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Estrogen therapy for osteoporosis in the modern era

  • Reading Hospital Tower Health


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.
Estrogen therapy for osteoporosis in the modern era
V. A. Levin
&X. Jiang
&R. Kagan
Received: 26 November 2017 /Accepted: 24 January 2018 /Published online: 8 March 2018
#International Osteoporosis Foundation and National Osteoporosis Foundation 2018
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 Womens 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 [57].
The Womens Health Initiative (WHI) was the largest
evidence-based long-term randomized clinical trial (RCT) in
The URL for CME credit is
*R. Kagan
Department of ObGyn, The Reading Hospital of Tower Health,
Reading, PA, USA
Department of ObGyn, Sidney Kimmel Medical College of Thomas
Jefferson University, Philadelphia, PA, USA
Department of Obstetrics, Gynecology and Reproductive Sciences,
UCSF, San Francisco, CA, USA
Sutter East Bay Medical Foundation, 2500 Milvia Street,
Berkeley, CA 94704, USA
Osteoporosis International (2018) 29:10491055
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.
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
5060 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 12-year use of transdermal
estrogen was associated with 3.43.7% 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 [1.86.8]) but not transdermal estrogen
(OR [95% CI] = 0.9 [0.51.6]) 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 1.98.3) compared with women using transdermal
regimens [19]. Similar results were reported elsewhere
[2023]. 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) 29:10491055
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
[20,2629]. 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 612 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) 29:10491055 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
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 [5456]. 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].
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) 29:10491055
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
[57]. 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,
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
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.
1. American College of Obstetrics and Gynecologists (2016) Practice
Bulletin Number 129: Osteoporosis
2. Kosla S, Cauly J, Compston J et al (2017) Addressing the crisis in
the treatment of osteoporosis: a path forward. J Bone Miner Res
3. Gambacciani M, Levancini M (2014) Hormone replacement thera-
py and the prevention of postmenopausal osteoporosis. Prz
Menopauzalny 13(4):213220
4. Jin J (2017) Hormone therapy for primary prevention of chronic
conditions in postmenopausal women. JAMA 318(22):2265
5. Cauley JA, Robbins J, Chen Z, Womens Health Initiative
Investigators et al (2003) Effects of estrogen plus progestin on risk
of fracture and bone mineral density:the Womens Health Initiative
randomized trial. JAMA 290:17291738
6. Anderson GL, Limacher M, Assaf AR, Womens Health Initiative
Steering Committee et al (2004) Effects of conjugated equine estro-
gen in postmenopausal women with hysterectomy: the Womens
Health Initiative randomized controlled trial. JAMA 291:17011712
7. Sheu A, Center J (2017) Osteoporosis in postmenopausal women:
key aspects of prevention and treatment. Med Today 18(4):2938
8. de Villliers TJ, Stevenson JC (2012) The WHI: the effect of hor-
mone replacement therapy on fracture prevention. Climacteric 15:
