1{
;.~
-ORIGINAL
CONTRIBUTION
Reduction
of Vertebral
Fracture
Risk
in Postmenopausal
Women
With
Osteoporosis
Treated With Raloxifene
ResultsFrom a 3- Year Randomized Clinical Trial
Bruce Ettinger,
Dennis
MD
M. Black,
Context
Raloxifene hydrochloride,
a selective estrogen receptor modulator,
prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these
women is not known.
PhD
Bruce H. Mitlak, MD
Ronald K. Knickerbocker,
Thomas
Nickelsen,
Objective
To determine the effect of raloxifene therapy on risk of vertebral
vertebraf fractures.
PhD
Design
The Multiple Outcomes of Raloxifene
center, randomized, blinded, placebo-controlled
MD
-
Hacry
K. Genant.
MD
Claus
Chcistiansen,
Pierre D. Delmas, MD, PhD
MD
Jacob Stakkestad, MD
Claus
C. Glüer,
---
Kathryn
Krueger,
J. Cohen,
Stephen Eckert,
Kristine
MD
PhD
MD, MPH
Paul Lips, MD, PhD
Steven R. Cummings,
MD
for the Multiple Outcomes of
Raloxifene Evaluation
(MORE)
Investigators
R
ALOXlFENE
a
HYDROCHLORIDE
nonsteroidal
15
benzothia-
phene that binds ta estrogen
receptars and inhibits bone resorption without stimulating the uterine endametrium in pastmenapausal
women.1 However, the effect of raloxifene on the risk of fracture is not knawn.
Observational studies in postmenapausaI women have suggested that langterm estragen therapy reduces the inciFor
-
editorial
comment
a multi-
Main Outcome
Measures
Incident vertebral fracture was determined radiographica//y at baseline and at scheduled 24- and 36-month visits. Nonverteoral fracture was
ascertained by interview at 6-month-interim
visits. Bone mineraI density was determined annually by dual-energy x-ray absorptiometry.
MD
E. Ensrud,
study,
Interventions
Participants were randomized to 60 mg/d or 120 mg/d of raloxif~ne
or to identica//y appearing placebo pills; in addition, aIl women received supplemental
calcium and cholecaJciferol.
PhD
Fredric
(MORE)
Setting and Participants
A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health
Organization criteria for having osteoporosis. The study began in 1994 and had upto
36 months of follow-up for primary efficacy measurements and nonserious adverse
events and up to 40 months of follow-up for serious adverse events.
MD
Jose R. Zanchetta,
Evaluation
trial.
and non-
see
p 687.
Results
At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%)
had at least 1 new vertebral fracture, including 10.1% of women receiving placebo,
6.6% ofthose receiving 60 mg/d of raloxifene, and 5.4% of th ose receiving 120mg/d
of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving
raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [Cl],
0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of
nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95 %
CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene
increased bone mineraI density in the femoral neck by 2.1% (60 mg) and 2.4% (120
mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P<0.001 for aIl comparisons). Women receiving raloxifene had increased risk of venous thromboembolus
vs
placebo (RR, 3.1 ; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast
pain and was associated with a lower incidence of breast cancer.
Conclusions
In postmenopausal women with osteoporosis, raloxifene increases bone
minerai density in the spine and femoral neck and reduces risk of vertebral fracture.
JAMA. 1999;282:637-645
dence of fracture!.)
but the efficacy
ofestrogen in reducing fractures has been
demonstrated in only 1 small prospective study... In addition, in the US Breast
Cancer Prevention TriaI,~ tamoxifen ci-
@1999I\mcrican \ledical ;\ssociation. Ail rights rescl.ed.
www.jama.com
Author r\lflllatlons, Flnanclal Disclosures, and a Ils!
of the MORE investlgators are listed at the end of this
article
Corresponding Author and Reprints: Bruce Ettinger ,
MD, Division of Research, Kaiser Permanente Medical Care Program, 3505 Broadway, 13th Floor, Oakland' CA 94611-5400 (e-mail: bxeOdor.kaiser.org).
