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Cauley JA, Robbins J, Chen Z, et al. Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density: The Women's Health Initiative Randomized Trial. JAMA. 2003;290(13):1729–1738. doi:10.1001/jama.290.13.1729
© 2019
Author Affiliations: Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa (Dr Cauley); Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento (Dr Robbins); Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman Arizona College of Public Health, University of Arizona, Tucson (Dr Chen); Research Institute at California Pacific Medical Center and Department of Epidemiology, University of California, San Francisco (Dr Cummings); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Ohio State University, Columbus (Dr Jackson); Women's Health Initiative Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr LaCroix and Ms Pettinger), Endocrine-Hypertension Division, Brigham and Women's Hospital, Boston, Mass (Dr LeBoff); Division of Preventive Medicine, University of Alabama at Birmingham (Dr Lewis); National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md (Dr McGowan); Department of Medicine and Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee (Dr Neuner); Stanford Center for Research in Disease Prevention, Department of Medicine, Stanford University, Palo Alto, Calif (Dr Stefanick); University at Buffalo, State University of New York, Buffalo (Dr Wactawski-Wende); and University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr Watts).
Context In the Women's Health Initiative trial of estrogen-plus-progestin therapy,
women assigned to active treatment had fewer fractures.
Objective To test the hypothesis that the relative risk reduction of estrogen
plus progestin on fractures differs according to risk factors for fractures.
Design, Setting, and Participants Randomized controlled trial (September 1993-July 2002) in which 16 608
postmenopausal women aged 50 to 79 years with an intact uterus at baseline
were recruited at 40 US clinical centers and followed up for an average of
5.6 years.
Intervention Women were randomly assigned to receive conjugated equine estrogen,
0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506)
or placebo (n = 8102).
Main Outcome Measures All confirmed osteoporotic fracture events that occurred from enrollment
to discontinuation of the trial (July 7, 2002); bone mineral density (BMD),
measured in a subset of women (n = 1024) at baseline and years 1 and 3; and
a global index, developed to summarize the balance of risks and benefits to
test whether the risk-benefit profile differed across tertiles of fracture
Results Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin
group and 896 women (11.1%) in the placebo group experienced a fracture (hazard
ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did
not differ in women stratified by age, body mass index, smoking status, history
of falls, personal and family history of fracture, total calcium intake, past
use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD
increased 3.7% after 3 years of treatment with estrogen plus progestin compared
with 0.14% in the placebo group (P<.001). The
HR for the global index was similar across tertiles of the fracture risk scale
(lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile,
HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24)
(P for interaction = .54).
Conclusions This study demonstrates that estrogen plus progestin increases BMD and
reduces the risk of fracture in healthy postmenopausal women. The decreased
risk of fracture attributed to estrogen plus progestin appeared to be present
in all subgroups of women examined. When considering the effects of hormone
therapy on other important disease outcomes in a global model, there was no
net benefit, even in women considered to be at high risk of fracture.
The Women's Health Initiative (WHI) trial of estrogen plus progestin
was a randomized, controlled, double-blind trial designed to determine the
effects of estrogen plus progestin compared with placebo on a number of important
chronic diseases of older women.1 After an
average follow-up of 5.2 years, the trial was stopped early because of safety
concerns. Hip and clinical vertebral fractures were significantly reduced
by 34% and total osteoporotic fractures by 24%. However, the overall risk-benefit
profile of estrogen plus progestin, summarized in a global index, was not
consistent with a viable intervention for primary prevention of chronic diseases
in postmenopausal women.