9. Richman S, Edusa V, Fadiel A, Naftolin F (2006) Low-dose estro-
gen therapy for prevention of osteoporosis: working our way back
to monotherapy. Menopause 13(1):148155
10. Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and
benefits of estrogen plus progestin in healthy postmenopausal
women: principal results from the Womens Health Initiative ran-
domized controlled trial. JAMA 288(3):321333
11. Fletcher SW, Colditz GA (2002) Failure of estrogen plus progestin
therapy for prevention. JAMA 288(3):366368
Osteoporos Int (2018) 29:10491055 1053
12. Shulman LP (2008) Transdermal hormone therapy and bone health.
Clin Interv Aging 3(1):5154
13. The North American Menopause Society (2017) The 2017 hor-
mone therapy position statement of the North American
Menopause Society. Menopause: J N Am Menopause Soc 24(7):
14. Baber RJ, Panay N, Fenton A, the IMS Writing Group (2016) 2016
IMS Recommendations on womens midlife health and menopause
hormone therapy. Climacteric 19(2):109150
15. Qaseem A, Forciea MA, McLean RM et al (2017) Treatment of low
bone density or osteoporosis to prevent fractures in men and wom-
en: a clinical practice guideline update from the American College
of Physicians. Ann Intern Med 166(11):818839
16. National Collaborating Centre for Womens and ChildrensHealth
(UK). Menopause: full guideline. London: National Institute for
Health and Care Excellence (UK); 2015 Nov 12. (NICE
Guideline, No. 23.) 11, long-term benefits and risks of hormone
replacement therapy (HRT) Available at https://www.ncbi.nlm. Accessed 9 Jan 2018
17. Warming L, Ravn P, Christiansen C (2005) Levonorgestrel and 17
beta-estradiol given transdermally for the prevention of postmeno-
pausal osteoporosis. Maturitas 50:7885
18. Abdi F, Mobedi H, Bayat F, Mosaffa N, Dolatian M, Tehrani F
(2017) The effects of transdermal estrogen delivery on bone mineral
density in postmenopausal women: a meta-analysis. Iranian J of
Pharm Res 16(1):380389
19. Scarabin P-Y, Oger E, Plu-Bureau G et al (2003) Differential asso-
ciation of oral and transdermal estrogen-replacement therapy with
venous thromboembolism risk. Lancet 362:428432
20. Canonico M, Oger E, Plu-Bureau G et al (2007) Estrogen and
Thromboembolism Risk (ESTHER) Study Group. Hormone thera-
py and venous thromboembolism among postmenopausal women:
impact of the route of estrogen administrationand progestogens: the
ESTHER study. Circulation 115:840845
21. Laliberte F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P
(2011) Does the route of administration for estrogen hormone ther-
apy impact the risk of venous thromboembolism? Estradiol trans-
dermal system versus oral estrogen-only hormone therapy.
Menopause 18:10521059
22. Olie V, Canonico M, Scarabin PY (2010) Risk of venous thrombo-
sis with oral versus transdermal estrogen therapy among postmen-
opausal women. Curr Opin Hematol 17:457463
23. Renoux C, Dellaniello S, Garbe E, Suissa S (2010) Transdermal
and oral hormone replacement therapy and the risk of stroke: a
nested case-control study. BMJ 340:c2519
24. KEEPS report: KEEPS results give new insight into hormone ther-
apy. Available at
2012-meeting/keeps-report. Accessed 9 Jan 2018
25. Cobin RH, Goodman NF (2017) American Association of Clinical
Endocrinologists and American College of Endocrinology position
statement on menopause2017 update. Endocr Pract 23(7):869880
26. Adami S, Rossini M, Zamberlan N, Bertoldo F, Dorizzi R, Lo
Cascio V (1993) Long-term effects of transdermal and oral estro-
gens on serum lipids and lipoproteins in postmenopausal women.
Maturitas 17(3):191196
27. Stevenson JC, Crook D, Godsland IF, Lees B, Whitehead MI
(1993) Oral versus transdermal hormone replacement therapy. Int
J Fertil Menopausal Stud 38(Suppl 1):3035
28. Crook D, Cust MP, Gangar KF et al (1992) Comparison of transder-
mal and oral estrogen-progestin replacement therapy: effects on se-
rum lipids and lipoproteins. Am J Obstet Gynecol 166(3):950955
29. Smith GI, Reeds DN, Okunade AL, Patterson BW, Mittendorfer B
(2014) Systemic delivery of estradiol, but not testosterone or progester-
one, alters very low density lipoprotein-triglyceride kinetics in post-
menopausal women. J Clin Endocrinol Metab 99(7):E1306E1310
30. West SG, Hinderliter AL, Wells EC, Girdler SS, Light KC (2001)
Transdermal estrogen reduces vascular resistance and serum choles-
terol in postmenopausal women. Am J Obstet Gynecol 184:926933
31. Cacciatore B, Paakkari I, Hasselblatt R, Nieminen MS, Toivonen J,
Tikkanen MI (2001) Randomized comparison between orally and
transdermally administered hormone replacement therapy regimens
of long-term effects on 24-hour ambulatory blood pressure in post-
menopausal women. Am J Obstet Gynecol 184:904909
32. Boardman HM, Hartley L, Eisinga A et al (2015) Hormone therapy
for preventing cardiovascular disease in post-menopausal women.
Cochrane Database Syst Rev 10(3):CD002229
33. Feeley K, Wells M (2001) Hormone replacement therapy and the
endometrium. J Clin Pathol 54(6):435440
34. Ettinger B, Pressman A, Van Gessel A (2001) Low-dosage esteri-
fied estrogens opposed by progestin at 6-month intervals. Obstet
Gynecol 98(2):205211
35. Genant HK, Lucas J, Weiss S et al (1997) Low-dose esterified
estrogen therapy: effects on bone, plasma estradiol concentrations,
endometrium, and lipid levels. Estratab/Osteoporosis Study Group.