JAMA, August 18, 1999-Vol
282, No 7
637
EFFECT OF RALùXIFENE
stuc.lygroup 2. the baseline radiographs
were scored using :1 semiqu:1ntitative
scalco.7for each vertebra (T-+-L-+). The
grading scores were set as O for none, 1
for mild, 2 for moderate, and 3 for severe fractures. After 36 months. a radiologist blinded to treatment group assignment graded the baseline and end
point radiographs using the same semiquantitative scale.6.7An incident fracture
was defined as a grade change of at least
1. If no fractures were detected after the
review ofbaseline and end point radiographs, the analysis stopped for that patient. For fractures observed at baseline
or end point, a second radiologist determined whether a fracture was present for
eachvertebra and also performed quantitative morphometry (with an incident
fracture defined as a decrease in anterior ,
mid, or posteriorvenebral height of at least
20% and at least 4 mm). Vertebral fractures were scored when they were conf1rIned by at least 2 of the 3 types of determinations from 2 independent semiquantitative readings and 1 quantitative
assessment.A new venebral fracture was
defined as an incident fracture of a vertebra that was not fractured at baseline.
We defined clinical venebral fractures as
incident fractures found at interim
6-month visits through additional unscheduled radiographies perforJt:1edbecauseofback pain suggestive of fractures.
When incident fractures were adjudicated
from these nonscheduled radiographs,
they were counted as a clinical fracture
as weIl as an incident fracture.
Nonvertebral fractures were determined by direct questioning every 6
months at each clinic visit. Fractures resulting from a traffic collision, a beating, or having been struck by a falling
or moving object were considered traumatic and were excluded from the
analysis. ln addition, pathologic fractures and those involving the fingers.
toes, and skull were excluded.
Assessment
of Bone MineraI Density
Spine and femoral neck bone minera.
density were measured annually by
dual-energy x-ray absorptiometry .A
central reading facility provided cor-
rection factors to adjust for intersite differences and changes in the performance of the densitometers over time!ti
Participants were required to discontinue the study if at I year they had experienced a bone minerai density decrease of at least ï% in their lumbar
spine or 10% in their femoral neck; if
at 2 years they had experienced a lumbar spine decrease of at least II% or
femoral neck decrease of at least 14%;
or if at any time du ring the study. they
had experienced more than 2 incident
vertebral fractures.
Assessment
of Adverse Events
Mammography was performed at baseline, was optional at 1 year, but was required after 2 and 3 years. Transvagina! ultrasonography was performed at
baseline, annually at 17 large clinical
centers, and in others if clinically indicàted. A total of 1781 women had a
baseline and at least 1 postbaseline
transvaginal
ultrasonography.
AlI
women were questioned about the adverse effects of treatment at each visit;
al! serious adverse effects reported for
up to 40 months of follow-up and alI
nonserious adverse effects reported for
up to 36 months of follow-up were analyzed regardless of the investigators' assessments of causality. Adverse events
that resulted in death, hospitalization,
cancer, permanent disability. or threat
to !ife were classified as serious. The
Coding Symbol and Thesaurus for AdverseReaction Terminology (COSTARn9
dictionary was used to categorize reported adverse events. We report aIl catego ries of adverse events for which frequency was different (P<.O5) between
the placebo and combined raloxifene
groups and for \vhich the incidence was
at !east 2% in any group.
Biochemical Assessment
of Physiologic Functions
and Bone Turnover
Hematologic. renal, and hepatic function was tested periodically during the
study. Markers ofbone turnover.ïncludingserum osteocalcin (El.SAOSTEO, CIS
Biointemational, Gifsur Yvette, France)IO
and the urinary type 1 collagen C-
@1999 ..\mcrical1\lcdic:11 ,\sS()ciaTiol1.
Ail righls rcscrved
ON FRACTURE
RISK
telopeplidc excretion, corrected for uriru\ry crcalinine excretion ( Crossl4lps, 05teometcr .:VS,Herlev, Denmark)," were
measurcd in 2622 women who were enrolled at Sl)me sites in North America,
Europe, and South America.