This article provides an updated final analysis of fracture end points
through the termination of the trial on July 7, 2002. We also tested the hypothesis
that the relative risk reduction of estrogen plus progestin on fracture differed
by risk factors for fracture. We report the lumbar spine and total hip bone
mineral density (BMD) outcomes for the subset of study participants undergoing
this assessment. Finally, we tested the hypothesis that the risk-benefit profile
of treatment with estrogen plus progestin differed across tertiles of fracture
Details of the WHI design are reported elsewhere.1,2 In
brief, 16 608 postmenopausal women with an intact uterus who were aged
50 to 79 years at baseline were randomized to either conjugated equine estrogen,
0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d, in a single tablet
(n = 8506) or placebo (n = 8102) and followed up for an average of 5.6 years
(Figure 1). Trial recruitment began
in September 1993 with the first randomization in December 1993. Follow-up
is ongoing, but the intervention was terminated approximately 3 years earlier
than planned because of an adverse effect on breast cancer and an excess risk
of events as determined by the global index assessment summarizing the balance
of risks and benefits.1 The protocol and consent
forms were approved by the institutional review boards of all participating
institutions and all women provided written informed consent.
Information on baseline risk factors for fractures was assessed in a
standardized manner by questionnaire, interview, and clinical examination.
Weight was measured on a balance beam scale while wearing indoor clothing.
Height was measured with a fixed stadiometer. Weight and height were used
to calculate body mass index (BMI; weight in kilograms divided by the square
of height in meters). Race/ethnicity categorization was based on self-declaration.
Information on falls, fracture history, family history of fracture, smoking,
alcohol consumption, and general health status was obtained by questionnaire.
Dietary calcium intake was assessed using a modification of the Block food
frequency questionnaire and expressed in milligrams per day.3 Information
on use of calcium supplements in the previous 2 weeks was obtained by an interviewer-administered
medication inventory. Total calcium intake was derived from the sum of dietary
and supplemental sources.
Information on medication use at baseline included use of estrogen,
progestin, thiazide diuretics, and thyroid medications. Participants were
asked to bring all medications, vitamins, and supplements to the clinic for
verification of current use. Information on past use of hormone therapy was
collected by questionnaire. Women were excluded if they reported use of tamoxifen.
Women using postmenopausal hormones at the initial screening could be enrolled
after a 3-month washout period. Information was collected on use of other
antiresorptive agents at baseline and follow-up years 1, 3, and 6. If a woman
initiated open-label use of hormone therapy or any selective estrogen receptor
modulator after randomization, she was required to discontinue study medications.
Reports of hip, vertebral, and other osteoporotic fractures except those
of the ribs, chest/sternum, skull/face, fingers, toes, and cervical vertebrae
were ascertained by a semiannual questionnaire. If a fracture was reported,
radiology reports were obtained. The initial report of the WHI estrogen-plus-progestin
trial was based on local adjudication.1 In
this report, hip fractures were centrally adjudicated. The agreement between
local and central adjudication for hip fracture was 94%. All other fractures
at clinical centers where BMD was not measured were locally adjudicated. All
adjudicators were blinded to treatment assignment. Fracture outcomes included
hip, wrist/lower arm, clinical vertebral, and total fractures.
In an attempt to summarize important aspects of health benefits vs risk,
a global index was created that included the earliest occurrence of coronary
heart disease, invasive breast cancer, stroke, pulmonary embolus, endometrial
cancer, colorectal cancer, hip fracture, or death due to other causes.1 Compared with total mortality, which may be relatively
insensitive, this index summarizes differences in the incidence of the 7 listed
diseases as well as other causes of mortality. The global index of these outcomes
played a supportive role in trial monitoring as the summary measure of the
overall balance of risks and benefits.
Bone mineral density of the lumbar spine (L2-L4), and total hip was
measured by dual x-ray absorptiometry (QDR 2000, 2000+, or 4500W, Hologic
Inc, Bedford, Mass) in 3 of the 40 US clinical centers (Pittsburgh, Pa, Birmingham,
Ala, and Tucson/Phoenix, Ariz). At these 3 BMD centers, women were excluded
if their femoral neck BMD was more than 3 SDs below the corresponding age-specific
mean (Z score ≤−3.0). Bone mineral density
was measured at baseline and years 1, 3, and 6. Because few women had yet
had BMD measured at year 6, our analyses are confined to measurements at baseline
plus years 1 and 3. The BMD clinical centers were chosen to provide maximum
racial diversity.
