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The major risk factors have been traditionally considered to be four (Table24.1),
although the recent introduction of tools to calculate absolute risk has reduced the
value of this analysis, since every relevant factor, and not only those in Table24.1, is
introduced and given the relative weight in the risk calculation. Age is a central risk
factor, something of particular importance in the clinical management of women
with PMO.Also important in anamnesis, potential causes of secondary osteoporosis
should be detected (Table24.2). Some of those are not too prevalent, and therefore
there is insufcient information about the size of the relative risk. Therefore, they
have not been included in the risk calculator algorithms.
In practical terms, it has been useful to separate risk factors in two groups, attend-
ing to whether they are modiable or not. There is little point in paying attention
to those that are unmodiable, such as age, ethnicity (e.g., lower risk in blacks as
compared with Caucasians), female gender, signicant loss of height (4cm at least)
[25], etc., but preventive measures may be taken against the modiable factors, such
as sedentariness, smoking, very low body mass index, or very low calcium intake
(<500mg/day, see below).
24.3.1.1 Predictive Potential Based onRisk Factors (Risk
Calculators)
The increased power of modern epidemiological databases together with the sophis-
tication of advanced computational statistics has allowed for the design of tools
Table 24.1 Major risk
factors for fragility fracture
Age
Fracture history after age 54
Parental hip fracture
Densitometry showing hip osteoporosis
Endocrine- metabolic History or actual hypogonadism
(anorexia nervosa, early menopause,
post-chemotherapy, etc.)
Cushing syndrome
Hyperthyroidism
Hyperparathyroidism
Diabetes mellitus
Nutritional Malabsorptive disease/malnutrition
Chronic liver disease
Chronic alcoholism
Drugs Glucocorticoids
Collagen diseases Osteogenesis imperfecta
Ehlers-Danlos syndrome
Marfan syndrome
Others Rheumatoid arthritis
Multiple myeloma
Prolonged immobility
Mastocytosis
Table 24.2
Main causes of
secondary osteoporosis
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with potential to predict the absolute risk of fracture. The Fracture Risk Assessment
algorithm (FRAX) from the World Health Organization (WHO) predicts the 10-year
risk of hip fracture or major osteoporotic fracture. FRAX is supported by potent sci-
entic societies, like the IOF or the National Osteoporosis Foundation (NOF).
Despite being customized to different countries or regions in the world, there
is a debate about the utility of FRAX.Retrospective and some prospective studies
have suggested that the predictive potential in practice is limited, specically in
some countries [26, 27]. Part, but not all, of the debate moves around the thresh-
old for intervention. Even so, the low sensitivity to predict fracture of the imaging
techniques (e.g., densitometry; see below) makes FRAX a very helpful instrument
[28]. Moreover, one key factor of FRAX has been the rehabilitation of clinical risk
factors, age mainly, in the decision-making.
24.3.2 Radiological Imaging
Several radiological techniques have been developed to provide information useful
in the assessment of the strength of the skeleton.
The most popular technique at present is dual X-ray absorptiometry (DXA), which
measures bone mineral density (BMD) at both the spine and the hip (Fig.24.2), and
that has been taken by the WHO as the gold standard to diagnose osteoporosis (hip
T-score ≤−2.5). Moreover, DXA may be used to monitor the response to treatment,
although with some limitations because accuracy is poor with variations of as much
as 7% in repeated measures.
The basis of DXA utility resides in that the absorption of X-ray is very sensitive
to the content of calcium in the tissue. Modern densitometry machines may mea-
sure both areal and volumetric densitometries, but areal densitometry is preferred
because it accounts for some two thirds of bone strength. In this way the tech-
nique offers a quantitative parameter that directly relates with the risk of fracture.
Moreover, recent technical developments have improved imaging so that deformi-
ties of the vertebral bodies may be identied and conventional X-ray assessments
are no longer necessary.
