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that risks were outweighing the benefits and that
the design-specified weighted log-rank test sta-
tistic for breast cancer crossed the designated
boundary, the independent DSMB decided to
stop prematurely the combined estrogen– prog-
estin (conjugated equine estrogens
(CEE)–medroxyprogesterone acetate (MPA))
treatment arm of the WHI study.
The justification for stopping the WHI study,
and the validity of a global index as a measure for
the risk/benefit ratio, have been discussed ever
since. The discussion was further fueled by pub-
lication of the Million Women Study, indicating
an even larger risk of breast cancer in HRT users
than reported in the WHI study
13
. The regula-
tory authorities and medical associations reacted
promptly. The US Preventive Services Task Force
(USPSTF) concluded that the harmful effects of
combined estrogen-and-progestin HRT were
likely to exceed the chronic disease prevention
benefits in most women
14
, and most organiza-
tions with guidelines on postmenopausal HRT
have followed and revised their recommenda-
tions. Following the premature stop of the WHI
study and the Million Women Study, HRT is
now generally considered an acceptable treat-
ment option for menopausal symptoms, but
most organizations recommend against the long-
term use of HRT for prevention. Also, the Euro-
pean Medicines Evaluation Agency (EMEA) no
longer consider HRT as a first-line treatment for
the long-term prevention of osteoporosis. HRT
remains an option for postmenopausal women
who are at high risk of future fractures, and who
are intolerant of, or contraindicated for, other
Reconciling risks and benefits of hormone
replacement therapy in a single outcome:
the QALY approach
J. M. Alt, Y. Zöllner and J. Ryan
28
255
HISTORICAL PERSPECTIVE
Although hormone replacement therapy (HRT)
is mainly prescribed for relief of vasomotor symp-
toms and urogenital atrophy, HRT has also been
indicated for the prevention of postmenopausal
osteoporosis. As shown by cohort studies and
randomized controlled trials, HRT increases
bone mineral density (BMD) and reduces the risk
for fractures
1–4
. In addition, there is evidence
that HRT reduces the risk for colorectal can-
cer
5,6
. HRT may also possibly reduce the risk of
cognitive decline and dementia
7
. Until 2002,
there was also fair evidence – mostly from large,
prospective cohort studies – that HRT could pro-
tect women against cardiovascular disease
8–10
.
However, the results from a secondary preven-
tion trial (Heart and Estrogen/progestin Replace-
ment Study (HERS) I and HERS II) did not
demonstrate any benefit in terms of cardiovascu-
lar protection
11,12
, and the results from the
Women’s Health Initiative (WHI)
1
study pub-
lished in 2002 showed that HRT was also not
effective for primary prevention of cardiovascular
disease. This latter outcome has considerably
changed the perceived balance of benefits and
harms of HRT. For the Data and Safety Monitor-
ing Board (DSMB), a ‘global index’ was devised
for the WHI studies to estimate the risk/benefit
ratio. The index included the two primary out-
comes coronary heart disease and invasive breast
cancer, plus stroke, pulmonary embolism,
endometrial cancer, colorectal cancer, hip frac-
ture and death due to other causes. It excluded
menopausal symptoms and other osteoporotic
fractures. Based on the ‘global index’, indicating
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POSTMENOPAUSAL OSTEOPOROSIS
medicinal products approved for the prevention
of osteoporosis
15
.
In 2004, the results from the WHI estrogen-
only treatment arm were published
16
. The data
showed a different picture in that the women on
unopposed CEE had no increased risk of breast
cancer (hazard ratio (HR) 0.77; 95% confidence
interval (CI) 0.59–1.01), even though the treat-
ment duration in the estrogen-only treatment
arm was longer than in the combined CEE–MPA
treatment arm (6.8 and 5.2 years, respectively),
whereas the protection against osteoporotic frac-
tures was confirmed. The estimated excess risk
for all monitored events was a non-significant
two events per 10 000 person-years
16
. The con-
clusion to be drawn from these studies in respect
to the overall risk–benefit profile of HRT
depends not only on the incidence of an event
but also on the weight that is placed on each of
the different events: breast cancer, cardiovascular
disease, osteoporotic fractures and cognition.
Such a weight could be the impact of an event on
the quality of life.
QUALITY OF LIFE WEIGHTS
Two of the most important outcome attributes
when comparing health states are survival dura-
tion and quality of life. Indeed, recently, the
American College of Obstetricians and Gynecol-
ogists (ACOG) has argued that any effort to
determine the net health effect of any treatment
is incomplete without an assessment of the effect
of the treatment on the quality of life
17
. The
‘global index’ used in the WHI was not based
upon women’s own assessment of their quality of
life, and it did not account for time in particular
states of health. In addition, outcomes with sig-
nificant impact on quality of life such as vertebral
or other osteoporotic fractures were not included.