StatisticaJ Analysis
The primary end points in each substudy were the effects of raloxifene on
incident vertebral fractures and bone
minerai density; a secondary end point
was any nonvertebral
fracture. The
sample si=e provided a greater than 90%
power (2-tailed t test, P<.05 significance level) to detect a 40% reduction
in vertebral fractures between pooled
raloxifene doses and placebo. Power
calculations were based on the assumptions that after 3 years, the cumulative
incidence of osteoporotic venebral fractures among women receiving placebo would be 7.2% for those free of
venebral fracture at baseline and 19.5%
for those \vith 1 or more fractures at
baseline. On the basis of observed incidence of vertebral fractures in the placebo group, the study's power was
slightly greater than predicted.
We included only women who had
incident fractures in vertebrae that were
not fractured at baseline. We examined 12 categories of nonvertebral fracture: humerus, wrist, hip, patella, tibia/
fibula, ankle, metatarsal, riblstemum,
clavicle, scapula, sacrum, and pelvis.
Using log-rank tests, we compared the
time to first occurrence of nonvertebrai fracture betWeen the raloxifene and
placebo groups. Adverse effects were
analyzed using X2 tests. AlI analyses
were performed as intention to treat (ie,
participants were classified according
to their substudy group and treatment
assignment
regardless of compliance). Missing postbaseline data were
imputed by carrying forward the last observation. AlI comparisons were 2 sided
and were performed at a P = .05 level
of significance. No adjustments were
made for multiple comparisons. The
number needed to treat \vas calculated as the reciprocal of the difference in venebral fracture incidence between treatment and placebo.
JAMA, Auj(uSI 18, 1999-Vol
282. No
639
Adverse Effects
After 36 months, 24.2% of the women
had serious adverse effects regardless of
treatment group. Venous thromboembolic events, including deep vein thrombophlebitis and pulmonary embolism,
were the only serious adverse effects believed to be causally related to raloxifene treatment; by 40 months. venous
Figure
2. Reduction
in New Vertebral
thosc adverse events experienced byat
least 2'Yoof the women in each group
and those for which the numbers and
percent;lges of women experiencing adverse events in the combined raloxifene groups differed from the placebo
group (P<.05). Vaginal bleeding was
reported by 62 (3.1%), 67 (3.4%), and
56 (2.8%) of \vomen in the placebo, the
60 mg of raloxifene, and the 120 mg of
raloxifene groups, respectively. In addition. the proportion of women reporting breast pain did not differ among
groups (data not shown).
A total of ï5-J. women (9.8%) withdrew from the study due ta an adverse
event: 527 women (10.3%) in the raloxifene groups and 227 women (8.8%)
in the placebo group (P = .04). Hot
Fractures Among
6828 Women
Who
Completed
0.5(95%
CI. 0.4.0.6)
the Study
RA,
I
I
Bone Minerai Density
and Bone Turnover
Compared with bone minerai density
in the placebo group, bone minerai density increased after 36 months by 2.1 %
and 2.6% at the femoral neck and spine
in the 60-mg raloxifene group and by
2.f% and 2.7% at the femoral neck and
spine in the 120-mg raloxifene group,
respectively (P<.001, alI comparisons) (FIGURE.. ) .In the raloxifene
groups, bone density of the hip peaked
at 2f months, and spinal density remained constant betWeen 2 and 3 years.
A total of 94 women (3.6%) assigned
to the placebo group, 28 (1.1%) assigned to the 60 mg of raloxifene group,
and 22 (0.9%) assigned to the l20 mg
of raloxifene group withdrew from the
study for having multiple fractures or
for excessive bone minerai density IO55,
a predefined study end point (P<.001
for each raloxifene dose vs placebo).
The median baseline serum osteocalcin concentration was 2...1 J.lg/L,and urinary excretion of C-telopeptide was 2..8
\,lg/rnmol of creatinine. After 36 months,
the serum osteocalcin concentrations decreasedbya median of8.6%, 26.3%, and
31.1%, and the urinary C-telopeptide excretion decreased by 8.1 %, 34.0%, and
31.5% in the placebo, the 60 mg of raloxifene, and the 120 mg of raloxifene
groups, respectively (P<.001 for each
raloxifene dose vs placebo).
thromboembolic
events had been reported by 8 (0.3%), 25 (1.0%), and 2-f
(1.0%) of alI patients in the placebo, the
60 mg of raloxifene, and the 120 mg of
raloxifene groups, respectively (RR, 3.1;
95% CI, 1.5-6.2 for both raloxifene
groups combined vs placebo).
