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JOURNAL OF BONE AND MINERAL RESEARCHVolume 23, Number 12, 2008

ubl!"#e$ o%l!%e o% Jul& 28, 2008' $o!( 10)13*+ JBMR)080-0-. 2008 Amer!/ % So/!e & or Bo%e %$ M!%er l Re"e r/#

Hormone Therapy Improves Femur Geometry Among EthnicallyDiverse Postmenopausal Participants in the Women’s Health Initiative

Hormone Intervention Trials

Zhao Chen ! Thomas " #ec$ % "ane A Cauley & Cora E 'e(is ) An*rea 'aCroi+ , Tamsen #ass-or* . Guanglin Wu !

Duane /herrill ! an* /cott Going 0

ABS RAC ( 'oss o- 1one strength un*erlies osteoporotic -ragility -ractures2 We hypothesi3e* that hormoneinterventions signi-icantly improve the structural geometry o- pro+imal -emur cross4sections2 /tu*y partici4

pants (ere -rom the Women’s Health Initiative hormone intervention trials5 either the con6ugate* e7uineestrogen 8CEE9 only 8 N place1o ))0 N CEE )%%9 trial or the estrogen 8E9 plus progestin 8P9 8 N place1o))! N E:P ,;&9 trial (ho (ere ,;D scans 1y D?A(ere con*ucte* at 1aseline year ! year & an* year .2 Femur geometry (as *erive* -rom hip D?A scansusing the hip structural analysis 8H/A9 metho*2 >i+e* e--ects mo*els (ith the intent4to4treat analysisapproach (ere use*2 There (ere no signi-icant *i--erences in treatment e--ects 1et(een the E4alone an* theE : P trial so the analyses (ere con*ucte* (ith participants com1ine* -rom 1oth trials2 Treatment 1ene-its8 p @ ;2;,9 on -emur geometry (ere o1serve* as early as ! yr a-ter the intervention2 From 1aseline to year .

section mo*ulus 8a measure o- ma+imum 1en*ing stress9 (as preserve* an* 1uc$ling ratio 8an in*e+ o- cortical insta1ility un*er compression9 (as re*uce* 1y hormone interventions 8 p @ ;2;,9 the *i--erences inthe percent changes -rom 1aseline to year . 1et(een (omen on hormone intervention versus (omen on

place1o (ere %2&D an* a heightene* ris$ o- -ractures (ith aging2 *ee* the meta4analysis o- Delmas an* /eeman sho(e*

Whereas estrogen therapy in postmenopausal (omen has 1een sho(n to re*uce rates o- all -ractures 1y %;B an* hip-ractures 1y F&;B 8! %9 the potential -or elevate* ris$ o-

1reast cancer an* stro$e contra*icts its use in osteoporosis prevention2 evertheless -urther evaluations o- e+istingstu*y *ata on estrogen e--ects on 1one may clari-y mecha4nisms o- interventions using similar 1iological path(ays2

The H/A so-t(are use* in the stu*y (as license* to Hologic 1y"ohns Hop$ins niversity2 Dr Cauley has receive* research sup4

port -rom >erc$ Company Eli 'illy Company P-i3er Phar4maceuticals an* ovartis Pharmaceuticals2 /he has also receive*consulting -ees -rom Eli 'illy Company an* ovartis Pharma4ceuticals2 Dr2 'aCroi+ serves as a consultant on /cienti-ic A*visoryCommittees -or stu*ies -un*e* 1y The Alliance -or #etter #oneHealth an* P-i3er Pharmaceuticals2 All other authors state thatthey have no con-licts o- interest2

no relationship 1et(een treatment e--ects on -racture ratesan* change in #>D2

At the simplest level an e--ective treatment coul* re*uce-ractures 1y ma$ing -alls less li$ely or 1y ma$ing 1onesstronger so that -ractures are less li$ely (hen -alls *o occur2Hormone therapy *oes seem to have e--ects that mightre*uce the li$elihoo* o- -alls2 For e+ample estrogen treat4ment improves preservation o- 1o*y lean mass a-ter meno4

pause 8)9 increases muscle strength 8,9 an* improves pos4tural 1alance2 8. 09 Ho(ever the magnitu*es o- these e--ectsare also 7uite small2 n the other han* there is a (ealth o- animal an* human *ata sho(ing that 1one strength *eclines(ith estrogen *epletion an* is improve* 1y restoration2 8I9

Although a use-ul clinical surrogate #>D is not itsel- a property that governs mechanical strength although it cer4tainly correlates in a general (ay (ith the strength o- oste4

! Division o- Epi*emiology an* #iostatistics niversity o- Ari3ona Tucson Ari3ona /A %Department o- a*iology "ohns Hop$insniversity #altimore >arylan* /A &Department o- Epi*emiology niversity o- Pitts1urgh Pitts1urgh Pennsylvania /A ) Divi4

sion o- Preventive >e*icine niversity o- Ala1ama at #irmingham #irmingham Ala1ama /A , Fre* Hutchinson Cancer esearchWomen’s Health Initiative Clinical Coor*ination Center /eattle Washington /A . Department o- Family an* Community >e*icine

niversity o- Ari3ona Tucson Ari3ona /A 0Department o- utritional /ciences niversity o- Ari3ona Tucson Ari3ona /A2

1+3*

A


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2 CHEN E AL)

oporotic 1ones2 It may 1e that un*erlying *imensionalchanges alter 1one strength in (ays that are not al(aysapparent in #>D2

#one strength 8see glossary -or more *etails9 is the -orcere7uire* to cause mechanical -ailure2 It cannot actually 1emeasure* on 1ones (ithin in*ivi*uals 1ut can 1e pre*icte*-rom engineering mo*els2 #asically an engineering mo*elis a simulation using *imensions o- an o16ect 8geometry9an* in-ormation a1out its material to pre*ict 1ehavior un4*er loa*2 At present noninvasive metho*s cannot evaluatetissue material properties so mo*els must assume constantvalues -rom e+ vivo e+periments2 It is also *i--icult to imagethe comple+ internal geometry o- 1ones -or simulationsespecially the -ine structural *etails that can only 1e image*(ith su--icient resolution at peripheral sites2 Even (henimage* (ith a*e7uate resolution engineering simulations(ith an accurate level o- structural *etail are prohi1itivelycomple+ even -or current computational resources2 8=9 Prac4tical engineering metho*s applie* to 1ones in vivo generallyassume simpli-ie* geometric mo*els that can 1e reasona1ly(ell speci-ie* -rom current CT metho*s2 Those higher ra4*iation *ose metho*s are not o-ten use* in large clinicaltrials an* most stu*ies have even more restricte* in-orma4tion on s$eletal e--ects2 For e+ample the 1ul$ o- the invivo evi*ence on estrogen e--ects comes -rom complete*stu*ies that mainly evaluate* treatments (ith D?A #>D2Whereas not su--icient -or &D engineering mo*els it is pos4si1le to e+tract limite* geometric in-ormation to provi*einsights into strength e--ects 1y reanaly3ing archive* D?Ascans (ith special so-t(are2