Arch Intern Med 157:26092615
36. Lemaitre RN, Weiss NS, Smith NL et al (2006) Esterified estrogen
and conjugated equine estrogen and the risk of incident myocardial
infarction and stroke. Arch Intern Med 166(4):399404
37. Smith NL, Heckbert SR, Lemaitre RN et al (2004) Esterified estro-
gens and conjugated equine estrogens and the risk of venous throm-
bosis. JAMA 292(13):15811587
38. Prestwood KM, Kenny AM, Unson C, Kulldorff M (2000) The
effect of low dose micronized 17[beta]-estradiol on bone turnover,
sex hormone levels, and side effects in older women: a randomized,
double blind, placebo-controlled study. J Clin Endocrinol Metab
39. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M (2003)
Ultralow-dose micronized 17[beta]-estradiol and bone density and
bone metabolism in older women. A randomized controlled trial.
JAMA 290:10421048
40. Sharp CA, Evans SF, Risteli L, Risteli J, Worsfold M, Davie MWJ
(1996) Effects of low- and conventional-dose transcutaneous HRT
over 2 years on bone metabolism in younger and older postmeno-
pausal women. Eur J Clin Investig 26:763771
41. Speroff L, Whitcomb RW, Kempfert NJ, Boyd RA, Paulissen JB,
Rowan JP (1996) Efficacy and local tolerance of a low-dose, 7-day
matrix estradiol transdermal system in the treatment of menopausal
vasomotor symptoms. Obstet Gynecol 88:587592
42. Ettinger B, Ensrud KE, Wallace R et al (2004) Effects of ultralow-
dose transdermal estradiol on bone mineral density: a randomized
clinical trial. Obstet Gynecol 104(3):443451
43. Lindsay R, GallagherC, Kleerekoper M et al (2002) Effect of lower
doses of conjugated equine estrogens with and without
medroxyprogesterone acetate on bone in early postmenopausal
women. JAMA 287:26682676
44. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH
(2001) Relief of vasomotor symptoms and vaginal atrophy with
lower doses of conjugated equine estrogens and
medroxyprogesterone acetate. Fertil Steril 75(6):10651079
45. Lobo RA, Bush T, Carr BR, Pickar JH (2001) Effects of lower
doses of conjugated equine estrogens and medroxyprogesterone
acetate on plasma lipids and lipoproteins, coagulation factors, and
carbohydrate metabolism. Fertil Steril 76(1):1324
46. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH (2001)
Effects of lower doses of conjugated equine estrogens and
medroxyprogesterone acetate on endometrial bleeding. Fertil
Steril 75(6):10801087
47. Pickar JH, Yeh I-T, Wheeler JE, Cunnane MF, Speroff L (2001)
Endometrial effects of lower doses of conjugated equine estrogens
and medroxyprogesterone acetate. Fertil Steril 76(1):2531
1054 Osteoporos Int (2018) 29:10491055
48. Lewiecki EM Prevention of osteoporosis, UpToDate. Available at
source=see_link#H3961780. Accessed 9 Jan 2018
49. Cosman F, de Beur SJ, LeBoff MS et al (2014) Cliniciansguideto
prevention and treatment of osteoporosis. Osteoporos Int 25(10):
50. Jiang X, Gruner M, Trémollieres F et al (2017) Diagnostic accuracy
of FRAX in predicting the 10-year risk of osteoporotic fractures
using the USA treatment thresholds: a systematic review and me-
ta-analysis. Bone 99:2025
51. Studd J (2009) Why are physicians reluctant to use estrogens for
anythingor do they prefer PROFOX?MenopauseInt15:5254
52. Ettinger B, Black DM, Mitlak BH et al (1999) Reduction of verte-
bral fracture risk in postmenopausal women with osteoporosis treat-
ed with raloxifene: results from a 3-year randomized clinical trial.