There are several disease-specific or generic
instruments for individuals to assess quality of
life, but, for the purpose of decision-making, it is
often desirable to measure health outcomes in a
single score that takes into account both quality
of life and survival duration. In health econom-
ics, the concept of ‘quality-adjusted life-years’
(QALYs) is commonly used for assessing the rel-
ative cost-effectiveness of two treatment options.
QALYs have several benefits. First, they assess
the quality of life of a patient. Second, they also
incorporate time in a particular health state.
Third, they can be comparable across different
therapeutic areas. Finally, they combine quality
and quantity of life into one single figure.
The assessment of quality of life, as used in
QALYs, is derived from the preferences of sub-
jects for health states. There are three main
methods for eliciting subjects’ preferences, or
utilities as they are often called. These methods
are the time trade-off method, the standard
gamble method and visual analog rating scales
(VAS)
18
. Briefly, with the time trade-off method,
a subject is given a choice between two alterna-
tives, one being the certain event that a pre-
existing chronic illness will continue for a specific
period, and the other alternative consisting of
undergoing a particular treatment that will
result in perfect health but will shorten the sub-
ject’s life-span. The time period of perfect health
in the second alternative is then altered until a
subject values both alternatives as the same. The
utility of the first alternative is calculated from
the ratio of the time during which health is per-
fect divided by the period during which health is
poor. With the standard gamble method, a sub-
ject is asked to choose between two alternatives,
one being a chronic illness that the subject is
100% certain to have for a specific number of
years. For the second alternative, a treatment is
introduced, which promises complete recovery at
a certain probability, but on the other hand is
associated with the risk that it will result in
death. The probability for the two possible
results of the second alternative are varied until
the subject is indifferent to both alternatives.
This probability is interpreted as the utility of
the first alternative. When non-preference-based
rating scales (such as VAS) are used to measure
utilities, subjects are instructed to mark on such
a scale where they feel a given health state ranks
on a range from death to perfect health.
Despite methodological differences, each of
the three methods results in a utility score for
any particular health state. These utility values
are then converted into a QALY by multiplying
the number of years a subject is in a particular
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RISKS AND BENEFITS OF HRT: THE QALY APPROACH
health state. For example, if someone values
three different health states at a utility of 1, 0.8
and 0.4, respectively, and spends 10, 40 and 20
years in each health state, then their total QALYs
would be 50. Their QALY value for each health
state would be 10 (1
× 10), 32 (0.8 × 40) and 8
(0.4
× 20). A health state of death is usually
assigned a utility value of 0.
Due to the general applicability and use
across different health states, QALYs are the
standard measure in cost–utility analyses. They
are the primary outcome used in assessing the
cost-effectiveness of health technology by the
National Institute for Clinical Excellence (NICE)
in England and Wales.
As demonstrated by the WHI, the effects of
HRT are numerous, and impact on different
health states. Therefore, a measure such as the
QALY, which can incorporate the preference of
the woman for each of these health states, as well
as the time spent in each state, is an important
tool for the decision-maker. In the following
sections, an attempt is made to balance the out-
comes ‘breast cancer’ and ‘osteoporotic fractures’
based on published data, and with a focus on
scores that combine the quality of life with
survival.
OSTEOPOROTIC FRACTURES
Osteoporotic fractures, particularly of the hip
and spine, are common among postmenopausal
women. These fractures are associated with sig-
nificant mortality, and also have a significant and
prolonged impact on quality of life, as hip frac-
tures in particular often result in loss of inde-
pendence. The event rates in postmenopausal
women without prevalent vertebral fractures are
45.4 per 1000 patient-years for any fracture,
15.2 for vertebral fracture, 4.7 for clinical verte-
bral fracture and 0.9 for hip fracture. In women
with prevalent vertebral fractures, the event rate
per 1000 patient-years for any fracture is 117.4,
and the event rates for vertebral fracture, clinical
vertebral fracture and hip fracture are 77.1, 25.7
and 5.8, respectively
19
. The lifetime risk of hip
fracture from age 50 onwards is estimated to be
about 17% for white women, and the lifetime
risk of a clinically diagnosed vertebral fracture is
about 16%
20
. The lifetime risk of suffering a ver-
tebral fracture is 32% (including ‘non-clinical’
fractures)
21
. Excess mortality after a hip fracture
ranges from 6 to 37%
22
. The risk of death is
greatest immediately after the fracture, and then
decreases over time. Nearly 8% of patients die
within 180 days from the event, with having
fractured femur mentioned on the death certifi-
cate, and this figure increases to nearly 25%
when deaths of all causes are counted
23
. The age-
adjusted relative risk to die within 3.8 years of
observation from a hip fracture is 6.68 (95% CI
3.08–14.52), and the age-adjusted relative risk
to die from a clinical vertebral fracture is 8.64
(95% CI 4.45–16.74)
22
. As clinical fractures
constitute only approximately one-third of all
vertebral fractures, the mortality from vertebral
fractures is often underestimated. Morphometric
vertebral fractures, which do not routinely come
to medical attention, are associated with a mod-
est excess morbidity and mortality (i.e. a relative
risk of hospitalization of 1.18 (95% CI
1.06–1.31), and a relative risk of mortality of
1.60 (95% CI 1.10–2.32))
24,25
.
