Ferrari S.L. Pocket Reference To Osteoporosis (2019)

Serge Livio Ferrari
Christian Roux Editors
Pocket Reference
to Osteoporosis
123
Pocket Reference
to Osteoporosis
Serge Livio Ferrari • Christian Roux
Editors
Pocket Reference
to Osteoporosis
Editors
Serge Livio Ferrari Christian Roux
Division of Bone Diseases Department of Rheumatology
Geneva University Hospital Paris Descartes University
and Faculty of Medicine Cochin Hospital
Geneva Paris
Switzerland France
ISBN 978-3-319-26755-5 ISBN 978-3-319-26757-9 (eBook)

https://doi.org/10.1007/978-3-319-26757-9
Library of Congress Control Number: 2018964428
© Springer Nature Switzerland AG 2019

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Preface
Every few seconds, a patient is admitted to a hospital with a

fragility fracture—namely, a fracture that occurred upon a
minimal trauma, such as falling from one’s own height.
Whether treated surgically or conservatively, the risk of
another fragility fracture is increased severalfold in such
patients, unless the underlying cause is recognized and appro-
priately managed. The bulk of fragility fractures are caused
by osteoporosis, a disease that affects nearly 300 million
people worldwide and is a particular burden for aging popu-
lations. In most cases, diagnosing osteoporosis and evaluating
fracture risk in due time, followed by appropriate treatment,
could have prevented even the first fracture. Unfortunately,
disorders of bone and mineral metabolism, including osteo-
porosis, are seldom taught to undergraduates. The resulting
relative lack of knowledge has led to under-recognizing and
undertreating the disease, with commonly less than 20% of
osteoporotic patients being appropriately managed. A “crisis
in osteoporosis” has therefore emerged that needs to be
appropriately addressed. Whether a GP or a specialist in
orthopaedics, endocrinology, rheumatology, gynaecology, or
other specialties, every doctor should be aware of osteoporo-
sis and be capable of managing the disease. This book has
been written by some of the most prominent authorities in
this field in order to provide the basic principles about osteo-
porosis in a practical way, in the hope of facilitating the diag-
nosis and treatment of devastating disease.
Geneva, Switzerland Serge Livio Ferrari

Paris, France Christian Roux
Contents
1 Pathophysiology of Osteoporosis�� 1
Serge Livio Ferrari
2 Diagnosis and Clinical Aspects of Osteoporosis�� 11

John A. Kanis
3 Evaluation of Fracture Risk �� 21

Eugene V. McCloskey
4 Prevention of Osteoporosis and Fragility

Fractures �� 31
René Rizzoli
5 Efficacy and Safety of Osteoporosis Treatment�� 43

Michael R. McClung
6 Management of Patients with Increased

Fracture Risk�� 59
Felicia Cosman
7 Management of Male Osteoporosis�� 71

Piet Geusens and Joop van den Bergh
8 Management of Glucocorticoid-Induced
Osteoporosis�� 81
Christian Roux
9 New Bone-Forming Agents�� 85

Socrates E. Papapoulos
Index�� 95
Contributors
Felicia Cosman, MD Helen Hayes Hospital, West Haverstraw,

NY, USA
Serge Livio Ferrari, MD Division of Bone Diseases, Geneva

University Hospital and Faculty of Medicine, Geneva,
Switzerland
Piet Geusens, MD Department of Internal Medicine,

Maastricht University Medical Center, Maastricht, The
Netherlands
John A. Kanis, MD Center for Metabolic Bone Diseases,

University of Sheffield Medical School, Sheffield, UK
Eugene V. McCloskey, MD Center for Metabolic Bone

Diseases, University of Sheffield Medical School, Sheffield,
UK
Michael R. McClung, MD Oregon Osteoporosis Center,

Portland, OR, USA
Socrates E. Papapoulos, MD Center for Bone Quality,

Leiden University Medical Center, Leiden, The Netherlands
René Rizzoli, MD Division of Bone Diseases, Geneva

University Hospitals and Faculty of Medicine, Geneva,
Switzerland
x Contributors
Christian Roux, MD Department of Rheumatology, Paris

Descartes University, Cochin Hospital, Paris, Paris, France
Jopp van den Bergh, MD, PhD Department of Internal

Medicine, Maastricht University Medical Center, Maastricht,
The Netherlands
Chapter 1
Pathophysiology
of Osteoporosis
Serge Livio Ferrari
1.1 Introduction
Bone is a dynamic tissue that is continuously removed and
replaced (i.e., remodeled) in order to (1) ensure adaptation of
the skeleton to weight-bearing (shape is function), (2) repair
microdamages (cracks) that result from mechanical stresses,
and (3) allow for mobilization of calcium from the skeleton in
order to maintain serum calcium homeostasis [1]. Bone
remodeling is initiated by the development and activation of
osteoclasts, the bone-resorbing cell, which then release growth
factors capable to activate osteoblasts, the bone-forming cell.
The activities of bone removal and deposition are therefore
coupled within each “bone multicellular unit” or BMU. After
the completion of growth, the bone size and mineral content
have reached its peak and will be maintained more or less
unchanged during the adult life in the absence of pathophysi-
ological conditions thanks to moderate levels of bone remod-
eling that are perfectly balanced between resorption and
formation within each BMU. In addition, the skeleton con-
tinuously responds to mechanical stimuli resulting from both
muscle contraction and weight-bearing, by directly stimulating
S. L. Ferrari (*)
Division of Bone Diseases, Geneva University Hospital and Faculty
of Medicine, Geneva, Switzerland
e-mail: [email protected]
© Springer Nature Switzerland AG 2019 1

S. L. Ferrari, C. Roux (eds.), Pocket Reference to Osteoporosis,
https://doi.org/10.1007/978-3-319-26757-9_1
2 S. L. Ferrari
bone formation (i.e., without prior resorption), a process

known as bone modeling. This process in particular is respon-
sible for the increased bone diameter and bone mass observed
in physically active individuals, furthermore in athletes. It is
controlled by osteocytes, which are terminally differentiated
osteoblasts that have lost their capacity to form new bone but
are entrenched in the bone and form a dense network of
“sensing” cells capable to respond to mechanical stimuli, as
well as to microdamages, and control both modeling and local
remodeling processes [2].
1.2 T
he Pathophysiological Bases
of Osteoporosis
Osteoporosis is a systemic skeletal disorder characterized
by a decrease of bone mineral mass together with altera-
tions of bone microstructure, particularly a reduction in the
number and/or thinning of trabeculae with a loss of trabecu-
lar bridges, cortical thinning, and increased cortical porosity
[3, 4]. These alterations are mainly the result of increased
bone turnover triggered by the dramatic decline of estrogen
levels in postmenopausal women. In men, aging and the
decline in both testosterone and estrogen levels also play a
role. At the cellular level, these endocrine disturbances lead
to the activation of new BMUs that spread throughout can-
cellous and cortical bone surfaces. Moreover, within these
foci of bone remodeling, a mismatch appears between the
activity of osteoclasts and osteoblasts, resulting in a negative
bone mineral balance (Fig. 1.1). Eventually, the senescence
of o
steocytes [5], together with the decline in physical func-
tions with aging, may lead to a decrease of modeling-based
bone formation.
In recent years, the key molecular mechanisms involved
in the bone remodeling and modeling processes and the
coupling between osteoblasts and osteoclasts have been
elucidated. Among them, the Wnt/LRP5/beta-catenin
Chapter 1 Pathophysiology of Osteoporosis 3
Increased number of remodeling units Resorbed cavity too large Newly formed packet of bone too small
Increased bone loss
Figure 1.1 Increased bone remodeling causes bone loss
canonical signaling pathway [6] and the RANKL/RANK/