Standard protocols for positioning and analysis were used by technologists
who were trained and certified by the University of California, San Francisco
bone densitometry reading center. The ongoing quality assurance program was
similar to that used in other studies.4
All primary analyses used time-to-event methods and are based on the
intention-to-treat principle. Outcome comparisons are presented as hazard
ratios (HRs) and nominal 95% confidence intervals (nCIs) from Cox proportional
hazards analyses stratified by age, prior fracture history, and randomization
status in the low-fat diet and calcium/vitamin D trials of the WHI. The calcium/vitamin
D trial is a randomized clinical trial testing whether calcium and vitamin
D supplements decrease the risk of hip fracture. Equal proportions of women
in the estrogen-plus-progestin and placebo groups participated in the calcium/vitamin
D trial. Nominal 95% CIs are presented throughout except for the hip fracture
outcome, which was 1 of 7 outcomes monitored by the data and safety monitoring
board. To account for the multiple outcomes, we also present adjusted 95%
CIs (aCIs) for hip fracture, as was specified in the trial monitoring plan.
Because a substantial number of women (42% taking estrogen plus progestin
and 36% taking placebo) stopped taking their study medications at some point
during the follow-up period,1 we examined the
sensitivity of the HR estimates and BMD changes to actual use of study medications.
In these analyses, participants' outcome data were censored 6 months after
they became nonadherent (taking <80% of or stopping study drug or initiating
nonstudy hormone therapy). The mean follow-up time in the sensitivity analysis
was 3.7 years.
The effect modification of fracture risk with estrogen plus progestin
by potential risk factors was assessed by Cox proportional hazards analyses
with tests of interaction between the risk factor and treatment assignment.
Women were divided into groups based on age, race/ethnicity, BMI,5 history of fracture, past use of hormone therapy,
falls in the previous 12 months, parental history of fracture, and total calcium
intake. In a subgroup of women with BMD measurements (n = 1024), we also examined
strata defined by a T score of less than −2.5 at the lumbar spine, total
hip, or femoral neck using the National Health and Nutrition Examination Survey
reference database for the hip and the manufacturer's database for the spine.
The race/ethnicity and BMD stratifications were limited to total fractures.
We report nominal P values throughout. In this risk
factor analysis, we explored more than 100 subgroups and, by chance alone,
at least 5 would be expected to be statistically significant at the P = .05 level.
We developed a summary fracture risk score in the placebo group using
methods developed by Black et al.6 Their index
identified 20 fracture risk factors. We did not have hip BMD measurements
for all women, nor did we have information on use of arms to stand from a
chair, "4 or fewer hours on feet per day," or height at age 25 years. Our
summary fracture risk score used current height and included race/ethnicity.
Variables that were significant (P<.10) in the
individual age-adjusted logistic regression hip fracture models were entered
into a multivariable model and included age, nonblack race/ethnicity, prior
fracture after age 55 years, fall in past 12 months, current smoking, BMI
of 22.4 or less, and no walking for exercise. Age, prior fracture, current
smoking, and BMI were all significant (P<.05)
and were included in the final risk factor set. The summary fracture risk
score was computed as described by Black et al.6 Briefly,
using the additive properties of the logistic function, the coefficients from
the final model were multiplied by a constant, rounded to the nearest integer,
multiplied by each individual's risk factor values, and then summed. The area
under the receiver operating characteristic curve for the final model was
0.785 (95% CI, 0.73-0.84) for hip fracture, indicating moderate predictive
Absolute differences and percentage changes in BMD of the lumbar spine
and total hip from baseline to year 1 and to year 3 were calculated. We used
linear regression to compare the rates of change in BMD in women randomized
to estrogen plus progestin vs placebo in the entire population with BMD and
in medication-adherent women. We adjusted for clinic site and race/ethnicity.
To test whether the risk-benefit profile of estrogen plus progestin
differed in women according to their risk of hip fracture, we examined the
HR (95% CI) of the global index across tertiles of the summary fracture risk
score. All analyses were performed using SAS statistical software, version
8.02 (SAS Institute Inc, Cary, NC).
