WKH SXUSRVH RI WKLV VWXG\ 2+ ' VHUXP OHYHOV EHORZ QJP/ZHUHGH¿QHGDVGH¿FLHQW7KLVYDOXHZDVFKRVHQ because of its generally accepted use as the lower limit of QRUPDO 2+ 'FRQFHQWUDWLRQVDWWKLV9$0HGLFDO&HQWHU +RZHYHUZHDOVRDQDO\]HGWKHIUHTXHQF\RIOHYHOVEHORZ QJP/DVWKLVLVWKHOHYHOXVHGE\WKH,20WRGH¿QHQRUPDO
2092/12-81(
The breakdown of subjects at each of these levels at Times 1–3 is presented in Figure 1. 3UHYDOHQFHRI 2+ 'GH¿FLHQF\ At Baseline it was IRXQGWKDWRIWKHVXEMHFWV KDGORZ 2+ D serum levels. Of these subjects, 107 were Caucasian RI ZHUH $$ RI DQG ZHUH RWKHUXQNQRZQ UDFH RI 7ZR tailed independent samples t-tests of the total 202 AA and Caucasian subjects revealed that AA subjects had VLJQL¿FDQWO\ORZHU 2+ 'OHYHOVDW%DVHOLQH M = 15.38, SD DVFRPSDUHGWR&DXFDVLDQV M SD [t , p @ 7\SH RI VXSSOHPHQWDWLRQ EHLQJ SUHVFULEHG DQG VXSSOHPHQWDWLRQUHVSRQVH Calcitriol at 0.25 micrograms/ day was the supplementation most commonly prescribed to patients at this VA Medical Center during the study period. Other standard supplementation strategies included HUJRFDOFLIHURO DW ,8 ZHHN RU FKROHFDOFLIHURO DW ,8GD\ 2I WKH VXEMHFWV ZKR KDG ORZ 2+ ' OHYHOV DW %DVHOLQH &DXFDVLDQ $$ RWKHU XQNQRZQ UDFH ZHUH SUHVFULEHG RUDO VXSSOHPHQWDWLRQ DW DQ\WLPHEXWRQO\ LQFUHDVHGWRQRUPDOOHYHOV 2I WKHVH VXEMHFWV ZHUH &DXFDVLDQ RI ZHUH $$ RI DQG ZDV RWKHUXQNQRZQ UDFH RI &KLVTXDUHWHVWVZHUHQRQVLJQL¿FDQW S! Supplementation strategies were inconsistent over the time periods as types and dosages often varied across VXEMHFWV1LQHW\¿YHSHUFHQWRIWKHVXEMHFWV Q ZLWK 3 data points were prescribed calcitriol at least one time. Of these subjects 85.5% took calcitriol as their only type of supplementation. Only 7 of these subjects ever took ergocalciferol and only 1 subject ever took cholecalciferol. ,QFUHDVH DFURVV WLPH SHULRGV Of the 64 subjects with 3 data points, 24 were Caucasian, 33 were AA, and 7 were other/unknown race. At Baseline, AAs had a PHDQ 2+ ' OHYHO RI QJP/ SD ZKLOH &DXFDVLDQVKDGDPHDQ 2+ 'OHYHORIQJP/ SD $UHSHDWHGPHDVXUHV$129$UHYHDOHGVLJQL¿FDQW mean differences between Caucasians and AAs over time [FGreenhouse Geisser p @ ,Q SRVW hoc analyses, comparing Baseline to Time 3, Caucasians LQFUHDVHGWKHLUPHDQ 2+ 'OHYHOV 7LPH M SD VLJQL¿FDQWO\ PRUH WKDQ $$V 7LPH M 16.64, SD >) p @)LJXUH illustrates the racial comparison of means across the three time periods.
DISCUSSION 2XU DQDO\VLV LQGLFDWHV WKDW 2+ ' GH¿FLHQF\ LV FRPPRQ in a community-dwelling elderly Veteran population JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21 Figure 1.
Time 1: Total Sample All Races (n=234) Vit D <20 ng/ml AA=61 Caucasian=77 Other/unknown=21
Vit D 20<32 ng/ml AA=13 Caucasian=30 Other/unknown=4
Vit D ш 32 ng/ml AA=4 Caucasian=17 Other/unknown=7
Time 1: Total Sample of AA & Caucasian (n=202) Vit D <20 ng/ml AA=61 Caucasian=77
Vit D 20<32 ng/ml AA=13 Caucasian=30
Vit D ш 32 ng/ml AA=4 Caucasian=17
Other/Unknown ethnic origin n=32
Time 2: Total Sample of AA & Caucasian (n=97) Vit D <20 ng/ml AA=39 Caucasian=29
Vit D 20<32 ng/ml AA=9 Caucasian=14
Vit D ш 32 ng/ml AA=1 Caucasian=5
Time 2 Missing Lab work n=105
Time 3: Total Sample of AA & Caucasian (n=57) Vit D <20 ng/ml AA=22 Caucasian=12
Vit D 20<32 ng/ml AA=8 Caucasian=4
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Vit D ш 32 ng/ml AA=3 Caucasian=8
Time 3 Missing Lab work n=40
92/12-81(21
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21 Figure 2.
Body mass index:%0,GDWDZDVDEOHWREHREWDLQHGIURPRIWKHSDWLHQWVZLWKGDWDWLPHSRLQWV7KHPHDQ%0, RIWKLVJURXSZDV 6' UDQJH ² 7KHUHZHUHQRVLJQLILFDQWUHODWLRQVKLSVIRXQGEHWZHHQ%0,DQG 2+ 'OHYHOVLQVXEMHFWVDW%DVHOLQHRUDW7LPH Differences in 25(OH)D level based on season: 7KHUHZHUHQRVLJQLILFDQWGLIIHUHQFHVIRXQGEHWZHHQ 2+ 'OHYHO DQGVHDVRQWKRXJKOHYHOVLQZLQWHUZHUHIRXQGWREHVOLJKWO\ORZHURQDYHUDJH
SDUWLFXODUO\DPRQJ$$V 7KHVH¿QGLQJVDUH consistent with those of previous studies.2, 15, 33–34 Notably, of WKHVXEMHFWVZKRZHUH 2+ 'GH¿FLHQWDWEDVHOLQHDERXW 80% were prescribed oral vitamin D supplementation at some WLPH+RZHYHUGHVSLWHRUDOVXSSOHPHQWDWLRQ 2+ 'OHYHOV GLGQRWLQFUHDVHWRWKHUDSHXWLF QJP/ LQPRVWVXEMHFWV 7KHVH¿QGLQJVVXJJHVWWKDWFXUUHQWFOLQLFDOSUDFWLFHV IRURUDOVXSSOHPHQWDWLRQDUHQRWVXI¿FLHQW. For the subset of subjects with data at three time points Q RXU¿QGLQJVLQGLFDWHWKDW$$VKDGVLJQL¿FDQWO\ less response to supplementation than Caucasians. Some potential explanations could be that AAs are less likely WR UHVSRQG WR WKH VSHFL¿F W\SH RI VXSSOHPHQWDWLRQ WKDW ZDVSUHVFULEHGUHTXLUHKLJKHUGRVHVRIVXSSOHPHQWDWLRQ UHTXLUH D ORQJHU GXUDWLRQ RI VXSSOHPHQWDWLRQ WKDQ Caucasians, or have lower rates of adherence. There have been a limited number of studies examining responses to VXSSOHPHQWDWLRQDVVRFLDWHGZLWKUDFH,Q 0DWVXRND and colleagues administered a vitamin D challenge test RQH FDSVXOH RI ,8 HUJRFDOFLIHURO WR \RXQJ blacks, 12 young whites, and 8 elderly whites.34 Although they found no difference between these groups in rate of response to the supplementation, this study was very limited in the type of supplementation used, the lack of an elderly black population, and the very small sample size.