The hip structure analysis 8H/A9 so-t(are use* in thisstu*y has 1een use* to evaluate treatment e--ects on the

pro+imal -emur in clinical trials an* o1servational stu*4ies2 8!;

an* a small clinical trial o- ol*er (omen2 8!;9 ne a*vantageo- the metho* is that it presents 1oth the conventional#>D an* the geometry o- three selecte* cross4sectionsthrough the pro+imal -emur2 Thus the changes in outer *imensions or in the amount o- 1one that can in*epen4*ently alter #>D in a cross4section can 1e tease* apartan* the *istri1ution e--ects that in-luence 1en*ing proper4ties can also 1e evaluate*2 These *ata -rom a larger Wom4en ’ s Health Initiative 8WHI9 place1o4controlle* trial (itha longer -ollo(4up an* inclu*ing younger postmenopausal(omen shoul* permit a clearer picture o- hormone therapyon -emur #>D an* on the un*erlying geometric strengthat a site (here the most costly osteoporotic -racturesoccur2

MA ERIALS AND ME HODS

The WHI study

The WHI is the largest (omen ’ s health stu*y in thenite* /tates2 Details regar*ing the inclusion an* e+clusion

criteria recruitment proce*ures participants characteris4tics hormone intervention regimens ran*omi3ation 1lin*4ing an* -ollo(4up can 1e -oun* in the previously pu1lishe*

papers2 8! % !)9

#rie-ly 2/2 (omen (ho (ere , ;ay &! %;;%2 The E : P intervention (asterminate* ∼ & yr 1e-ore the planne* *ate 1ecause o- ana*verse e--ect on 1reast cancer an* a glo1al in*e+ sho(ingthat the ris$s e+cee*e* 1ene-its2 8%9

In the E4alone trial !; 0&= postmenopausal (omen (ith prior hysterectomy (ere ran*omly assigne* 1y clinical cen4ter to receive either ;2.%, mgJ* con6ugate* e7uine estrogen8CEE9 or place1o2 esults -rom interim *ata analysis 1ythe WHI Data an* /a-ety >onitoring #oar* suggeste*that CEE increases stro$e an* *ecreases the ris$ o- hip-ractures 1ut *oes not provi*e overall 1ene-it -or chronic*isease prevention in postmenopausal (omen (ho ha*hysterec4 tomy2 Hence the E4alone trial (as terminate* 1yFe1ruary%;;) a-ter an average -ollo(4up time o- .2 yr ! yr 1e-orethe sche*ule* closeout *ate 8>arch %;;,92 8!9

Participants in this study

This stu*y inclu*e* a su1group o- participants 8n ! !&9 in the WHI hormone trials (ho (ere recruite* -romthree WHI #>D clinical centers 8Pitts1urgh PA /A#irmingham A' /A an* TucsonJPhoeni+ AZ /A9an* (ho receive* total 1o*y spine an* hip 1one scans 1yD?A 8KD %;;; %;;;: or ),;;W Hologic Waltham>A /A92 The #>D centers (ere chosen to enrich the

*ata (ith in-ormation on minority (omen2

DXA scans and HSA

D?A scans (ere con*ucte* at 1aseline an* at years ! &an* . *uring the intervention2 /tan*ar* protocols -or posi4tioning an* analysis (ere use* 1y technicians (ho (eretraine* an* certi-ie* 1y the D?A manu-acturer an* 1y theWHI D?A coor*ination center at the niversity o- Cali4-ornia at /an Francisco2 The ongoing 7uality assurance pro4gram monitore* spine an* hip phantom scans an* revie(e*a ran*om sample o- all su16ect scans an* -lagge* those (ith


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T A#'E !2 # A/E'I E C HA ACTE I/TIC/ F THE / T DL P A TICIPA T/ M>EA N /D N 8B9O

E + P E alone

Place o!N " ##$%

Treatment !N " &'(% p

Place o!N " ##)%

Treatment !N " #**% p

Age at screening 8yr9 .&20 N 02; .&2) N 02& ;2, = .&2, N 02. .&2) N 020 ;2I0ILears since menopause !)2% N 2! !)2& N =2) ;2 00 !=2) N !;2! !=2) N !;2; ;2=)&

Height 8$g9 !.!2, N ,2= !.!2) N ,2= ;20%) !.!2, N .2! !.;2= N .2& ;2!%%Weight 8cm9 0&2= N !.2% 0&2! N !)2) ;2);. 002 N !,2. 002 N !,2. ;2=0;#o*y mass in*e+ 8$gJm %9 % 2& N ,2 % 2! N ,2% ;2)=! %=2 N ,2. &;2; N ,2. ;2)0IDietary energy 8$cal9 !.=.2; N 0!&2) !0!02; N 0;;2= ;2.,, !.0&2; N 0.02. !.0=2. N 0);2= ;2=;;Total e+pen*iture -rom physical activity 8>ET/9 !%2% N !)20 !;2= N !&2% ;2%%& =2) N !!2, !;2; N !&2; ;2,;!Total calcium inta$e 8mg9 !;&.2, N &&2! !;%=20 N &;2) ;2 ; =%%20 N % 2! =,.2. N &%2! ;2)%0Total vitamin D inta$e 8 g9 2= N ;2) 20 N ;2& ;20! 02 N ;2& 2; N ;2& ;20%&Total 1o*y lean mass 8$g9 & 2% N ,2, &020 N ,2! ;2!,; & 2 N ,2. & 2, N ,2, ;2))%Total 1o*y percent -at 8B9 )&2, N 02& )&2 N 02% ;2,!, ),20 N .2, ).2! N .20 ;2&=.Hologic total 1o*y #>D 8gJcm %9 ;2== N ;2!; ;2== N ;2!; ;20.= !2;! N ;2!! !2;; N ;2!! ;2,)=Hologic spine #>D 8gJcm %9 ;2=, N ;2!. ;2=) N ;2!, ;2%.! ;2= N ;2!0 ;2=0 N ;2!. ;2.%%Hologic hip #>D 8gJcm %9 ;2 ) N ;2!) ;2 & N ;2!% ;2&0) ;2 . N ;2!, ;2 . N ;2!& ;2I,%Ethnicity

White &.& 8 %2&B9 )! 8 &2!B9 ;2;&= &!0 80;2=B9 &!0 80,2!B9 ;2!%&#lac$ ,; 8!!2&B9 & 802.B9 =& 8%;2 B9 .0 8!,2=B9