OPG system [7] have emerged as playing essential roles in,
respectively, bone-forming and bone resorption processes.
In addition, the role of the immune system and the central
nervous system on the regulation of bone turnover starts to
be better appreciated. In turn, these remarkable progresses
in the understanding of the pathophysiology of osteoporo-
sis have delineated new targets for therapeutic
developments.
1.3 The Role of Osteoclasts

The osteoclast (OC) is a bone tissue-specific multinucleated
cell that differentiates from hematopoietic stem cells similar
to those giving rise to monocyte/macrophage. Mature osteo-
clasts adhering to the bone surface both produce and secrete
HCl, which acidifies and dissolves the bone mineral, and
proteolytic enzymes, mainly metalloproteases and cathepsin
K, which digest the bone matrix, releasing in the circulation-
specific collagen fragments, such as CTx, which in turn are
used as clinical markers of bone turnover.
4 S. L. Ferrari
Osteoclastogenesis is activated by a number of pro-

inflammatory cytokines, including interleukin-1, interleukin-6,
and TNF alpha, which can be expressed by both T cells in the
bone marrow and bone cells themselves [8]. This explains why
systemic inflammatory disorders, such as rheumatoid arthritis,
cause accelerated bone loss. However the only two factors
that are both necessary and sufficient to induce osteoclast dif-
ferentiation are colony-stimulating factor-1 (CSF-1 or M-CSF)
and receptor activator of nuclear factor kappa b (RANK)
ligand (RANKL). The mature, multinucleated OC is further
activated by RANKL binding to its receptor RANK.
To counteract the differentiation and activation of osteo-
clasts, osteoblasts/stromal cells also produce osteoprotegerin
(OPG), a decoy receptor which binds RANKL, preventing its
own binding to RANK (Fig. 1.2). Thereby, OPG negatively
regulates osteoclastogenesis, promotes apoptosis of mature
osteoclasts, and ultimately inhibits bone resorption [9]. Hence,
it is not so much the absolute level of RANKL and OPG in
the bone environment as much as the RANKL/OPG ratio
that determines whether bone resorption will be stimulated or
inhibited. In turn the discovery of RANKL/OPG led to the
CFU-M Pre-fusion
osteoclast
Osteoclasts RANKL
Formation
inhibited RANK
OPG
Hormones
Growth factors Function and survival
Cytokines inhibited
Osteoblas
Osteoblasts
Bone formation
Bone resorption
Figure 1.2 Osteoprotegerin (OPG), the natural antagonist of

RANK ligand, inhibits osteoclastogenesis. (Adapted from Boyle
et al. Nature. 2003;423:337–342.)
development of a human monoclonal antibody against

RANKL, denosumab, to prevent osteolysis and bone loss [7]
(see Chap. 5).
1.3.1 Control of Bone Resorption
Because the production of RANKL as well as other cyto-

kines is downregulated by estrogen (Fig. 1.3), postmeno-
pausal women suffer from an increased RANKL/OPG ratio
that is a direct explanation for their accelerated bone turn-
over and bone loss [10].
Parathyroid hormone (PTH) is the other main hormone to
be implicated in the pathogenesis of bone loss. Contrarily to
estrogen receptors, the PTH/PTHrP receptor is expressed on
osteoblasts rather than osteoclasts. PTH signaling in osteo-
blasts stimulates osteoclastogenesis, which is largely medi-
ated by an increase in RANKL, concomitant decrease of
OPG production, and therefore increase of the RANKL/
OPG ratio [11]. This situation is reached when PTH levels are
M-CSF, RANKL
IL-1, TNF-α Precursor
IL-6, TGF-β,..... (Osteoclast)
Precursor
(Osteoblast)
Estrogens
Apoptosis
Apoptosis Cytokines
TGF-β RANK-L
Osteoblast
Osteoclast
Figure 1.3 Estrogen controls cytokine production in bone and bone

remodeling
6 S. L. Ferrari
elevated, such as during poor calcium intake, vitamin D defi-

ciency, chronic renal failure, or in case of primary hyperpara-
thyroidism due to pathophysiological growth of the
parathyroid gland(s). In all these situations, increased PTH
levels cause accelerated bone loss.
1.4 The Role of Osteoblasts

Osteoprogenitor cells arise from multipotential mesenchymal
stem cells (MSCs) that give rise to a number of cell lineages
including those for osteoblasts (OB), chondrocytes, and adipo-
cytes [12]. Once osteoblasts are fully differentiated and become
activated, they will fulfill their two major actions, namely, synthe-
size new bone matrix first (i.e., the osteoid), mainly constituted
of type I collagen, then mineralize this osteoid by triggering the
deposition of calcium-phosphate crystals named hydroxyapatite.
This specific function involves tissue non-specific alkaline phos-
phatase (TNAP), which catalyzes the hydrolysis of phosphate
esters at the osteoblast surface to provide a high phosphate
concentration to initiate the bone mineralization process [13].
Whether or not osteoblastogenesis is impaired with aging
remains uncertain. On one side, some in vitro experiments sug-
gest that MSC proliferation and survival, as well as their dif-
ferentiation into osteoblasts, are reduced from bone explants
of elderly subjects compared to younger individuals. A reduced
number of osteoblasts (and osteocytes; see below) and/or their
impaired ability to synthesize new bone matrix in response to
biomechanical stimulation has also been advocated as a poten-
tial mechanism for the reduced skeletal response to physical
activity in the elderly (compared to growing and younger sub-
jects) [14]. In turn, the aging skeleton seems to accumulate
more fat cells resulting from the preferential differentiation of
MSCs into adipocytes in the bone marrow [15].
1.4.1 Control of Bone Formation
Several signaling molecules play major roles in controlling dif-

ferentiation toward the osteoblastic lineage. These include
insulin-like growth factor 1 (IGF-1) and other growth factors

