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Another interesting concept would be TSEC, a combination of bazedoxifene
with conjugated estrogens as a possible alternative to classical hormonal treatment
and which opens up the possibility of different combinations.
Meanwhile, the rapid developments in the molecular biology of the ER activa-
tion cascade, together with advances in genomics and chemistry and proteomics,
make us optimistic about the future of different estrogen modulators in the medium
term.
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© Springer Nature Switzerland AG 2019
F. R. Pérez-López (ed.), Postmenopausal Diseases and Disorders,
https://doi.org/10.1007/978-3-030-13936-0_24
J. J. Hidalgo-Mora
Service of Obstetrics and Gynecology, Hospital Clínico Universitario-INCLIVA,
Valencia, Spain
A. J. Cano-Marquina
Service of Radiology, Hospital de Sagunto, Valencia, Spain
A. Szeliga
Department of Gynecological Endocrinology, Poznan University of Medical Sciences,
Poznan, Poland
M. Á. García-Pérez (
*)
Department of Genetics, University of Valencia, Burjassot, Valencia, Spain
Institute of Health Research INCLIVA, Valencia, Spain
e-mail: miguel.garcia@uv.es
A. Cano (
*)
Service of Obstetrics and Gynecology, Hospital Clínico Universitario-INCLIVA,
Valencia, Spain
Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
e-mail: antonio.cano@uv.es
24
Management ofOsteoporosis
inPostmenopausal Women
J.J.Hidalgo-Mora, AntonioJ.Cano-Marquina, A.Szeliga,
MiguelÁngelGarcía-Pérez, andA.Cano
24.1 Introduction
Osteoporosis is a systemic disease of the skeleton consisting of a reduction of
bone mass and deterioration of bone microarchitecture. Loss of bone strength and
increased risk for fragility fracture are the consequences. Osteoporosis translates
in the bone, as for other systems in the body, the impact of aging, which imposes a
progressive deterioration of the biological regulators. There is a gradual, unfavor-
able disequilibrium between bone formation and bone resorption, which leads to the
mentioned net loss of bone mass and disintegration of bone architecture.
The development of osteoporosis in concomitance with aging is universal, but
as for other noncommunicable chronic diseases (NCD), the progression is asym-
metrical. The variables responsible of the individual differences are several, among
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them, genetic susceptibility, lifestyle, hormonal problems, etc. Also important, the
propensity to fall, a strong variable with an impact in the risk of fracture, varies
between individuals.
Because aging is a global phenomenon, osteoporosis occupies a privileged posi-
tion among the causes of morbidity and mortality. According to the International
Osteoporosis Foundation (IOF), it is estimated that the disease affects 200 million
people worldwide [1]. Common sites for osteoporotic fracture are the spine and the
hip but also the distal forearm, pelvis, proximal humerus, ribs, and distal femur.
Given the population trends, the impact of the disease is expected to increase. So
the 1.66 million hip fractures diagnosed worldwide in 1990 are estimated to reach
6.26 million in 2050 [1].
Osteoporotic fractures are followed by increased mortality and loss of healthy
life years (HLY). Hip fracture, for example, requires hospitalization in most cases
and is associated with risk of death. Data from Sweden forecast that around 1% of
all deaths are due to hip fracture, something that is only slightly lower to deaths due
to breast cancer [2].
Osteoporosis particularly affects women. Studies from different sources estimate
that one in three women over age 50 will suffer osteoporotic fractures, the cor-
responding gures in men being one in ve [3–5]. The reasons are that women
(1) have more fragile bone architecture, (2) have a longer life expectancy, and (3)
suffer menopause. The impact of menopause resides in the high sensitivity of bone
metabolism to estrogens. The size of the effect is huge, and postmenopausal osteo-
porosis (PMO) is the most prevalent form of the disease as opposed to involutional
osteoporosis, which is that due to aging.
24.2 Biological Background
24.2.1 The Tissue Structure ofBone
Against its static appearance, the structure of bone is subjected to a continuous
process of change, which is known as bone turnover or bone remodelling. There is
of course inert material, composed of hydroxyapatite, a calcium salt, which gives
consistency, and that contributes to the stable shape. There is also organic compo-
nents, including cells and a thick network of collagen that, once mineralized with
hydroxyapatite, provides a strong structure, which warrants both resistance and
exibility to absorb impact energy without breaking.