Hispanic %; 8)2,B9 &. 802%B9 &% 802%B9 &!802)B9 ative American . 8!2)B9 & 8;2.B9 ) 8;2=B9 & 8;20B9AsianJPaci-ic Islan*er ; 8;2;;B9 ) 8;2 B9 ! 8;2%B9 ; 8;2;B9

ther % 8;2,B9 ) 8;2 B9 ; 8;2;B9 ) 8!2;B9/mo$ing

ever %%, 8,%20B9 %.= 8,&2=B9 ;20=0 %& 8,)2;B9 %&= 8,.2=B9 ;2.I.Past !.; 8&02,B9 !00 8&,2,B9 !,! 8&)2%B9 !&, 8&%2!B9Current )% 8=2 B9 ,& 8!;2.B9 ,% 8!!2 B9 ). 8!!2;B9

Physical -unction@=; %.& 8.!20B9 &;% 8.;2=B9 ;20=% &!; 80;2,B9 &;% 80&2 B9 ;2%0% =; !.& 8& 2&B9 !=) 8&=2!B9 !&; 8%=2.B9 !;0 8%.2%B9

Hormone use ever &)0 80 20B9 &=0 80=2!B9 ;2 ,! % ! 8.%2=B9 %,! 8,=2,B9 ;2!&;Past 0. 8!02%B9 8!02,B9 !&& 8%=2 B9 !)= 8&,2&B9Current ! 8)2!B9 !0 8&2)B9 && 802)B9 %%8,2%B9

Duration o- prior hormone use one &)0 80 20B9 &=0 80 2=B9 ;2=%% % ! 8.%2=B9 %,! 8,=2,B9 ;2I.0@, yr 0; 8!,2=B9 ! 8!.2!B9 == 8%%2%B9 !;, 8%)2=B9, to @!; yr !& 8&2;B9 !) 8%2 B9 &% 802%B9 &&802 B9!; to @!, yr 8!2 B9 . 8!2%B9 !) 8&2!B9 !) 8&2&B9!,: yr & 8;20B9 , 8!2;B9 %! 8)20B9 != 8)2,B9

ethnicities other than non4Hispanic (hite (omen to con4-irm the -in*ings -rom the complete cohort2

/cans con*ucte* . mo a-ter stopping the trial (ere e+4clu*e* -rom all the analyses an* 1ecause -e( (omen ha*year = -ollo(4up in-ormation (e use* only the -irst . yr o- -ollo(4up *ata2 All statistical analyses (ere con*ucte* us4ing /TATA 8version =2%92

RESUL S

haracteristics of the study participants at aseline

Participants ’ 1aseline characteristics are presente* 1y in4tervention assignment in Ta1le !2 A total o- ))! an* ,;&(omen (ere -rom the place1o an* the intervention arms o- the E : P respectively2 In the E4alone trial ))0 (omen-rom the place1o an* )%% -rom the intervention arm (ereinclu*e*2 In the E : P trial the percentage o- 1lac$ (omen

(as higher in the place1o arm than in the intervention arm8!!2&B versus 02.B92 In contrast the percent o- Hispanic(omen (as lo(er in the place1o arm than in the interven4tion arm 8)2,B versus 02%B p ;2;&=92 o signi-icant*i--erences in other measures (ere o1serve* 1et(een theintervention an* the place1o arm in either the E : P o r

E4alone trials2#aseline #>D an* -emur geometry measures (ere simi4lar 1et(een the intervention an* the correspon*ing place1ogroup in 1oth trials 1ut there (ere signi-icant *i--erences in#>D an* -emur geometry 1et(een the t(o trials2

han,es in -.D and ,eometry caused yinterventions

The average -ollo(4up time (as )2) N %2% yr -or the par4ticipants inclu*e* in this analysis the E : P trial stoppe*earlier than the E4alone trial resulting in an average -ollo(4


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up time o- )2% N %2% versus )2, N %2% yr -or theE4alone trial2E4alone an* E : P trials (ere com1ine* in all the analysis

1ecause no signi-icant *i--erence in treatment e--ects 1e4t(een the t(o trials (as -oun* 8*ata not sho(n92 #>D an*-emur geometric measures -rom 1aseline to year . aresho(n in Ta1le %2 Group t 4tests (ere use* to e+amine the*i--erences in H/A measures 1et(een the hormone inter4vention an* the place1o group at each visit2 The resultssho(e* that #>D (as increase* an* that the un*erlyinggeometry o- -emur cross4sections (as altere* in the *irec4tion o- greater strength (ith the hormone intervention2/tarting at year ! o- the intervention #>D cortical thic$4ness cross4sectional area 8C/A9 an* section mo*ulus at allthree -emoral sites 1ecame higher in the intervention arm incomparison (ith the place1o arm although not all the *i-4-erences reache* the statistical signi-icance at ;2;,2

uter *iameters (ere slightly narro(er in the interventiongroup 1ut the *i--erences 1et(een the intervention an* the

place1o group (ere very small an* none o- them (erestatistically signi-icant2 # s at all regions 1ecame signi-i4cantly smaller in the intervention arm in comparison (iththe place1o arm (ith the e+ception at year & at the inter4trochanter an* sha-t region2 Centers o- mass 8centroi*s9 o- each cross4section (ere *isplace* signi-icantly to(ar* thecenter o- the 1one 8value closer to ;2,9 (ith treatmentin*icating that the *istri1ution o- 1one tissue in cross4sections (as altere* to 1e more symmetrical2

Figure ! compares the *i--erences in the percent changes-rom 1aseline to year . 1et(een (omen on hormone inter4vention versus (omen on place1o2 These *ata suggeste*signi-icant positive intervention e--ects 8 p @ ;2;,9 -rom

1aseline to year . on all measures (ith the e+ception o- theouter *iameter at the -emoral narro( nec$ an* intertro4chanter regions2 With the e+ception o- sha-t outer *iameteroverall e--ects o- hormone interventions seeme* to 1egreater in magnitu*e at the intertrochanter region in com4

parison (ith the other t(o -emoral regions2

/on,itudinal data analysis on intervention effects

>i+e* e--ects mo*els (ere use* to e+amine interventione--ects on the geometric parameters an* #>D in the three-emoral regions2 For the longitu*inal *ata analysis eachmeasure -rom the H/A program (as the *epen*ent vari4a1le in the correspon*ing ran*om e--ects mo*el2 The in*e4

pen*ent varia1les (ere hormone treatment visit 8; ! &.9 an* the interaction term 1et(een hormone treatmentan* visit2 Figure % sho(s the intervention e--ect on #>Dan* geometry at the -emur narro( nec$2 The pre*icte*values -rom the mi+e* e--ects mo*el in*icate* that(omen (ho receive* hormone interventions ha* higher #>D C/A cortical thic$ness an* section mo*ulus an*lo(er # com4 pare* (ith their place1o counterparts2 Thee--ects on -emur #>D an* geometry at the intertrochanter an* sha-t regions (ere similar to the narro( nec$ region8*ata not sho(n92 esults -rom these longitu*inal mo*elscon-irme* signi-i4 cant hormone e--ects on most o- theH/A parameters e+4 cept -or outer *iameter2

o signi-icant con-oun*ing -actors (ere i*enti-ie* -or therelationship 1et(een hormone intervention an* -emur