that stimulate bone formation, as well as cytokines, particularly
interleukin-6, which exert negative effects. Hence decreased
levels of IGF-1, which has also been related to poor protein
intake, may contribute to decreased bone mass with aging [16].
The essential role of wingless (Wnt) canonical signaling on
bone formation was understood when loss-of-function muta-
tions in the low-density lipoprotein receptor-related protein 5
(LRP5), a Wnt receptor expressed in bone cells, were discov-
ered to cause the osteoporosis-pseudoglioma syndrome
(OPPG), an autosomal recessive disorder characterized by
extremely low BMD and skeletal fragility [17]. On the oppo-
site, gain-of-function mutation in LRP5 causes high bone
mass (HBM) phenotypes and diverse sclerosing bone dyspla-
sias. Furthermore, mutations in or near the SOST gene, cod-
ing for sclerostin, were found responsible for the rare
sclerosing bone dysplasias, sclerosteosis, and van Buchem
disease type 1 [18, 19]. Similar to LRP5 HBM mutations,
SOST mutations are characterized by a marked increase in
bone mass. Expression of the SOST gene product, sclerostin,
is restricted to osteocytes in adults and was revealed as an
osteocyte-specific negative regulator of bone formation [20,
21] (Fig. 1.4). Production of sclerostin by osteocytes is rapidly
decreased by mechanical loading and by PTH [22, 23].
Whether sclerostin expression is increased, or inappropriate,
Mesenchymal
stem cells
Mature
Pre-osteoblast
osteoblasts
lining cells
X X
New bone
Bone
Osteocyte
Sclerostin
Figure 1.4 Sclerostin produced by osteocytes inhibits bone formation

8 S. L. Ferrari
with aging and contributes directly to osteoporosis remains

unclear. Nevertheless its discovery has allowed the develop-
ment of neutralizing monoclonal antibodies with remarkable
bone-forming properties [24] (see Chap. 9).
1.5 Conclusion
The loss of bone mineral mass and the microstructural altera-
tions that fragilize bone, leading to osteoporosis, result from
complex cellular and molecular mechanisms. Those are repre-
sented by increased osteoclast numbers and activity driven
primarily by RANK ligand and a relatively weaker bone-
forming response by osteoblasts, which are negatively con-
trolled by sclerostin from osteocytes. In turn, these mechanisms
have become the target for osteoporosis treatment.
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4. Zebaze RM, Ghasem-Zadeh A, Bohte A, et al. Intracortical remod-
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7. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of
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R. Protein intake, IGF-1 and osteoporosis. Osteoporos Int.
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Chapter 2
Diagnosis and Clinical
Aspects of Osteoporosis
John A. Kanis
2.1 Introduction
The internationally agreed description of osteoporosis is “a
systemic skeletal disease characterized by low bone mass and
microarchitectural deterioration of bone tissue with a conse-
quent increase in bone fragility and susceptibility to fracture”
[1]. This description captures the notion that low bone mass is
an important component of the risk of fracture but that other
abnormalities occur in the skeleton that contribute to skeletal
fragility. Thus, ideally, clinical assessment of the skeleton
should capture all these aspects of fracture risk. At present,
however, the assessment of bone mineral is the only aspect
that can be readily measured in clinical practice, and it now
forms the cornerstone for the description of osteoporosis.
2.2 Diagnosing Osteoporosis

Although diagnosis of the disease relies on the quantitative
assessment of bone mineral density, which is a major determi-
nant of bone strength, the clinical significance of osteoporosis
J. A. Kanis (*)
Center for Metabolic Bone Diseases, University of Sheffield
Medical School, Sheffield, UK

12 J. A. Kanis
lies in the fractures that arise. In this respect, there are some
analogies with other multifactorial chronic diseases. For
example, hypertension is diagnosed on the basis of blood
pressure, whereas an important clinical consequence of
hypertension is stroke.
Because a variety of non-skeletal factors contribute to frac-
ture risk, the diagnosis of osteoporosis by the use of bone
mineral density (BMD) measurements is at the same time an
assessment of a risk factor for the clinical outcome of fracture.
For these reasons, there is a distinction to be made between
the use of BMD for diagnosis and for risk assessment [2].
Bone mineral density is most often described as a T- or
Z-score, both of which are units of standard deviation (SD).
The T-score describes the number of SDs by which the BMD
in an individual differs from the mean value expected in
young healthy individuals (Fig. 2.1). The operational defini-
tion of osteoporosis is based on the T-score for BMD [3]
assessed at the femoral neck and is defined as a value for
BMD 2.5 SD or more below the young female adult mean
(T-score less than or equal to −2.5 SD) [4]. The Z-score
describes the number of SDs by which the BMD in an indi-
vidual differs from the mean value expected for age and sex.
It is mostly used in children and adolescents. The recom-
mended reference range by the for calculating the T-score is
the National Health and Nutrition Examination Survey
(NHANES) III reference database for femoral neck mea-
surements in Caucasian women aged 20–29 years [5]. The
diagnostic criteria for men use the same female reference
range as that for women. In clinical practice osteoporosis is
commonly defined as a T-score applied to other sites (e.g.,
lumbar spine).
2.3 Osteoporotic Fractures

An osteoporotic fracture describes a fracture event arising
from trauma that in a healthy individual would not give rise to
fracture. A widely adopted approach is to consider fractures
Chapter 2 Diagnosis and Clinical Aspects of Osteoporosis 13
Percent of population
0.6 15 50 85 >99
Osteoporosis Low bone Normal

mass
–4 –3 –2 –1 0 1 2 3 4
Bone mineral density (SD units or T-score)
Figure 2.1 The distribution of bone mineral density in young healthy

women in standard deviation units and threshold values for osteopo-
rosis and low bone mass (osteopenia). SD standard deviation
from low energy trauma as being osteoporotic. “Low energy”

is defined as a fall from a standing height or less. However,
osteoporotic patients more frequently sustain fractures after
“high-energy” trauma than their non-osteoporotic counter-
parts [6]. An approach increasingly used is to characterize
fracture sites as osteoporotic when they are associated with
low bone mass and their incidence rises with age after the age
of 50 years [7]. The most common fractures defined in this
way are those at the hip, spine, and forearm (Fig. 2.2), but
many other fractures after the age of 50 years are related at
least in part to low BMD and should be regarded as osteopo-
rotic. These include fractures of the humerus, ribs, tibia (in
women but not including ankle fractures), pelvis, and other
14 J. A. Kanis
Figure 2.2 Typical sites of osteoporotic fracture: wrist (left), spine

(center), and hip (right)
femoral fractures. Under this schema, the fracture sites that

would be excluded include those at the ankle, hands, and feet,
including the digits, skull and face, and kneecap.
2.3.1 Hip Fracture
Hip fracture is the most serious osteoporotic fracture.