Multiple Outcomes of Raloxifene Evaluation (MORE)
Investigators. JAMA 282(7):637645
53. Studd J (2011) PROFOX’—the post HRT nightmare. Climacteric
54. Studd J (2009) Estrogens as first-choice therapy for osteoporosis pre-
vention and treatment in women under 60. Climacteric 12:206209
55. Khastgir G, Studd JWW, Holland N et al (2001) Anabolic effect of
estrogen replacement on bone in postmenopausal women with os-
teoporosis: histomorphometric evidence in a longitudinal study. J
Clin Endocrinol Metab 86:289295
56. Khastgir G, Studd J, Holland N et al (2001) Anabolic effect of long-
term estrogen replacement on bone collagen in elderly postmeno-
pausal women with osteoporosis. Osteoporosis Int 12:465470
57. Muscat Baron Y, Brincat MP, Galea R, Calleja N (2007) Low in-
tervertebral disc height in postmenopausal women with osteoporot-
ic vertebral fractures compared to hormone-treated and untreated
postmenopausal women and premenopausal women without frac-
tures. Climacteric 10:314319
58. FA Tm, Pouilles JM, Ribot C (2001) Withdrawal of hormone re-
placement therapy is associated with significant vertebral bone loss
in postmenopausal women. Osteoporos Int 12:385390
59. Watts NB, Cauley JA, Jackson RD et al (2017) No increase in
fractures after stopping hormone therapy: results from the womens
health initiative. J Clin Endocrinol Metab 102(1):302308
60. An expert committee of the National Osteoporosis Foundation
(2014) The clinicians guide to prevention and treatment of osteo-
porosis. Available at
20OSTEOPOROSIS.pdf. Accessed 9 Jan 2018
61. Lobo R, Pickar J, Stevenson J, Mack W, Hodis H (2016) Back to
the future: hormone replacement therapy as part of a prevention
strategy for women at the onset of menopause. Atherosclerosis
62. Johnson SR, Ettinger B, Macer JL, Ensrud KE, Quan J, Grady D
(2005) Uterine and vaginal effects of unopposed ultralow-dose
transdermal estradiol. Obstet Gynecol 105(4):779787
63. Kaunitz AM (2014) Extended duration use of menopausal hormone
therapy. Menopause 21(6):679681
Osteoporos Int (2018) 29:10491055 1055
... Thyroid hormones are responsible for bone growth and development at physiologic levels. Studies have reported that the balance between bone formation and resorption is disrupted in postmenopausal women due to decreasing estrogen levels in the postmenopausal period and the risk of osteopenia and osteoporosis increases [13]. Since it is assumed that there is no or minimal loss of bone mass in the premenopausal period [14], only premenopausal women were included in the study among LT4 users. ...
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Background Long-term use of L-Thyroxine (LT4), the synthetic thyroxine hormone used for thyroid hormone replacement therapy, is an important risk factor for osteoporosis. The aim of this study was to investigate the differences between mandibular cortical index (MCI) and trabecular bone fractal dimension (FD) values on panoramic radiographs of patients using LT4 and control subjects. Methods A total of 142 female patients, 71 cases and 71 controls, were analyzed in the study. Ages were matched in case and control groups and the mean age was 36.6 ± 8.2 (18 to 50) years. MCI consisting of C1 (Normal Mandibular Cortex), C2 (Moderately Resorbed Mandibular Cortex) and, C3 (Severely Resorbed Cortex) scores was determined for case and control groups. Fractal analysis was performed using ImageJ on selected regions of interest from the gonial and interdental regions. The box-count method was used to calculate FD values. Wilcoxon signed-rank test, Mann-Whitney U test, and Spearman correlation analysis were applied to compare the measurements. Statistical significance of differences was established at P < 0.05 level. Results FD values did not show statistically significant differences between case and control groups (p > 0.05). The mean FD in the right gonial region was 1.38 ± 0.07 in the case group and 1.38 ± 0.08 in the control group (p = 0.715). The mean FD in the right interdental region was 1.37 ± 0.06 in the cases and 1.36 ± 0.06 in the control group (p = 0.373). The mean FD in the left gonial region was 1.39 ± 0.07 in the cases and 1.39 ± 0.07 in the control group (p = 0.865). The mean FD in the left interdental region is 1.37 ± 0.06 in the cases and 1.38 ± 0.05 in the control group (p = 0.369). The most common MCI score was C1, with 62% in the cases and 83.1% in the control group. MCI scores showed a statistically significant difference between cases and controls (p = 0.016, p < 0.05). While the C2 score was higher in the cases, the C1 score was higher in the controls. Conclusions LT4 use was not associated with the FD of mandibular trabecular bone, but was associated with MCI values of cortical bone. Further studies on larger samples with different imaging modalities and image processing methods are needed.