LIMITATIONS The most notable limitation to acknowledge in the interpretation of the data from our study is that the retrospective chart review design did not allow control of the type of vitamin D supplementation prescribed. Of the VXEMHFWVZLWKGDWDRQVXSSOHPHQWDWLRQWKHPDMRULW\ took calcitriol as their only form of supplementation. This homogeneity of supplementation type limits the ability to compare effectiveness or identify whether the lack of response ZDVVSHFL¿FWRFDOFLWULRO Additionally, the study was not able to document adherence to supplementation as this was not recorded in the charts. Subjects could also have been taking overWKHFRXQWHU 27& YLWDPLQ'VXSSOHPHQWDWLRQZKLFKZDV
2292/12-81(
not documented. Some subjects were not prescribed any VXSSOHPHQWDWLRQ GHVSLWH KDYLQJ ORZ 2+ ' OHYHOV ,W should be noted that VA patients often receive care from multiple providers outside the VA, which increases the possibility that follow-ups and supplementation for low serum levels were handled by an outside provider and not recorded in the subject’s VA medical chart. Another limitation of the study was a lack of access to information on each subject’s amount of sunlight H[SRVXUH 7KRXJK VXQOLJKW LV D VLJQL¿FDQW VRXUFH RI vitamin D production, the impact of the amount of H[SRVXUH RQ 2+ ' OHYHOV ZDV QRW DYDLODEOH 8VLQJ seasonal information derived from the date as a proxy IRU VXQOLJKW H[SRVXUH VLJQL¿FDQW GLIIHUHQFHV LQ 2+ D levels were not found. Furthermore, it was not possible WRDVVHVVWKHFRQQHFWLRQEHWZHHQ 2+ 'GH¿FLHQF\DQG dietary intake as the investigators were unable to obtain information about intake of any vitamin D-rich foods from the charts.
CONCLUSIONS AND RECOMMENDATIONS Results of this study indicate that inconsistent responses to supplementation across individuals may have multifaceted origins. Future research should examine physician-based factors such as supplementation and laboratory follow-ups as well as patient-based factors such as adherence, OTC use, UV-B/sunlight exposure, and dietary intake. Additionally, ZKLOHPDQ\VWXGLHVKDYHIRXQGWKDWUDFHFDQSOD\DVLJQL¿FDQW UROHLQWKHULVNIRUGH¿FLHQF\WKHUHKDVEHHQOLWWOHIRFXVRQ WKHUROHRIUDFHLQUHVSRQVHWRVXSSOHPHQWDWLRQ2XU¿QGLQJV suggest that racial differences may exist in one’s propensity to respond to oral supplementation. Future research should be done to validate if this trend is applicable across other populations while controlling the type and dosage of vitamin D supplementation. Additional studies are needed to verify RXU¿QGLQJVRIUDFLDOGLVSDULW\ ,QGLYLGXDOL]HGVXSSOHPHQWDWLRQJXLGHOLQHVWRRYHUFRPH 2+ ' GH¿FLHQF\ PD\ QHHG WR EH WDLORUHG WR DGGUHVV ULVN IDFWRUV VXFK DV UDFH DJH %0, OLPLWHG VXQOLJKW JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21
exposure, and low dietary intake of vitamin D-rich foods. For example, research has shown that obese individuals UHTXLUH KLJKHU GRVHV RI RUDO YLWDPLQ ' VXSSOHPHQWDWLRQ to achieve optimal levels as compared to individuals with QRUPDO%0,9 Despite very conservative recommendations IRUGDLO\LQWDNHRIYLWDPLQ'WKH,20GRHVDFNQRZOHGJH that age may play a role in the body’s need for vitamin D DQGVWUDWL¿HVUHFRPPHQGDWLRQVEDVHGRQDJHJURXS30 This strategy may also be applicable to the risk factors of race and melanin content as suggested by Hall and colleagues in 2010.177KHVHIDFWRUVDIIHFWWKHIUHTXHQF\RIORZ 2+ D serum levels and, as the current study indicates, may be associated with different supplementation responses. Future research should include longer, larger studies which focus on establishing individualized supplementation guidelines across at-risk groups. Though this retrospective study did not afford the opportunity to examine the long-term effects of vitamin D supplementation on health outcomes, this is an important research opportunity for future studies. Vitamin D GH¿FLHQF\KDVEHHQDVVRFLDWHGZLWKPDQ\KHDOWKFRQGLWLRQV DQG WKH XVH RI RUDO VXSSOHPHQWDWLRQ WR UHSODFH GH¿FLHQW individuals may lead to improved outcomes.
REFERENCES:
+ROLFN0)9LWDPLQ'GHÀFLHQF\N Engl J Med. 2007; ²
+ROLFN 0) +LJK SUHYDOHQFH RI YLWDPLQ ' LQDGHTXDF\ DQG LPSOLFDWLRQVIRUKHDOWKMayo Clinic Proc. 2006; ²
%LVFKRII)HUUDUL+$*LRYDQQXFFL(:LOOHWW&HWDO(VWLPDWLRQ RIRSWLPDOVHUXPFRQFHQWUDWLRQVRIK\GUR[\YLWDPLQ'IRU PXOWLSOHKHDOWKRXWFRPHVAm J Clin Nutr. ²
*OHUXS + 0LNNHOVHQ . 3RXOVHQ / HW DO &RPPRQO\ UHFRPPHQGHG GDLO\ LQWDNH RI YLWDPLQ ' LV QRW VXIÀFLHQW LI VXQOLJKWH[SRVXUHLVOLPLWHGJ Intern Med. ²