All those material components organize according to two different basic struc-
tures, cortical and trabecular bone.
Cortical bone, the main component of long bones, is comprised of successive
apposition of osteons, basic organizations composed of concentric layers of com-
pact bone (lamellae) encircling a central canal (Haversian canal). The strength pro-
vided by such a structure is optimal.
Trabecular bone, which is found in the vertebral bodies or the distal portions
of long bones, has a spongelike structure. A network of interconnected trabecular
plates provides a structure in which the energy is transmitted efciently while main-
taining a light texture. The intertrabecular spaces are lled with bone marrow.
J. J. Hidalgo-Mora et al.
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24.2.2 The Cells inBone
The three basic cell types in bone are osteoclasts, osteoblasts, and osteocytes. All
the three work in a harmonious and continuous process that governs bone turnover
and regularly provides renovated bone.
Osteoclasts and osteoblasts derive from progenitor cells in the near bone mar-
row and articulate a process within the so-called bone multicellular unit (BMU)
(Fig.24.1).
Bone remodelling results from a program in which resorption, a responsibility
of osteoclasts, is the initial step. Osteoclasts rstly differentiate to become multi-
nuclear cells capable of digesting damaged bone areas [6]. As a result of a coupled
and well-concatenated process, osteoblasts differentiate subsequently and start syn-
thesizing protein in the form of a matrix called osteoid, which lls up the cavities
created by osteoclasts. This is the phase of bone formation. Osteoid undergoes a
slow process of mineralization along several months in order to consolidate new
bone. One crucial condition during this process is that the balance between resorp-
tion and formation is nally neutral, i.e., the volume of renovated bone equals that
digested, so that there is not a net loss of material.
Osteocytes are key cells that derive from the osteoblasts that leave buried under
the osteoid. Although apparently isolated within a mineralized mass, osteocytes
are interconnected through a network of cytoplasmic dendritic processes extending
through a thick net of canaliculi. This sophisticated system acts as a sensitive sensor
capable of detecting areas of bone fatigue (microcracks, etc.) in which remodelling
is desirable [7].
Bone-lining cells
Osteocytes
Marrow capillary
OC
OB
Fig. 24.1 The basic multicellular unit (BMU) includes the coupled collaboration between osteo-
clasts, osteoblasts, and osteocytes. The canopy of the bone lining cells and one associated marrow
capillary are also included in the gure. There is a net of canaliculi that serves to interconnect
osteocyte dendritic processes. (With permission of Elsevier from Khosla S, etal. Trends Endocrinol
Metab. 2012; 23:576–81. Permission conveyed through Copyright Clearance Center, Inc.)
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There is a very detailed knowledge of the molecular mechanisms subserving
the elaborated process of bone renovation (for review see [8, 9]). Osteocytes are
the main regulatory cells involved in the control of bone resorption and forma-
tion, modulating the function of osteoclasts and osteoblasts at a molecular level.
One key step is the contribution of osteocytes to the secretion of a crucial cyto-
kine, the receptor activator of nuclear factor κB ligand (RANKL), which plays
a necessary role in the differentiation of osteoclasts from progenitor cells [6].
Interleukin-1 (IL-1), interleukin-11 (IL-11), interleukin-17 (IL-17), tumor necrosis
factor-α (TNF-α), and prostaglandin E2 contribute to increased RANKL secretion,
while 17beta- estradiol downregulates its production [10]. Osteocytes modulate
bone turnover by secretion of not only RANKL but also other specic factors,
like sclerostin (SOST) and Dickkopf-1 (DKK1), inhibitors of osteoblast activity,
as well as macrophage colony-stimulating factor (M-CSF) and osteoprotegerin
(OPG), substances regulating osteoclast functions. Results from previously con-
ducted studies indicate that RANKL, acting on its receptor located on precursor
cells, cooperates with M-CSF in osteoclastogenesis upregulation. On the other
hand, osteocytes produce also OPG, a soluble factor inactivating RANKL, nitric
oxide, and transforming growth factor β (TGFβ), and thus contribute to decrease in
osteoclast formation [11].