Most hip fractures follow a fall from the standing position.
About one third of elderly individuals fall annually, and
5% will sustain a fracture with 1% suffering a hip fracture
[8]. Hip fracture is painful and nearly always necessitates
hospitalization.
The two main hip fracture types, cervical or trochanteric,
have a somewhat different natural history and treatment. In
many countries both fracture types occur with equal fre-
quency, though the average age of patients with trochanteric
fractures is approximately 5 years older than for cervical
fractures. Displaced cervical fractures have a high incidence
of malunion and osteonecrosis following internal fixation,
and the prognosis is improved with hip replacement.
Trochanteric hip fractures appear to heal normally after
adequate surgical management. For both fracture types,
there is a high degree of morbidity and appreciable mortal-
ity that depend in part on the age, the treatment given, and
the associated morbidity. Up to 20% of patients die in the
first year following hip fracture, mostly as a result of serious
Annual Incidence (rate/1,000)

40
Vertebral
30 Distal forearm
Proximal humerus
Hip
20
10
0
50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89
Age (years)
Figure 2.3 Incidence (rate/1000 per annum) by age of fractures at

the sites shown in women from Malmo, Sweden. Vertebral fractures
are those coming to clinical attention [Drawn from data in 12]
underlying medical conditions, and less than half of survi-

vors regain the level of function that they had prior to the
hip fracture [9, 10].
Incidence rates for hip fracture increase exponentially
with age in both men and women (Fig. 2.3). Rates for men at
any age are about half that in women. There is a remarkable
heterogeneity in the age-adjusted and sex-adjusted incidence
for hip fracture in various regions of the world which varies
more than tenfold [11]. The highest incidence rates have been
observed in Northern Europe.
2.3.2 Vertebral Fracture
Vertebral fracture is the most difficult osteoporosis-related

fracture to define. The problem arises in part because the
diagnosis is made on a change in the shape of the vertebral
body and a substantial proportion of vertebral deformities
are clinically silent or not attributable to osteoporosis. About
one in three vertebral deformities reaches immediate clinical
16 J. A. Kanis
attention through either back pain, height loss, or other func-

tional impairment [12]. Scheuermann’s disease (osteochon-
dritis) and vertebral osteoarthritis are common disorders that
give rise to deformities not attributable to osteoporosis.
The deformities that result from osteoporotic fracture are
classified as a crush fracture (involving compression of the
entire vertebral body), a wedge fracture (in which there is
anterior height loss), and biconcavity (where there is relative
maintenance of the anterior and posterior heights with cen-
tral compression of the end-plate regions).
The vast majority of vertebral fractures are a result of
moderate or minimal trauma. Falls account for only about
one third of new clinical vertebral fractures, and most are
associated instead with other activities such as lifting or
changing position.
Incidence rates can be expressed as the incidence of verte-
bral deformity (morphometric fractures) or the incidence of
clinically overt fractures (clinical vertebral fractures) [13]. The
incidence of vertebral morphometric deformities, as with other
osteoporotic fractures, is greater in women than in men and
rises with age. The age-related increase is less steep than that
of hip fractures (see Fig. 2.3), and the variation between coun-
tries is less marked. The incidence of clinically evident verte-
bral fractures is 20–40% that of morphometric fractures [12].
2.3.3 Distal Forearm Fracture
The most common distal forearm fracture is Colles’ fracture

associated with dorsal angulation and displacement of the
distal fragment of the radius, often accompanied by a fracture
of the ulna styloid process. The cause of fracture is usually a
fall on the outstretched hand. Although fractures of the wrist
cause less morbidity than hip fractures, are rarely fatal, and
seldom require hospitalization, the consequences are often
underestimated. Fractures are painful, usually require one or
more reductions, and need 4–6 weeks in plaster.Approximately
1% of patients with a forearm fracture become dependent as
a result of the fracture, but nearly half report only fair or poor
functional outcome at 6 months [8, 14].
Forearm fractures display a different pattern of incidence
from that of hip or spine fractures. In many countries, rates
increase linearly in women between the ages of 40 and
65 years and then stabilize. In other countries, incidence rises
progressively with age (see Fig. 3.3). Forearm fractures are
much less frequent in men; the incidence is commonly con-
stant between the ages of 20 and 80 years, and where this
rises, it does so at a much slower rate than in women.
2.3.4 All Fractures
A majority of fractures in patients aged 50 years or more are

attributable to osteoporosis. The incidence rates of proximal
humeral, pelvic, and proximal tibial fractures rise steeply with
age and are greater among women than among men. At the
age of 50 years, rib, vertebral, and forearm fractures are the
most commonly found fractures in men, whereas in women
the most common fractures comprise distal forearm, verte-
bral, rib, and proximal humeral fractures. Over the age of
85 years, hip fracture is the most frequent fracture among
men and women but still accounts for only approximately
one third of all osteoporotic fractures [7].
2.4 Burden of Disease

There are different ways of expressing the burden of dis-
ease. From an individual perspective, the likelihood of frac-
ture from the age of 50 years is a useful metric (Table 2.1).
The remaining lifetime probability in women at the meno-
pause of a fracture at any one of these sites exceeds that of
breast cancer (approximately 12%), and the likelihood of a
fracture at any of these sites is 40% or more in Western
Europe [15], a figure close to the probability of coronary
heart disease.
18 J. A. Kanis
Table 2.1 Remaining lifetime probability of a major osteoporotic

fracture at the age of 50 and 80 years in men and women from
Sweden [15]
At 50 years At 80 years
Site Men Women Men Women
Forearm 4.6 20.8 1.6 8.9
Hip 10.7 22.9 9.1 49.3
Spine 8.3 15.1 4.7 8.7
Humerus 4.1 12.9 2.5 7.7
Any of these 22.4 46.4 15.3 31.7
With kind permission from Springer Science and Business Media
The number of new fractures in 2010 in the EU was esti-

mated at 3.5 million, comprising approximately 620,000 hip
fractures, 520,000 vertebral fractures, 560,000 forearm frac-
tures, and 1,800,000 other fractures [8]. Thus, hip, vertebral,
forearm, and “other fractures” accounted for 18%, 15%, 16%,
and 51% of all fractures, respectively. Two thirds of all inci-
dent fractures occurred in women. Osteoporotic fractures
accounted for €37.4 billion in direct costs in the 27 EU coun-
tries [16, 17].
2.5 Conclusion
The high societal and personal costs of osteoporosis pose chal-
lenges to public health and physicians, particularly since most
patients with osteoporosis remain untreated. Moreover, age is
an important risk factor for fractures, and the elderly popula-
tion is projected to increase in the majority of countries, which
will increase the burden of fracture. Projections for Europe
indicate that the number of osteoporotic fractures will increase
by 28% from 3.5 million in 2010 to 4.5 million in 2025 [16].
The operational definition of osteoporosis, based on spine
or hip BMD T-scores evaluated by DXA scans, has proven a
practical tool in identifying affected individuals at higher risk
of fragility fractures. However, because the pathophysiologi-