0DODEDQDQ $ 9HURQLNLV ,( +ROLFN 0) 5HGHÀQLQJ YLWDPLQ ' LQVXIÀFLHQF\Lancet. ²
&DQQHOO--+ROOLV%:=DVORII0HWDO'LDJQRVLVDQGWUHDWPHQW RI YLWDPLQ ' GHÀFLHQF\ Expert Opin Pharmacotherapy. ²
&DOYR06:KLWLQJ6-3XEOLFKHDOWKVWUDWHJLHVWRRYHUFRPH EDUULHUV WR RSWLPDO YLWDPLQ ' VWDWXV LQ SRSXODWLRQV ZLWK VSHFLDOQHHGVJ Nutr. ² 2RPV 0( 5RRV -& %H]HPHU 3' HW DO 3UHYHQWLRQ RI ERQH ORVV E\ YLWDPLQ ' VXSSOHPHQWDWLRQ LQ HOGHUO\ ZRPHQ $ UDQGRPL]HG GRXEOHEOLQG WULDO J Clin Endocrinol Metab. ² :RUWVPDQ - 0DWVXRND /< &KHQ 7& HW DO 'HFUHDVHG ELRDYDLODELOLW\ RI YLWDPLQ ' LQ REHVLW\ Am J Clin Nutr. ²
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
)LVFHOOD . )UDQNV 3 9LWDPLQ ' UDFH DQG FDUGLRYDVFXODU PRUWDOLW\ )LQGLQJVIURPDQDWLRQDO86VDPSOHAnn Fam Med. ² 1HVE\2·'HOO 6 6FDQORQ .6 &RJVZHOO 0( HW DO +\SRYLWDPLQRVLV ' SUHYDOHQFH DQG GHWHUPLQDQWV DPRQJ $IULFDQ $PHULFDQ DQG ZKLWH ZRPHQ RI UHSURGXFWLYH DJH 7KLUG 1DWLRQDO +HDOWK DQG 1XWULWLRQ ([DPLQDWLRQ 6XUYH\ ² Am J Clin Nutr; ² &KHQ7&&KLPHK)/X=0DWKLHX-3HUVRQ.6=KDQJ $ HW DO )DFWRUV WKDW LQÁXHQFH WKH FXWDQHRXV V\QWKHVLV DQG GLHWDU\ VRXUFHV RI YLWDPLQ ' Arch Biochem Biophys. ² +DUULV 66 'DZVRQ+XJKHV % 6HDVRQDO FKDQJHV LQ SODVPD K\GUR[\YLWDPLQ ' FRQFHQWUDWLRQV RI \RXQJ $PHULFDQ EODFNDQGZKLWHZRPHQAm J Clin Nutr ² +ROLFN 0) (QYLURQPHQWDO IDFWRUV WKDW LQÁXHQFH WKH FXWDQHRXV SURGXFWLRQ RI YLWDPLQ ' Am J Clin Nutr. VXSSO 66 +DUULV 66 6RWHULDGHV ( &RROLGJH -6 HW DO 9LWDPLQ ' ,QVXIÀFLHQF\ DQG +\SHUSDUDWK\URLGLVP LQ D /RZ ,QFRPH 0XOWLUDFLDO (OGHUO\ 3RSXODWLRQ J Clin Endocrinol Metab. ² 0RRUH &( 0XUSK\ 00 +ROLFN 0) 9LWDPLQ ' ,QWDNHV E\ &KLOGUHQDQG$GXOWVLQWKH8QLWHG6WDWHV'LIIHUDPRQJ(WKQLF *URXSVJ Nutr. ² +DOO /0 .LPOLQ 0* $URQRY 3$ HW DO 9LWDPLQ ' LQWDNH QHHGHG WR PDLQWDLQ WDUJHW VHUXP +\GUR[\YLWDPLQ ' FRQFHQWUDWLRQV LQ SDUWLFLSDQWV ZLWK ORZ VXQ H[SRVXUH DQG GDUN VNLQ SLJPHQWDWLRQ LV VXEVWDQWLDOO\ KLJKHU WKDQ FXUUHQW UHFRPPHQGDWLRQVJ Nutr. ² &UDQQH\ $ +RUVOH\ 7 2·'RQQHOO 6 HW DO (IIHFWLYHQHVV DQG 6DIHW\ RI 9LWDPLQ ' LQ 5HODWLRQ WR %RQH +HDOWK (YLGHQFH 5HSRUW7HFKQRORJ\ $VVHVVPHQW 1R 3UHSDUHG E\ WKH 8QLYHUVLW\ RI 2WWDZD (YLGHQFHEDVHG 3UDFWLFH &HQWHU 82 (3& XQGHU &RQWUDFW 1R ²² $+54 3XEOLFDWLRQ 1R(5RFNYLOOH0' $JHQF\IRU+HDOWKFDUH5HVHDUFK DQG4XDOLW\ *LQGH$$/LX0&&DPDUJR&$-U'HPRJUDSKLFGLIIHUHQFHV DQG WUHQGV RI YLWDPLQ ' LQVXIÀFLHQF\ LQ WKH 86 SRSXODWLRQ ²Arch Intern Med. ² $DURQ -( *DOODJKHU -& 1RUGLQ %(& 6HDVRQDO YDULDWLRQ RI KLVWRORJLFDORVWHRPDODFLDLQIHPRUDOQHFNIUDFWXUHVLancet. ² 'H/XFD +) 2YHUYLHZ RI JHQHUDO SK\VLRORJLF IHDWXUHV DQG IXQFWLRQVRIYLWDPLQ'Am J Clin Nutr. ; VXSSO 6² 6 /LX376WHQJHU6/L+HWDO7ROOOLNHUHFHSWRUWULJJHULQJRID YLWDPLQ'PHGLDWHGKXPDQDQWLPLFURELDOUHVSRQVHScience. ² $KRQHQ 0+ 7HQNDQHQ / 7HSSR / HW DO 3URVWDWH FDQFHU ULVN DQG SUHGLDJQRVWLF VHUXP K\GUR[\YLWDPLQ ' OHYHOV )LQODQG Cancer Cause Control. ²
92/12-81(23
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21 *LRYDQQXFFL ( /LX < 5LPP (% HW DO 3URVSHFWLYH VWXG\ RI SUHGLFWRUV RI YLWDPLQ ' VWDWXV DQG FDQFHU LQFLGHQFH DQG PRUWDOLW\LQPHQJ Natl Canc Inst. ; ² *RUKDP('*DUODQG&)*DUODQG)&HWDO9LWDPLQ'DQG SUHYHQWLRQRIFRORUHFWDOFDQFHUJ Steroid Biochem Mol Biol. ² =LWWHUPDQQ$9LWDPLQ'DQGGLVHDVHSUHYHQWLRQZLWKVSHFLDO UHIHUHQFHWRFDUGLRYDVFXODUGLVHDVHProg Biophys Mol Biol. ² =LWWHUPDQQ$6FKOHLWKRII66.RHUIHU59LWDPLQ'LQVXIÀFLHQF\ LQ FRQJHVWLYH KHDUW IDLOXUH :K\ DQG ZKDW WR GR DERXW LW" Heart Fail Reviews. ² 'DR&13DWHO32YHUWRQ(7HWDO/RZYLWDPLQ'DPRQJ+,9 LQIHFWHGDGXOWV 3UHYDOHQFHRIDQGULVNIDFWRUVIRUORZYLWDPLQ 'OHYHOVLQDFRKRUWRI+,9LQIHFWHGDGXOWVDQGFRPSDULVRQWR SUHYDOHQFHDPRQJDGXOWVLQWKH86JHQHUDOSRSXODWLRQClin Infect Dis ²
2492/12-81(
0HKWD 6 *LRYDQQXFFL ( 0XJXVL )0 HW DO 9LWDPLQ ' VWDWXV RI +,9LQIHFWHG ZRPHQ DQG LWV DVVRFLDWLRQ ZLWK +,9 GLVHDVH SURJUHVVLRQ DQHPLD DQG PRUWDOLW\ PLoS ONE. H ,20 ,QVWLWXWH RI 0HGLFLQH Dietary Reference Intakes for Calcium and Vitamin D. :DVKLQJWRQ '& 7KH 1DWLRQDO $FDGHPLHV3UHVV $ORLD-)7DOZDU6$3ROODFN6HWDO$UDQGRPL]HGFRQWUROOHG WULDO RI YLWDPLQ ' VXSSOHPHQWDWLRQ LQ $IULFDQ $PHULFDQ ZRPHQArch Intern Med. ² 9LHWK5%LVFKRII)HUUDUL+%RXFKHU%-HWDO7KHXUJHQWQHHG WRUHFRPPHQGDQLQWDNHRIYLWDPLQ'WKDWLVHIIHFWLYHAm J Clin Nutr. ² 'DZVRQ+XJKHV % 5DFLDOHWKQLF &RQVLGHUDWLRQV LQ PDNLQJ UHFRPPHQGDWLRQV IRU YLWDPLQ ' IRU DGXOW DQG HOGHUO\ PHQ DQGZRPHQAm J Clin Nutr. VXSSO 66 0DWVXRND /< :RUWVPDQ - &KHQ 7& HW DO J Lab Clin Med. ²
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
R
I
G
I
N
A
L
C
O
M
M
U
N
I
C