Baseline characteristics including risk factors for fracture were similar
in the 8506 women randomized to estrogen plus progestin and the 8102 women
in the placebo group (Table 1).
The mean age of the women was 63 years; 44% were older than 65 years. Examination
of risk factors for fractures revealed that 74% had no prior history of hormone
use; 10% were current smokers; 39% had a personal history of fracture; 12%
reported a maternal history of hip fracture; 33% reported at least 1 fall
in the previous 12 months; 14% had experienced at least 1 fracture after age
55 years; and 23% were considered to be at higher risk of fracture based on
our summary fracture risk score. Use of a bisphosphonate at baseline was low
(approximately 1%) but increased to about 6% among women in the estrogen-plus-progestin
group and to 10% among women in the placebo group by year 6. Use of raloxifene
and calcitonin was low in each group (<2%) by year 6.
In the subgroup of 1024 women with BMD measurements, there was no difference
in baseline BMD by treatment randomization (Table 1). Only 4% of women in the estrogen-plus-progestin group
and 6% of women in the placebo group were considered to have osteoporosis
at the total hip using World Health Organization criteria.7
We compared the characteristics of women in the BMD subsample with the
remaining women. As expected, there were larger proportions of nonwhite women
and women reporting never using hormones in the BMD subsample. This may have
reflected the lower prevalence of hormone use among minority women.8 Other risk factors for fracture, such as age and body
weight, did not differ.
A total of 733 women (8.6%) in the estrogen-plus-progestin group and
896 (11.1%) in the placebo group experienced a fracture during the follow-up
period of 5.6 years. There were 52 hip fractures in the treatment group and
73 in the placebo group. There were 189 lower arm/wrist fractures in the treatment
group and 245 in the placebo group; there were 41 clinical vertebral fractures
in the treatment group and 60 in the placebo group. Overall fracture rates
per 10 000 person-years in the estrogen-plus-progestin and placebo groups,
respectively, were: hip fracture, 11 and 16; wrist/lower arm, 44 and 62; clinical
vertebral, 11 and 17; and total fractures, 152 and 199.
Estrogen plus progestin reduced the risk of hip fracture by 33% (HR,
0.67; 95% nCI, 0.47-0.96; 95% aCI, 0.41-1.10) (Table 2). In subgroup analyses, estrogen plus progestin decreased
the risk of hip fracture by 60% among women who reported a baseline calcium
intake of more than 1200 mg/d but not among women with lower calcium intake
(P for interaction = .02). Estrogen plus progestin
reduced the risk of hip fracture in women with a BMI of less than 25 (HR,
0.50; 95% nCI, 0.28-0.90) and with a BMI of 25 to less than 30 (HR, 0.67;
95% nCI, 0.37-1.20) but not in women with a BMI of 30 or more; however, the
interaction of hormone therapy with BMI was not statistically significant
(P = .41). The risk of hip fracture was reduced by
estrogen plus progestin to a similar degree in women stratified by age, smoking,
fall and fracture history, past use of hormone therapy, parental fracture
history, years since menopause, and summary fracture risk score.
Hazard ratios for total fractures were also lower for women randomized
to estrogen plus progestin in virtually all subgroups examined and did not
differ from the overall HR (Table 3).
There was no significant interaction between treatment assignment and race/ethnicity
for total fractures. When participants were stratified by summary fracture
risk score, the annualized incidence of total fractures in the placebo group
was 1.3%, 2.0%, and 2.7% in the lowest, middle, and highest risk groups, respectively,
with similar HRs for total fractures (HR, 0.82; 95% nCI, 0.66-1.02 for the
lowest risk group; HR, 0.68; 95% nCI, 0.58-0.81 for the middle risk group;
and HR, 0.85; 95% nCI, 0.70-1.03 for the highest risk group) (Table 3). The HR for all nonspine fractures was 0.75 (95% nCI, 0.68-0.83).