cal definition of osteoporosis is more complex and includes
dimensions that are not fully appreciated by DXA, a majority
of fragility fractures still occurs in osteopenic subjects.
References
1. Anonymous. Consensus Development Conference. Diagnosis,
prophylaxis and treatment of osteoporosis. Am J Med.
1993;94:646–50.
2. Kanis JA, McCloskey EV, Johansson H, et al. European guid-
ance for the diagnosis and management of osteoporosis in post-
menopausal women. Osteoporos Int. 2013;24:23–57.
3. [No authors listed]. Assessment of fracture risk and its appli-
cation to screening for postmenopausal osteoporosis. World
Health Organ Tech Rep Ser. 1994;843:1–129.
4. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd,
Khaltaev N. A reference standard for the description of osteo-
porosis. Bone. 2008;42:467–75.
5. Looker AC, Wahner HW, Dunn WL, et al. Updated data on
proximal femur bone mineral levels of US adults. Osteoporos
Int. 1998;8:468–86.
6. Sanders KM, Pasco JA, Ugoni AM, et al. The exclusion of high
trauma fractures may underestimate the prevalence of bone
fragility fractures in the community: the Geelong Osteoporosis
Study. J Bone Miner Res. 1998;13:1337–42.
7. Kanis JA, Oden A, Johnell O, Jonsson B, de Laet C, Dawson
A. The burden of osteoporotic fractures: a method for setting
intervention thresholds. Osteoporos Int. 2001;12:417–27.
8. Kanis JA on behalf of the World Health Organization Scientific
Group. Assessment of osteoporosis at the primary health-
care level. Technical Report. WHO Collaborating Centre for
Metabolic Bone Diseases, University of Sheffield, UK, 2008.
http://www.shef.ac.uk/FRAX/pdfs/WHO_Technical_Report.pdf.
Accessed 5 Jan 2016.
9. Poór G, Atkinson EJ, O'Fallon WM, Melton LJ 3rd. Determinants
of reduced survival following hip fractures in men. Clin Orthop
Rel Res. 1995;319:260–5.
10. Melton LJ 3rd. Adverse outcomes of osteoporotic fractures in
the general population. J Bone Miner Res. 2003;18:1139–41.
20 J. A. Kanis
11. Kanis JA, Odén A, McCloskey EV, Johansson H, Wahl D,

Cooper C, IOF Working Group on Epidemiology and Quality
of Life. A systematic review of hip fracture incidence and prob-
ability of fracture worldwide. Osteoporos Int. 2012;23:2239–56.
12. Kanis JA, Johnell O, Oden A, et al. Risk and burden of vertebral
fractures in Sweden. Osteoporos Int. 2004;15:20–6.
13. O’Neill TW, Cockerill W, Matthis C, et al. Back pain, disability
and prevalent vertebral fracture: a prospective study. Osteoporos
Int. 2004;15:760–5.
14. Kaukonen JP, Karaharju EO, Porras M, Lüthje P, Jakobsson
A. Functional recovery after fractures of the distal forearm:
analysis of radiographic and other factors affecting the outcome.
Ann Chir Gynaecol. 1988;77:27–31.
15. Kanis JA, Johnell O, Oden A, et al. Long-term risk of osteopo-
rotic fracture in Malmo. Osteoporos Int. 2000;11:669–74.
16. Hernlund E, Svedbom A, Ivergård M, et al. Osteoporosis in
the European Union: medical management, epidemiology and
economic burden. A report prepared in collaboration with the
International Osteoporosis Foundation (IOF) and the European
Federation of Pharmaceutical Industry Associations (EFPIA).
Arch Osteoporos. 2013;8:136.
17. Svedbom A, Hernlund E, Ivergård M, et al. Osteoporosis in the
European Union: a compendium of country-specific reports.
Arch Osteoporos. 2013;8:137.
Chapter 3
Evaluation of Fracture
Risk
Eugene V. McCloskey
3.1 Introduction
The World Health Organization (WHO) diagnostic criterion
for osteoporosis, launched in 1994 [1], was based on the bone
mineral density (BMD) T-score (<−2.5) and is still used in
many healthcare systems as a necessary requirement for
reimbursement of osteoporosis therapies that reduce fracture
risk. However, as implied by this chapter title, and indeed the
definition of osteoporosis itself (see Chap. 2), there is more to
the assessment of fracture risk than simply the identification
of BMD-defined osteoporosis.
3.2 Non-invasive Skeletal Assessments
3.2.1 Measurements of Bone Mass
Dual-energy X-ray absorptiometry (DXA) is by far the most

commonly used assessment of bone mass and has been vali-
dated for the assessment of fracture risk in many studies [2].
E. V. McCloskey (*)
Center for Metabolic Bone Diseases, University of Sheffield
Medical School, Sheffield, UK

22 E. V. McCloskey
DXA scanners measure the attenuation through the body of

X-ray beams with two different photon energies [3] with regard
to two reference materials, namely, bone mineral (hydroxyapa-
tite) and soft tissue (defined within a reference area adjacent to
the bone region of interest). Edge detection software is used to
find the bone outline at skeletal sites, most commonly the lum-
bar spine and proximal femur. The technique is fast and uses a
low radiation dose. Several manufacturers provide DXA equip-
ment with subtle but occasionally important differences in volt-
ages used, filtering mechanisms, edge detection, and soft tissue
thickness adjustments. For these reasons, care needs to be taken
when comparing results from the same patients scanned across
different makes of equipment – ideally, patients should be
scanned on the same equipment over time, where possible. The
main indication for the measurement of BMD by DXA is the
presence of risk factors, such as prior fracture, family history of
fracture, causes of secondary osteoporosis (e.g. rheumatoid
arthritis, glucocorticoid use, etc.), and lifestyle factors with only
small variation across healthcare systems. Some clinical guide-
lines now recommend the formal assessment of fracture risk
prior to BMD assessment (see below) [4].
Quantitative computed tomography (QCT) is a potential
alternative to DXA but largely remains a research tool. It offers
the advantage of providing a true volumetric density as well as
an assessment of bone microstructure [3]. The X-ray dose is
substantially higher than DXA although recent developments
targeting the peripheral skeleton (tibia and radius/ulna) provide
lower exposures. In QCT, a reference phantom of known com-
position is scanned together with the patient to permit expres-
sion of the results in calcium hydroxyapatite equivalent BMD.
Quantitative ultrasound (QUS) is also a common tool
used in the assessment of bone mass (it may also capture
bone structure, but its contribution to the clinical utility of
QUS appears marginal). The heel is the only validated skel-
etal site for the clinical use of QUS and predicts fragility
fracture in postmenopausal women (hip, vertebral, and global
fracture risk) and older men, independently of axial BMD [5].
Axial DXA at the spine and femur remains the preferred
measurement for making therapeutic decisions and should be
used if possible.
Chapter 3 Evaluation of Fracture Risk 23
3.2.2 Measurements of Bone Structure
Non-invasive imaging can assess bone macrostructure and