... Declining estrogen levels in perimenopausal and postmenopausal women lead to a rapid loss of bone mineral density and thus predispose to increased fractures [79]. Estrogen therapy and hormone therapy (estrogen plus progesterone combination) aim to stabilize bone remodeling to pre-menopausal equilibrium states [51]. ...
Osteoporosis affects a significant number of postmenopausal women in the United States. Screening is performed using clinical assessments and bone mineral density scans via dual x-ray absorptiometry. Oral therapy is indicated to prevent pathologic fractures in those deemed at increased risk following screening. Bisphosphonates including alendronate, ibandronate, and risedronate are currently first-line oral therapeutics in fracture prevention following the diagnosis of osteoporosis. Hormonal therapies include estrogen-containing therapies, selective estrogen receptor modulators, and other compounds that mimic the effects of estrogen such as tibolone. Lifestyle modifications such as supplementation and physical activity may also contribute to the prevention of osteoporosis and are used as adjuncts to therapy following diagnosis. These therapeutics are limited primarily by their adverse effects. Treatment regimens should be tailored based on significant risk factors demonstrated by patients, adverse effects, and clinical response to treatment. The most severe risk factors relevant to pharmacological selection involve hormone replacement therapies, where concern for venous thrombosis, coronary artery disease, breast, and uterine cancer exist. Bisphosphonates are most commonly associated with gastrointestinal discomfort which may be mitigated with proper administration. Although adverse effects exist, these medications have proven to be efficacious in the prevention of vertebral and non-vertebral fractures in post-menopausal women. Fracture risk should be weighed against the risk of adverse events associated with each of the regimens, with clinical judgment dictating the treatment approach centered around patient goals and experiences.
... It is our assumption that such a correlation between Plt count and BMD is also present in women; however, since aging has an extremely potent effect on BMD in women (Table 2), it may be difficult to delineate the relationship between BMD and other factors, independent of age. It is likely that a factor linking aging to lower BMD in women is a lower level of estrogen [11,12], with age-related estrogen withdrawal in women leading to decreased BMD through a variety of mechanisms [13]. ...
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A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.
Traditional Chinese medicine suggests that Ginseng and Astragalus Decoction (GAD) may effectively treat postmenopausal osteoporosis (PMO). However, the exact mechanism of action for GAD remains unclear. This study aims to utilize network pharmacology and molecular docking technology to explore the potential mechanism of GAD in treating PMO. The main chemical components of GAD were identified by consulting literature and traditional Chinese medicine systems pharmacology database. GeneCards and online mendelian inheritance in man were used to identify PMO disease targets, and Cytoscape 3.8.2 software was used to construct a herb-disease-gene-target network. The intersection of drug targets and disease targets was introduced into the search tool for the retrieval of interacting genes platform to construct a protein-protein interaction network. Additionally, we further conducted gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses, followed by molecular docking between active ingredients and core protein targets. We have identified 59 potential targets related to the treatment of PMO by GAD, along with 33 effective components. Quercetin and kaempferol are the compounds with higher degree. In the protein-protein interaction network, IL6, AKT1, and IL1B are proteins with high degree. The enrichment analysis of gene ontology and KEEG revealed that biological processes involved in treating PMO with GAD mainly include response to hormones, positive regulation of phosphorylation, and regulation of protein homodimerization activity. The signal pathways primarily include Pathways in cancer, PI3K-Akt signaling pathway, and AGE-RAGE signaling pathway. Molecular docking results indicate that kaempferol and quercetin have a high affinity for IL6, AKT1, and IL1B. Our research predicts that IL6, AKT1, and IL1B are highly likely to be potential targets for treating PMO with GAD. PI3K/AKT pathway and AGE-ARGE pathway may play an important role in PMO.