The Kaplan-Meier estimates of cumulative hazards for each type of fracture
indicated that the differences between treatment groups began to develop soon
after randomization and implementation of the study medication (Figure 2). The difference in the cumulative incidence of fractures
between women assigned to estrogen plus progestin and those assigned to placebo
increased over time. The Kaplan-Meier curves suggest continuing beneficial
effects of estrogen plus progestin on fracture reduction throughout the observation
Exclusion of follow-up time for nonadherence had little effect on the
HRs (hip fracture, HR, 0.63; 95% nCI, 0.38-1.06; wrist/lower arm, HR, 0.67;
95% nCI, 0.54-0.84; vertebral fracture, HR, 0.60; 95% nCI, 0.38-0.95; total
fractures, HR, 0.72; 95% nCI, 0.64-0.81).
Estrogen plus progestin showed consistent positive effects on BMD. Total
hip BMD increased a mean of 1.7% during the first year of estrogen-plus-progestin
treatment and improved by 3.7% by year 3 compared with a loss of 0.44% at
year 1 and a 0.14% improvement at year 3 in the placebo group (P<.001) (Figure 3A). Similar
findings were observed at the lumbar spine (Figure 3B). After 1 year of hormone therapy, the mean percentage
change in BMD was 3.3% higher at the lumbar spine and 2.1% higher at the total
hip. After 3 years of treatment, the percentage difference in favor of hormone
therapy was greater, with mean differences of 4.5% and 3.6% at the lumbar
spine and total hip, respectively. A total of 194 (36%) women in the estrogen-plus-progestin
group and 249 (32%) in the placebo group had a year 6 BMD measurement. By
year 6, the percentage increase in lumbar spine BMD was 7.5% in women in the
estrogen-plus-progestin group compared with 2.6% in the placebo group. Sensitivity
analyses limited to adherent women revealed larger increases in BMD; the average
percentage increase in BMD from baseline to year 3 was 7.6% in the lumbar
spine and 4.5% in the total hip among women randomized to estrogen plus progestin
compared with 1.5% and −0.3%, respectively, among women randomized to
Among women in the lowest tertile of fracture risk based on our summary
fracture risk score, the global index HR was 1.20 (95% nCI, 0.93-1.58); in
the middle tertile of risk, the HR was 1.23 (95% nCI, 1.04-1.46); and in the
highest tertile of risk, the HR was 1.03 (95% nCI, 0.88-1.24). The interaction
between treatment effect and summary fracture risk on the global index was
not significant (P = .54). Thus, there was no evidence
of a net benefit, even in women at high risk of fracture.
The WHI estrogen-plus-progestin trial is the first randomized clinical
trial demonstrating that combination postmenopausal hormone therapy reduces
the risk of fractures at the hip, vertebrae, and wrist. These findings are
consistent with observational data9,10 and
several recent meta-analyses of the efficacy of hormone therapy in reduction
of fractures in postmenopausal women.11-13 Torgersen
and Bell-Syer12 reported a greater effect among
women younger than 60 years with little or no benefit observed among older
women. However, this conclusion was primarily based on one study in each age
group.14 In the WHI, we found no evidence that
the effect differed by age or time since menopause.
The overall benefit vs risk of estrogen-plus-progestin therapy is a
central focus of the WHI. Overall, the global index showed a nominally significant
15% increase in the estrogen-plus-progestin group, indicating more harm than
benefit in women randomized to hormone therapy.1 Since
estrogen plus progestin has shown a beneficial effect on fracture incidence,
there is interest in determining whether there might be a subgroup of women
at high risk of fracture for whom the benefits from estrogen plus progestin
would outweigh the risks. In the analyses described here, we found no evidence
that the efficacy of estrogen plus progestin differed according to any risk
factors for fractures, including age, BMI, smoking, history of falls, calcium
intake, personal and family history of fracture, and past use of hormones.