The impact of vertebral and hip fractures on
menopausal women’s quality of life was investi-
gated using the time trade-off method by Toste-
son and co-workers in 2001
26
. This study found
that 114 women with one or more vertebral frac-
tures valued this health state with a utility of
0.82 (95% CI 0.76–0.87). For hip fractures, 67
women valued this health state at a utility of
0.63 (95% CI 0.52–0.74). These were compared
with 199 women without fractures, who valued
their health state at a utility value of 0.91 (95%
CI 0.88–0.94). Estimated QALY differences
(fracture minus non-fracture subjects) were
equivalent to losses of 20–58 days and 23–65
days of perfect health per year for vertebral frac-
ture and hip fracture subjects, respectively,
depending on age
26
. Among older women, qual-
ity of life is profoundly threatened by hip frac-
ture. A study in 195 older women showed that
80% would rather be dead than experience the
loss of independence by a ‘bad’ hip fracture. On
an interval scale between 0 and 1, a ‘bad’ hip
fracture was valued at 0.05 and a ‘good’ hip frac-
ture which permits maintaining independent liv-
ing in the community at 0.31
27
.
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POSTMENOPAUSAL OSTEOPOROSIS
The burden that osteoporotic fractures
place on women, their social supports and the
health-care system is substantial, and the
consequences of postmenopausal osteoporosis in
terms of morbidity, mortality and costs have
been quoted extensively as justification for pre-
ventive treatment
28,29
. HRT is among the most
cost-effective treatments for prevention of osteo-
porosis and osteoporotic fractures
30,31
. It not only
increases BMD, but also reduces the risk of frac-
tures. Two systematic reviews of all randomized
trials of HRT that reported or collected fracture
data from women who had used HRT for at least
12 months showed an overall 33% reduction in
vertebral fractures (95% CI 45–98), and an over-
all 27% reduction in non-vertebral fractures
(95% CI 0.56–0.94). Women younger than 60
years had a larger reduction in non-vertebral
fractures (i.e. a relative risk (RR) of 0.67, 95% CI
0.46–0.98), compared with women with a mean
age of 60 years or older (RR 0.88, 95% CI
0.71–1.08). For hip and wrist fractures alone, the
effectiveness of HRT appeared to be more
marked (RR 0.60, 95% CI 0.40–0.91), particu-
larly for women younger than 60 years (RR 0.45,
95% CI 0.26–0.79)
3,4
. A statistically significant
beneficial effect of HRT on fracture incidence
was also reported in the WHI study
2,16
. When
considering all confirmed osteoporotic fracture
events that occurred from enrollment to discon-
tinuation of the CEE–MPA treatment arm of the
trial in July 2002, 733 of 8506 women (8.6%) in
the estrogen-plus-progestin group and 896 of
8102 women (11.1%) in the placebo group expe-
rienced a fracture (HR 0.76, 95% CI adjusted for
multiple testing 0.63–0.92, nominal 95% CI
0.69–0.85)
2
. Reductions for hip and for vertebral
fracture both amounted to 34% (nominal 95%
CI 0.45–0.98 and 0.44–0.98, respectively)
2
.
With estrogen-only treatment, an even further
decreased risk for hip (HR 0.61, 95% CI
0.41–0.91), vertebral (HR 0.62, 95% CI
0.42–0.93) and total fractures (HR 0.70, 95%
CI 0.63–0.79) was reported
16
. The annualized
percentage of all fractures was 1.39% (503 out of
5310 patients) in the CEE treatment group, and
1.95% (724 out of 5429 patients) in the placebo
group. Total hip bone mineral density (BMD),
measured in a subset of 1024 women, increased
3.7% after 3 years of treatment with estrogen
plus progestin, compared with 0.14% in the
placebo group (p < 0.001)
2
.