A
T
I
O
N
5DFLDO'LIIHUHQFHLQ5HVSRQVH WR9LWDPLQ'6XSSOHPHQWDWLRQ 'HQLVH0.UHVHYLF513K'-HQQLIHU('HQWRQ%6&KULVWRSKHU-%XUDQW3K'0XUDOLGKDU3DOODNL0'
Conflict of Interest:$OODXWKRUVOLVWHGKDYHFRQWULEXWHGVXIÀFLHQWO\WRWKH SURMHFWWREHLQFOXGHGDVDXWKRUVDQGDOOWKRVHZKRDUHTXDOLÀHGWREH DXWKRUVDUHOLVWHGLQWKHDXWKRUE\OLQH7RWKHEHVWRIRXUNQRZOHGJHQR FRQÁLFWRILQWHUHVWÀQDQFLDORURWKHUH[LVWV Acknowledgements:7KLVPDQXVFULSWLVWKHUHVXOWRIZRUNVXSSRUWHGE\WKH XVHRIUHVRXUFHVDQGIDFLOLWLHVDWWKH/RXLV6WRNHV&OHYHODQG'HSDUWPHQW RI9HWHUDQV$IIDLUV0HGLFDO&HQWHUVSHFLÀFDOO\WKH*HULDWULF5HVHDUFK (GXFDWLRQDQG&OLQLFDO&HQWHU *5(&& Background:'HÀFLHQF\LQK\GUR[\YLWDPLQ' >2+@' LVFRPPRQ HVSHFLDOO\LQWKHHOGHUO\DQG$IULFDQ$PHULFDQV $$ :KLOH 2+ 'GHÀFLHQF\LVDVVRFLDWHGZLWKPXOWLSOHQHJDWLYHKHDOWKRXWFRPHV FXUUHQWUHFRPPHQGDWLRQVIRUVXSSOHPHQWDWLRQRIWKLVGHÀFLHQF\PD\EH LQVXIÀFLHQW Objective:7RGHWHUPLQHWKHSUHYDOHQFHRI 2+ 'GHÀFLHQF\WKHH[WHQW RIYLWDPLQ'VXSSOHPHQWDWLRQDQGWKHHIIHFWRIVXSSOHPHQWDWLRQRQ 2+ 'OHYHOVLQDQHOGHUO\9HWHUDQSRSXODWLRQ7KHVWXG\DOVRIRFXVHGVSHFLÀFDOO\ RQWKHUROHRIUDFHLQWKHULVNIRU 2+ 'GHÀFLHQF\DQGLQWKHUHVSRQVHWR YLWDPLQ'VXSSOHPHQWDWLRQ Methods:$UHWURVSHFWLYHFKDUWUHYLHZZDVFRQGXFWHGRILQIRUPDWLRQ LQFOXGLQJ 2+ 'VHUXPOHYHOVSUHDQGSRVWVXSSOHPHQWDWLRQUDFHDQG YLWDPLQ'VXSSOHPHQWDWLRQ6XEMHFWVZHUHFRPPXQLW\GZHOOLQJ9HWHUDQV \HDUV IROORZHGE\D9$JHULDWULFFOLQLF$WRWDORIFKDUWVZHUHUHYLHZHG &DXFDVLDQ$$RWKHUXQNQRZQUDFH ,QIRUPDWLRQFROOHFWHG WKURXJKWKHFKDUWUHYLHZZDVDQDO\]HGE\FRPSDULQJWKHPHDQVRI 2+ ' OHYHOVSUHDQGSRVWVXSSOHPHQWDWLRQDFURVVUDFHVDQGDFURVVWLPHV Results:$W%DVHOLQHVXEMHFWV ZHUH 2+ 'GHÀFLHQW QJPO :KLOHRIWKHPZHUHVXSSOHPHQWHGRQO\ RI DFKLHYHG QRUPDO 2+ 'VHUXPOHYHOV$$V Q KDGVLJQLÀFDQWO\ORZHU%DVHOLQH OHYHOVFRPSDUHGWR&DXFDVLDQV Q DQGGLIIHUHQFHVZHUHFRQVLVWHQW DFURVVWLPH)HZHU$$VWKDQ&DXFDVLDQVLQFUHDVHGWRQRUPDO $$ &DXFDVLDQ Conclusions:&RQVHUYDWLYHRUDOYLWDPLQ'VXSSOHPHQWDWLRQLVODUJHO\ LQHIIHFWLYHDWDFKLHYLQJWKHUDSHXWLFVHUXPOHYHOVHVSHFLDOO\IRU$$V)XWXUH UHVHDUFKLVQHHGHGWRIRFXVRQLQGLYLGXDOL]HGVXSSOHPHQWDWLRQVWUDWHJLHV DQGWDUJHWHGULVNIDFWRUVVXFKDVUDFH KEYWORDS: Veterans Q*HULDWULFVQ Race and ethnicity Q Nutrition
Author Affiliations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orresponding Author:'HQLVH0.UHVHYLF513K'*HULDWULF5HVHDUFK (GXFDWLRQDQG&OLQLFDO&HQWHU/RXLV6WRNHV&OHYHODQG9$0HGLFDO&HQWHU& : (XFOLG$YH&OHYHODQG2+'HQLVH.UHVHYLF#YDJRY² ²H[W ²² )D[
INTRODUCTION
V
LWDPLQ ' ' RU ' V\QWKHVLV LV GHSHQGHQW RQ exposure of 7-dehydrocholesterol in the skin to UV-B/ sunlight exposure and also on dietary intake. The liver
1892/12-81(
FRQYHUWVWKHLQDFWLYHIRUPRIYLWDPLQ' 'RU' IURPWKH VNLQDQGGLHWWRK\GUR[\YLWDPLQ' >2+@' RUFDOFLGLRO1 7KHNLGQH\WKHQFRQYHUWV 2+ 'WRWKHELRORJLFDOO\DFWLYH GLK\GUR[\YLWDPLQ' >2+@' RUFDOFLWULRO1 )DFWRUV WKDW FRQWULEXWH WR 2+ ' GH¿FLHQF\ Worldwide, it has been estimated that one billion people KDYH 2+ ' GH¿FLHQF\1–5 /HYHOV RI 2+ ' DUH related to the interaction of multiple factors including UV-B/sunlight exposure,4,6 dietary intake,1,6–7 age,6,8 and body mass.9 While UV-B/sunlight exposure and dietary LQWDNHLQFUHDVH 2+ 'VHUXPOHYHOVDJHGHFUHDVHVWKH activity of 7-dehydrocholesterol in the skin,6,8 and obesity decreases the bioavailability of vitamin D in the body.9 5DFHDQGPHODQLQFRQWHQWVLJQL¿FDQWO\FRQWULEXWHWRWKH ULVNRIEHFRPLQJ 2+ 'GH¿FLHQW$IULFDQ$PHULFDQV $$ KDYH EHHQ IRXQG WR KDYH ORZHU PHDQ VHUXP OHYHOV than Caucasians because of both biological and social factors.10–11 6SHFL¿FDOO\ PHODQLQ LQ GDUNHU VNLQQHG individuals acts as a natural sunscreen to block UV-B rays, reducing vitamin D synthesis.12–14 Additionally, AAs have been found to have lower intake of vitamin D-rich foods or supplements than other races, partly attributed to the prevalence of lactose intolerance in this population.15–16 Recent evidence indicates that AA individuals with low sun exposure need higher vitamin D intake to maintain a healthy vitamin D status as compared to Caucasian individuals.17 These factors contribute to a higher rate of 2+ 'GH¿FLHQF\LQ$$V +HDOWK ULVNV DVVRFLDWHG ZLWK 2+ ' GH¿FLHQF\ Vitamin D regulates calcium and phosphorus absorption DQGKDVEHHQLGHQWL¿HGDVDQLPSRUWDQWIDFWRULQDFKLHYLQJ optimal health.6–7,18–19/RZ 2+ 'OHYHOVFRUUHODWHZLWK low calcium levels and often lead to rickets, osteoporosis, osteomalacia, pain, and fractures.2,20 Recently vitamin ' KDV EHHQ LGHQWL¿HG DV DQ LPPXQRPRGXODWRU DQG LV associated with the prevention of autoimmune diseases, infectious diseases, and cardiovascular diseases.1–2,21 /RZ VHUXP 2+ ' OHYHOV KDYH EHHQ DVVRFLDWHG ZLWK higher risk of cardiovascular mortality, which may help explain the higher rate of cardiovascular deaths in AAs as compared to Caucasians.10/RZVHUXPOHYHOVRI 2+ D have also been associated with increased risks of tuberculosis22 and cancers of the colon and prostate.23–24 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21