Breast cancer was less frequent in the
women receiving raloxifene. By -f0
months, 54 women had a confirmed diagnosis of breast cancer (RR, 0.3; 95%
CI, 0.2-0.6 for both raloxifene groups
combined vs placebo). Ten women had
endometrial cancers: 4 in the placebo
group, 4 in the 60 mg of raloxifene group,
and 2 in the l20 mg of raloxifene group.
A total of 83 adverse effects occurred in at least 2% of the women in
any treatment group. TABLE41ists only
25,
pooled raloxifene groups (RR, 0.9; 95%
Cl.O.8-1.1) (TABLE) and FIGURE)). The
analyses of individual fracture sites for
pooled raloxifene groups and placebo
showed 237 wrist, 62 ankle, and SB hip
fractures.Among aIl 12 categories of nonvertebral fractures. only the ankle fracture risk reduction was statistic:lIly significant (Figure 3).
D
Placebo
.60
I
mgld
rI Rak>xj'..'e
HydrochkJlide
~
I
0.7 (95%
I
j 20
.J:
...
1;
"
1::
~
.120
mgld
of Rek)x~ene
CI, 0.6-0.9)
I
HydrochkJrkje
1
I"
E
"
"O
ü
.5
~
~ 10,
..I
RR, 0.6 (95%
E
~
10
o.
o
~
Cf, 0.4-0.9)
,
AR,
,
0.5 (95%
I
CI. 0.3-0.7)
I
--,
Preexist.'g Froct~
No PreexistingFractures
--Wamen
dence
did ar did nat have vertebral
fracture
at the beginning
of study.
RR indicates
relative
nsk; Cl, confi-
interval.
Table 3. Nonvertebral
Fractures in 5129 Women
Therapy and 2576 Women Receiving Placebo
Receiving
Raloxifene
Hydrochloride
-
No. (%)ofWomen
Placebo
Nonvertebral
Wrist
---
Raloxifene
fracture
Relative Risk
(95% Cl).
09(0.8-1.1)
fracture
Ankle fracture
O.~lQ.~
Hip fracture
1.1
(0:!::.].:El
.Cl indicates
conrJdence
inteNal.
C1:>
1999..\mcrican Mcdic:ll r\sSociation. AIl rights rescr\.cd.
JAMA, AUgUSI 18. 1999-VoI282.
No.7641
-!-
EFFECT OF RALOXIFENE
observations that the effect of fracture
reduction is not clearlv related to the
increase in bone min~ral density,16.11
suggesting that other factors also contribu te to prevention of fractures. In-
ON FRACTURE
RISK
nificant reduction (RR, 0.6, 95% CI,
0.5-0.8) in the risk of vertebral and nonvertebral fracture, but the study did not
report this subgroup's risk for nonvertebral fracture only. I-I Based on the ob-
Dllring sllrveillance of the uterus by
ultrasonography, about I in 12 of the
women stlldied were round to have at
least trace amounts of fluid in the endometrial cavity .In previous stUdies, endeed. lower bone turnover in elderly
served rate of fractures in the placebo
dometrial fluid was detected in 6% to
women is associated \vith decreased risk
group, our study had 80%, 38%, and
ll% or asymptomatic postmenopausal
of hip fracture independent of bone
12% power to detect a 20% reduction in
women in the absence of associated padensity.16.li
risk (placebo vs pooled raloxifene
thology.2...2S0rthewomen round to have
We did not observe a significant re- groups) in total nonspine, wrist, and hip
endometrial fluid, 52 (31%) had underduction in nonspine fractures after 3
fractures. respectively. However, there gone an endometrial biopsy; none of the
years. However, the cumulative inciwas a greater number of women rewomen treated with raloxifene were
dence curves for nonvertebral fractures
moved from the placebo group beround to have endometrial hyperplasia
begin to diverge after about 2 years. AIcause of rapid bone loss or multiple veror endometrial carcinoma. Thus, raloxthough this trend was not significant at
tebral fractures during the trial. Because irene-associated endometrial fluid ac3 years, the MORE study is continuing
these women were at high risk of noncumulation appears to be clinically unfor another vear to assess the effects of
vertebral fractures. their removal may
important. The study was not designed
4 years of raÎoxifene treatment.
