Estrogen therapy for osteoporosis in the modern era

Abstract

Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal women to receive appropriate guidance for the prevention and management of osteoporosis. The Women’s Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone, leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used. This review will focus on the prior and current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT.

Full text

CONCISE CLINICAL REVIEW
Estrogen therapy for osteoporosis in the modern era
V. A. Levin
1
&X. Jiang
1,2
&R. Kagan
3,4
Received: 26 November 2017 /Accepted: 24 January 2018 /Published online: 8 March 2018
#International Osteoporosis Foundation and National Osteoporosis Foundation 2018
Abstract
Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral
density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered
one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal
women to receive appropriate guidance for the prevention and management of osteoporosis. The Women’s Health Initiative
(WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures
in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone,
leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for
osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of
HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and
reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal
HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD),
and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in
menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be
considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and
the once Blowest dose for shortest period of time^concept should no longer be used. This review will focus on the prior and
current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of
low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT.
Keywords Bone mineral density (BMD) .Hormone therapy (HT) .Menopause .Osteoporosis
Clinical relevance
Osteoporosis is a disorder that affects the integrity and
strength of bones. Specifically, it results in low bone mass,
microarchitectural disruption, skeletal fragility, and decreased
bone strength, leading to increased risk of fracture [1].
Osteoporotic fractures lead to substantial morbidity and mor-
tality [2]. Therefore, it is imperative to establish best practice
guidelines to prevent and treat osteoporosis in postmenopaus-
al women, the greatest affected population.
Many factors affect bone development and architecture,
with endogenous estrogen being a major component in evo-
lution of bone. Since the major cause of osteoporosis in men-
opause is the loss of bone due to estrogen deficiency, hormone
therapy (HT) is a rational therapy to use for prevention of
osteoporosis [3]. HT in the form of either combined estrogen
and progesterone or estrogen alone has been shown to be
effective in reducing the number of both vertebral and
non-vertebral fractures in postmenopausal women [4], with
efficacy equivalent to that of bisphosphonates [5–7].
The Women’s Health Initiative (WHI) was the largest
evidence-based long-term randomized clinical trial (RCT) in
The URL for CME credit is https://cme.nof.org/Activity/6238861/Detail.
aspx
*R. Kagan
kaganr@Sutterhealth.org
1
Department of ObGyn, The Reading Hospital of Tower Health,
Reading, PA, USA
2
Department of ObGyn, Sidney Kimmel Medical College of Thomas
Jefferson University, Philadelphia, PA, USA
3
Department of Obstetrics, Gynecology and Reproductive Sciences,
UCSF, San Francisco, CA, USA
4
Sutter East Bay Medical Foundation, 2500 Milvia Street,
Berkeley, CA 94704, USA
Osteoporosis International (2018) 29:1049–1055
https://doi.org/10.1007/s00198-018-4414-z

women aged 50 to 79 years, showing various effects of HT,
including prevention of fractures at the hip, vertebrae, and
other sites [8]. This was significant as the study subjects in
both arms of the WHI-HT were patients not necessarily at
increased risk of fracture. Thus, prior studies showing HT
for prevention of bone loss and osteoporosis-related fractures
were supported by the findings in the WHI-HT [8].
The primary endpoint of WHI-HT was efficacy of HT in
prevention of coronary vascular events and not its effect on
bone fracture risk [9]. The estrogen plus progestin (CEE +
MPA) arm of the study was discontinued in 2002 after
5.6 years of follow-up due to increased risks of invasive breast
cancer, coronary heart disease events, stroke, and pulmonary
embolism among treated women [10,11]. Subsequently, the
estrogen (CEE) alone arm of the study was discontinued in
2004 after almost 7 years of follow-up due to increased risk of
stroke in the treatment group; however, unlike combined hor-
mone treatment with estrogen and progestin, estrogen alone
did not appear to affect (either increase or decrease) heart
disease or increase the risk of breast cancer. Just as the com-
bined therapy, estrogen alone showed a reduction in the risk of
hip fracture [6]. These published findings were shocking, cre-
ated havoc, and resulted in a paradigm shift with women
discontinuing HT around the world. Moreover, medical soci-
eties based their recommendations for treatment of osteoporo-
sis solely on this data, dismissing the benefit of HT on bone
stabilization and prevention of fracture.