Due to estrogen deficiency, postmenopausal women may suffer from an imbalance in bone metabolism that leads to bone fractures. Isoflavones, a type of phytoestrogen, have been suggested to improve bone metabolism and increase bone mass. Therefore, isoflavones are increasingly recognized as a promising natural alternative to hormone replacement therapy for postmenopausal women who face a heightened risk of osteoporosis and are susceptible to bone fractures. This study aimed to evaluate the efficacy of isoflavone interventions on bone mineral density (BMD) in postmenopausal women by means of systematic review and meta-analysis. The electronic database searches were performed on PubMed, Embase, Scopus, and Cochrane Library databases, covering literature up to April 20, 2023. A random-effects model was used to obtain the main effect estimates, with a mean difference (MD) and its 95% confidence interval (CI) as the effect size summary. The risk of bias assessment was conducted using the Risk of Bias 2 (RoB2) tool. A total of 63 randomized controlled trials comparing isoflavone interventions (n = 4,754) and placebo (n = 4,272) were included. The results indicated that isoflavone interventions significantly improved BMD at the lumbar spine (MD = 0.0175 g/cm2; 95% CI, 0.0088 to 0.0263, P < 0.0001), femoral neck (MD = 0.0172 g/cm2; 95% CI, 0.0046 to 0.0298, P = 0.0073), and distal radius (MD = 0.0138 g/cm2; 95% CI, 0.0077 to 0.0198, P < 0.0001) in postmenopausal women. Subgroup analysis showed that the isoflavone intervention was effective for improving BMD when the duration was ≥ 12 months and when the intervention contained genistein of at least 50 mg/day. This systematic review and meta-analysis suggests that isoflavone interventions, especially those containing genistein of at least 50 mg/day, can effectively enhance BMD in postmenopausal women.
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Inconsistent data suggest that flaxseed supplementation may have a role in sex hormones. We aimed to carry out a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating effects of flaxseed supplementation on sex hormone profile. PubMed, Scopus, Embase, Cochrane Library, Web of Science databases, and Google Scholar were searched up to March 2023. Standardized mean difference (SMD) was pooled using a random-effects model. Sensitivity analysis, heterogeneity, and publication bias were reported using standard methods. The quality of each study was evaluated with the revised Cochrane risk-of-bias tool for randomized trials, known as RoB 2. Finding from ten RCTs revealed that flaxseed supplementation had no significant alteration in follicle-stimulating hormone (FSH) (SMD: −0.11; 95% CI: −0.87, 0.66: p = 0.783), sex hormone-binding globulin (SHBG) (SMD: 0.35; 95% CI: −0.02, 0.72; p = 0.063), total testosterone (TT) levels (SMD: 0.17; 95% CI: −0.07, 0.41; p = 0.165), free androgen index (FAI) (SMD = 0.11, 95% CI: −0.61, 0.83; p = 0.759), and dehydroepiandrosterone sulfate (DHEAS) (SMD: 0.08, 95%CI: −0.55, 0.72, p = 0.794). Flaxseed supplementation had no significant effect on sex hormones in adults. Nevertheless, due to the limited included trials, this topic is still open and needs further studies in future RCTs.
Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β‐catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid‐induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy‐derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO‐A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 μM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/β‐catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β‐catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and β. These data suggest that genistein could induce bone remodeling through Wnt/β‐catenin pathway activation.
Restoring bone homeostasis is the key to the treatment of osteoporosis. How to increase osteogenic ability or inhibit osteoclast activity has always been a topic of great concern. In recent years, short peptides with biological activity have received great attention in bone repair. However, the application of short peptides is still limited due to the lack of a stable and targeted delivery system. We designed poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles modified by alendronate (AL) to transport osteogenic peptides (OGP) (AL‐PLGA@P NPs). Benefiting from the high affinity of AL for hydroxyapatite, AL‐PLGA@P NPs have the ability to target bone. In this delivery system, OGP that promotes osteogenesis synergizes with AL, which inhibits osteoclasts, to regulate bone homeostasis, which gives them more advantages in the treatment of osteoporosis. Our data showed that nanoparticles could selectively deliver peptides to the bone surface without systemic toxicity. Moreover, nanoparticles could upregulate osteogenesis‐related factors (ALP, Runx‐2, BMP2) and downregulate osteoclast‐related factors (TRAP, CTSK) in vitro. With AL‐PLGA@P NPs, bone microarchitecture and bone mass were improved in ovariectomized osteoporosis rats. Therefore, this study proposes a novel osteoporosis‐based drug system that effectively improves bone density. This article is protected by copyright. All rights reserved
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The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees. Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT. For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended. This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociación Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d’études de la ménopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Società Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.