have decreased the ability to detect a sta- or powered to examine effects of raloxOnly a few other agents have been
tistically significant effect.
ifene on endometrial cancer. The adtested for their effects on nonvertebral
The women receiving raloxifene had
verse events of leg cramps and periphfractures, and few studies have been prian increased incidence of venous thromeral edema were also reported more
marily designed to evaluate the effect of
boembolic events compared with the
rrequently in the women given raloxitreatment on a specific nonvertebral frac- women receiving placebo. Overall, the
fene; these symptoms have also been reture such as the hip.18.19A combination
RR for venous thromboembolic events ported in women receiving estrogen reof calcium and cholecalciferol bas been
was approximately 3, which is compaplacementtherapy.26
shown to significanùy reduce the risk of
rable to that reported for postmenoWe conclude that 3 years of raloxinonvertebral fractures in elderly wompausaI women receiving estrogen
fene treatment preserves bone density ,
en 18and elderly men. 18.19
In the MORE
therapy in obse"rvational studies!I-13 for
reduces bone turnover, and reduces the
trial, alI women received calcium and
those in a prospective trial of estrogen
incidence or venebral fractUres in POstcholecalciferol
supplements. which
therapy!O and for those receivingtamenopausal women with osteoporosis.
might have attenuated the risk of fracmoxifen for prevention of breast canDivision of Research, Kaiser pertures in both placebo and raloxifene
cer .~Breast cancer was statistically sig- Author AffilIations:
manente,
Oakland,
Calif (Dr Ettinger)
and Departgroups. Among 13388 women at high
nificanùy less frequent in the women
ments of Epidemiology
and Biostatistics(Drs
Black and
risk of breast cancer. a median of 4.5
receiving raloxifene. an effect similar to
Cummings),
Radiology (Dr Genant), and Medicine (Dr
Cummings),
Unive~ity
of CaJifomia, San Francisco; Eli
years of treatment with tamoxifen prothat reported for tamoxifen in the Breast
Lilly and Co, Indianapolis,
Ind (Drs Mitlak, Knickerduced a nonsignificant trend for reducCancer Prevention Trial.~
bocker, Nickelsen, Krueger, Cohen, and Eckert); Cention in risk of hip and wrist fractures.~
In the Hean and Estrogen/Progestin ReTable 4. Adverse Events With Incidence of at least 2% and Differing Significantly
placement Study (HERS) of 2705
for Women Receiving Raloxifene Hydrochloride
Than for Women Receiving Placebo
women with heart disease, those receivNo.(%)
ing estrogen and progestin for an aver.
d
.Placebo
Raloxitene. 60 mg/d
Raloxitene, 120 mg/d
p
age of 4 years
in nonvertebral
dld
not
fractures
show
a re
compared
uctlon
Adverse
Events
{n = 2576)
with
those receiving a placebo?O The Fracture Intervention TriaP2 reported that
2027 women with vertebral fractures
who were treated with alendronate had
a reduced risk of nonvenebral fractures. However. in a parallel4-year study
of 4272 women who had no vertebral
fracture, the reduction in risk of nonvertebral fracture with alendronate was
not statistically significant. A subset of
women with femoral neck t scores
belo\v -2.5 showed a statistically sig-
(n = 2557)
{n = 2572)
Value.
Raioxitene
Influenzasyndrome
Hot flashes
Legcramps
Peripheral
edema
Endometrial
cavityfluid*
293{11.4)
165(6.4)
96(3.7)
114{4.4)
43 (5.7)
; -~- .
'HypertenSIon
.
2~1J9.0)
Hypercholesterolemia
121 (4.7)
Hematuria
346{13.5)
249 i9.7)
178i7.0i
134{5.2)
60 iB.1i
.01
<.001
<.001
<.01
.02
~94 (7.5)
.01
<.001
<.01
Placebo
55(2.1i
17~(6.9)
55 (2.2)
35(1.4j
~(~
.Combned
raIoxifene groups VS placOOo.
tOnIy t-ot flashes di"ered significantly between 60 mg and 120 mg dosages
+Amon9 2262 women who had transva9nalldtrasonography.