6LPLODUO\ 2+ ' GH¿FLHQF\ KDV EHHQ DVVRFLDWHG ZLWK increased levels of C-reactive protein, hypertension, and congestive heart failure.26–27 Emerging evidence supports DQ DVVRFLDWLRQ EHWZHHQ 2+ ' GH¿FLHQF\ DQG WKH progression and all-cause morbidity and mortality related WR+XPDQ,PPXQRGH¿FLHQF\9LUXV +,9 GLVHDVH28–29 &XUUHQWUHFRPPHQGDWLRQVIRUYLWDPLQ'LQWDNH The ,QVWLWXWH RI 0HGLFLQH ,20 XVHV QJP/ WR HVWDEOLVK 'LHWDU\5HIHUHQFH,QWDNHVIRUYLWDPLQ'30 However, this OHYHOLVEDVHGRQO\RQVNHOHWDOKHDOWKEHQH¿WVDQGWKHUHLV growing consensus that at least 32 ng/mL is a more ideal goal with regard to other health outcomes.2–3,29,31 Current UHFRPPHQGDWLRQV IRU YLWDPLQ ' LQWDNH IURP WKH ,20 RI±,8GD\30PD\EHLQVXI¿FLHQWWRDFKLHYH WKHUDSHXWLFOHYHOV QJP/ 1–2,11,13,19,21,32
OBJECTIVE: 7KH SXUSRVH RI WKLV VWXG\ ZDV WR GHWHUPLQH WKH SUHYDOHQFHRI 2+ 'GH¿FLHQF\LQDQROGHUFRPPXQLW\ GZHOOLQJ 9HWHUDQ SRSXODWLRQ SURYLGH LQIRUPDWLRQ RQ the extent of oral vitamin D supplementation for subjects LGHQWL¿HG DV 2+ ' GH¿FLHQW DQG WKH HIIHFW RI WKDW VXSSOHPHQWDWLRQRQVHUXPOHYHOVDQG IRFXVRQWKHUROHRI UDFHLQ 2+ 'GH¿FLHQF\DQGLQWKHUHVSRQVHWRWUHDWPHQW 7KH UHVHDUFKHUV K\SRWKHVL]HG WKDW D PDMRULW\ RI WKHVXEMHFWVZRXOGKDYH 2+ 'OHYHOVOHVVWKDQQJ P/ WKHPDMRULW\RIVXEMHFWVZKRZHUHGH¿FLHQWZRXOG EH VXSSOHPHQWHG DQG ZRXOG VXEVHTXHQWO\ LQFUHDVH WR WKHUDSHXWLFOHYHOV QJP/ DQG $$VXEMHFWVZRXOG KDYH VLJQL¿FDQWO\ ORZHU PHDQ 2+ ' VHUXP OHYHOV
Table 1.6XEMHFW'HPRJUDSKLFVDQG&RPRUELGLWLHV
Subject Demographics Age
Race
*HQGHU 2+ 'VHUXPOHYHO
n=
%
²\UV
²\UV
²\UV
²\UV
\UV
&DXFDVLDQ
$IULFDQ$PHULFDQ $$
2WKHUXQNQRZQ
0DOH
)HPDOH
QJP/
QJP/
QJP/
n=
%
Acute Renal Failure
Arthritis
$VWKPD
&DQFHU0DOLJQDQF\
&RJQLWLYH,PSDLUPHQW
&RURQDU\$UWHU\'LVHDVH
'HSUHVVLRQ
'LDEHWHV
Osteoporosis
6HL]XUH'LVRUGHU
7K\URLG'LVHDVH
Subject Co-morbidities
n = 234
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
92/12-81(19
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21
as compared to Caucasians at baseline and following supplementation.
METHOD: 'HVLJQ DQG 3URFHGXUH A retrospective chart review was conducted between 2008 and 2009 on 234 communitydwelling Veterans cared for in the geriatric clinic of a 0LGZHVWHUQ9HWHUDQV$IIDLUV 9$ 0HGLFDO&HQWHUORFDWHGDW ODWLWXGH12XURXWFRPHVRILQWHUHVWZHUH 2+ 'OHYHOV measured at up to three time periods (Time 1 [Baseline], Time 2 [3 months after Baseline], Time 3 [6 months after %DVHOLQH@ &KDUWV ZHUH UHYLHZHG LI WKHUH ZDV DW OHDVW RQH UHFRUGHG 2+ ' VHUXP OHYHO 7KH GDWH HDFK EORRG OHYHO was drawn was recorded and categorized into season. Seasons were divided into the time periods of December 21st – March 20th ZLQWHU 0DUFKst–June 20th VSULQJ -XQHst– September 20th VXPPHU DQG6HSWHPEHUst – December 20th IDOO 6HDVRQDOLQIRUPDWLRQZDVXVHGDVDSUR[\IRUVXQOLJKW exposure, which was not available due to the retrospective nature of the study. The data collection tool also included information about health status and demographic information for age range, gender, and race. Race was a self-reported category in the patient’s medical record. The design and procedure of this study were approved by the VA facility’s Research and Development Committee and determined H[HPSWIURPUHYLHZE\WKH,QVWLWXWLRQDO5HYLHZ%RDUGGXHWR the retrospective chart review design. 6DPSOH All subjects were patients followed in the *HULDWULF &OLQLF DJHG RU ROGHU ZHUH RU ROGHU 2I WKH 9HWHUDQV ZHUH PDOH 7KH VWXG\ FRQVLVWHG RI &DXFDVLDQ 9HWHUDQV $$9HWHUDQV DQG9HWHUDQVRIRWKHUXQNQRZQ UDFH 6HH 7DEOH IRU D GHVFULSWLRQ RI VXEMHFW demographics, including co-morbidities. $QDO\VHV The statistical software program SPSS 15.0 was used for data analysis. Univariate analyses including GHVFULSWLYHVWDWLVWLFVDQGIUHTXHQFLHVZHUHXVHGWRH[DPLQH all variables. Bivariate tests including independent t-tests, &KLVTXDUHV DQG UHSHDWHG PHDVXUHV $129$V ZHUH used to analyze relationships between variables and to test assumptions. (1RWH 6XI¿FLHQW VDPSOH VL]H ZDV RQO\ available for the Caucasian and AA race categories for purposes of cross-racial analysis.