Risk factors for fracture were combined in a summary fracture risk score,
and we found that estrogen plus progestin reduced fractures to a similar degree
in women who were considered at low, medium, and high risk of fracture. Even
among women who were considered at high risk of fracture, the HR for the global
index did not indicate net benefit. These results imply that the benefit of
fracture reduction does not outweigh the risks of cardiovascular disease and
breast cancer, even in women at higher risk of fracture. In addition, the
fracture risk score gives substantial weight to increasing age, and another
analysis of WHI data found a 2-fold increase in dementia among women aged
65 years or older who were randomized to estrogen plus progestin vs those
randomized to placebo.15
The WHI is the first randomized controlled trial to include a large
group of nonwhite women. Among black women, estrogen plus progestin reduced
the risk of total fractures by 42%; however, this outcome did not achieve
statistical significance because of the small number of fractures in this
subgroup of women. Nevertheless, there was no evidence of an interaction between
treatment and race/ethnicity.
Treatment with estrogen plus progestin resulted in consistent positive
effects on BMD in the lumbar spine and total hip. Similar to other antiresorptive
therapies, the increase in BMD was greatest in the lumbar spine, a site that
contains a large proportion of trabecular bone. The differences in BMD that
we observed between the estrogen-plus-progestin group and the placebo group
were consistent with results from a recent meta-analysis of hormone therapy
for prevention and treatment of osteoporosis in postmenopausal women.11
Unlike in other randomized trials of osteoporosis treatments, women
enrolled in the WHI were, for the most part, healthy. Hip fracture rates were
about 50% lower than expected for a similar age-matched cohort.16 Although
BMD measurements were confined to a small sample of the enrollees, a relatively
small proportion of women in the WHI had osteoporosis at the baseline assessment.
Hence, the study results are likely to be applicable to healthy postmenopausal
women. The bisphosphonate trials showed a reduction in risk of hip and nonspine
fractures in women with osteoporosis but not in women without osteoporosis.17-20 It
may be that treatment with estrogen plus progestin reduces fractures in women
without osteoporosis through a reduction in falls and improvement in muscle
strength, although the evidence for this is sparse and conflicting.21-23 Other trials that
have examined fracture reduction in participants without osteoporosis are
limited by the small number of participants, and the failure to observe a
treatment effect may be a consequence of inadequate statistical power to detect
an effect.
In the Heart and Estrogen/Progestin Replacement Study (HERS), there
was no effect of estrogen-progestin therapy on clinical fractures.24,25 Indeed, continued open-label follow-up
of the women in HERS reported a higher rate of hip
fracture among women originally randomized to estrogen plus progestin.26 The lack of observed benefit on fractures in HERS
was interpreted as being consistent with the lack of benefit observed with
other agents in women without osteoporosis.19,20 It
is not apparent why the WHI and HERS findings differ because both trials enrolled
women without osteoporosis. The women in HERS were, on average, slightly older
and all had coronary heart disease and reported a higher prevalence of medications
such as nitrates27 and statins28 that
may influence bone. Finally, the sample size of WHI was much larger than that
of HERS, which may have provided the necessary power to detect a treatment
Strengths of the WHI include its randomized design, large sample size
of ethnically diverse postmenopausal women across a wide age range, complete
follow-up for outcomes on 93% of the women randomized, and confirmation of
all fractures by medical record. There are, however, a number of limitations.
Only one estrogen-progestin formulation was tested, although it was the most
commonly prescribed postmenopausal hormone therapy regimen in the United States
at the time the study was designed. Furthermore, no prior trials have demonstrated
differential effects by type of estrogen or for unopposed or combination therapy
on BMD.11 The WHI estrogen-only trial is ongoing,
with completion anticipated in 2005. Fractures are also secondary end points
of that randomized trial.
A number of screening tools have been developed to identify women with
osteoporosis. For the most part, these tools have only poor to moderate specificity
and have not been validated in populations other than the ones for which they
were created.29 We developed a summary fracture
risk score using risk factors for hip fracture similar to the method developed
by Black et al.6 While this score correlated
with the risk of fracture, the ratio of highest to lowest risk was modest
(2.0). Bone mineral density and prevalent vertebral fractures are stronger
predictors of future fracture,29,30 but
we did not collect these data for all women in the trial; hence, we were unable
to identify a group of women with severe osteoporosis in whom the benefits
of estrogen plus progestin might exceed the risks.