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Due to its minimal systematic adverse effects, transdermal estrogen is widely used for the prevention of osteoporosis in postmenopausal women. The present meta-analysis aimed to clarify the effects of transdermal estrogen on bone mineral density (BMD) of postmenopausal women. Studies were identified by searching electronic databases including Cochrane Library, MEDLINE, Embase , and CINAHL databases, and also the Sciences Citation Index. Systematic review of articles was published between January 1989 to February 2016.Reference lists of the included articles were also evaluated and consultations were made with relevant experts. While 132 studies included the desired keywords, only nine clinical trials met the inclusion criteria and were finally reviewed. The pooled percent change in BMD was statistically significant in favor of transdermal estrogen. According to resulting pooled estimate, lumbar spine BMD one and two years after transdermal estrogen therapy was respectively 3.4% (95% CI: 1.7-5.1) and 3.7% (95% CI: 1.7-5.7) higher than the baseline values. The test for heterogeneity was not statistically significant based on the I² heterogeneity index. One-two years of transdermal estrogen delivery can effectively increase BMD and protect the bone structure in postmenopausal women.
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Context: The Women's Health Initiative (WHI) hormone therapy (HT) trials showed protection against hip and total fractures but a later observational report suggested loss of benefit and a rebound increased risk after stopping. Objective: To examine fractures after discontinuation of HT Design and Setting: Two placebo-controlled randomized trials Patients: 15,187 WHI participants who continued active HT or placebo through the intervention period and did not take HT in the post-intervention period Interventions: Conjugated equine estrogen + medroxyprogesterone acetate (CEE+MPA) in naturally menopausal women and conjugated equine estrogen (CEE) alone in women with prior hysterectomy Main Outcome Measures: Total and hip fractures through 5 years after discontinuation Results: Hip fractures were infrequent (∼2.5 per 1,000 person years), similar between both trials and former HT and placebo groups. There was no difference in total fractures in the CEE+MPA trial for former HT vs former placebo (28.9 per 1,000 person years and 29.9 per 1,000 person years respectively) (hazard ratio [HR] 0.97; 95% CI 0.87, 1.09, p=0.63); however, in the CEE alone trial, total fractures were higher in former placebo users (36.9 per 1,000 person years) compared with former active group (31.1 per 1,000 person years), suggestive of a residual benefit of CEE against total fractures (HR 0.85, 95% CI 0.73, 0.98, p=0.03). Conclusions: We found no evidence for increased fracture risk, either sustained or transient, for former HT users compared with prior placebo women after stopping HT. There was residual benefit for total fractures in former HT users from the CEE-alone study.
Recommendation: the use of menopausal hormone therapy in symptomatic postmenopausal women should be based on consideration of all risk factors for cardiovascular disease, age, and time from menopause. 2. Recommendation: the use of transdermal as compared with oral estrogen preparations may be considered less likely to produce thrombotic risk and perhaps the risk of stroke and coronary artery disease. 3. Recommendation: when the use of progesterone is necessary, micronized progesterone is considered the safer alternative. 4. Recommendation: in symptomatic menopausal women who are at significant risk from the use of hormone replacement therapy, the use of selective serotonin re-uptake inhibitors and possibly other nonhormonal agents may offer significant symptom relief. 5. Recommendation: AACE does not recommend use of bioidentical hormone therapy. 6. Recommendation: AACE fully supports the recommendations of the Comité de l'Évolution des Pratiques en Oncologie regarding the management of menopause in women with breast cancer. 7. Recommendation: HRT is not recommended for the prevention of diabetes. 8. Recommendation: In women with previously diagnosed diabetes, the use of HRT should be individualized, taking in to account age, metabolic, and cardiovascular risk factors. Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; BMI = body mass index; CAC = coronary artery calcification; CEE = conjugated equine estrogen; CEPO = Comité de l'Évolution des Pratiques en Oncologie; CAD = coronary artery disease; CIMT = carotid intima media thickness; CVD = cardiovascular disease; FDA = Food and Drug Administration; HDL = high-density lipoprotein; HRT = hormone replacement therapy; HT = hypertension; KEEPS = Kronos Early Estrogen Prevention Study; LDL = low-density lipoprotein; MBS = metabolic syndrome; MPA = medroxyprogesterone acetate; RR = relative risk; SERM = selective estrogen-receptor modulator; SSRI = selective serotonin re-uptake inhibitor; VTE = venous thrombo-embolism; WHI = Women's Health Initiative.