BREAST CANCER
Breast cancer is considered the most relevant
adverse outcome from prolonged HRT use, and
the greatest worry for the patient. Even though
the mortality has been greatly reduced thanks to
new therapies and earlier diagnosis, the risk of
dying is still high. The lifetime risk of having
breast cancer in the USA is 13%, and the risk of
dying from it is approximately 23%. The lifetime
risk of dying from breast cancer in the USA is
3%
32
. In Europe, the risk differs between coun-
tries. Overall, approximately 350 000 cases are
diagnosed per year and approximately 130 000
women die per year of breast cancer, which cor-
responds to a death rate of approximately 37%
33
.
The WHI estrogen-plus-progestogen study
demonstrated a slightly increased risk of getting
breast cancer compared with non-users, and the
risk appears to increase with years of use. The
WHI data indicated a 26% increased risk (95%
CI 1.00–1.59) for invasive breast cancer in cur-
rent HRT users after a mean treatment period of
5.2 years of combined HRT versus placebo
1
, and
the HERS indicated a similar (statistically not
significant) 27% increased risk (95% CI
0.84–1.94)
34
. The relative risk in the Million
Women Study was 1.66 (95% CI 1.58–1.75) in
current users. Past users were not at an increased
risk (1.01, 95% CI 0.94–1.09)
13
. The results of
the WHI estrogen-alone study came as a sur-
prise, as the hazard ratio of being diagnosed with
breast cancer was 0.77 (95% CI 0.59–1.01) after
a mean treatment duration of 6.8 years
16
. The
rapid decline of the risk after stopping HRT
reported in an earlier meta-analysis
35
has been
confirmed by the Million Women Study
13
. This
finding is quite puzzling, as cancer is considered
to be an autonomous process.
Relatively few studies estimating utility val-
ues for different breast cancer stages have been
conducted to date. Chie and colleagues
36
found
that utility scores did not differ significantly
between clinical phases of breast cancer. Another
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RISKS AND BENEFITS OF HRT: THE QALY APPROACH
study estimated utility values based on 41
patients with early-stage breast cancer undergo-
ing chemotherapy. Using the VAS, time trade-off
and standard gambling techniques, they esti-
mated utility values of 0.77 (standard deviation
(SD) 0.15; n = 41), 0.90 (SD 0.12; n =41) and
0.93 (SD 0.10; n = 38), respectively
18
. Two stud-
ies provided utility estimates for women with
advanced breast cancer. One study used a VAS to
assess quality of life during different treatments
for advanced breast cancer. A total of 84 women
were interviewed. The utility values for patients
on hormonal therapies, mild chemotherapies
and intensive chemotherapies were 0.628, 0.651
and 0.483, respectively. When not split by
treatment, they rated their health at between
0.368 and 0.680
37
. The second study used a
standard gamble approach in 129 oncology
nurses across five countries. For partial response,
stable disease, progressive disease and terminal
disease, utility values of 0.81, 0.62, 0.41 and
0.16, respectively, were estimated
38
. Whether
the mortality rate from breast cancer is increased
in HRT users remains inconclusive
13,39
. Earlier
studies indicated a better prognosis of breast
cancer that had been diagnosed in HRT users,
possibly because of less advanced tumor
spread
40,41
.
BALANCING OUTCOMES: BREAST
CANCER AND OSTEOPOROTIC
FRACTURES
Accepting an increased risk of breast cancer, the
major question remains whether the beneficial
effects on bone are outweighed by the negative
effects on the breast. Only a few studies so far
have used quantitative decision analysis to deter-
mine the net effect of HRT on women’s health.
Studies that were performed before the results
from the WHI were published showed that HRT
increased quality-adjusted life-years and was
cost-effective relative to no therapy
42–45
but
these analyses started from the assumption that
HRT had a positive effect on coronary heart dis-
ease prevention. However, even when taking into
account that HRT does not provide cardiovascu-
lar protection
46
, or, as indicated by the WHI,
that HRT puts women at an increased risk of
coronary heart disease, stroke, pulmonary
embolism and breast cancer
1
, and despite
methodological differences, several studies have
still indicated a net beneficial health effect of up
to 20 years’ treatment with HRT in symptomatic
women
47–49
. Menopausal symptoms may affect
as many as 75–80% of women at or around the
time of the menopause, and almost one-third of
postmenopausal women report symptoms that
last up to 5 years after a natural menopause. Hot
flushes can even persist for up to 15 years in 20%
or more of women, and for the many women
who experience hot flushes and other
menopausal symptoms, these have a profound
impact on the quality of life
50–52
. Utility values
as low as 0.64 (95% CI 0.57–0.71) have been
reported for severe menopausal symptoms and of
0.85 (95% CI 0.80–0.90) for mild symptoms,
using the time trade-off method
53
. HRT effec-
tively alleviates menopausal symptoms (i.e. a
77% reduction in frequency (95% CI 58.2–87.5)
and an 87% reduction in symptom severity
(95% CI 0.08–0.22) for HRT relative to
placebo)
54
. The increase in the utility weight is
0.18 for women with mild symptoms, and 0.42
for women with severe symptoms
55
. The gain in
quality-adjusted life-years with HRT thus
depends on the severity of the women’s symp-
toms and its impact on the quality of life, and
probably also on the age at which HRT is
started
39
.