#>D or geometry2 A**ing age ethnicity height (eighttotal 1o*y percent lean mass an* smo$ing *i* not alter the-in*ings o- these mi+e* e--ects mo*els although mo*el -it4ness (as mo*estly improve* 8*ata not sho(n92 Interventione--ects (ere not signi-icantly *i--erent 1y ethnic group asin*icate* 1y nonsigni-icant interaction terms 1et(een eth4nicity an* treatment 8*ata not sho(n92

Sensitivity analysis/ensitivity analyses (ere con*ucte* 1y restricting the

analysis to (omen (ho ha* ta$en at least ;B o- the as4signe* stu*y pills2 esults -rom the sensitivity analysessho(e* the same *irection 1ut stronger treatment e--ects8*ata not sho(n9 supporting the -in*ings o- the intent4to4treat analyses2

DISCUSSION

As in other stu*ies 8%&D cause* 1y treatment (ith con6ugate*e7uine estrogen either alone 8E4alone9 or in com1ination

(ith progestin 8E : P9 (hen contraste* (ith place1o2 oneo- the e--ects on #>D or on the un*erlying geometry *i-4-ere* signi-icantly 1et(een E4alone an* E : P suggestingthat the treatment e--ects (ere e+clusively cause* 1y estro4gen2 The geometric changes un*erlying the increase in -e4mur #>D (ere signi-icant 1ut (ere also 1oth su1tle an*comple+2

ur *ata suggeste* that *iameters o- -emur cross4sections in treatment groups e+pan*e* more slo(ly (ithtime 8Figs2 ! an* %9 1ut *i--erences only reache* signi-i4cance at the sha-t2 Femur cross4sections in treatment groups*i* sho( signi-icant increases in the amount o- 1one sur-aceas (ell as an alteration o- the *istri1ution o- the material(ithin cross4sections evi*ent as a shi-t in the centroi*2 ur

interpretations o- these e--ects an* their mechanical signi-i4cance are as -ollo(s2

Indirect effects on one stren,th

It is (ell esta1lishe* that 1one tissue respon*s to me4chanical loa* an* that the loa* is primarily me*iate* 1ymuscle -orces2 #ecause estrogen has positive e--ects onmuscle strength 8%.9 it might stimulate a positive s$eletala*aptation response in*epen*ent o- its *irect e--ects on

1one tissue2 I- geometry e--ects (ere eliminate* 1y a*6ust4ing -or 1o*y lean mass this (oul* suggest that the s$eletale--ects (ere entirely in*irect2 Correction -or percent leanmass *i* not eliminate the geometry e--ect2 Hence (e con4clu*e that treatment e--ects o- hormone therapy are mainly

cause* 1y a *irect in-luence on 1one rather than to ana*aptation to a treatment in*uce* increase in muscle loa*2

Estro,en and load sensitivity

>echanostat theory hol*s that 1one geometry a*apts toensure that ma+imum tissue strains 8*e-ormations9 -rom

prevalent loa*s remain (ithin certain limits2 8%09 /trains are proportional to stresses (hich un*er a given loa*ing con4*ition are *etermine* 1y geometry2 A num1er o- investi4gators 8% 9 Frost among them 8%=9 have speculate* that es4


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T A#'E %2P ?I>A' F E> #>D A D G E >ET L > EA/ E>E T/ F > # A/E'I E T L EA . #L H > E I TE E TI

-aseline 0ear $ 0ear ( 0ear 1

Femoral narro( nec$

Place o

!N "222%

Hormone

!N "3*&%

Place o

!N "2'1%

Hormone

!N "2*'%

Place o

!N ")'*%

Hormone

!N ")((%

Place o

!N "1'(%

Hormone

!N "&*(%


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#>D 8gJcm %9Cross4sectional area 8cm %9

;20! N ;2!&%2;) N ;2&0

;20! N ;2!%%2;& N ;2&,

;20! N ;2!&%2;) N ;2&0

;20& N ;2!&Q%2; N;2&. R

;20% N ;2!)%2;0 N ;2);

;20, N ;2!&Q%2!) N ;2& Q

;20! N ;2!&%2;, N ;2)!

;20) N ;2!&Q%2!% N ;2& Q

uter *iameter 8cm9 &2;! N ;2%! &2;! N ;2%! &2;& N ;2%& &2;% N ;2%! &2;) N ;2%, &2;% N ;2%! &2;, N ;2%) &2;) N ;2%&/ection mo*ulus 8gJcm &9 ;2=! N ;2%; ;2=! N ;2!= ;2=% N ;2%! ;2=) N ;2!= ;2=, N ;2%, ;2=0 N ;2%; ;2=) N ;2%% ;2=0 N ;2%!Cortical thic$ness 8cm9 ;2!) N ;2;& ;2!) N ;2;% ;2!) N ;2;& ;2!) N ;2;&Q ;2!) N ;2;& ;2!) N ;2;&Q ;2!& N ;2;& ;2!) N ;2;&Q#uc$ling ratio !%2,, N %2=! !%2,! N %2.= !%2. N %2=% !%2%) N %2..Q !%2, N &2;! !!2 N %2,=Q !%2 ) N &2;& !%2! N %2Centroi* position ;2),= N ;2;!. ;2), N ;2;!. ;2), N ;2;!, ;2), N ;2;!. ;2),0 N ;2;!0 ;2),= N ;2;!. R ;2),. N ;2;!= ;2), N ;2;!

Intertrochanter #>D 8gJcm %9 ;20% N ;2!) ;20! N ;2!& ;20% N ;2!) ;20& N ;2!& ;20% N ;2!, ;20, N ;2!&Q ;20! N ;2!) ;20) N ;2!&QCross4sectional area 8cm %9 &2,; N ;2.= &2) N ;2.) &2,! N ;2.= &2,0 N ;2., &2,, N ;20& &2.. N ;2..Q &2,% N ;20% &2.% N ;2.,Q

uter *iameter 8cm9 ,2!% N ;2&& ,2!& N ;2&) ,2!& N ;2)! ,2!) N ;2&, ,2!, N ;2&. ,2!& N ;2&% ,2!= N ;2)! ,2!. N ;2&)/ection mo*ulus 8gJcm &9 %2=! N ;2.& %2 = N ;2.! %2=& N ;2. %2= N ;2.& %2=0 N ;2.0 &2;. N ;2.& R %2= N ;20! &2;& N;2.% R