@1999..\mcric:111
Mcdical c\ssociatiol1.Ali rights rcscn.ed.
345{13.4)
269 (11.6it
178(6.9)
168{6.5)
66 (8.7i
of raloxifene.
JAMA, AUgUSI 18, 1999-Vol
282, No.7643
/1
EFFECT OF RALO\!FENE
nata, MD, PhD, Hospital General De Asturias, Oviedo;
Fernando Escobar, MD, PhD, and Manuel Muiioz, MD,
Endocrine Unit Hospital Unive"ita!io
$. Cecilio, Granada;
Jardi Farrerons, MD, PhD, Hospital De La Santa Creu I
San! Pau, and Adolfo Diez-Perez, MD, PhD, Hospital
Del Mar, Barcelona; and Federico Hawkins, MD, PhD,
Ho~pital12
De Octubre,
Madrid.
Sweden.
Sverker
L/unghall, MD, and Karin La"son, MD, Acadernic Hospital Uppsala; Dan Mellstr"m.
,"'D, PhD, Uppsala Uni:
ve"ity, Goteborg; Britt-Marie Nyhall-Wàhlin,
MD, and
Mats Palmér, MD, Uppsala University, Orebro; Goran
ross, MD, Uppsala University, Linkoping. United Kingdom' Richard Eastel', BSc, MB. ChB, The Osteoporosis
Centre,
University
of Sheffield;
Ignac Fogelman,
BSc,
MD, Guy's Hospital,
London; Robert Landray, MCCHB, Synexus Ltd; David W, Purdie, MB, ChB, MD, The
Un",ersity of Hull, Centre for Metabolic
Bone Disease;
David M, Reid, MB, ChB, MD. University
of Aberdeen; lan Smith, BMS, MB, ChB, NHS Trust Royal Preston Hospital,
Lancashire;
BS, Llandough
Hospital,
States' Cora Lewis, MD,
Michael
D, Stone,
South Glamorgan.
MSPH, University
BA, MB,
United
of Ala-
bama, Birmingham,
and William J. Shergy, MD, Clinical Research Rheumatology
Associates, Ala; Robert C.
Biesbroeck, MD, Valley Endocrine Associates, PC, Mesa,
and Michael J. Maricic, MD, University of Arizona Health
Sciences Center, Tucson, Ariz; Thomas T. Aoki, MD,
Aoki Diabetes Research Institute, Sacramento,
Claude
D. Arnaud, MD, and Steven T. Harris, MD. University
of California, San Francisco, Elizabeth Ba"ett-Connor,
MD, University of California, San Diego, David J. Bay-
Irvine, Charles
F, Sharp, )r, MD, Huntington
Memorial
Hospital, Stuart l, Silverman, MD, University of California, los Angeles, West los Angeles-Veterans
Affairs Medical Center, Osteoporosis Medical Center; Frederick Singer, MD, John Wayne Cancer Institute at St
John's Health Center, Santa Monica, and Stuart R. Weiss,
MD, San Diego Endocrine and MedicaJ Clinic, San Diego,
Calif; David A. Podlecki, MD, longmont
Clinic, longmont, Colo; Robert lang, MD, Osteoporosis
Evaluation Center, Hamden, Conn; Mark P Ettinger, MD, Clinical Research Center of South Florida, Marvin A. Heuer,
MD, Florida Medical and Research Institute, and Silvina levis, MO, University of Miami; Nelson B. Watts,
MD, Emory University, Atlanta, Ga; Richard D. Wasnich,
MD, Hawaii Osteoporosis
Center, Honolulu;
Sheldon
Berger, MD, Chicago Center for Clinical Research, and
Murray J. Favus, MD, Unive~ity
of Chicago Medical
Center, Chicago, and Robert G. Trapp, MD, The Arthritis Center, Springfield,l1/; M. Rashid Khairi, MD, Physicians Research Group, Indianapolis,
and Randall R.
Stol!z, MD, GFI Research Center,lnd;
MD, University of Kansas, Kansas City;
MD, University of louisville,
Ky; Alan
ton Ochsner Clinic, New Orleans, la;
MD, Maine Center
cation, St )oseph's
Barbara P.lukert,
Christine l. Cook,
Bu~hell, MD, AIClifford ). Rosen,
for Osteoporosis Research and EduHospital, Bangor, Me; Michael A.