Noteworthy, recent studies indicate that interleukin-20 (IL-20) is considered a
relevant factor in regulation of osteoclasts activity. IL-20 has the ability to upregu-
late the expression of RANK and other markers of osteoclast differentiation (like
nuclear factor of activated T-cells c1 [NFATc1], c-Fos, cathepsin K, and tartrate-
resistant acid phosphatase [TRAP]). Additionally IL-20 stimulates production of
cathepsin G by osteoclasts, which subsequently contributes to the increase of solu-
ble RANKL (sRANKL) secretion from osteoblasts, thus osteoclastogenesis promo-
tion [12].
24.2.3 The Key Role ofEstrogens
Clinical investigators in the middle of the previous century already detected the
association between ovarian function and bone metabolism. More recent basic work
detected the presence of estrogen receptor (ER) mRNA expression in cell cultures
and in both animal and human tissues [13–15]. Soon afterward, both the ERα and
the ERβ were found in histological sections of the growth plate and in mineralized
bone as well as in cell cultures of the three bone cellular types.
The experimental work has run in parallel with a series of clinical ndings.
Observations in individuals with genetic deciencies conrmed that estrogens were
the key regulator of bone metabolism not only in women but also in men [16, 17],
and clinical studies in ovariectomized women proved that treatment with estrogens
prevented bone loss [18]. The evidences have accumulated throughout the years
to generate a solid body of knowledge conrming the crucial role of estrogens as
regulators of bone metabolism [19].
J. J. Hidalgo-Mora et al.
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One important point to understand the role of estrogens relates with the patho-
physiological basis of PMO.The neutral balance in the process of bone remodel-
ling, mentioned above as a condition to maintain the integrity of bone mass, starts
being unbalanced as a result of aging. Resorption progressively separates from for-
mation, which stays behind. In fact, involutional osteoporosis is the result of the
prolongation of that slow disequilibrium during years.
Menopause in women imposes an acceleration of that process, and this has been
proved to be the responsibility of estrogens that, therefore, act as the closing gate
preventing the rapid loss of bone. Estrogens are, therefore, bone anti-resorptives.
Clinical observation is consistent with that premise, and, for example, there is
already an initial increase of bone loss during the perimenopausal years, when there
are only slight reductions in the ovarian output of estrogens [20]. Also studies with
bone biochemical markers across the menopausal transition are eloquent since there
is an increase of markers of bone resorption in parallel with the decline in circulating
estrogens. As a result of the coupling process between osteoclasts and osteoblasts,
there is also an increase in markers of bone formation but of lower magnitude [21].
The identication of ER in osteocytes and osteoblasts raises questions about a
potential effect of estrogens on both cell types. The action on osteocytes has been
indirectly evaluated through histological assessments in bone biopsies during the
use of analogues of gonadotropin-releasing hormone (aGnRH) [22]. There is an
increase in cell apoptosis, which seems to be probably followed by an osteoclasto-
genic response emanating from signals released from the dying osteocytes [23]. The
mechanism for the apoptosis of osteocyte associated with estrogen loss is unknown,
although animal experiments suggest that might be related with increase of oxida-
tive stress [24].
The action of estrogens on osteoblasts is less apparent. As for osteocytes, estro-
gens reduce apoptosis of osteoblasts, although the mechanisms for such an effect
are still elusive (for review, see [19]).
24.3 Diagnosis ofPostmenopausal Osteoporosis
There are three main tools, clinical history, radiological imaging, and biochemical
markers. All the three have to be used under the framework of a basic principle:
the assessment of PMO and the interventions to reduce risk or treat the established
disease need to be organized bearing in mind that the objective should always be the
reduction of fragility fracture.
24.3.1 Clinical Assessment
Clinical history should be always the rst and necessary step in every evaluation
of PMO.Two important measures at this step are to identify major risk factors for
fragility fracture and to discard secondary osteoporosis.
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