Description: This guideline updates the 2008 American College of Physicians (ACP) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women. This guideline is endorsed by the American Academy of Family Physicians. Methods: The ACP Clinical Guidelines Committee based these recommendations on a systematic review of randomized controlled trials; systematic reviews; large observational studies (for adverse events); and case reports (for rare events) that were published between 2 January 2005 and 3 June 2011. The review was updated to July 2016 by using a machine-learning method, and a limited update to October 2016 was done. Clinical outcomes evaluated were fractures and adverse events. This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density, including pharmaceutical prescriptions, calcium, vitamin D, and estrogen. Evidence was graded according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Target audience and patient population: The target audience for this guideline includes all clinicians. The target patient population includes men and women with low bone density and osteoporosis. Recommendations recommendation 1: ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence). Recommendation 2: ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence). Recommendation 3: ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. (Grade: weak recommendation; low-quality evidence). Recommendation 4: ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low-quality evidence). Recommendation 5: ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. (Grade: strong recommendation; moderate-quality evidence). Recommendation 6: ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. (Grade: weak recommendation; low-quality evidence).
Objectives: The aim of this study was to conduct a systematic review and meta-analysis on the performance of the WHO's Fracture Risk Assessment (FRAX) instrument in predicting 10-year risk of Major Osteoporotic Fractures (MOF) and Hip Fractures (HF), using the USA treatment thresholds, in populations other than their derivation cohorts. Design: EMBASE and MEDLINE database were searched with search engine PubMed and OVID as well as Google Scholar for the English-language literature from July 2008 to July 2016. Limiting our search to articles that analyzed only MOF and/or HF as an outcome, 7 longitudinal cohorts from 5 countries (USA, Poland, France, Canada, New Zealand) were identified and included in the meta-analysis. SAS NLMIXED procedure (SAS v 9.3) was applied to fit the Hierarchical Summary Receiver Operating Characteristics (HSROC) model for meta-analysis. Forest plot and HSROC plot was generated by Review Manager (RevMan v 5.3). Results: Seven studies (n=57,027) were analyzed to assess diagnostic accuracy of FRAX in predicting MOF, using 20% as the 10-year fracture risk threshold for intervention, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) were 10.25% (3.76%-25.06%), 97.02% (91.17%-99.03%) and 3.71 (2.73-5.05), respectively. For HF prediction, using 3% as the 10-year fracture risk threshold, six studies (n=50,944) were analyzed. The mean sensitivity, specificity, and DOR along with their 95% confidence intervals (CI) were 45.70% (24.88%-68.13%), 84.70% (76.41%-90.44%) and 4.66 (2.39-9.08), respectively. Conclusions: Overall, using the 10year intervention thresholds of 20% for MOF and 3% for HF, FRAX performed better in identifying patients who will not have a MOF or HF within 10years, than those who will. A substantial number of patients who developed fractures, especially MOF within 10years of follow up, were missed by the baseline FRAX assessment.
Considerable data and media attention have highlighted a potential "crisis" in the treatment of osteoporosis. Specifically, despite the availability of several effective drugs to prevent fractures, many patients who need pharmacological therapy are either not being prescribed these medications or if prescribed a medication, are simply not taking it. Although there are many reasons for this "gap" in the treatment of osteoporosis, a major factor is physician and patient concerns over the risk of side effects, especially atypical femur fractures (AFFs) related to bisphosphonate (and perhaps other antiresorptive) drug therapy. In this perspective, we review the current state of undertreatment of patients at increased fracture risk and suggest possible short-, intermediate-, and long-term approaches to address patient concerns, specifically those related to AFF risk. We suggest improved patient and physician education on prodromal symptoms, extended femur scans using dual-energy X-ray absorptiometry (DXA) to monitor patients on antiresorptive treatment, better identification of high-risk patients perhaps using geometrical parameters from DXA and other risk factors, and more research on pharmacogenomics to identify risk markers. Although not the only impediment to appropriate treatment of osteoporosis, concern over AFFs remains a major issue and one that needs to be resolved for effective dissemination of existing treatments to reduce fracture risk. © 2017 American Society for Bone and Mineral Research.