Cortical thic$ness 8cm9 ;2%= N ;2;. ;2%= N ;2;. ;2%= N ;2;. ;2&; N ;2!; ;2%= N ;2;. ;2&! N ;2!!Q ;2%= N ;2;. ;2&; N ;2;.Q#uc$ling ratio !;2)& N %2) !;2,% N %2%= !;2&0 N %2&, !;2! N %2%! !;2) N %2)0 =2 . N %2;=Q !;2.. N %2)) !;2!! N %2! QCentroi* position ;2)&, N ;2;!0 ;2)&) N ;2;!0 ;2)&, N ;2;!0 ;2)&. N ;2;!0 ;2)&& N ;2;! ;2)&, N ;2;!0 R ;2)&& N ;2;!= ;2)&) N ;2;!0

/ha-t#>D 8gJcm %9 !2!) N ;2!= !2!& N ;2! !2!, N ;2!= !2!. N ;2! !2!0 N ;2%; !2!= N ;2!I R !2!) N ;2%; !2! N ;2!I R

Cross4sectional area 8cm %9 &2!; N ;2,& &2;= N ;2,; &2!& N ;2,& &2!, N ;2,% &2! N ;2,. &2%& N ;2,! &2!% N ;2,. &2%% N ;2,;uter *iameter 8cm9 %2 0 N ;2! %2 0 N ;2!= %2 0 N ;2! %2 . N ;2%! %2 0 N ;2! %2 . N ;2%; %2 N ;2! %2 . N ;2!

/ection mo*ulus 8gJcm &9 !2.& N ;2&! !2.% N ;2%= !2., N ;2&! !2.. N ;2&; !2.= N ;2&% !20! N ;2&; !2.0 N ;2&% !20; N ;2&;Cortical thic$ness 8cm9 ;2); N ;2; ;2); N ;2; ;2)! N ;2; ;2)! N ;2; ;2)% N ;2;= ;2)& N ;2;I R ;2); N ;2; ;2)% N ;2;I R

#uc$ling ratio &20 N ;2=& &20 N ;2=% &20& N ;2 &2. N ;2 0 &2.0 N ;2=! &2,& N ;2 ;Q &2 ; N ;2=) &2,0 N ;2Centroi* position ;2)=. N ;2;!; ;2)=0 N ;2;!; R ;2)=. N ;2;!; ;2)= N ;2;!; R ;2)=0 N ;2;!; ;2)== N ;2;!;Q ;2)=0 N ;2;!; ;2)== N ;2;! R

Q p @ ;2;! an* R p @ ;2;,5 signi-icant levels -or the *i--erence 1et(een the hormone intervention an* the place1o group2


8/12

8 CHEN E AL)

FI:) 1) Di--erence in percent change in hip #>D an* geometry 1et(een the intervention an* place1o groups -rom 1aseline to

progressively less 1one mass 8thinner cortices9 as *iameter increases2 I- carrie* too -ar strength 1egins to 1e compro4mise* 1y suscepti1ility to local 1uc$ling un*er compressiveloa*s2 In smooth thin4(alle* hollo( tu1es this occurs (henthe ratio o- outer *iameter to (all thic$ness 8# 9 e+cee*sa -actor o- !;2 8&%9 # can only 1e cru*ely estimate* -romD?A *ata 1y com1ining measure* *imensions (ith a

mo*el an* 1ecause pro+imal -emurs are not strictly hollo(it is uncertain (hat values estimate* 1y this metho* areactually unsta1le2 I- local 1uc$ling *oes contri1ute tostrength loss a treatment4in*uce* re*uction in suscepti1il4ity shoul* supplement positive treatment e--ects on C/Aan* section mo*ulus2 A *e-initive conclusion on thestrength contri1ution o- local 1uc$ling (oul* re7uire more

year .2 All p @ ;2;! e+cept a p ;2;, an* 1 p @ ;2;, -or the *i--er4sophisticate* &D engineering metho*s 8&&9 than are possi1leence in percent changes 1et(een the hormone intervention an*

the place1o group2

trogen in-luences mechanostat threshol*s perhaps 1yaltering the sensitivity o- 1one cells to mechanical stimuli2 A

1one cell culture assay 1y #a$$er et al28&;9 sho(e* that inthe presence o- estra*iol cultures pro*uce* higher signallevels un*er e7uivalent mechanical stimulus2 Higher signallevels -or a given stimulus shoul* e--ectively re*uce thelevel o- strain necessary -or an osteogenic e--ect thus theresponse shoul* alter geometry so that ma+imum stressesare re*uce* -or a given loa* 8assuming no e--ect on theelastic mo*ulus that coul* not 1e measure*92 ur o1serva4tion that section mo*uli are higher in (omen on hormonetherapy suggests that their 1en*ing stresses are lo(er (hensu16ecte* to an e7uivalent muscle loa*2 This is consistent(ith the con6ecture that estrogen increases the loa* sensi4tivity o- 1one tissue an* is (orthy o- -urther stu*y2

Effects on centroid position

/everal stu*ies have sho(n that 1one loss in the aging pro+imal -emur is not uni-orm an* ten*s to 1e greater onthe superior4lateral than on the in-erior me*ial regions o- cross4sections2 In*ee* the cross4sectional analysis o- ca4*aver -emur nec$s 1y >ayhe( et al28! 9 coul* not sho( anyage tren*s in cortical thinning on the in-erior4me*ial sur4-aces o- the -emoral nec$ in either men or (omen2 nee--ect o- pre-erential 1one loss -rom lateral regions isthat the center o- mass o- the cross4section shi-ts to(ar* theme*ial corte+2 A me*ial shi-t in the centroi* position (asevi*ent in the HA E/ survey o- the 2/2 population in

1oth men an* (omen2 8! 9 The e--ect (as greater in -emo4ral nec$s o- (omen (ith -ractures o- the hip 8&!9 an*in -emoral nec$ 1iopsies o- -racture cases 8! 9 than un-rac4ture* controls2 A treatment4in*uce* lateral shi-t in thecentroi* position re*uces ma+imum *istance to the outer cortical sur-ace 8*ma+ 9 causing positive e--ects on /> an*on # 2

Effects on suscepti ility to local uc4lin,

The generali3e* e+pansion o- -emur *iameter accompa4nying the aging process seems to preserve 1en*ing strength8/>9 in the presence o- net 1one loss 1ut it is achieve* (ith

to construct -rom %D D?A *ata2 evertheless D?A esti4mates o- # s seem to e+plain (hy lo( #>D is pre*ictiveo- hip -racture an* (hy men -racture at higher #>D levelsthan (omen2 8!. &)9 The o1servation that hormone therapysigni-icantly re*uces # suggests that treatment improvescortical sta1ility in the pro+imal -emur supplementing its

positive e--ects on C/A an* />2 It may 1e important tonote that although # s are re*uce* (ith treatment atearly time points they return to 1aseline a-ter . yr(hereas val4 ues in untreate* in*ivi*uals continue to rise2This may sug4 gest that hormone therapy pro*uces an age*isplacement in the onset o- -ragility 1ut consistent (iththe epi*emiologi4 cal evi*ence *oes not prevent itentirely2