We tested for interactions of estrogen plus progestin with a number
of risk factors for fracture; none were significant. However, differential
benefit could occur in the absence of significant interactions if the baseline
risk of fracture is different in the various subgroups. For example, the absolute
risk of fracture was 2-fold higher in the high-risk fracture group compared
with the low-risk group. Hence, even if the HRs did not differ in the 2 groups,
the absolute number of fractures prevented would be greater in the high-risk
The WHI enrolled a large group of ethnically diverse women, but we had
limited power to test for an interaction between treatment and race/ethnicity.
We had a relatively high rate of discontinuation of study drug in the active
treatment group, but sensitivity analyses limited to adherent women yielded
similar results. Assessment of vertebral fractures was limited to clinically
symptomatic fractures, which represent only about one third of all vertebral
fractures.31 Finally, the global index was
designed to focus on potentially life-threatening events and therefore included
hip fractures, which have been shown to have significant morbidity32 and mortality,33 but
not other fractures, such as vertebral fractures. Vertebral fractures have
also been associated with an increased risk of mortality34 and
disability.35 In a separate analysis, the overall
balance of risks and benefits of hormone therapy on quality of life did not
show a clinically significant benefit.36
In conclusion, estrogen plus progestin increases BMD and reduces the
risk of fracture in healthy postmenopausal women and appears to do so regardless
of presence or absence of risk factors. When considering the effects of hormone
therapy on other important disease outcomes in a global model, there was no
net benefit in this study, even in women considered to be at high risk of
fracture. Given the overall unfavorable risk-benefit ratio and the availability
of other agents for prevention and treatment of osteoporosis, treatment with
estrogen plus progestin should not be recommended for prevention or for treatment
of osteoporosis in women without vasomotor symptoms. Before the combination
of estrogen and progestin is considered for the purpose of fracture prevention,
women should be fully informed of the potential adverse effects.
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Chapter 1, Definition, Specifications and Classification of Solvent-borne Coating , Applications of Solvent-borne Coating , Market Segment by Regions;
Chapter 2, Manufacturing Cost Structure, Raw Material and Suppliers, Manufacturing Process, Industry Chain Structure;
Chapter 3, Technical Data and Manufacturing Plants Analysis of Solvent-borne Coating , Capacity and Commercial Production Date, Manufacturing Plants Distribution, R&D Status and Technology Source, Raw Materials Sources Analysis;
Chapter 4, Overall Market Analysis, Capacity Analysis (Company Segment), Sales Analysis (Company Segment), Sales Price Analysis (Company Segment);
Chapter 5 and 6, Regional Market Analysis that includes United States, China, Europe, Japan, Korea & Taiwan, Solvent-borne Coating Segment Market Analysis (by Type);
Chapter 7 and 8, The Solvent-borne Coating Segment Market Analysis (by Application) Major Manufacturers Analysis of Solvent-borne Coating ;
Chapter 9, Market Trend Analysis, Regional Market Trend, Market Trend by Product Type Hydrocarbon Solvent, Oxygenated Solvent, Others, Market Trend by Application Transportation, Consumer Products, Heavy Equipment & Machinery;
Chapter 10, Regional Marketing Type Analysis, International Trade Type Analysis, Supply Chain Analysis;
Chapter 11, The Consumers Analysis of Global Solvent-borne Coating ;
Chapter 12, Solvent-borne Coating Research Findings and Conclusion, Appendix, methodology and data source;
Chapter 13, 14 and 15, Solvent-borne Coating sales channel, distributors, traders, dealers, Research Findings and Conclusion, appendix and data source.