While the WHI is the largest RCT shedding light on HT, it
was limited to the evaluation of two hormone formulations:
conjugated equine estrogen (CEE) 0.625 mg/day +
medroxyprogesterone acetate (MPA) 2.5 mg/day or CEE
0.625 mg/day alone. It was also limited to one dose of estro-
gen (CEE 0.625 mg daily) and an oral route of administration
[6,9,12]. Furthermore, it is difficult to extrapolate the results
of the WHI to the general population as the subjects were
older, past the average age of menopause (mean age of
63.3 years), further away from initiation of menopause (mean
length of time since menopause > 12 years), and asymptom-
atic women [5,9,12].
Given these limitations and results from subsequent
studies, other governing bodies, such as the American
College of Obstetricians and Gynecologists (ACOG), the
International Menopause Society (IMS), the North
American Menopause Society (NAMS), and others, pro-
posed updated recommendations for HT in menopausal
women. Subsequent studies evaluated different dosages
and routes of estrogen therapy, including the transdermal
patch and ultra-low-dose estrogens, to assess potential ben-
efits on bone preservation while minimizing the proposed
risks of HT observed in the WHI. This clinical review will
summarize these studies and new recommendations for HT
as a primary prevention and treatment for osteoporosis in
appropriately selected postmenopausal women.
Observations
Randomized controlled trials and observational studies show
that standard-dose HT, which was proposed by the manufac-
turer and approved by registration authorities to suit the aver-
age patient needs, reduces postmenopausal osteoporotic frac-
tures of the hip, spine, and all non-spine fractures in women
with and without osteoporosis [5,6,13]. In the WHI-HT, both
intervention arms combined (CEE + MPA and CEE alone)
showed statistically significant reduced hip fracture incidence
of 33% (p= 0.03), with six fewer fractures per 10,000 person-
years overall [13]. The 2016 IMS Recommendations on men-
opause hormone therapy (MHT) stated that in the age group
50–60 years or within 10 years after menopause, the benefits
of MHT are most likely to outweigh any risk and can be
considered as first-line therapy for fracture prevention [14].
The initiation of standard HTafter the age of 60 years or more
than 10 years after menopause exclusively for fracturepreven-
tion must be individualized and is not generally recommend-
ed. Conversely, the American College of Physicians (ACP)
supported against HT in their clinical practice guideline for
the treatment of osteoporosis in women, stating that high-
quality evidence from the WHI showed that HTwas associat-
ed with increased risk for venous thromboembolic (VTE),
cerebrovascular events, invasive breast cancer, and node-
positive tumors in one study [15].
On the other hand, the National Institute for Health and
Care Excellence (NICE) proposed that the route of HT can
impact the severity of adverse events, suggesting that there
are alternative routes of HT that can benefit postmenopausal
women [16]. Warming and colleagues, in their 2-year study
comparing a combination HT transdermal patch versus a pla-
cebo among osteopenic postmenopausal women, showed that
BMD measurements at the lumbar spine, hip, and total body
increased by 8, 6, and 3% (p< 0.001) in the HT groups com-
pared to placebo [17]. A recently published meta-analysis of
nine clinical trials showed that 1–2-year use of transdermal
estrogen was associated with 3.4–3.7% increase in lumbar
spine BMD compared to baseline [18]. Scarbin et al. in a
multicenter hospital-based case-control study showed that oral
(OR [95% CI] = 3.5 [1.8–6.8]) but not transdermal estrogen
(OR [95% CI] = 0.9 [0.5–1.6]) is associated with increased
risk of VTE in postmenopausal women. Additionally, those
who used oral therapies had an estimated VTE risk of 4.0
(95% CI 1.9–8.3) compared with women using transdermal
regimens [19]. Similar results were reported elsewhere
[20–23]. On the contrary, the results of the Kronos Early
Estrogen Prevention Study (KEEPS), a 4-year double-blinded
RCT of low-dose oral or transdermal estrogen or placebo giv-
en to healthy women ages 42 to 59 within 3 years after men-
opause, suggested no statistically significant differences in
rates of VTE between the three groups; however, the absolute
numbers of adverse events were very small in all three
1050 Osteoporos Int (2018) 29:1049–1055

treatment groups, making definitive conclusions impossible
[24]. Further RCTs or population-based prospective studies
are needed to corroborate these findings.