RESULTS: )RU WKH SXUSRVH RI WKLV VWXG\ 2+ ' VHUXP OHYHOV EHORZ QJP/ZHUHGH¿QHGDVGH¿FLHQW7KLVYDOXHZDVFKRVHQ because of its generally accepted use as the lower limit of QRUPDO 2+ 'FRQFHQWUDWLRQVDWWKLV9$0HGLFDO&HQWHU +RZHYHUZHDOVRDQDO\]HGWKHIUHTXHQF\RIOHYHOVEHORZ QJP/DVWKLVLVWKHOHYHOXVHGE\WKH,20WRGH¿QHQRUPDO
2092/12-81(
The breakdown of subjects at each of these levels at Times 1–3 is presented in Figure 1. 3UHYDOHQFHRI 2+ 'GH¿FLHQF\ At Baseline it was IRXQGWKDWRIWKHVXEMHFWV KDGORZ 2+ D serum levels. Of these subjects, 107 were Caucasian RI ZHUH $$ RI DQG ZHUH RWKHUXQNQRZQ UDFH RI 7ZR tailed independent samples t-tests of the total 202 AA and Caucasian subjects revealed that AA subjects had VLJQL¿FDQWO\ORZHU 2+ 'OHYHOVDW%DVHOLQH M = 15.38, SD DVFRPSDUHGWR&DXFDVLDQV M SD [t , p @ 7\SH RI VXSSOHPHQWDWLRQ EHLQJ SUHVFULEHG DQG VXSSOHPHQWDWLRQUHVSRQVH Calcitriol at 0.25 micrograms/ day was the supplementation most commonly prescribed to patients at this VA Medical Center during the study period. Other standard supplementation strategies included HUJRFDOFLIHURO DW ,8 ZHHN RU FKROHFDOFLIHURO DW ,8GD\ 2I WKH VXEMHFWV ZKR KDG ORZ 2+ ' OHYHOV DW %DVHOLQH &DXFDVLDQ $$ RWKHU XQNQRZQ UDFH ZHUH SUHVFULEHG RUDO VXSSOHPHQWDWLRQ DW DQ\WLPHEXWRQO\ LQFUHDVHGWRQRUPDOOHYHOV 2I WKHVH VXEMHFWV ZHUH &DXFDVLDQ RI ZHUH $$ RI DQG ZDV RWKHUXQNQRZQ UDFH RI &KLVTXDUHWHVWVZHUHQRQVLJQL¿FDQW S! Supplementation strategies were inconsistent over the time periods as types and dosages often varied across VXEMHFWV1LQHW\¿YHSHUFHQWRIWKHVXEMHFWV Q ZLWK 3 data points were prescribed calcitriol at least one time. Of these subjects 85.5% took calcitriol as their only type of supplementation. Only 7 of these subjects ever took ergocalciferol and only 1 subject ever took cholecalciferol. ,QFUHDVH DFURVV WLPH SHULRGV Of the 64 subjects with 3 data points, 24 were Caucasian, 33 were AA, and 7 were other/unknown race. At Baseline, AAs had a PHDQ 2+ ' OHYHO RI QJP/ SD ZKLOH &DXFDVLDQVKDGDPHDQ 2+ 'OHYHORIQJP/ SD $UHSHDWHGPHDVXUHV$129$UHYHDOHGVLJQL¿FDQW mean differences between Caucasians and AAs over time [FGreenhouse Geisser p @ ,Q SRVW hoc analyses, comparing Baseline to Time 3, Caucasians LQFUHDVHGWKHLUPHDQ 2+ 'OHYHOV 7LPH M SD VLJQL¿FDQWO\ PRUH WKDQ $$V 7LPH M 16.64, SD >) p @)LJXUH illustrates the racial comparison of means across the three time periods.
DISCUSSION 2XU DQDO\VLV LQGLFDWHV WKDW 2+ ' GH¿FLHQF\ LV FRPPRQ in a community-dwelling elderly Veteran population JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21 Figure 1.
Time 1: Total Sample All Races (n=234) Vit D <20 ng/ml AA=61 Caucasian=77 Other/unknown=21
Vit D 20<32 ng/ml AA=13 Caucasian=30 Other/unknown=4
Vit D ш 32 ng/ml AA=4 Caucasian=17 Other/unknown=7
Time 1: Total Sample of AA & Caucasian (n=202) Vit D <20 ng/ml AA=61 Caucasian=77
Vit D 20<32 ng/ml AA=13 Caucasian=30
Vit D ш 32 ng/ml AA=4 Caucasian=17
Other/Unknown ethnic origin n=32
Time 2: Total Sample of AA & Caucasian (n=97) Vit D <20 ng/ml AA=39 Caucasian=29
Vit D 20<32 ng/ml AA=9 Caucasian=14
Vit D ш 32 ng/ml AA=1 Caucasian=5
Time 2 Missing Lab work n=105
Time 3: Total Sample of AA & Caucasian (n=57) Vit D <20 ng/ml AA=22 Caucasian=12
Vit D 20<32 ng/ml AA=8 Caucasian=4
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Vit D ш 32 ng/ml AA=3 Caucasian=8
Time 3 Missing Lab work n=40
92/12-81(21
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21 Figure 2.
Body mass index:%0,GDWDZDVDEOHWREHREWDLQHGIURPRIWKHSDWLHQWVZLWKGDWDWLPHSRLQWV7KHPHDQ%0, RIWKLVJURXSZDV 6' UDQJH ² 7KHUHZHUHQRVLJQLILFDQWUHODWLRQVKLSVIRXQGEHWZHHQ%0,DQG 2+ 'OHYHOVLQVXEMHFWVDW%DVHOLQHRUDW7LPH Differences in 25(OH)D level based on season: 7KHUHZHUHQRVLJQLILFDQWGLIIHUHQFHVIRXQGEHWZHHQ 2+ 'OHYHO DQGVHDVRQWKRXJKOHYHOVLQZLQWHUZHUHIRXQGWREHVOLJKWO\ORZHURQDYHUDJH
SDUWLFXODUO\DPRQJ$$V 7KHVH¿QGLQJVDUH consistent with those of previous studies.2, 15, 33–34 Notably, of WKHVXEMHFWVZKRZHUH 2+ 'GH¿FLHQWDWEDVHOLQHDERXW 80% were prescribed oral vitamin D supplementation at some WLPH+RZHYHUGHVSLWHRUDOVXSSOHPHQWDWLRQ 2+ 'OHYHOV GLGQRWLQFUHDVHWRWKHUDSHXWLF QJP/ LQPRVWVXEMHFWV 7KHVH¿QGLQJVVXJJHVWWKDWFXUUHQWFOLQLFDOSUDFWLFHV IRURUDOVXSSOHPHQWDWLRQDUHQRWVXI¿FLHQW. For the subset of subjects with data at three time points Q RXU¿QGLQJVLQGLFDWHWKDW$$VKDGVLJQL¿FDQWO\ less response to supplementation than Caucasians. Some potential explanations could be that AAs are less likely WR UHVSRQG WR WKH VSHFL¿F W\SH RI VXSSOHPHQWDWLRQ WKDW ZDVSUHVFULEHGUHTXLUHKLJKHUGRVHVRIVXSSOHPHQWDWLRQ UHTXLUH D ORQJHU GXUDWLRQ RI VXSSOHPHQWDWLRQ WKDQ Caucasians, or have lower rates of adherence. There have been a limited number of studies examining responses to VXSSOHPHQWDWLRQDVVRFLDWHGZLWKUDFH,Q 0DWVXRND and colleagues administered a vitamin D challenge test RQH FDSVXOH RI ,8 HUJRFDOFLIHURO WR \RXQJ blacks, 12 young whites, and 8 elderly whites.34 Although they found no difference between these groups in rate of response to the supplementation, this study was very limited in the type of supplementation used, the lack of an elderly black population, and the very small sample size.