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20753 Surnames | 136293 Records | 2775 Reunions
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Photo #68497
Last Name: Crowell
First Name : Joseph
Middle Name: Doane
Subject's City: Providence
Subject's State: RI
Subject's County: Providence
Subject's Country: US
Date: 1851-1900
Photographer's City:
Photographer's State:
Type** : B&W
Comments: Joseph Doane Crowell (Nee: ) | Providence RI US | 1851-1900 | Comments: Picture taken in Providence during the Civil War in which Joseph Doane Crowell, son of Theophilus Crowell and Dorcas Harding, served in the 1st RI Cavalry. Shell jacket is cavalry, stripes are for 2 years (so far) service. Joseph b 26 June 1822 Chatham, MA m 1853 Harriet Stymer, b 1835 the daughter of Martin Stymer and Anna Perry. Joseph died 16 Jul 1873 in Providence RI, Harriet died 12 Nov 1914 Providence. They are buried Mineral Springs Cemetery, Pawtucket.
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ORGANIZER: VampireBrigade
EVENT DATE: Oct 02, 2016
VampireBrigade ISF wrote -
Ian Somerhalder Foundation Worldwide Donations Page...
I have created this page because so many people have not been able to donate to http://isfoundation.com because donations have been restricted to US Residents only.
Well now, anyone and everyone from all over the world can donate to #ISF here.
This page is directly linked to #ISF so 100% of your donations will go directly to them towards a better future for animals, people and the environment.
Please give generously any amount large or small is always appreciated.
Join my team and help me spread the word.
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Thank you all for being so amazing! Your generous donations are appreciated by #ISF! Your personal contributions will go far in making this world and all its creatures in it a better place.
I am so grateful, thanks again for being so kind and generous to our cause.
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I am, at heart, a documentarian and sentimentalist. Our experiences and relationships make us who we are. Everyone has a story. It would be an honor to capture yours in an honest and unique way. My shooting style is mostly unobtrusive and relaxed, with an eye towards unscripted moments and unique details.
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David is my better half, the one who gets things done and keeps me on track while my head is in the clouds taking pretty pictures. He has many different roles: second shooter, office manager, accountant, cheerleader, and father to our amazing son. He teaches me to be responsible and appreciate the finer things in life, and I encourage him to have fun and find the beauty in the everyday. We learn from one another constantly, and try to remind ourselves to always be present, and to act with intention and with no regrets.
We have an amazing son Miles, born nearly 3 months premature at 2 lbs 3 oz. He teaches us that every day is a precious gift.
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Programming Guide
| WideStudio Index
Table of contents
The timer
How to use the timerDrop an instance of the WSCvtimer class on the section [NonGUI] of the object box dialog on some window or some form, and set the interval of firing by millisecond. It will fire the event WSEV_ACTIVATE after the interval. So set the event procedure with WSEV_ACTIVATE to the timer.
There are two kind of the timers. One fires only once, but the other continuously fires at every interval. If the property: "cont" is True, it will continuously fires. It is possible to start or stop the timer by the property: "running". If the property: "cont" is False,after firing,the timer will stop and the property: "running" will become False.
|Copyright(C) WideStudio Development Team, 1999-2005
|Last modified: Jan 05, 2005


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Eye Treatments
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Travis Lewis Scouting Report
|Oklahoma Sooners
|Jersey Number:
|Height & Weight:
|6'2 - 227 lbs.
2012 NFL Draft Prospect Scouting Report:
Travis Lewis, OLB, Oklahoma
One interesting facet to Lewis' game is that although he is a very good tackler, he is not physical or active when taking on lineman as a blitzer. He wraps up the ball carrier well and drives through his hips. Lewis takes good pursuit angles and does well to bring his man down quickly and cleanly. When working through the pile, he becomes hesitant and even lowers his head on contact. Rarely slows down his attack in order to disengage from blockers.
Shows good instincts when in open space whether reading his assignment. He performs in zone more consistently than in man. He has nice patience and feels his way through the play in zone. When in man, he is usually too physical and can be lost with a quick change of direction. Currently has very little skills as a pass rusher. Lacks the explosiveness to hit the edge or split the gap between blockers.
Lewis will need to iron out his style of play. He tends to play off his emotions at times which can both be a good and bad thing.