Bolognese,
MO, Osteoporosis
Analysis Center,
man S. Koval, MD, Centerfor
Rheumatologyand
NorBone
Research, Philip levin, MD, Greater Baltimore Medical Center, Baltimore, and Nathan Wei, MD, Arthritis
& Osteoporos~
Centerof Maryland, Frederick, Md; Robert M. Neer, MO, Massachusetts General Hospital, Boston; Kristine E. Ensrud, MD, Veterans Affairs Medical
link, MD, Musculoskeletal
Disease Center, Loma Linda
University and Pettis Veterans Affairs Medical Center,
Loma Linda, Bruce Ettinger,
MD, Division
of Research, Kaiser Permanente,
Oakland,
Richard O. Kamrath, MD, John Muir Health Network/The
Osteoporosis Center, Robert Marcus,
MD, Department
of
Veterans Affairs Medical
Center, Palo Alto, Sidney
University,
Omaha, liIeb; Keith S. Usiskin, MD, Morristown Memorial
Hospital, Morristown,
N); Arnold M.
Rosenblatt,
Moses,
MD,
The IIVine Clinical
Research
Center,
Center, Unive~ity
of Minnesota, MInneapolis;
louis V,
Avioli, MD, Washington
Unive~ity
School of Medicine, St louis, Mo; Robert R. Recker, MD, Creighton
MD,
State University
of New York Health
Sci-
ence Center,
Research
Center
erman,
ON FRACTURE
Louis L. Shane, MD,
Service, White
Physician's
Plains, Ethel Siris, MD,
RISK
Clinical
Irvine
to ClinlcJI Research, Jrvine, and Stuart WeinMD, North Shore University
Hospital,
NY;
MicheJle Hooper, MD, University
Hospitals of Cleveland, James H. Liu, MD,
University
of Cincinnati,
DJvid 8acha, MD, Crystal Arthritis
Center,
Akron,
Ohio; William C. Orr, PhD, Lynn HeaJth Science Insütute, Oklahoma
City, Okla; Jane A. Cauley,
MD,
DrPH, University of Pittsburgh,
Solomon Epstein, MD,
Allegheny
University of the Health Sciences, Allegheny, and Susan 8. Ward, MD, Jefferson Osteoporosis
Center, Jefferson, Pa; Joseph Tucci, MD, Roger Williams Medical Center, Providence,
RI; Norman
H. 8ell,
MD, Medical University of South Carolina,
Charleston, SC; William Applegate,
MD, and Suzanne Satterfield, MD, DrPH, University
of Tennessee, Memphis;
M. Cedars and Stanley 8. Cohen, MD, Metroplex
Clinical Research Center,
Dallas, Tex; Clarl< McKeever, MD, Research for Health/Health
Advance
Veronica K. Piziak, MD, PhD, Scott & White Clinic, Ju~
lio Rosenstock, MD, Dallas Diabetes Endocrine Center, Dallas, and Sherwyn L. Schwartz, MD, Diabetes &
Glandular
Disease Clinic, Tex; C. Deal and Robert
Downs,
MD, Virginia
Commonwealth
University,
Richmond;
8arbara Drinkwater,
PhD, Pacific Medical
Center, Seattle, Wash; and Noel8inkJey,
MD, university of Wisconsin Hospital & Clinics, Madison.
Contributions:
Erin Walls, ELS, assisted in preparaüon of the manuscript;
the Medical Ediüng Department, Ka;ser Foundation
Research Institute,
also provided editorial assistance.
Fundlng/Support:
The research was supported
by a
grant from Eli LiJIy and Cornpany.
Dlsclalmer:
Data were analyzed at Lilly Research Laboratories, El; Lilly and Co.
Acknowledgment:
We thank Ty McClure,
PhD, for
statistical programming
and Leo Plouffe, MD, for review and advice on the manuscript.
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(o 199~ ,\mCriî'a"
Mcdical .'\ss()ciatio". ,\Il rights r(,5"r\-cd
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Augusl
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!999-Vol
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