microstructure. Lateral imaging of the spine using DXA is
now a well-established method for vertebral fracture assess-
ment (VFA), so that a single device can capture two well-
established risk factors for fracture (BMD and the presence
or absence of vertebral fracture; Fig. 3.1). VFA can be under-
taken in patients at higher risk of having a prevalent vertebral
fracture, for example, in older individuals, patients with his-
torical or measured height loss, self-reported prior fracture,
and long-term glucocorticoid therapy [6].
Figure 3.1 Vertebral fracture

assessment image from a dual-
energy X-ray absorptiometry
scanner of the thoracic and
lumbar spine showing a verte-
bral fracture at the thoraco-
lumbar junction
24 E. V. McCloskey
More recently, a third clinically applicable, DXA-based

assessment has been developed, namely, the trabecular bone
score (TBS). TBS is a grey-level textural measurement origi-
nally derived from lumbar spine DXA images that appears to
be an index of bone microarchitecture. Prospective studies
have shown that TBS predicts fracture in postmenopausal
women and older men, independently of BMD [7]. DXA can
also be used to examine macrostructural parameters such as
hip shape, buckling index, and femoral neck length although
these are not commonly used in clinical practice. More
detailed microstructural imaging using high-resolution
peripheral QCT is available as a research tool [8].
3.2.3 Measurements of Bone Turnover
Despite the knowledge that high bone turnover is often det-

rimental and that inhibitors of bone turnover are beneficial,
the uptake of bone turnover markers (BTM) in clinical use
has been slowed by concerns about their variability and inad-
equate quality control [9]. BTM predict fracture risk, though
weakly, and treatment-induced changes in specific markers
account for a substantial proportion of fracture risk reduc-
tion. More recent, better validated markers for bone forma-
tion, such as serum aminoterminal propeptide of type I
collagen (PINP), and bone resorption, serum carboxy
(C)-terminal telopeptide (CTX), are increasingly available
and are being incorporated into monitoring algorithms of
osteoporosis therapies. Uncertainties over their clinical use
continue to be resolved through the development and adop-
tion of international reference standards.
3.3 Assessment of Fracture Risk

The principal difficulty with the use of BMD alone for risk
assessment is that BMD has high specificity but low sensitiv-
ity for future fractures. Thus, the majority of hip and other
osteoporotic fractures will occur in individuals with BMD
Table 3.1 Summary of the characteristics of three available fracture

risk assessment tools
Garvan Qfracture FRAX
Externally Yes (a few Yes (UK Yes
validated countries) only)
Calibrated No No Yes
Applicability Unknown UK 64
countries
Falls as an input Yes Yes No
BMD as an input Yes No Yes
variable
Prior fracture as an Yes Yes Yes
input
Family history as No Yes Yes
an input
Output Incidence Incidence Probability
Treatment response No No Yes
assessed
values above the osteoporosis threshold [1]. In clinical prac-

tice, many still use the multiple skeletal site approach (lowest
T-score of the spine, hip, or femoral neck) in the belief that
this improves the sensitivity of the technique but without
recognizing that this does not enhance the performance of
the test in terms of predictive value (the gain in sensitivity is
offset by a loss of specificity).
In the past 20 years, a great deal of research has taken
place to identify factors other than BMD that contribute to
fracture risk. Examples include age, sex, a prior fracture, a
family history of fracture, and lifestyle risk factors such as
physical inactivity and smoking. Some of these risk factors
are partially or wholly independent of BMD; they can there-
fore enhance the information provided by BMD alone or,
conversely, if strongly correlated with BMD can be used for
fracture risk assessment in the absence of BMD tests [10].
26 E. V. McCloskey
Several fracture prediction tools are available and increas-

ingly used in clinical practice. All have limitations (Table 3.1),
but all perform better than the simple use of a single risk fac-
tor (e.g. BMD) alone.
Only the FRAX® tool has been calibrated to rates of frac-
ture and mortality per individual country and has been shown
to identify a risk amenable to currently available treatments.
It is a computer-based algorithm (http://www.shef.ac.uk/
FRAX) that provides models for the assessment of 10-year
fracture probability in men and women using easily obtained
clinical risk factors, with or without femoral neck BMD
(Fig. 3.2).
FRAX calculates the 10-year probability of major osteo-
porotic fractures (hip, clinical spine, humerus, or wrist frac-
ture) and the 10-year probability of hip fracture alone. At
present, 68 FRAX models are available for 64 countries. In
the absence of a FRAX model for a particular country, a sur-
rogate country should be chosen, based on the likelihood that
it is representative of the index country. In addition to the
web-based calculator, the tool is also available in other
formats including being available on densitometers and

Figure 3.2 Screenshot of the UK FRAX® calculation tool showing

the risk factors and outputs of 10-year probabilities of major osteo-
porotic and hip fractures
Clinical risk factors Clinical risk factors
FRAX BMD
High Intermediate* Low T-score≤–2.5 T-score T-score >–1

>–2.5 and ≤–1
Treat BMD Treat FRAX
Reassess
FRAX High* Low
High Low Treat
Treat
*Thresholds may be country-specific. For example, *Thresholds may be country-specific. For example,
lower and upper limits can be determined by risk in they may be determined by cost-effectivenes
those without risk factors and those with a prior analyses.
fracture.
Figure 3.3 Approaches to the use of fracture risk assessment using

FRAX® in different guidelines depending on DXA availability
smartphones. FRAX is incorporated into a large number of

assessment guidelines [11], some of which recommend the
use of FRAX prior to BMD measurement (e.g. in the UK and
Europe) [12, 13] and some which recommend BMD first
(e.g. the USA; Fig. 3.3) [14], largely determined by the avail-
ability of DXA equipment. A recent study testing the UK
approach, based on FRAX hip fracture probabilities, has
shown a 28% reduction in hip fractures [15].
3.4 Conclusion
The advent of risk assessment algorithms indicates that pre-
vention of fractures is better targeted on the basis of fracture
probability using multiple risk factors rather than BMD
alone. Increasingly, guidelines are implementing risk-based
assessment and intervention into routine clinical practice.
Notwithstanding, diagnostic criteria remain of value in quan-
tifying the burden of disease, the development of strategies
to combat osteoporosis, and at least for the immediate
future, as a criterion for reimbursement in many healthcare
systems.
28 E. V. McCloskey
References
1. [No authors listed]. Assessment of fracture risk and its appli-
cation to screening for postmenopausal osteoporosis. Report
of a WHO Study Group. World Health Organ Tech Rep Ser.
1994;843:1–129.
2. Johnell O, et al. Predictive value of BMD for hip and other frac-
tures. J Bone Miner Res. 2005;20(7):1185–94.
3. Genant HK, et al. Noninvasive assessment of bone mineral and
structure: state of the art. J Bone Miner Res. 1996;11(6):707–30.
4. National Institute for Health and Care Excellence NICE
Clinical Guideline 146. Osteoporosis: assessing the risk of fragil-
ity fracture. 2012. DOI: guidance.nice.org.uk/CG146.
5. Knapp KM. Quantitative ultrasound and bone health. Salud
Publica Mex. 2009;51(Suppl 1):S18–24.
6. International Society for Clinical Densitometry, Official
Positions 2015 ISCD Combined. 2015.
7. Silva BC, et al. Trabecular bone score: a noninvasive ana-
lytical method based upon the DXA image. J Bone Miner Res.
2014;29(3):518–30.
8. Boutroy S, et al. In vivo assessment of trabecular bone microar-
chitecture by high-resolution peripheral quantitative computed
tomography. J Clin Endocrinol Metab. 2005;90(12):6508–15.
9. Vasikaran S, et al. International Osteoporosis Foundation and
International Federation of Clinical Chemistry and Laboratory
Medicine position on bone marker standards in osteoporosis.
Clin Chem Lab Med. 2011;49(8):1271–4.
10. Kanis JA. on behalf of the WHO Scientific Group, Assessment of
osteoporosis at the primary health-care level. Technical Report.
2008, WHO Collaborating Centre, University of Sheffield, UK:
Sheffield.
11. Kanis JA, et al. SCOPE: a scorecard for osteoporosis in Europe.
Arch Osteoporos. 2013;8(1–2):144.
12. Kanis JA, et al. European guidance for the diagnosis and man-
agement of osteoporosis in postmenopausal women. Osteoporos
Int. 2013;24(1):23–57.
13. Compston J, et al. Diagnosis and management of osteopo-
rosis in postmenopausal women and older men in the UK:
National Osteoporosis Guideline Group (NOGG) update 2013.
Maturitas. 2013;75(4):392–6.
14. Dawson-Hughes B, et al. Implications of absolute fracture

risk assessment for osteoporosis practice guidelines in the
USA. Osteoporos Int. 2008;19(4):449–58.
15. Shepstone L, et al. Screening in the community to reduce frac-
tures in older women (SCOOP): a randomised controlled trial.
Lancet. 2018;391(10122):741–7.
Chapter 4
Prevention
of Osteoporosis
and Fragility Fractures
René Rizzoli
4.1 Introduction
A fracture represents a structural failure of the bone whereby
the forces applied to the bone exceed its load-bearing capacity.
Therefore, besides bone geometry, mass, density, microstruc-
ture, and material level properties, the direction and magnitude
of the applied load also determine whether a bone will frac-
ture. Almost all fractures, even those qualified as “low-trauma”
fractures, occur as the result of some injury, for instance, a fall
from standing height or bending forward to lift heavy objects
for vertebral fracture. While available pharmacological inter-
vention is primarily aimed at restoring bone strength (i.e.,
reducing bone fragility) by altering bone turnover and/or
material level properties, a variety of preventive measures for
osteoporotic fractures are capable of influencing both compo-
nents of fracture risk: mechanical overload, for example, falls,
and mechanical incompetence, such as osteoporosis (Fig. 4.1).
R. Rizzoli (*)
Division of Bone Diseases, Geneva University Hospitals and
Faculty of Medicine, Geneva, Switzerland

32 R. Rizzoli
Falls Osteoporosis
Sway
Muscle strength
Neuro-Muscular impairment
Mechanical overload Mechanical incompetence
Fracture
Physical exercise
Nutrition
Vitamin D Fracture repair
Rehabilitation
Prevention of subsequent fracture
Figure 4.1 Prevention of osteoporotic fracture by physical exercise,

nutrition (calcium, protein), and vitamin D
4.2 Physical Activity

Immobilization is an important cause of bone loss [1].
Immobilized patients may lose as much bone in a week when
confined to bed as they would otherwise lose in a year. At the
tissue level, immobilization results in a negative balance, the
amount of bone resorbed being greater than that formed. At
the cellular level, immobilization results in an increased
osteoclastic resorption associated with a decrease in osteo-
blastic formation. The amount of weight-bearing exercise that
is optimal for skeletal health in patients with osteoporosis is
not known, but exercise forms an integral component of its
management [2, 3]. Physiotherapy is an important component
of rehabilitation after fracture [4]. At all times, increased
muscle strength may prevent falls by improving confidence
and coordination and contribute to reducing fracture risk by
maintaining bone mass through a stimulation of bone forma-
tion and a decrease of bone resorption [5].
Mixed loading exercise appears to be effective to reduce
bone loss in postmenopausal women [6–8] and in men [9].
Some prevention of hip fracture by physical activity has been
Chapter 4 Prevention of Osteoporosis and Fragility... 33
consistently reported [10]. Jumping on one leg daily during

12 months is associated with an increased cortical thickness
of the femoral neck [10].
The potential side effects and limitations of physical activ-
ity in osteoporotic patients have been reviewed, as reported
in 39 intervention studies (Table 4.1) [11].
Both aerobic activity and resistance training are of benefit
to older people. Resistance exercise training is a stimulus for
muscle protein synthesis and appears to be beneficial to
rebuild muscle mass, strength, and performance in the elderly
[5]. Dietary proteins following physical exercises magnify de
novo muscle protein synthesis [12, 13]. The American Heart
Association and the American College of Sports Medicine
encourage older adults to complete 30–60 min of moderate
intensity aerobic exercise per day (150–300 min/week) or
20–30 min of vigorous intensity exercise per day (75–150 min/
week) [14]. For healthy older adults, exercise of 10–15 min per
session with eight repetitions for each muscle group is a rea-
sonable goal.
Table 4.1 Physical activity in osteoporotic patients

Patients at high risk of fracture (with prevalent fracture or with
glucocorticoid therapy): avoid trunk flexion exercise; however,
trunk extension exercise and abdominal stabilization exercise
are safe (level 2, grade A).
Patients recovering from hip fracture: weight-bearing exercises
are recommended from day 18 (level 2, grade A).
Patients with osteoporosis: aerobic physical activity and
progressive resistance training are safe (level 2, grade A). They
should avoid powerful twisting movements of the trunk (level 3,
grade C).
Patients with spinal cord injury (without recent fracture):
progressive lower limb resistance training or body-weight-
supported treadmill (level 2, grade A). Avoid maximal strength
testing, for instance, by electrical stimulation (level 3, grade C).
Level of evidence (1, RCTs; 2, RCTs with limitation or very convincing
observational studies; 3, observational studies; 4, anecdotal evidence)
and recommendations grades (A, strong; B, intermediate; C, weak)
34 R. Rizzoli
4.3 Prevention of Falls

The risk of falling increases with age. Most falls in elderly are
due to intrinsic and extrinsic or environmental factors
(Table 4.2) [15].
4.3.1 Intrinsic Factors
The risk of falling increases with the number of disabilities.