Compared with oral estrogen therapy (ET), transdermal ET
is associated with greater reduction in sympathetic tone, little
to no increases in C-reactive protein, and an overall reduced
risk for atherosclerotic vascular disease [12,25]. These differ-
ences can be explained by physiology as transdermal estrogen
avoids first-pass metabolism in the liver, which permits the
administration of lower doses of unmetabolized estradiol di-
rectly to the blood stream, avoiding overproduction of triglyc-
erides. Multiple studies showed statistically significant reduc-
tion in serum triglyceride levels with the transdermal route
compared to increased triglyceride levels with oral therapy
[20,26–29]. Decreased triglycerides result in decreased car-
diovascular events in postmenopausal women. Additionally,
because oral estrogens affect hepatic lipid metabolism and
may lead to supersaturation of bile acids by cholesterol and
gallstone formation, postmenopausal women taking oral ET
may have increased risk of gallbladder disease, cholecystec-
tomy, and biliary tract surgery [9]. As stated above, transder-
mal ET may avoid this increased risk due to absence of first-
pass metabolism [9]. Furthermore, previous studies have dem-
onstrated that transdermal estrogen decreases the incidence of
coronary artery disease (CAD) by reducing systolic blood
pressure and vascular resistance, while elevating cardiac
stroke volume and cardiac output [18,30,31]. These findings
suggest that transdermal estrogen not only preserves BMD,
but also may serve as cardio-protection for young postmeno-
pausal women [18]. On the other hand, it is important to un-
derstand that HT should not be solely used for either primary
or secondary prevention of cardiovascular disease. This was
supported by a meta-analysis by Boardman et al. which inves-
tigated the prevention of cardiovascular disease via HT in
40,410 postmenopausal women. The analysis concluded that
primary or secondary prevention of cardiovascular disease
events via HT has minimal benefit and can cause an increase
in the risk of stroke and venous thromboembolic events [32].
They did, however, find through subgroup analysis that those
who started HT less than 10 years after menopause had lower
mortality and coronary heart disease [32].
In addition to differences in route of administration, ET
differs in risk-benefit profile depending on the dosage of
estrogen used with lower doses of estrogen still preserving
BMD. Commonly used low and ultra-low doses of estrogen
listed in Table 1not only minimize the risks of ET, but also
make it possible for clinicians to offer estrogen monotherapy
using less often progestogen (e.g., q 6–12 month) to women
with intact uterus for endometrial protection. This is of course
only in the setting of careful monitoring for abnormal uterine
bleeding and performing endometrial biopsy if indicated [33,
34]. Genant et al. showed in a 2-year RCT that 101 women
receiving continuous unopposed oral esterified estrogens
(EEs) at 0.3 mg/day had positive bone and lipid changes with-
out inducing clinically relevant endometrial hyperplasia [35].
EEs and CEEs have been found to produce similar serum
levels of estrone and estradiol [36], with less risk of VTE
associated with EEs relative to CEEs [37]. Prestwood et al.
showed that oral ultra-low-dose micronized 17β-estradiol at
0.25 mg/day not only reduced biochemical markers of bone
turnover to a degree comparable to an estrogen dose of
1.0 mg/day, but the lower dose estrogen resulted in a side
effect profile similar to that of placebo [38]. They found in a
subsequent RCT that oral ultra-low-dose micronized 17β-
estradiol at 0.25 mg/day for 3 years compared to placebo
resulted in significant increases in hip, spine, and total BMD
among postmenopausal women [39]. The effect on bone pres-
ervation with low-dose estrogen therapy has also been ob-
served with the transdermal route. It has been observed that
women given transdermal estradiol at either the conventional
0.050 mg/day dosing or the half strength dose of 0.025 mg/
day resulted in a reduction in bone turnover markers to a
similar degree [40].
Furthermore, lower than standard doses of estrogen thera-
py, regardless of route of administration, have been shown to
serve the dual purpose of preserving BMD and relieving men-
opausal symptoms [9]. This was seen in a 12-week RCT of
324 women who received a low-dose, 7-day matrix estradiol
transdermal system that delivers 0.025 mg of 17β-estradiol
daily for 7 days and experienced relief in their vasomotor
symptoms, namely a decrease in hot flush frequency by 84%
[41]. Ettinger et al. showed that even a lower dose of trans-
dermal estradiol at 0.014 mg/day, which is adequate for hot
flash relief in some women, has beneficial skeletal benefits
[42]. This was also seen in the HOPE (Health, Osteoporosis,
Progestin, Estrogen) trial: a large RCT with lower doses of
Table 1 Bone-sparing doses of
estrogen FDA-approved dose* Commonly used low
or ultra-low dose
Oral conjugated estrogens (mg/day) 0.625 0.45 or 0.3
Oral micronized 17β-estradiol (mg/day) 0.5 0.25
Oral esterified estrogens (mg/day) 0.3 –
Transdermal 17β-estradiol (μg/day) 25 14
*Source: Epocrates in athenahealth® version 16.11 (last updated on Jan 9, 2018)
Osteoporos Int (2018) 29:1049–1055 1051

CEE (0.45 and 0.3 mg/day), with or without a lower dose of
MPA (1.5 mg/day). Findings showed prevention of the loss of
spine and hip BMD, reduced bone turnover, improvement in
vasomotor symptoms, vaginal atrophy, lipid profiles, bleeding
profiles, and endometrial hyperplasia in women on HT
[43–47].