LIMITATIONS The most notable limitation to acknowledge in the interpretation of the data from our study is that the retrospective chart review design did not allow control of the type of vitamin D supplementation prescribed. Of the VXEMHFWVZLWKGDWDRQVXSSOHPHQWDWLRQWKHPDMRULW\ took calcitriol as their only form of supplementation. This homogeneity of supplementation type limits the ability to compare effectiveness or identify whether the lack of response ZDVVSHFL¿FWRFDOFLWULRO Additionally, the study was not able to document adherence to supplementation as this was not recorded in the charts. Subjects could also have been taking overWKHFRXQWHU 27& YLWDPLQ'VXSSOHPHQWDWLRQZKLFKZDV
2292/12-81(
not documented. Some subjects were not prescribed any VXSSOHPHQWDWLRQ GHVSLWH KDYLQJ ORZ 2+ ' OHYHOV ,W should be noted that VA patients often receive care from multiple providers outside the VA, which increases the possibility that follow-ups and supplementation for low serum levels were handled by an outside provider and not recorded in the subject’s VA medical chart. Another limitation of the study was a lack of access to information on each subject’s amount of sunlight H[SRVXUH 7KRXJK VXQOLJKW LV D VLJQL¿FDQW VRXUFH RI vitamin D production, the impact of the amount of H[SRVXUH RQ 2+ ' OHYHOV ZDV QRW DYDLODEOH 8VLQJ seasonal information derived from the date as a proxy IRU VXQOLJKW H[SRVXUH VLJQL¿FDQW GLIIHUHQFHV LQ 2+ D levels were not found. Furthermore, it was not possible WRDVVHVVWKHFRQQHFWLRQEHWZHHQ 2+ 'GH¿FLHQF\DQG dietary intake as the investigators were unable to obtain information about intake of any vitamin D-rich foods from the charts.
CONCLUSIONS AND RECOMMENDATIONS Results of this study indicate that inconsistent responses to supplementation across individuals may have multifaceted origins. Future research should examine physician-based factors such as supplementation and laboratory follow-ups as well as patient-based factors such as adherence, OTC use, UV-B/sunlight exposure, and dietary intake. Additionally, ZKLOHPDQ\VWXGLHVKDYHIRXQGWKDWUDFHFDQSOD\DVLJQL¿FDQW UROHLQWKHULVNIRUGH¿FLHQF\WKHUHKDVEHHQOLWWOHIRFXVRQ WKHUROHRIUDFHLQUHVSRQVHWRVXSSOHPHQWDWLRQ2XU¿QGLQJV suggest that racial differences may exist in one’s propensity to respond to oral supplementation. Future research should be done to validate if this trend is applicable across other populations while controlling the type and dosage of vitamin D supplementation. Additional studies are needed to verify RXU¿QGLQJVRIUDFLDOGLVSDULW\ ,QGLYLGXDOL]HGVXSSOHPHQWDWLRQJXLGHOLQHVWRRYHUFRPH 2+ ' GH¿FLHQF\ PD\ QHHG WR EH WDLORUHG WR DGGUHVV ULVN IDFWRUV VXFK DV UDFH DJH %0, OLPLWHG VXQOLJKW JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21
exposure, and low dietary intake of vitamin D-rich foods. For example, research has shown that obese individuals UHTXLUH KLJKHU GRVHV RI RUDO YLWDPLQ ' VXSSOHPHQWDWLRQ to achieve optimal levels as compared to individuals with QRUPDO%0,9 Despite very conservative recommendations IRUGDLO\LQWDNHRIYLWDPLQ'WKH,20GRHVDFNQRZOHGJH that age may play a role in the body’s need for vitamin D DQGVWUDWL¿HVUHFRPPHQGDWLRQVEDVHGRQDJHJURXS30 This strategy may also be applicable to the risk factors of race and melanin content as suggested by Hall and colleagues in 2010.177KHVHIDFWRUVDIIHFWWKHIUHTXHQF\RIORZ 2+ D serum levels and, as the current study indicates, may be associated with different supplementation responses. Future research should include longer, larger studies which focus on establishing individualized supplementation guidelines across at-risk groups. Though this retrospective study did not afford the opportunity to examine the long-term effects of vitamin D supplementation on health outcomes, this is an important research opportunity for future studies. Vitamin D GH¿FLHQF\KDVEHHQDVVRFLDWHGZLWKPDQ\KHDOWKFRQGLWLRQV DQG WKH XVH RI RUDO VXSSOHPHQWDWLRQ WR UHSODFH GH¿FLHQW individuals may lead to improved outcomes.
REFERENCES:
+ROLFN0)9LWDPLQ'GHÀFLHQF\N Engl J Med. 2007; ²
+ROLFN 0) +LJK SUHYDOHQFH RI YLWDPLQ ' LQDGHTXDF\ DQG LPSOLFDWLRQVIRUKHDOWKMayo Clinic Proc. 2006; ²
%LVFKRII)HUUDUL+$*LRYDQQXFFL(:LOOHWW&HWDO(VWLPDWLRQ RIRSWLPDOVHUXPFRQFHQWUDWLRQVRIK\GUR[\YLWDPLQ'IRU PXOWLSOHKHDOWKRXWFRPHVAm J Clin Nutr. ²
*OHUXS + 0LNNHOVHQ . 3RXOVHQ / HW DO &RPPRQO\ UHFRPPHQGHG GDLO\ LQWDNH RI YLWDPLQ ' LV QRW VXIÀFLHQW LI VXQOLJKWH[SRVXUHLVOLPLWHGJ Intern Med. ²