24.3.2.1 DXA inPractice
The simplicity of DXA use and the low radiation of the technique invite to perform
universal screening in women as soon as they enter menopause. However, and for
general population, that should never be done before the age in which a minimum
fracture risk already exists, and this occurs at 65years. This is a general dictum of
most scientic societies, such as the US Preventive Services Task Force (USPSTF)
(level B recommendation) [29]. This is not the case, however, in women with any
risk factor, as those mentioned in Tables 24.1 and 24.2.
Another important point concerning DXA refers to the potential for monitor-
ing, which may apply to women with or without treatment. The limited accuracy
of the technique has been already mentioned, and substantial changes need to have
occurred to get a reliable report. Of course, this also depends on the speed of loss,
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but it seems wise to wait for at least 1year before performing a second DXA, and,
ideally, the interval should extend to 2years. This will help to prevent diagnostic
errors and to reduce unnecessary anxiety in women.
24.3.2.2 Imaging Alternatives toDXA
The poor accuracy of DXA in monitoring BMD evolution and the issue of bone
quality motivated a National Institutes of Health consensus conference, which
urged to search for imaging alternatives [30].
High-resolution peripheral quantitative computed tomography (HR-pCT) pro-
vides purely trabecular BMD, which may be more sensitive to therapy. Also, there
is already experience, although most in the research setting, which separately mea-
sures trabecular and cortical bone architecture with HR-pCT (Fig.24.3). Translating
this information into assessment of bone quality remains as a challenging issue at
present.
There is experience with other techniques. Quantitative ultrasound has been
extensively investigated due to the low cost and the easiness to use in the ofce.
Much of the work has been performed on the calcaneus, with the speed and atten-
uation of sound as principal variables. Quantitative ultrasound has demonstrated
Hip Left
CueLL.Fem Cauc.
Fem Neck version 2.3
1.190
0.440
25 AGE
% YOUNG popul. 82.0
T-score −1.38
% for AGE 96.7
Z-score −0.22
Change % %/Year
Short 3.5 2.4
Long 4.7 2.7
80
B
M
D
27/03/02
27/03/02
0.755
13/10/00 0.729
22/06/00 0.721
L H
Fig. 24.2 Standard report of a densitometry scan of the hip. The X–Y diagram shows BMD in the
Y-axis (g/cm
2
) and age (years) in the X-axis. The middle line represents the mean population value
as a function of age. Scans at different dates may allow for follow-up studies
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predictive potential of fragility fractures that, together with the poor correlation
with BMD, has been taken to claim that the technique is measuring parameters
related with bone quality. However, several insufciencies, like a monitoring per-
formance even worse than that of DXA and the variety of techniques and param-
eters, moved the International Society of Clinical Densitometry to prioritize DXA
as the reference technique [31].
Magnetic resonance is attractive because of the lack of radiation. The 3T tech-
nology has been shown to offer enhanced trabecular bone architecture imaging but
mainly restricted to peripheral bones. Efforts to get quality information from the
proximal femur are still challenging. There is much hope in the potential of this
technology, although the actual state is far from becoming competitive with the
easy-to-perform DXA [32].
Trabecular bone score (TBS) is a new technological procedure that aims at giv-
ing information about bone texture and microarchitecture. The method consists of
software that works on the spine imaging provided by some specic densitometers.
The understanding is that the standard DXA offers a global assessment of bone
density in the area of interest, while TBS would be capable of distinguishing the
irregularities of the density map, something that would be close to the bone micro-
architecture. It seems that TBS might improve the fracture risk prediction of con-
ventional DXA in specic cases, like, for example, diabetes [33, 34] or women with
osteoarthritis [35], but the experience is still short [36].
24.3.3 Biochemical Markers
The metabolic activity of osteoclasts and osteoblasts releases different molecular
products that should be accessible for measurement in blood or urine. Since both
types of cells are coupled at the BMU, markers of either cell should work as reliable
indicators of the resorption activity. Ideally, bone markers should form the most
Fig. 24.3 A micro-CT gure of mice bones shows that the technique offers clear separation
between cortical and trabecular bones. Information may be obtained about a list of parameters
concerning the trabecular network, such as number of trabeculae, trabecular thickness, etc.