Despite the decreased estrogen levels in menopausal wom-
en and the clear benefits of HT, bisphosphonates, instead of
HT, are the first-line therapy for the primary prevention of
osteoporosis. However, currently available RCTs on efficacy
of bisphosphonates for primary prevention of osteoporosis
neither showed nor had adequate power to support fracture
prevention in non-osteoporotic women [48]. Indeed, only oral
CEE has been shown to reduce the risk of fracture in both
osteoporotic and non-osteoporotic women [2]. National
Osteoporosis Foundation (NOF) guidelines [49]recommend
pharmacotherapy for postmenopausal women with low bone
mass (T-score between −1.0 and −2.5), if the Fracture Risk
Assessment Tool (FRAX) calculated a 10-year probability of
hip fracture (HF) reaches 3% or a 10-year probability of any
major osteoporosis-related fracture (MOF) is ≥20%. The ac-
curacy of FRAX using aforementioned 10-year USA treat-
ment threshold for fracture risk prediction has been questioned
by a meta-analysis of seven large population-based longitudi-
nal cohort studies from five countries [50]. The study findings
suggest that a substantial number of patients who developed
fractures, especially MOF within 10 years of follow up, were
missed by the baseline FRAX assessment using the 10-year
intervention thresholds of 20% for MOF and 3% for HF [50].
Therefore, correctly identifying and subsequently treating
those non-osteoporotic menopausal women at risk of fracture
remains a challenge. Due to dual benefits of HT on bone and
vasomotor symptoms (VMS), young peri- or postmenopausal
women with VMS and low bone mass are the best candidates
for hormone monotherapy, provided no contraindication ex-
ists. Otherwise, bisphosphonates can be combined with a se-
lective serotonin reuptake inhibitor (SSRI) to aid in prevention
of osteoporosis and treatment of VMS [51]. Selective estrogen
receptor modulators (SERMs), such as raloxifene (60 mg/
day), have been shown to increase BMD and reduce the risk
of vertebral fractures but not non-vertebral fractures in women
with osteoporosis [52]. A single oral pill of bazedoxifene/CEE
(20/0.45 mg) is also available in the USA for the treatment of
VMS and prevention of postmenopausal osteoporosis; how-
ever, there are no fracture data for this therapy [48]. While HT
can have significant side effects, the above alternative thera-
pies also have contraindications and side effects that maybe
just as harmful. Adverse effects of raloxifene include venous
thromboembolism (VTE), leg cramps, and death from stroke
[1]. Side effects of bisphosphonates include osteonecrosis of
the jaw, abnormal bone histology, and associations with atyp-
ical femur fractures (AFF) [1,51,53]. Furthermore, gastroin-
testinal side effects are common in that 30% of women require
proton pump inhibitors (PPI), which themselves can have neg-
ative effects on bone health. PPI in observational studies have
been found to decrease BMD and increase osteoporotic hip
fractures after 5 years of use [51,53]. Of interest, studies of
bone histology in osteoporotic women taking transdermal es-
tradiol for 6 years showed that estrogen correlates with con-
tinuing collagen production evidenced by increase in collagen
as well as intermediate and mature collagen cross-links in
cancellous and cortical bone [54–56]. A study evaluating in-
tervertebral discs that are 100% collagen and make up one-
quarter of the length of the spine showed that estrogens protect
the spine by maintaining the size of the individual and total
intervertebral disc space as well as the length of the spine;
however, bisphosphonates do not [54,57]. While
bisphosphonates and raloxifene demonstrate fracture preven-
tion in women with osteoporosis, there is no data regarding
fracture reduction among women without osteoporosis.
The continued effect on BMD and fracture prevention after
discontinuing osteoporosis therapies remains a concern. It is
suggested that there may be residual BMD and fracture benefit
after discontinuation of bisphosphonate therapy, making this
an appealing option [1]. On the other hand, most studies show
no lasting benefit on bone after estrogen discontinuation.