0DODEDQDQ $ 9HURQLNLV ,( +ROLFN 0) 5HGHÀQLQJ YLWDPLQ ' LQVXIÀFLHQF\Lancet. ²
&DQQHOO--+ROOLV%:=DVORII0HWDO'LDJQRVLVDQGWUHDWPHQW RI YLWDPLQ ' GHÀFLHQF\ Expert Opin Pharmacotherapy. ²
&DOYR06:KLWLQJ6-3XEOLFKHDOWKVWUDWHJLHVWRRYHUFRPH EDUULHUV WR RSWLPDO YLWDPLQ ' VWDWXV LQ SRSXODWLRQV ZLWK VSHFLDOQHHGVJ Nutr. ² 2RPV 0( 5RRV -& %H]HPHU 3' HW DO 3UHYHQWLRQ RI ERQH ORVV E\ YLWDPLQ ' VXSSOHPHQWDWLRQ LQ HOGHUO\ ZRPHQ $ UDQGRPL]HG GRXEOHEOLQG WULDO J Clin Endocrinol Metab. ² :RUWVPDQ - 0DWVXRND /< &KHQ 7& HW DO 'HFUHDVHG ELRDYDLODELOLW\ RI YLWDPLQ ' LQ REHVLW\ Am J Clin Nutr. ²
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
)LVFHOOD . )UDQNV 3 9LWDPLQ ' UDFH DQG FDUGLRYDVFXODU PRUWDOLW\ )LQGLQJVIURPDQDWLRQDO86VDPSOHAnn Fam Med. ² 1HVE\2·'HOO 6 6FDQORQ .6 &RJVZHOO 0( HW DO +\SRYLWDPLQRVLV ' SUHYDOHQFH DQG GHWHUPLQDQWV DPRQJ $IULFDQ $PHULFDQ DQG ZKLWH ZRPHQ RI UHSURGXFWLYH DJH 7KLUG 1DWLRQDO +HDOWK DQG 1XWULWLRQ ([DPLQDWLRQ 6XUYH\ ² Am J Clin Nutr; ² &KHQ7&&KLPHK)/X=0DWKLHX-3HUVRQ.6=KDQJ $ HW DO )DFWRUV WKDW LQÁXHQFH WKH FXWDQHRXV V\QWKHVLV DQG GLHWDU\ VRXUFHV RI YLWDPLQ ' Arch Biochem Biophys. ² +DUULV 66 'DZVRQ+XJKHV % 6HDVRQDO FKDQJHV LQ SODVPD K\GUR[\YLWDPLQ ' FRQFHQWUDWLRQV RI \RXQJ $PHULFDQ EODFNDQGZKLWHZRPHQAm J Clin Nutr ² +ROLFN 0) (QYLURQPHQWDO IDFWRUV WKDW LQÁXHQFH WKH FXWDQHRXV SURGXFWLRQ RI YLWDPLQ ' Am J Clin Nutr. VXSSO 66 +DUULV 66 6RWHULDGHV ( &RROLGJH -6 HW DO 9LWDPLQ ' ,QVXIÀFLHQF\ DQG +\SHUSDUDWK\URLGLVP LQ D /RZ ,QFRPH 0XOWLUDFLDO (OGHUO\ 3RSXODWLRQ J Clin Endocrinol Metab. ² 0RRUH &( 0XUSK\ 00 +ROLFN 0) 9LWDPLQ ' ,QWDNHV E\ &KLOGUHQDQG$GXOWVLQWKH8QLWHG6WDWHV'LIIHUDPRQJ(WKQLF *URXSVJ Nutr. ² +DOO /0 .LPOLQ 0* $URQRY 3$ HW DO 9LWDPLQ ' LQWDNH QHHGHG WR PDLQWDLQ WDUJHW VHUXP +\GUR[\YLWDPLQ ' FRQFHQWUDWLRQV LQ SDUWLFLSDQWV ZLWK ORZ VXQ H[SRVXUH DQG GDUN VNLQ SLJPHQWDWLRQ LV VXEVWDQWLDOO\ KLJKHU WKDQ FXUUHQW UHFRPPHQGDWLRQVJ Nutr. ² &UDQQH\ $ +RUVOH\ 7 2·'RQQHOO 6 HW DO (IIHFWLYHQHVV DQG 6DIHW\ RI 9LWDPLQ ' LQ 5HODWLRQ WR %RQH +HDOWK (YLGHQFH 5HSRUW7HFKQRORJ\ $VVHVVPHQW 1R 3UHSDUHG E\ WKH 8QLYHUVLW\ RI 2WWDZD (YLGHQFHEDVHG 3UDFWLFH &HQWHU 82 (3& XQGHU &RQWUDFW 1R ²² $+54 3XEOLFDWLRQ 1R(5RFNYLOOH0' $JHQF\IRU+HDOWKFDUH5HVHDUFK DQG4XDOLW\ *LQGH$$/LX0&&DPDUJR&$-U'HPRJUDSKLFGLIIHUHQFHV DQG WUHQGV RI YLWDPLQ ' LQVXIÀFLHQF\ LQ WKH 86 SRSXODWLRQ ²Arch Intern Med. ² $DURQ -( *DOODJKHU -& 1RUGLQ %(& 6HDVRQDO YDULDWLRQ RI KLVWRORJLFDORVWHRPDODFLDLQIHPRUDOQHFNIUDFWXUHVLancet. ² 'H/XFD +) 2YHUYLHZ RI JHQHUDO SK\VLRORJLF IHDWXUHV DQG IXQFWLRQVRIYLWDPLQ'Am J Clin Nutr. ; VXSSO 6² 6 /LX376WHQJHU6/L+HWDO7ROOOLNHUHFHSWRUWULJJHULQJRID YLWDPLQ'PHGLDWHGKXPDQDQWLPLFURELDOUHVSRQVHScience. ² $KRQHQ 0+ 7HQNDQHQ / 7HSSR / HW DO 3URVWDWH FDQFHU ULVN DQG SUHGLDJQRVWLF VHUXP K\GUR[\YLWDPLQ ' OHYHOV )LQODQG Cancer Cause Control. ²
92/12-81(23
5$&,$/5(63216(729,7$0,1'6833/(0(17$7,21 *LRYDQQXFFL ( /LX < 5LPP (% HW DO 3URVSHFWLYH VWXG\ RI SUHGLFWRUV RI YLWDPLQ ' VWDWXV DQG FDQFHU LQFLGHQFH DQG PRUWDOLW\LQPHQJ Natl Canc Inst. ; ² *RUKDP('*DUODQG&)*DUODQG)&HWDO9LWDPLQ'DQG SUHYHQWLRQRIFRORUHFWDOFDQFHUJ Steroid Biochem Mol Biol. ² =LWWHUPDQQ$9LWDPLQ'DQGGLVHDVHSUHYHQWLRQZLWKVSHFLDO UHIHUHQFHWRFDUGLRYDVFXODUGLVHDVHProg Biophys Mol Biol. ² =LWWHUPDQQ$6FKOHLWKRII66.RHUIHU59LWDPLQ'LQVXIÀFLHQF\ LQ FRQJHVWLYH KHDUW IDLOXUH :K\ DQG ZKDW WR GR DERXW LW" Heart Fail Reviews. ² 'DR&13DWHO32YHUWRQ(7HWDO/RZYLWDPLQ'DPRQJ+,9 LQIHFWHGDGXOWV 3UHYDOHQFHRIDQGULVNIDFWRUVIRUORZYLWDPLQ 'OHYHOVLQDFRKRUWRI+,9LQIHFWHGDGXOWVDQGFRPSDULVRQWR SUHYDOHQFHDPRQJDGXOWVLQWKH86JHQHUDOSRSXODWLRQClin Infect Dis ²
2492/12-81(
0HKWD 6 *LRYDQQXFFL ( 0XJXVL )0 HW DO 9LWDPLQ ' VWDWXV RI +,9LQIHFWHG ZRPHQ DQG LWV DVVRFLDWLRQ ZLWK +,9 GLVHDVH SURJUHVVLRQ DQHPLD DQG PRUWDOLW\ PLoS ONE. H ,20 ,QVWLWXWH RI 0HGLFLQH Dietary Reference Intakes for Calcium and Vitamin D. :DVKLQJWRQ '& 7KH 1DWLRQDO $FDGHPLHV3UHVV $ORLD-)7DOZDU6$3ROODFN6HWDO$UDQGRPL]HGFRQWUROOHG WULDO RI YLWDPLQ ' VXSSOHPHQWDWLRQ LQ $IULFDQ $PHULFDQ ZRPHQArch Intern Med. ² 9LHWK5%LVFKRII)HUUDUL+%RXFKHU%-HWDO7KHXUJHQWQHHG WRUHFRPPHQGDQLQWDNHRIYLWDPLQ'WKDWLVHIIHFWLYHAm J Clin Nutr. ² 'DZVRQ+XJKHV % 5DFLDOHWKQLF &RQVLGHUDWLRQV LQ PDNLQJ UHFRPPHQGDWLRQV IRU YLWDPLQ ' IRU DGXOW DQG HOGHUO\ PHQ DQGZRPHQAm J Clin Nutr. VXSSO 66 0DWVXRND /< :RUWVPDQ - &KHQ 7& HW DO J Lab Clin Med. ²
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION