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Hormone replacement therapy
L. B. Tankó and C. Christiansen
20
INTRODUCTION
Ever since the early reports by Fuller Albright in
the 1940s
1
, major efforts have been dedicated to
research aiming towards a better understanding
of the role of estrogens in the regulation of bone
turnover. The sudden and pronounced drop in
circulating estrogens of ovarian origin after the
menopause is by now unequivocally recognized
as a major risk factor for osteoporosis. By using
specific biomarkers of bone cell function, numer-
ous follow-up studies have demonstrated the
rapid and marked acceleration of osteoclast-
mediated bone resorption unmatched by simul-
taneous bone formation as the major cause
underlying the negative calcium balance charac-
teristic of osteoporotic postmenopausal women
(e.g. references 2–4).
SCREENING
As with most primary prevention, the best
results and cost/benefit ratios can be achieved if
treating those who benefit the most from clinical
management countering the adverse trends
accompanying the menopause. The sine qua non
of finding these individuals is effective screening.
Below is a list of criteria that should be satisfied
before large-scale screening is undertaken:
(1) The disease should be common and serious
regarding its outcomes;
(2) The natural disease history should be under-
stood;
(3) Good screening tests should be available;
(4) Acceptable treatment should be available.
Ideally, it would be desirable to distinguish those
women in their 50s who are most likely to
develop osteoporosis by old age, and who are at
the greatest risk of long-term complications such
as vertebral and hip fracture(s). Emerging evi-
dence suggests that combined measures of bone
mass and bone turnover using tomoabsorptio-
metry and biomarkers, respectively, offer useful
proxies of risk (e.g. references 5–7). Showing an
example from our own results, Table 1 illustrates
the baseline characteristics of participants of a
long-term follow-up study that monitored bone
loss in early-postmenopausal women. Fast losers
Table 1 Baseline characteristics of ‘fast losers’ versus ‘normal losers’. Values are expressed as mean ± SD
Fast losers Normal losers
Baseline BMC (g) 3.09 ±0.56 3.15 ± 0.48
Height (m) 161.6 ± 5.8 160.2 ± 5.6
Weight (kg) 62.9 ± 12.5
*
67.3 ± 12.7
CrossLaps (ng/ml) 0.43 ± 0.17
**
0.33 ± 0.14
Osteocalcin ( ng/ml) 11.0 ± 4.8
**
9.0 ± 4.8
Bone loss/15 years (%) 22.4 ± 8.5
***
13.5 ± 9.4
*
p < 0.1;
**
p < 0.01;
***
p < 0.001; BMC, bone mineral content
185
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were leaner and had significantly elevated levels
of bone formation and bone resorption markers,
indicating accelerated bone turnover.
When assessing bone markers 15 years later,
‘fast losers’ still had ~30% higher levels com-
pared with ‘normal losers’ (p < 0.001).
This finding also illustrates that body fat-
derived endogenous estradiol plays an important
compensatory role in the modulation of bone
turnover in postmenopausal women lacking
ovarian estradiol. Figure 1 shows bone turnover
characteristics measured by bone markers as a
function of total body fat mass, emphasizing that
the more pronounced is body fatness, the smaller
is the negative calcium balance.
Figure 2 indicates the decrease in bone min-
eral density (BMD) at different skeletal sites over
the 15-year observation period. ‘Fast losers’, by
definition, lost significantly more BMD at all
sites compared with ‘normal losers’ (p < 0.01)
Figure 3a indicates the relative risk of verte-
bral fractures in women with low bone mass and
accelerated bone turnover compared with con-
trols and those with high bone mass and slow
bone loss. Figure 3b indicates that the risk of
fractures increases exponentially with increasing
rate of bone loss.
The conclusions relevant to screening can be
summarized as follows:
(1) Fast losers had increased bone turnover,
which persisted over the 15-year follow-up
period;
(2) Fast losers had approximately 1 standard
deviation less bone mass after 15 years;
(3) Fast bone loss may predispose to fractures
almost to the same extent as low bone mass;
(4) Low bone mass and fast rate of bone loss are
additive risk factors;
(5) Rate of loss should be included in the risk
stratification of postmenopausal women.
These findings also emphasize the need to com-
bine bone mass and bone turnover assessments,
which facilitates the prediction of bone status of
the elderly, and thus the selection of individuals
who can benefit most from preventive measures
(Figure 4).
186
600
400
200
15
10 20 30 40
10
5
FUCa/Cr (mmol/mol)
BGP (ng/ml)
Bone resorption
Bone formation
Fat (kg)
Figure 1 Bone resorption and formation in
postmenopausal women as a function of total body fat
mass. BGP, bone Gla protein; FUCa/Cr, fasting
urinary calcium corrected for creatinine
POSTMENOPAUSAL OSTEOPOROSIS
WHY THE SKELETAL EFFECTS OF
HRT SHOULD NOT BE
NEGLECTED
Currently, there are numerous antiresorptive
therapies available on the market for the reversal
of postmenopausal bone loss. Most, if not all,
Change in BMD (%)
100
80
60
FN
Arm Spine Hip
FN FN
Figure 2 Changes in bone mineral density (BMD)
(%) in ‘fast losers’ and ‘normal losers’ during a 15-year
follow-up. F, fast loser (> 3% change in BMD per
year); N, normal loser (< 3% change in BMD per year)
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fractures remains a weak point of osteoporosis
therapy. This is seemingly least true for hormone
replacement therapy (HRT). Historically, sup-
port for the use of estrogen replacement therapy
for the prevention of bone loss and fractures
comes from three lines of evidence. First, ran-
domized clinical trials consistently show that this
choice of therapy prevents postmenopausal bone
loss (e.g. references 8 and 9). Second, observa-
tional studies consistently suggest that post-
menopausal HRT reduces the risk of vertebral,
hip and other types of osteoporotic fractures
10,11
.
Third, early analyses of risk–benefit studies of
187
Table 2 The relative effect of bisphosphonates on
trabecular and cortical bone tissue. Extrapolating
from these results, 2 years of treatment would
increase 100% trabecular bone by 8.0% and 100%
cortical bone by 0.8%
Trabecular/ % Change in
cortical BMD
Spine 60/40 4.5
Hip 30/70 2.5
Total body 20/80 1/5
Arm 10/90 1/0
New ROI arm 65/35 5/0
ROI, regions of interest; BMD, bone mineral density
vs. normals vs. high bone mass,
slow losers
20
16
12
8
3
2
1
0
0
2
4
6
–1 –3 –6
Rate of bone loss (%)
RRRR
(a)
(b)
Figure 3 (a) Relative risk (RR) of osteoporotic
fractures in women with low bone mass and
accelerated bone loss versus normal controls and those
with high bone mass and slow bone loss. (b) Relative
risk (RR) of osteoporotic fractures as a function of the
rate of bone loss.
*
p < 0.001
+Woman
at
50 years
Woman
at
50 years
Woman
at
50 years
BONE MASS
STATUS
at 50 years
Measurement
of
BIOCHEMICAL
MARKERS
Prediction
of
RATE OF
BONE LOSS
Measurement of
BONE MASS
and
BIOCHEMICAL
MARKERS
Prediction of
BONE MASS
STATUS
at 70 years
=
+=
+=
BONE MASS
measurement
Figure 4 The value of combined bone mass and
biomarker measurements in early-postmenopausal
women for long-term prediction of bone status
HORMONE REPLACEMENT THERAPY
approved medications act sufficiently in bone
compartments comprising mainly trabecular
bone, but the effect at skeletal sites with cortical
bone is less impressive. As an example, Table 2
illustrates the effect of bisphosphonate treatment
at skeletal sites with different ratios of trabecular
to cortical bone. Extrapolating from these
results, the effect of 2 years of treatment would
be to increase trabecular bone by 8% and corti-
cal bone by 0.8%.
In other words, many therapeutic options are
available for the prevention of vertebral frac-
tures, but the prevention of non-vertebral
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HRT for postmenopausal women indicated an
increase in life-expectancy for most post-
menopausal women, since protection against hip
fracture and coronary heart disease would out-
weigh the increase in the risk of breast can-
cer
10,12
. This latter perception was recently chal-
lenged by the Women’s Health Initiative (WHI)
study
13,14
, yet, from the skeletal point of view,
this study was the largest randomized setting
that provided ultimate evidence for the ability of
HRT to protect against hip fracture, the most
feared complication of osteoporosis due to its sig-
nificant contribution to morbidity and mortality
in the elderly. No comparable evidence suggests
that selective estrogen receptor modulators
(SERMs) or bisphosphonates currently available
can provide this therapeutic benefit.
Figure 5 summarizes percentage changes in
spine BMD during treatment with effective
doses of antiresorptive agents, clearly demon-
strating the potentials of HRT (estradiol plus
norethisterone acetate).
Figure 6 indicates that the relative benefits of
HRT were greater at all skeletal sites when com-
pared with an effective daily dose of alendronate
in the Early Postmenopausal Intervention Cohort
(EPIC) trial
15
.
Another critical issue is the percentage of
women who respond to HRT. As shown in Fig-
ure 7, summarizing data from six different trials,
the number of non-responders was very small.
188
0
8
4
Raloxifene
60
mg
Levormelo-
xifene
1.25–40
mg
Alendronate
5
mg
Ibandronate
2.5 mg
Kliogest
1 mg
Kliogest
2 mg
% Change in BMD from baseline
Figure 5 The relative potentials of different antiresorptive treatments for increasing bone mass. Kliogest
®
is
estradiol + norethisterone acetate. BMD, bone mineral density
To ta l
forearm
Total
body
Total
hip
Spine
10
8
6
4
2
0
–2
–4
BMD (%)
E
2
+ NETA
Alendronate 5 mg
Figure 6 Changes in bone mineral density (BMD)
with hormone replacement therapy (estradiol (E
2
) plus
norethisterone acetate (NETA)) versus alendronate at
different skeletal sites
15
POSTMENOPAUSAL OSTEOPOROSIS
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Who are typically the non-responders? We
and others have repeatedly pointed out that
smoking considerably attenuates the efficacy of
oral HRT
16
. In smokers, the increase in serum
estradiol during oral HRT is approximately half
that in non-smokers, which can be explained by
accelerated hepatic degradation of the sex steroid
entering the portal circulation (first-pass effect).
Figure 8 illustrates the phenomenon.
Thus, being a non-responder as a smoker can
be effectively bypassed by prescribing transder-
mal HRT to women who smoke
16
. When in
doubt, measurements of bone turnover may be
informative regarding adequate response to the
applied antiresorptive therapy.
IMPLICATIONS OF THE
PROGESTIN COMPONENT FOR
OVERALL EFFICACY
In women with an intact uterus, HRT means
estrogen plus a progestin therapy. The primary
role of the progestin is to protect the
endometrium from chronic estrogen exposure,
which may promote carcinogenesis and lead to
endometrial cancer. However, observations sug-
gest that selection of the progestin may have
critical implications for overall benefits in terms
of increasing bone mass. Figure 9 illustrates the
effects of different progestins and estradiol either
alone or in combination on BMD during a 2-year
treatment period
17–19
.
Whereas medroxyprogesterone acetate
(MPA) by itself tended to accelerate bone loss
compared with placebo
17,18
, norethisterone
acetate (NETA) tended to decelerate bone loss
20
.
Figure 10 shows results reported by Abdalla and
colleagues illustrating that NETA by itself pro-
vided effective prevention of postmenopausal
bone loss during a 12-month treatment period.
Estrogen alone increases BMD, which can be
further enhanced by NETA but not by MPA
21
.
This phenomenon can be attributed to the slight
androgenic properties of NETA. Whereas oral
estrogen increases sex hormone-binding globulin
secretion from the liver that limits the bioavail-
ability of estradiol, the androgenic properties of
NETA may inhibit this response, ensuring sus-
tained high bioavailability of estradiol. In addi-
tion, androgenic effects may also result in the
stimulation of bone formation
22
.
During conventional HRT there is a rapid
decrease in bone resorption, followed by a slowly
progressive decrease in bone formation (cou-
pling). After 2–3 years of therapy, the increase in
BMD may reach a maximum level
23
. Although
this gain may provide a considerable relative pro-
tection against fractures, in certain cases further
increases would be desirable. The application of
androgenic progestins may maintain a relative
‘uncoupling’ between bone resorption and
189
alpha BMC (% per year)
Pre HRT Placebo
123456
Figure 7 Changes in bone mineral content (BMC)
in premenopausal and postmenopausal women
treated with either placebo or hormone replacement
therapy (HRT) (six different trials). Pre, premeno-
pausal women
E
2
(pmol/l)
Low dose Medium dose High dose
Non-smokers
Smokers
300
250
200
150
100
50
0
Figure 8 Serum estradiol (E
2
) during oral hormone
replacement therapy in non-smokers and smokers
16
HORMONE REPLACEMENT THERAPY
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formation, thereby opening up a wider range of
positive calcium balance (i.e. therapeutic win-
dow). The relative impact of conventional HRT
and some other antiresorptive agents versus
estradiol plus NETA is illustrated in Figure 11.
This extra benefit can be particularly benefi-
cial for preserving or increasing hip BMD. In
other words, due consideration should be given
to this therapeutic option when the aim of ther-
apy is to counter rapid bone loss from the hip and
prevention of hip fracture. Androgenic effects
can potentially facilitate preservation of skeletal
muscle mass, which may have indirect implica-
tions for the prevention of hip fracture (by
decreasing the risk of falls).
KEY CONCLUSIONS
(1) Early-postmenopausal women with low
bone mass and elevated bone turnover are
candidates for HRT;
190
E
Postmenopausal
Bone resorption
Bone formation
Premenopausal
Bone turnover
Negative bone balance
Positive bone balance
Calcitonin Bisphosp. E
+ NETA
Figure 11 The relative impact of different antiresorptive therapies on bone resorption and formation in
postmenopausal women. E, estrogen; NETA, norethisterone acetate; Bisphosph., bisphosphonate
% Change in BMD from baseline
Placebo
MPA
Progesterone
NETA
Estradiol
Estradiol + MPA
–4
–3
–2
–1
1
2
3
4
5
Estradiol + NETA
Figure 9 Individual and combined effects of the
two components of hormone replacement therapy.
BMD, bone mineral density; MPA, medroxypro-
gesterone acetate; NETA, norethisterone acetate
0
40
41
42
43
44
45
612
Time (months)
Metacarpal BMC (mg/mm)
NETA
Placebo
Figure 10 Changes in bone mineral content (BMC)
during 12-month treatment with norethisterone
acetate (NETA)
POSTMENOPAUSAL OSTEOPOROSIS
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HORMONE REPLACEMENT THERAPY
(2) HRT provides effective protection not only
for vertebral but also for non-vertebral
bone;
(3) Smokers should be treated with transdermal
HRT to avoid limited efficacy;
(4) Progestins with androgenic properties such
as NETA may be preferential, especially
when intending to protect the hip.
191
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New physiologic approach to prevention of
postmenopausal osteoporosis
B. Ettinger and J. S. Lee
INTRODUCTION
The purpose of this review is to summarize the
epidemiologic and clinical trial evidence for
estrogen’s physiologic role in skeletal health
among aging women. Emerging data from these
studies indicate a need to redefine the levels at
which estrogen physiologic adequacy is achieved,
and support the use of much lower estrogen
doses than are currently prescribed.
EPIDEMIOLOGIC STUDIES
Multiple epidemiologic studies have shown a
relationship between low endogenous estradiol
levels and low bone mineral density in post-
menopausal women. In the Study of Osteo-
porotic Fractures (SOF) cohort of US women
over age 65 years, estradiol was undetectable
(< 5 pg/ml) in about one out of four. Compared
with these women, those whose endogenous
serum estradiol levels were 10–25 pg/ml had
4.9% higher bone mineral density (BMD) at the
hip and 6.8% higher BMD at the lumbar spine
1
.
In the Rotterdam Study of Dutch women aged
55 years and older, one-third of women had
estradiol levels below 5 pg/ml, and again spinal
BMD was about 6% higher among women
whose serum estradiol levels exceeded 7 pg/ml,
compared with those with very low levels
2
.In
another US cohort of women aged 65–75 years,
one-third had serum estradiol levels less than
9 pg/ml; their hip BMD was 14% lower and
spine BMD was 9% lower than in those women
whose estradiol levels exceeded 13.3 pg/ml
3
.
In these same studies, an inverse relationship
between BMD and sex hormone-binding
globulin (SHBG) was also seen. Estradiol circu-
lates bound to SHBG, and levels of SHBG deter-
mine in large part the amount of bioavailable
estradiol. Higher levels of SHBG lowered
bioavailable circulating estradiol, and this was
linked to lower BMD. These substantial BMD
differences persisted after adjustment for multi-
ple risk factors including body mass index
1–3
.
Bone turnover appears to be an independent
risk factor for fracture
4
. Endogenous estradiol
and bioavailable estradiol are inversely related to
bone turnover; compared with those with higher
levels of endogenous estradiol, women with lev-
els in the lower one-third showed 10–20%
higher levels of bone turnover markers
1,3
.
As expected from these key physiologic differ-
ences in BMD and bone turnover, women with
very low estradiol levels have been uniformly
shown to have higher risks for fracture
1,2,4,5
. In
the SOF cohort, very low estradiol was associated
with more than twice the risk of hip or spine frac-
ture (Figure 1), and adjustment for estradiol
binding to SHBG further strengthened the asso-
ciations between estradiol and fracture risk (Fig-
ure 2)
5
. Associations between serum estradiol and
fracture risk have now been confirmed in two
European cohorts
2,4
. In the OFELY observational
study (Os des Femmes de Lyon) of post-
menopausal French women aged 50–89 years
(mean age 64 years), during 5 years of follow-up,
women with low endogenous serum estradiol lev-
els had twice the risk of any fracture than did
women with higher levels of serum estradiol (Fig-
ure 3)
4
. In the Rotterdam Study, compared with
women with estradiol levels > 7 pg/ml, those
with levels < 5 pg/ml showed twice the risk of
incident vertebral fracture during 6.5 years of fol-
low-up (Figure 4)
2
. This latter study also con-
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