Bone loss following discontinuation of HT is similar to bone
loss following menopause, often referred to as Bcatch up bone
loss^[58]. However, recently published research findings
from two WHI-HT trials (CEE + MPA and CEE alone) sug-
gested no evidence for increased fracture risk 5 years after
stopping HT among former HT users compared with former
placebo users. The study also showed residual benefit for total
fractures in former HT users from the CEE-alone trial [59]. If
HT needs to be discontinued in women at high risk of fracture,
the 2014 NOF guideline recommends that it should be re-
placed with another pharmacological agent such as bisphos-
phonate or denosumab for continued bone protection [60].
Conclusions
Physicians around the world reserve the use of HT to women
with moderate-severe vasomotor symptoms with the concept
of Blowest dose for the shortest period of time^despite the
various benefits of HT, including prevention and management
of osteoporosis, improved sexual function in women with
vaginal atrophy, decreased cardiovascular events, improved
mood, and overall improved quality of life [13]. This practice
was a direct result of the initial data presented from the WHI
studies. However, given the limitations of the WHI and sub-
sequent studies showing multiple benefits of HT, it is essential
to challenge biases and reservations of HT for women. More
importantly, physicians should consider the role of HT with
the concept of Bappropriate dose, duration, regimen, and route
of administration^as this can differ for each patient [13,61].
1052 Osteoporos Int (2018) 29:1049–1055

HT has been shown to be efficacious in reducing the num-
ber of vertebral and non-vertebral fractures in postmenopausal
women, with efficacy equivalent to that of bisphosphonates
[5–7]. Furthermore, HT decreases the incidence of all
osteoporosis-related fractures, including vertebral and hip
fractures, even in women not at high risk of fracture and
women not diagnosed with osteoporosis [8]. HT should be
offered to menopausal woman younger than 60 years of age
or within 10 years of menopause, especially those with VMS,
for primary prevention and treatment of osteoporosis [3,8,13,
53]. Shared decision making is always recommended while
counseling patients about the benefits/risks of HT.
Ultra-low dose of transdermal estradiol (14 μg per day)
monotherapy for 2 years has shown a significant increase in
BMD and prevention of bone loss without increased risk of
endometrial hyperplasia and vaginal bleeding compared to
placebo [62]; however, the prescription of low-dose estrogens
in monotherapy in women with an intact uterus is not current-
ly recommended and requires adequate surveillance in highly
selected patients. Perhaps ultra-low-dose transdermal estradiol
(Table 1) can be given to women aged 60 and older for the
modest increases in estrogenic action to preserve skeletal in-
tegrity without significant breast effects and endometrial stim-
ulation due to the lower progestogen dose required for endo-
metrial protection [3]. Additionally, the use of transdermal
preparations has been shown to less likely increase the risk
of VTE, stroke, and CAD than oral preparations. Thus, these
low-dose non-oral HT options may be considered for women
with cardiovascular risk factors (e.g., diabetes, hypertension,
and obesity), women of advancing age, and for those who
choose extended duration use of HT for bone protection [42,
61,63].
Learning objectives
1. To learn the emerging evidence on estrogen therapy and
revisit the role of estrogen for primary prevention and
treatment of osteoporosis.
2. To understand that risk profiles of estrogen therapy vary
depending on formulation, dosage, duration, and route of
administration.
3. To comprehend the necessity of adjusting the once
Blowest dose for shortest period of time^concept to
Bappropriate dose, duration, regimen, and route of
administration^individualized to each patient.
Clinical tips
1. Hormone therapy (HT) should be offered for the primary
prevention and treatment of osteoporosis in appropriate
menopausal women younger than 60 years of age or with-
in 10 years of menopause, especially when menopausal
symptoms are present.
2. Emerging evidence suggests that the once Blowest dose
for shortest period of time^concept should be adjusted to
Bappropriate dose, duration, regimen, and route of
administration^individualized to each patient
3. Transdermal and low-dose HT have shown to have a low
adverse effect profile while still proving to be efficacious
in increasing BMD. Lack of documented benefit of
bisphosphonates for non-osteoporotic women along with
unique physiologic impact and dual benefits of non-oral
HT regimens, including ultra-low-dose regimens, the use
of appropriate estrogen or HT regimens for the primary
prevention of osteoporosis should be considered even in
selected women who are not suffering from severe
menopause-associated symptoms.
Compliance with ethical standards
Conflict of interest None for VL andXJ, R Kagan has received research
grants and support from Therapeutics MD (paid to Sutter Health), and has
served as a consultant to Amgen, Merck, and Pfizer.
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