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appropriate approach to assess resorption, with the added advantage of being real
time. However, important conditions are specicity of cell type to prevent contami-
nation from other sources and an appropriate correspondence between resorption
and the cellular output of the marker in question.
Much has been advanced in this eld in the latter years. Although there is a list of
candidates, scientic societies like the IOF or the Federation of Clinical Chemistry
and Laboratory Medicine have selected the degradation products of type I collagen,
both the carboxy (CTX-1) and the amino-terminals (NTX-1) like the most consoli-
dated option for assessing resorption. Formation markers have been less popular,
but again, the procollagen type I propeptide, an osteoblast-derived protein, is pre-
ferred, and more specically the N-terminal fraction, PINP, has been selected in
most studies.
24.4 Prevention andTreatment
Osteoporosis shares with other NCD a long subclinical period. There is, therefore,
room for risk reduction strategies before the incidence of a clinical event, in this
case the fragility fracture. Since age is a decisive risk factor and the peak preva-
lence of fractures occurs in older subjects (80years for hip fracture), PMO offers
a splendid opportunity for risk reduction. Lifestyle plays a crucial role at all ages,
and, when risk is sufciently high, the pharmacological option should be at hand.
24.4.1 Lifestyle
Osteoporosis is not different to other NCD, and omission of toxics (essentially
smoking and excessive alcohol), balanced nutrition, and physical activity (PA) are
the three pivotal measures.
Smoking has a detrimental dose-response effect on bone metabolism. The third
National Health and Nutrition Examination Survey, 1988–1994 (NHANES-III),
already proved an inverse association between cotinine, a metabolite of nicotine,
and BMD in 14,060 subjects, men and women [37]. There are also data about frac-
tures. The analysis of data from the Women’s Health Initiative study concluded that
tobacco use was an independent risk factor for fragility fracture [38].
24.4.1.1 Nutrition
Protein
This eld has advanced dramatically in recent years. From calcium, which has been
a common variable in clinical guides, attention has been shifted to protein intake.
European investigators have found how decisive is the diet with adequate protein
intake to accomplish a good bone capital during childhood and adolescence [39].
This mechanism reproduces at more advanced age, since increase in diet protein is
followed by a lower bone loss and a reduction of fragility fractures [40–42].
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Calcium
A sufcient intake of calcium has been claimed in the vast majority of clinical
guides. There is evidence showing that the consumption of calcium is followed by
an increase in the blood circulating levels, which induces a reduction in the lev-
els of parathyroid hormone (PTH). PTH is one main regulator of serum calcium, a
crucial second messenger, so that when the circulating level of calcium decreases,
PTH mobilizes calcium from the skeleton, the main reservoir. Vitamin D modulates
the efciency of intestinal calcium absorption. The daily recommended amount of
calcium, which oscillates between 1000 and 1500mg depending on the individual
prole, has been ne-tuned in more recent publications [43]. Because data from pop-
ulations with very low calcium intake show good bone health, and because increases
in calcium intake may perhaps entail some risk, scientic societies of the UK like the
National Osteoporosis Society recommend a daily amount slightly lower (700mg)
[44]. This agrees with experimental studies showing that the balance between intake
and losses of calcium in the body moves around 700–750mg [45].
The caution with excessive calcium ingestion is reinforced by data showing that
the risk of urolithiasis [46], cardiovascular disease [47, 48], or even fractures [49]
might increase. This evidence comes from observational studies in most cases, but
because calcium supplementation, even when administered with vitamin D, has no
[50] or a very limited protective effect, and only with older, institutionalized adults
[51], discretion in recommending calcium intake is mandatory.
24.4.1.2 Physical Activity
There are two potential strengths in favor of the preventive role of PA, the reduction
in the propensity to fall and the improvement of the density and quality of bone.