The outcomes of the quantitative decision
analyses discussed above all indicated a net
harmful effect of HRT for asymptomatic
women
47–49
, although the study by Kim and
Kwok showed that the reduction in life
expectancy would only be in the order of several
days
49
. More important, however, is that these
models only accounted for hip fractures, whereas
the HRT-associated reduction in vertebral frac-
tures and the impact thereof on the quality of life
were not included. The lifetime risk for hip and
vertebral fractures in the general population by
far exceeds the lifetime risk of developing breast
cancer, and the impact of hip and vertebral frac-
tures on quality of life and survival is consider-
able, compared with breast cancer. When com-
paring the effect of HRT on both hip and
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260
POSTMENOPAUSAL OSTEOPOROSIS
vertebral fractures (five fewer hip fractures and
approximately six fewer vertebral fractures per
10 000 person-years)
1
with the potential risk of
breast cancer (i.e. eight more cases of breast
cancer per 10 000 person-years)
1
, it appears that
the balance is clearly in favor of HRT, even in
asymptomatic women.
1. Rossouw JE, Anderson GL, Prentice RL, et al.
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262
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In postmenopausal women, using currently
available treatment options, we should be able to
implement a new strategy emerging from the
following concept: prevent, treat and maintain
(PTM). The need to clarify this matter is critical.
As has already been evidenced for other clinical
conditions, it would be ideal to achieve a ration-
ale regarding the use of available treatment
options, in order to optimize the balance
between the efficacy of a drug and its potential
side-effects. According to current knowledge, the
priorities that should be considered for the satis-
factory management of osteoporosis are: first,
prevention of postmenopausal bone loss with
preservation and/or restoration of normal bone
structure and skeletal health; and second, pre-
vention of first and/or subsequent fractures with
a decrease of fracture risk that should be both
statistically significant and clinically relevant.
Furthermore, considering that this treatment
should probably be continued long-term, phar-
macological choices should take into account –
primary end-point, cost/effectiveness issues and
side-effects according to the mechanism of
action.
In addition, patients with low bone mass and
osteoporosis have several different clinical
profiles. In our daily clinical practice, we see
patients with different expectations: early-
postmenopausal women, with and without
menopausal symptoms, for whom the aim is to
relieve symptoms, prevent bone loss and main-
tain bone density level; patients with osteoporo-
sis, for whom it is essential to prevent the first
vertebral fracture; and patients with prevalent
Prevent, treat and maintain: how to
optimize the management of postmenopausal
osteoporosis
D. Agnusdei
29
263
There is now a consensus that osteoporosis should
be defined as a disease of decreased bone strength
rather than a disease of decreased bone mass, and
that all efficacious drugs should demonstrate
increases in bone strength as evidenced by a
decrease in fracture incidence. Bone strength pri-
marily reflects the integration of bone density and
bone quality
1
. From a skeletal metabolism stand-
point, osteoporosis may be defined as a conse-
quence of the imbalance of the physiological
process of bone turnover (or coupling), i.e. a lack
of equilibrium between the activity of osteoblasts
(bone-forming cells) and osteoclasts (bone-resorb-
ing cells), with a relative increase in the activity of
the latter
2
.
Osteoporosis is the most common metabolic
bone disease among postmenopausal women, and
it has a large impact on public health. All skeletal
sites can be affected, with progressive bone min-
eral density (BMD) reduction and microarchitec-
tural deterioration of bone tissue leading to an
increase in fracture risk. Although bone mass is
still the major determinant of bone strength,
other determinants including bone geometry,
bone material properties and bone microstructure
play an important role as well
3
.
Although pharmacological interventions to
prevent bone loss are necessary in patients at the
greatest risk of fracture, the first priority in
osteoporosis secondary prevention should be to
avoid falls, the major determinant of fractures in
the elderly. A therapeutic choice must include
treatments that are effective in reducing the risk
and incidence of fractures, demonstrated in con-
trolled clinical trials.
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