+omparison 5ith results from other studies

The results -rom this stu*y support previous -in*ings on positive e--ects o- hormone interventions on -emur geom4

etry -rom an o1servational stu*y 8!&9 an* -rom a &4yr inter4vention stu*y2 8!;9 Despite the *i--erences in age groups an**uration o- interventions our results are similar to the &4yr stu*y Greenspan et al2 in ol*er (omen suggesting signi-i4cant treatment e--ects 1y hormones on 1one C/A /> CTan* # in the -emoral narro( nec$ intertrochanter an*sha-t regions although there (ere some *i--erences in re4sults2 For e+ample (hereas # s a-ter treatment (ere sig4ni-icantly smaller in all regions than place1o in this stu*ythe smaller stu*y on an ol*er cohort 1y Greenspan et al2 *i*not o1serve a positive e--ect at the an* IT regions(here 1uc$ling (oul* 1e li$ely2 We also note that consis4tent (ith the report o- Greenspan et al2 8!;9 geometric e-4

-ects o- hormone therapy (ere greatest at the IT region incomparison (ith the an* sha-t2 Interestingly this (asalso evi*ent in the alen*ronate cohort o- Greenspan et al2an* (ith 1oth alen*ronate an* *enosuma1 treatments in areport on postmenopausal (omen 1y #ec$ et al28&,9 Thegreater e--ect may have something to *o (ith the interac4tion 1et(een treatment an* loa* response at that highlystresse* site an* may 1e (orthy o- -urther stu*y2

This is the -irst stu*y o- this $in* that inclu*e* multi4racialJethnic groups2 This paper is also uni7ue in its stu*y

population interventions measurements an* longitu*inal


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FI:) 2) Pre*icte* pro+imal -emur geometry 1y intervention 1ase* on the ran*om e--ects mo*el 8mean an* /E92 SPre*icte* value isthe pre*icte* mean o- H/A measurement 1ase* on the ran*om e--ects mo*el2 -i+e* e--ects parameters ran*om e--ects parameterse resi*ual error2 Q p @ ;2;, QQ p @ ;2;!2

analysis approach -or evaluating e--ects on -emur geometryin a large cohort o- postmenopausal (omen2

Study limitations

ur primary interest (as in *elineating treatment e--ectson -emur geometry 1ut there are limitations to the D?A4

1ase* metho*ology -or that purpose2 #ecause the geometryis *erive* -rom a %D image the metho* can only evaluateresistance to 1en*ing in the plane o- the D?A image an*one cannot 1e certain that treatment e--ects are e7uivalent(ith respect to 1en*ing in other *irections2 Di--iculties inachieving consistent positioning o- the -emur in that planema$e the metho* relatively imprecise2 8&.9 Although (esuspect that hormone therapy has a small suppressive e--ecton periosteal apposition the imprecision o- this metho* isli$ely 1ehin* our ina1ility to *e-initively conclu*e thatthis is so2 ne possi1le con-oun*er is that the H/A algo4

rithms assume that 1one tissue minerali3ation is that o- normal a*ult 1one tissue an* this may have an e--ect on theresults2 The magnitu*e o- the e--ect o- hormone therapy onmean tissue minerali3ation 1ase* on 1iopsy *ata seems to

1e small 8&09 1ut i- -emurs o- untreate* postmenopausal(omen are un*erminerali3e* the H/A metho* may over4estimate the geometric change cause* 1y treatment2 otethat the minerali3ation e--ect (oul* not in-luence treatmentchanges in outer *iameter or location o- the centroi* (hich*o not re7uire the assumption2

We shoul* also point out that e+perience (ith H/A inlarge o1servational stu*ies in*icate that pre*ictive mo*elsusing -emur geometry only e7ual the per-ormance o- #>Don the same population2 8!. !09 The pro1lem (ith #>D is itis nonspeci-ic 1ecause a given value may 1e pro*uce* 1yseveral *i--erent un*erlying -actors2 Furthermore #>D has

1een -ar less use-ul in treatment monitoring than in -racture pre*iction2 8& & 9The H/A metho* e+ten*s the value o- theD?A *ata 1y provi*ing mechanical insights into the un*er4lying e--ects that alter the #>D as (ell as into the changesin 1one tissue *istri1ution that are not evi*ent in #>D2

The stu*y sho(e* that 1oth E4alone an* E : P signi-i4cantly improve* -emur strength as estimate* -rom hipstruc4 ture analysis in age an* ethnically *iverse

postmenopausal (omen *uring an intervention lasting ,yr2 Intervention e--ects (ere very similar 1et(een the t(ohormone trials although the stu*y participants *i--ere* insome 1aseline characteristics an* in 1aseline #>D an*

-emur geometry2 With multiple time points o- measurements *uring the in4 tervention this stu*ysho(e* that the magnitu*e o- the hormone interventione--ects on hip geometry may vary (ith time as suggeste*

1y a signi-icant interaction term o- interventionassignment an* years o- intervention2 ever4 theless the*i--erences in rates o- changes (ere small 1e4 t(een time

points an* shoul* 1e interprete* (ith caution2 We (erea1le to e+amine a large num1er o- covariates inclu*ingage raceJethnicity #>I 1aseline hormone use an* 1o*ycomposition as con-oun*ing -actors an* e--ect mo*i-iers2The results -rom this stu*y in*icate that the in4


10/12

tervention e--ects o- hormones on -emur geometry (erenot signi-icantly con-oun*e* or mo*i-ie* 1y thesecovariates in this WHI cohort2

+onclusions

A geometric assessment o- the e--ects o- hormone inter4vention on the pro+imal -emur in*icate* signi-icant in4creases in the amount o- 1one tissue in measure* cross4sections that shoul* improve resistance to a+ially *irecte*loa*s2 There (ere also signi-icant treatment e--ects on thescan plane *istri1ution o- that tissue2 >e*ial shi-ts in thecenter o- mass associate* (ith pre-erential 1one loss onlateral sur-aces (ere reverse* (ith treatment2 This ha*

positive e--ects on resistance to 1en*ing loa*s an* on esti4mates o- suscepti1ility to local 1uc$ing2 We (ere only a1leto *etect suppresse* periosteal apposition 1y hormonetherapy at the pro+imal -emur sha-t 1ut not at the narro(nec$ an* intertrochanter regions (here the e--ect might-urther re*uce 1uc$ling suscepti1ility2 verall there (ere

positive e--ects o- hormone therapy on the structure o- the-emur un*erlying the changes in #>D2

AC6NO;LED:MEN S

This stu*y (as -un*e* 1y IA>/J IH5 ;! A ;)=)!!2

REFERENCES

!2 An*erson G' 'imacher > Assa- A #ass-or* T #eres-or*/A #lac$ H #on*s D #runner #r3ys$i Caan #Chle1o(s$i Cur1 D Gass > Hays " Heiss G Hen*ri+ /Ho(ar* # Hsia " Hu11ell A "ac$son "ohnson UC "u**H Uotchen "> Uuller ' 'aCroi+ AZ 'ane D 'anger D'asser 'e(is CE >anson " >argolis U c$ene "

’ /ullivan >" Phillips ' Prentice ' iten1augh C o14 1ins " ossou( "E /arto G /te-anic$ >' an Horn 'Wacta(s$i4Wen*e " Wallace Wassertheil4/moller / %;;)E--ects o- con6ugate* e7uine estrogen in postmenopausal(omen (ith hysterectomy5 The Women ’ s Health Initiativeran*omi3e* controlle* trial2 "A>A 2+1( !0;!

%2 ossou( "E An*erson G' Prentice ' 'aCroi+ AZUooper1erg C /te-anic$ >' "ac$son D #eres-or* /AHo(ar* # "ohnson UC Uotchen "> c$ene " %;;% is$san* 1ene-its o- estrogen plus progestin in healthy postmeno4

pausal (omen5 Principal results From the Women ’ s HealthInitiative ran*omi3e* controlle* trial2 "A>A 288( &%!' >argolis U' %;;, Post4menopausal hormone therapy an* 1o*y compositionVa su14stu*y o- the estrogen plus progestin trial o- the Women ’ sHealth Initiative2 Am " Clin utr 82( .,! Goo*paster #H evitt >C Tylavs$y FAHarris T# %;;, Estrogen replacement muscle compositionan* physical -unction5 The Health A#C /tu*y2 >e* /ci /portsE+erc 3-( !0)!

.2 aessen T 'in*mar$ # 'agerstrom C 'arsen HC Persson I%;;0 Early postmenopausal hormone therapy improves pos4tural 1alance2 >enopause 15(!)

02 aessen T 'in*mar$ # 'arsen HC !==0 #etter postural 1al4ance in el*erly (omen receiving estrogens2 Am " 1stet Gy4necol 1--( )!%iner es 18(!0 !

!;2 Greenspan /' #ec$ T" esnic$ > #hattacharya Par$er A %;;, E--ect o- hormone replacement alen*ronate or

com4 1ination therapy on hip structural geometry5 A &4year*ou1le4 1lin* place1o4controlle* clinical trial2 " #one

>iner es20( !,%,

!!2 usi4 asi U #ec$ T" /emanic$ '> Daphtary >> CransGG Desaiah D Harper UD %;;. /tructural e--ects o- ralo+i4-ene on the pro+imal -emur5 esults -rom the multiple out4comes o- ralo+i-ene evaluation trial2 steoporos Int 1-( ,0,< , .2

!%2 usi4 asi U /emanic$ '> Zanchetta " #oga*o CE Eri$4sen EF /ato > #ec$ T" %;;, E--ects o- teriparati*e MrhPTH8!4&)9Otreatment on structural geometry o- the pro+imal -emur in el*erly osteoporotic (omen2 #one 3iner es1artin # #urr D# != ) on4invasive measurement o- long 1one cross4sectional moment o- inertia 1y photon a1sorptiom4etry2 " #iomech 1-( !=,C De 'aet CE Ho-man A itter4lin*en AG #ec$ T" Pols HA %;;0 Femoral nec$ #>D is astrong pre*ictor o- hip -racture suscepti1ility in el*erly menan* (omen 1ecause it *etects cortical 1one insta1ility5 The

otter*am /tu*y2 " #one >iner es 22(!0 !

%;2 Patterson E Uristal A Coates " Tylavs$y FA iten4 1augh C an Horn ' Caggiula AW /netselaar ' !==. 'o(4-at *iet practices o- ol*er (omen5 Prevalence an* implications-or *ietary assessment2 " Am Diet Assoc +A2-%)2 Uomulainen > Uroger H Tuppurainen >T Hei$$inen A>Alhava E Hon$anen "urvelin " /aari$os$i / !=== Preven4tion o- -emoral an* lum1ar 1one loss (ith hormone replace4ment therapy an* vitamin D& in early postmenopausal (omen5A population41ase* ,4year ran*omi3e* trial2 " Clin En*ocrinol>eta1 85( ,).


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meta1olism2 A place1o controlle* %4year prospective trial ont(o estrogen4progestin regimens in healthy postmenopausal(omen2 >aturitas 2%.2 "aco1sen DE /amson >> Ue3ic / erhaar H" %;;0 Post4menopausal H T an* ti1olone in relation to muscle strengthan* 1o*y composition2 >aturitas *8(0

%02 Frost H> !==. Perspectives5 A propose* general mo*el o- theSmechanostat 8suggestions -rom a ne( s$eletal41iologic para4*igm92 Anat ec 255( !&=

% 2"arvinen T' Uannus P /ievanen H %;;& Estrogen an* 1oneVa repro*uctive an* locomotive perspective2 " #one>iner es 18(!=%!

%=2 Frost H> !=== n the estrogen41one relationship an* post4menopausal 1one loss5 A ne( mo*el2 " #one >iner es15(!)0&

&;2 #a$$er AD Ulein4 ulen* " Tanc$ E Al1ers GH 'ips P#urger EH %;;, A**itive e--ects o- estrogen an* mechanicalstress on nitric o+i*e an* prostaglan*in E% pro*uction 1y 1onecells -rom osteoporotic *onors2 steoporos Int 1&,2 #ec$ T" 'e(iec$i E> >iller PD Felsen1erg D 'iu L Ding# 'i1anati C %;; E--ects o- *enosuma1 on the geometry o- the pro+imal -emur in postmenopausal (omen in comparison(ith alen*ronate2 " Clin Densitom 11( &,!eunier P" %;;,In-luence o- estrogen therapy at conventional an* high *oses

on the *egree o- minerali3ation o- iliac 1one tissue5 A 7uanti4tative microra*iographic analysis in postmenopausal (omen2#one 3ari9ona>edu

eceive* in original -orm >arch != %;; revise* -orm "une !;%;; accepte* "uly %, %;; 2

A ENDI= 1( :LOSSAR> OF ERMS

Ce% ro!$( location o- the center o- mass o- the har* tis sue in thecross4section an* (here 1en*ing stresses are 3ero 8also calle*neutral a+is9 measure* 1y H/A -rom the mineral mass pro-ile2

se* in computing the C/>I an* /> 1ut also use-ul in evaluat4ing the symmetry o- a cross4section 1ecause -ragile an* ITcross4sections are more asymmetric 1ecause o- greater *i--erencesin cortical thic$ness on opposite margins2

Cro""?"e/ !o% l re @CSA ( total 1one sur-ace in a cross4section e+clusive o- so-t tissue spaces an* pores2 Forces *irecte*

along a long 1one 8a+ial -orces9 are *istri1ute* over the C/Ahence a+ial compressive stress varies inversely (ith C/A2

Cro""?"e/ !o% l mome% o !%er ! @CSMI (The cross4sectionalsur-ace (eighte* 1y the s7uare o- *istance -rom the center o- masso- the cross4section2 #en*ing stress (ithin a cross4section *epen*sinversely on the C/>I *ivi*e* 1y the *istance -rom the center o- mass2

:eome r!/ " re% #( that component o- strength that governsstresses an* not the a1ility o- the material to (ithstan* them

8(hich currently cannot 1e measure* 1y noninvasive metho*s92 Ametho* that evaluates only geometry 8H/A an* CT41ase* meth4o*s9 can only assess geometric strength2

:eome r& or " ru/ ur l eome r&( the *imensions o- the sup4 porting material (ithin an o16ect e+presse* in engineering termsespecially (ithin cross4sections2

Lo/ l bu/ l!% ( A -ailure mo*e (here thin relatively -lat re4gions o- a structure un*er compressive loa*s may 1en* 8-ol* or crumple9 locally lea*ing to complete -ailure2

Se/ !o% mo$ulu" @SM ( ma+imum 1en*ing stress in a cross4sectionis locate* at ma+imum *istance -rom the center o- mass 8*ma+ 9 an*is thus inversely relate* to the /> (here /> C/>IJ* ma+ 2

S re% #(the loa*ing -orce applie* un*er a speci-ic con*itionthat causes internal stresses to e+cee* the material limits2 T(omaterial en*points are commonly use*5 ultimate strength is the-orce that causes complete material -ailure (hereas yiel* strengthis the -orce that causes permanent material *amage to initiate2

The latter is usually use* in pre*ictive mo*els 1ecause o- the largevaria1ility in 1ehavior o- comple+ o16ects li$e 1ones 1et(eenyiel* an* complete -ailure2

S re""( -orce concentrations 8per unit area9 (ithin an o16ect-rom applie* loa*s2 Types o- stress 8i2e2 tension compressiontorsion an* shear9 *epen* on ho( loa*s are applie* 1ut magni4tu*es *epen* entirely on geometry o- the o16ect2

A ENDI= 2( SHOR LIS OF ;HIINVES I:A ORS

Program --ice5 8 ational Heart 'ung an* #loo* Institute#ethes*a >D9 Eli3a1eth a1el "ac7ues ossou( /hari 'u*4lam 'in*a Pottern "oan >cGo(an 'eslie For* an* ancyGeller2

Clinical Coor*inating Center 8Fre* Hutchinson Cancer esearchCenter /eattle WA95 oss Prentice Garnet An*erson An*rea'aCroi+ Charles '2 Uooper1erg uth E2 Patterson Anne >c4Tiernan 8Wa$e Forest niversity /chool o- >e*icine Winston4/alem C9 /ally /huma$er 8>e*ical esearch 'a1s Highlan*Heights UL9 Evan /tein 8 niversity o- Cali-ornia at /an Fran4cisco /an Francisco CA9 /teven Cummings2Clinical Centers5 8Al1ert Einstein College o- >e*icine #ron+

L9 /ylvia Wassertheil4/moller 8#aylor College o- >e*icineHouston T?9 "enni-er Hays 8#righam an* Women ’ s HospitalHarvar* >e*ical /chool #oston >A9 "oAnn >anson 8#ro(n

niversity Provi*ence I9 Annlouise 2 Assa- 8Emory niver4sity Atlanta GA9 'a(rence Phillips 8Fre* Hutchinson Cancer

esearch Center /eattle WA9 /hirley #eres-or* 8George Wash4ington niversity >e*ical Center Washington DC9 "u*ith Hsia8'os Angeles #iome*ical esearch Institute at Har1or4 C'A>e*ical Center Torrance CA9 o(an Chle1o(s$i 8Uaiser Per4

manente Center -or Health esearch Portlan* 9 EvelynWhitloc$ 8Uaiser Permanente Division o- esearch a$lan*CA9 #ette Caan 8>e*ical College o- Wisconsin >il(au$ee WI9"ane >orley Uotchen 8>e*/tar esearch InstituteJHo(ar* ni4versity Washington DC9 #ar1ara 2 Ho(ar* 8 orth(estern

niversity ChicagoJEvanston I'9 'in*a an Horn 8 ush >e*i4cal Center Chicago I'9 Henry #lac$ 8/tan-or* Prevention e4search Center /tan-or* CA9 >arcia '2 /te-anic$ 8/tate niver4sity o- e( Lor$ at /tony #roo$ /tony #roo$ L9 Dorothy'ane 8The hio /tate niversity Colum1us H9 e1ecca "ac$4son 8 niversity o- Ala1ama at #irmingham #irmingham A'9Cora E2 'e(is 8 niversity o- Ari3ona TucsonJPhoeni+ AZ9Tamsen #ass-or* 8 niversity at #u--alo #u--alo L9 "ean Wac4

mailto:[email protected]:[email protected]


12/12

ta(s$i4Wen*e 8 niversity o- Cali-ornia at Davis /acramentoCA9 "ohn o11ins 8 niversity o- Cali-ornia at Irvine CA9 F2Allan Hu11ell 8 niversity o- Cali-ornia at 'os Angeles 'os An4geles CA9 Ho(ar* "u** 8 niversity o- Cali-ornia at /an Diego'a"ollaJChula ista CA9 o1ert D2 'anger 8 niversity o- Cin4cinnati Cincinnati H9 >argery Gass 8 niversity o- Flori*aGainesvilleJ"ac$sonville F'9 >arian 'imacher 8 niversity o- Ha(aii Honolulu HI9 Davi* Cur1 8 niversity o- Io(a Io(aCityJDavenport IA9 o1ert Wallace 8 niversity o- >assachu4settsJFallon Clinic Worcester >A9 "u*ith c$ene 8 niversity o- >e*icine an* Dentistry o- e( "ersey e(ar$ "9 orman

'asser 8 niversity o- >iami >iami F'9 >ary "o ’ /ullivan8 niversity o- >innesota >inneapolis > 9 Uaren >argolis8 niversity o- eva*a eno 9 o1ert #runner 8 niversityo- orth Carolina Chapel Hill C9 Gerar*o Heiss 8 niversityo- Pitts1urgh Pitts1urgh PA9 'e(is Uuller 8 niversity o- Ten4nessee >emphis T 9 Uaren C2 "ohnson 8 niversity o- Te+asHealth /cience Center /an Antonio T?9 o1ert #r3ys$i 8 ni4versity o- Wisconsin >a*ison WI9 Gloria E2 /arto 8Wa$e For4est niversity /chool o- >e*icine Winston4/alem C9 Denise

#on*s 8Wayne /tate niversity /chool o- >e*icineJHut3el Hos4 pital Detroit >I9 /usan Hen*ri+2

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