Data in the latter years have supported those two assumptions.
The regular practice of PA is supposed to increase the neuromuscular coordi-
nation that should improve equilibrium. The expected reduction in falls has been
reported [52].
The other strength of PA resides in the expected increase of bone resistance as a
result of the response to the mechanical overload brought with exercise. The experi-
ences of microgravity environments, as that of astronauts in space travels, have been
eloquent. Increased bone resorption, in the presence of unchanged rates of bone for-
mation, rapidly leads to net loss of bone mass [53]. Moreover, an association exists
between body mass index and bone mass, and it is brown fat, which is promoted as
a result of PA, the variant more clearly related with BMD [54].
Clinical studies support the above data. Both BMD data with DXA, ultrasound
attenuation in the heel, and bone quality as measured by HR-pCT have found
improvement of different sizes with PA during childhood and adolescence [55] or
in young women [56, 57]. Protective effect has been found also in the case of post-
menopausal women [58] although some discrepancies exist in what concerns the
type of exercise, namely, resistance exercise vs. resistance training combined with
high-impact or weight-bearing exercise [59].
The prospects in what refers the risk of fracture, given the overall benet in bone
resistance plus the expected reduction in falls, should be encouraging. This has been
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indeed the conclusion of 1 meta-analysis including 22 cohort studies, which found
an inverse association between PA and total fracture risk, especially hip and wrist
fractures [60]. However this position is not unanimous [61], so further research is
still required.
24.4.2 Hormone Therapy
The decline in the production of estrogens is the key factor in PMO.Moreover, this
hormonal loss produces symptoms and quality of life deterioration in many women.
Consequently, the administration of estrogens seems the most appropriate interven-
tion to revert the lost benets.
In the specic area of PMO, there is a wealth of studies showing how estrogens
(or hormone therapy, HT, in a more general denomination that includes the option
of combination with progestogens when women have a uterus) stop the process of
menopausal bone loss and even recover the accumulated losses. But even more,
HT reduces the risk of fragility fracture, as shown in the WHI study [62]. These
data are important because HT demonstrated anti-fracture efcacy even in general,
nonselected population.
Hormones do not seem to have a signicant residual effect after treatment with-
drawal, with most of the BMD gain being lost in 1–2years [63].
Despite so, the present indication of HT is only the treatment of symptoms
associated with menopause. The unfavorable balance resulting from the increase
in breast cancer risk or cardiovascular disease was the trigger of this limitation.
Even so, the European Medicines Agency accepts the use of HT for the “preven-
tion of osteoporosis in postmenopausal women at high risk of future fractures who
are intolerant of, or contraindicated for, other medicinal products approved for the
prevention of osteoporosis” [64].
It cannot be discarded that a better knowledge of the actions of HT at either the
breast or the vasculature might change that restricted position in the future.
24.4.3 Pharmacological Management
One key point that needs to be insistently stressed is that the purpose of treating
osteoporosis is the reduction of the risk of fracture. The target should be fracture,
and not BMD, although it is well known that both are related. That means that in
women with low BMD who have a low risk of fracture, pharmacological treatment
should not be used. Most women living the postmenopausal period only require
lifestyle habits to reduce the risk of osteoporosis. Some of them will already have
densitometric osteoporosis, but as far as age is not advanced, the risk is probably
low and lifestyle should keep being the best recommendation. Of course, drugs will
have to be used in some women because the fracture risk is high enough. There are
several treatment options.
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24.4.3.1 Selective Estrogen Receptor Modulators (SERMs)
SERMs dene a few families of compounds with afnity for the ER.However,
the molecular differences with estrogens determine that binding to the receptor
is followed by an array of actions moving between the extremes of pure agonism
and absolute antagonism. These properties depend on the binding molecule but
also of the target tissue [65]. That property converts SERMs in very attractive
molecules, with the potential to achieve estrogenic or antiestrogenic effects a la
carte.
Raloxifene and bazedoxifene are the two SERMs approved for treating osteopo-
rosis. The pivotal studies have shown that both raloxifene and bazedoxifene achieve
increases in BMD and reduce the risk for vertebral but not hip fractures [66, 67].
There was a protective effect against nonvertebral fractures in corresponding post
hoc analyses [67, 68].
Raloxifene has demonstrated reduction in the risk for breast cancer [69], although
as for estrogens and also for bazedoxifene, an increase in deep vein thrombosis was
apparent in the pivotal studies.
Bazedoxifene has demonstrated a more antagonistic effect than raloxifene in
endometrium, and this interesting property has been taken as the basis for develop-
ment of new formulations in which bazedoxifene is mixed with estrogens (conju-
gated equine estrogens, 0.45mg/day) to counterbalance the oncogenic potential of
estrogens on the endometrium. The potential advantage of bazedoxifene against
progestogens is that it probably deactivates their oncogenic potential in the breast.
There is still insufcient information about endometrial safety of the estrogen-
bazedoxifene combination.
Health economy analyses have shown acceptable cost-effectiveness of SERMs
[70, 71]. SERMs are a good option for starting treatment in PMO, because they are
effective in vertebral fracture, which is the most prevalent in not such older women.
Moreover, a reduction of breast cancer risk needs to be considered as an additional
benet. So, selection of a SERM and, at an age in which hip fracture may be a real
threat, the option of an alternative may be adequate [
72].
24.4.3.2 Other Anti-resorptives
Bisphosphonates
Bisphosphonates are a family of molecules that share a high afnity by the calcium
salts in the bone (hydroxyapatite), where they remain for years. Once the area is
digested by osteoclasts as a result of the remodelling process, bisphosphonates
enter into the cytoplasm and create a series of dysfunctions leading to osteoclast
apoptosis. Nitrogen-containing bisphosphonates (alendronate, risedronate, iban-
dronate, pamidronate, and zoledronate) are particularly potent in that regard [73].
As a consequence, there is a decrease in bone remodelling that stabilizes in a few
months.
Some bisphosphonates are administered intravenously when a rapid action is
needed because their gastrointestinal absorption is poor. The oral administration
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may be daily, weekly, or monthly. According to meta-analyses of the pivotal studies,
the anti-fracture efcacy moves around relative risk 0.4–0.6 for vertebral fracture
and 0.6–0.8 for nonvertebral fracture [74]. Ibandronate has not provided data about
hip fracture.
Safety is an important issue. Osteonecrosis of the jaw (ONJ) and atypical
femoral fracture have been reported, usually in oncological individuals using
high dosages but also in long-term users. A systematic review of the International
Task Force on Osteonecrosis of the Jaw concluded that the incidence oscil-
lates between 0.001 and 0.01%, which is ten times more than that in untreated
general population [75]. The association with atypical femoral fractures comes
from observational studies, although ofcial agencies as EMA have recognized
them as an adverse effect [76]. The absolute gures of these fractures are very
low when compared with the typical ones, suffered by the untreated popula-
tion. This should not be, therefore, an argument to refrain from treating when
indicated [77].
There is a difculty with adherence of bisphosphonates, and this impacts effec-
tiveness. It is estimated that there is a global increased risk of 28% in hip fracture
and of 43% in vertebral fracture as a consequence of the poor adherence to bisphos-
phonates [78].
Denosumab
The rst biological option for treating osteoporosis is denosumab, a totally human
antibody against RANKL.The Fracture Reduction Evaluation of Denosumab in
Osteoporosis Every 6Months (FREEDOM) is the pivotal study that demonstrated
a 68% reduction in vertebral fractures, a 20% in nonvertebral fractures, and a 40%
in hip fractures with denosumab [79]. The anti-resorptive power of denosumab is
higher than of bisphosphonates, as shown in comparative studies with alendronate
[80, 81].
Adverse effects are not different to bisphosphonates in what refers to the drastic
reduction in bone remodelling, so ONJ [
82] and atypical femoral fractures have
been described as well, although in less number, possibly because of the more
recent appearance of denosumab in the market [83]. Denosumab, in turn, bears a
specic group of adverse events, which relate with the role of RANKL as an immu-
nological agent. A higher susceptibility to infections, such as those of the urinary
tract, cellulitis, etc., is observed [84].
Adherence seems to be better for denosumab than for bisphosphonates [85]
something subsequently suggested by a retrospective 2-year assessment [86].
The optimal use of denosumab has been presented in a position statement of the
European Menopause and Andropause Society (EMAS) [87]. Essentially, deno-
sumab is most appropriate for women with PMO and high risk of fracture so that
it should be used as a rst-line option with women of advanced age or with risk
of hip fracture.
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24.5 Conclusion
Osteoporosis should be addressed from the infancy, but menopause is a crucial
moment for women. It is important to take care of the skeleton along the whole life
by adhering to a healthy lifestyle, which is particularly so at menopause and the
years that follow. This is appropriate and sufcient for most women. Whether HT is
prescribed because of menopausal symptoms, additional benet is expected for the
bones. When fracture, and not just low BMD, is a risk of enough size, osteoporotic
medications should be considered. SERMs may be a good option during the years
in which vertebral fracture is a threat. Moreover, SERMs protect breast and have
no risk of ONJ or atypical femoral fractures. Then, when age adds sufcient risk,
bisphosphonates may be of help, and also denosumab should enter as an option in
cases of higher risk or when bisphosphonates are not eligible.
References
1. International Osteoporosis Foundation. What is osteoporosis-epidemiology. https://www.iof-
bonehealth.org/epidemiology. Accessed 8 Apr 2019.
2. Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B, Oglesby AK.The components of excess
mortality after hip fracture. Bone. 2003;32:468–73.
3. Kanis JA, Johnell O, Oden A, et al. Long-term risk of osteoporotic fracture in Malmö.
Osteoporos Int. 2000;11:669–74.
4. Melton LJ, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL.Bone density and fracture
risk in men. J Bone Miner Res. 1998;13:1915–23.
5. Melton LJ III, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective. How many
women have osteoporosis? J Bone Miner Res. 1992;7:1005–10.
6. Lorenzo J, Horowitz M, Choi Y.Osteoimmunology: interactions of the bone and immune sys-
tem. Endocr Rev. 2008;29:403–40.
7. Atkins GJ, Findlay DM.Osteocyte regulation of bone mineral: a little give and take. Osteoporos
Int. 2012;23:2067–79.
8. Nakashima T, Hayashi M, Fukunaga T, etal. Evidence for osteocyte regulation of bone homeo-
stasis through RANKL expression. Nat Med. 2011;17:1231–4.
9. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA. Matrix-embedded
cells control osteoclast formation. Nat Med. 2011;17:1235–41.
10. Bandeira F, Costa AG, Soares Filho MA, Pimentel L, Lima L, Bilezikian JP.Bone markers and
osteoporosis therapy. Arq Bras Endocrinol Metabol. 2014;58:504–13.
11. Niedźwiedzki T, Filipowska J.Bone remodeling in the context of cellular and systemic regula-
tion: the role of osteocytes and the nervous system. J Mol Endocrinol. 2015;55:R23–36.
12. Wang HH, Hsu YH, Chang MS.IL-20 bone diseases involvement and therapeutic target poten-
tial. J Biomed Sci. 2018;25:38.
13. Arts J, Kuiper GG, Janssen JM, etal. Differential expression of estrogen receptors alpha
and beta mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology.
1997;138:5067–70.
14. Braidman IP, Davenport LK, Carter DH, Selby PL, Mawer EB, Freemont AJ.Preliminary in
situ identication of estrogen target cells in bone. J Bone Miner Res. 1995;10:74–80.
15. Vidal O, Kindblom LG, Ohlsson C.Expression and localization of estrogen receptor-beta in
murine and human bone. J Bone Miner Res. 1999;14:923–9.
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