Impairments of gait, mobility, and balance have been the
most consistently identified risk factors for falls and fall-
related injuries [15]. Thus, the risk of falling increases with
reduced visual acuity or diminished sensory perception of the
lower extremities. Chronic illnesses such as various neuro-
logical disorders, heart diseases, stroke, urinary incontinence,
depression, and impaired cognitive functions increase the risk
of falling. Medications such as hypnotics, antidepressants, or
sedatives are associated with falls [16].
4.3.2 Environmental (Extrinsic) Risk Factors

Potential hazards that can be found in the home include slip-
pery floors, unstable furniture, and insufficient lighting.
Table 4.2 Risk factors 1. Impaired mobility, disability

associated with falls
2. Impaired gait and balance
3. Neuromuscular or
musculoskeletal disorders
4. Age
5. Impaired vision
6. Neurological, heart
disorders
7. History of falls
8. Medication
9. Cognitive impairment
Modifiable factors such as correcting decreased visual acuity

[17], reducing consumption of medication that alters alertness
and balance, and improving the home environment (slippery
floors, obstacles, insufficient lighting, and handrails) are
important measures aimed at preventing falls [15, 18, 19].
Recently, a multitask music-based training such as Jaques-
Dalcroze eurhythmic exercises has been shown to reduce gait
and balance variability and lower fracture incidence [20, 21].
Some studies, although not all, have reported fall risk reduc-
tion in the elderly that practice Tai Chi [22]. Large trials have
shown that it is possible to reduce falls [18, 23], and meta-
analyses have concluded that reducing falls can be associated
with a lower fracture risk [24].
4.4 Nutrition
There is a high prevalence of calcium, protein, and vitamin D
deficiency in the elderly population [25–28], which plays a
significant role in osteoporosis, sarcopenia, and in fracture
risk [29–31]. Malnutrition appears to be more severe in
patients with hip fracture than in the general aging popula-
tion. Mechanisms for alterations of protein use in older per-
sons are inadequate intake of protein, reduced ability to use
available protein (e.g., anabolic resistance and tissue redistri-
bution of amino acids), and a greater need for protein (e.g., in
inflammatory diseases). Dietary proteins have a direct effect
on key regulatory proteins and growth factors involved in
muscle metabolism, such as mammalian target of rapamycin
(mTOR) and insulin-like growth factor-1 (IGF-1) [5].
Branched-chain amino acids lead to activation of mTOR, and
aromatic amino acids (which are particularly prevalent in
dairy protein) lead to increased IGF-1 resulting in greater
muscle mass and strength. Recommended dietary allowance
for protein in adults is 0.8 g of protein per kilogram of body
weight each day (g/kg BW/d). A low dietary intake of protein
(0.45 g/kg BW) in elderly healthy women, a level quite com-
mon in patients presenting with hip fracture, is associated
with a reduction in plasma IGF-1 levels and in skeletal mus-
cle fiber atrophy [32].
36 R. Rizzoli
A low protein intake could be particularly detrimental

since it alters the conservation of muscle and bone integrity
with aging [25, 29]. Protein malnutrition can favor the occur-
rence of hip fracture by increasing the propensity to fall as a
result of muscle weakness and of impairment in movement
coordination, by affecting protective mechanisms, and thus by
reducing the energy required to fracture an osteoporotic
proximal femur and/or by decreasing bone mass [31]. In addi-
tion to lower IGF-1, a low protein intake is associated with
decreased intestinal absorption of calcium and secondary
hyperparathyroidism [33].
There is a positive correlation between bone mineral mass
and spontaneous protein intake in women [34], with a meta-
analysis showing that 1–4% of bone mineral density (BMD)
variance could be explained by protein intakes. In a prospec-
tive study carried out on more than 40,000 women in Iowa,
higher protein intake was associated with a reduced risk of
hip fracture [35].
Whereas a gradual decline in caloric intake with age can
be considered as an appropriate adjustment to the progres-
sive reduction in energy expenditure, the parallel reduction in
protein intake may be detrimental for maintaining the
integrity and function of several organs or systems, including
skeletal muscle and bone [25]. Intakes of at least 1 g/kg body
weight of protein are recommended in the general manage-
ment of patients with osteoporosis [36] and even 1.2 g/kg in
the elderly [29, 36, 37].
A state of malnutrition at admission in elderly patients
with hip fracture followed by an inadequate food intake dur-
ing hospital stay can adversely influence their clinical out-
come. Intervention studies using a simple oral dietary
preparation that normalizes protein intake can improve the
clinical outcome after hip fracture [25, 38] and reduce the
length of stay for rehabilitation in hospital [39]. Thus, suffi-
cient protein intakes are necessary to maintain the function
of the musculoskeletal system and to decrease the medical
complications that occur after an osteoporotic fracture [39].
4.4.1 Calcium and Vitamin D
At every stage of life, adequate dietary intakes of key bone

nutrients such as calcium and vitamin D contribute to bone
health and reduce the risk of osteoporosis and fracture later
in life [30, 40]. Dietary sources of calcium are the preferred
option, and calcium supplementation should only be targeted
to those who do not get sufficient calcium from their diet and
who are at high risk for osteoporosis. Calcium-rich foods such
as dairy products contain additional nutrients that may also
contribute to bone health [41].
The recommended nutrient intakes (RNI) are at least
1000 mg of calcium and 800 international units (IU) of vita-
min D per day in men and women over the age of 60 years
[27, 42]. As dairy is the main source of calcium, calcium- and
vitamin D-fortified dairy products (such as yogurt and milk)
providing around 40% of the RNI of calcium (400 mg) and
200 IU of vitamin D per portion are valuable options, likely
to improve long-term adherence [41, 42]. When pharmaco-
logical calcium supplements are needed, they should be taken
with a meal to improve tolerance and increase calcium
absorption.
Most randomized controlled trial evidence for the efficacy
of interventions is based on co-administration of the agent
with calcium and vitamin D supplements [40]. Calcium and
vitamin D supplements decrease secondary hyperparathy-
roidism and reduce the risk of proximal femur fracture, par-
ticularly in the elderly living in nursing homes. Intakes of at
least 1000 mg/day of calcium and 800 IU of vitamin D can be
recommended in the general management of patients with
osteoporosis [37, 42].
A recent meta-analysis has concluded that calcium supple-
ments without co-administered vitamin D were associated
with an increased risk of myocardial infarction [43].
Cardiovascular outcomes were not primary endpoints in any
of the studies, and this analysis is the subject of controversy.
Large long-term observational studies have not confirmed
38 R. Rizzoli
this hypothesis [44, 45]. There was no increased risk when

calcium was of dietary origin [43].
Vitamin D has both skeletal and extra-skeletal benefits
[29]. The potential effect of vitamin D on skeletal muscle
strength is receiving attention. Vitamin D supplements alone
may reduce the risk of fracture and of falling provided the
daily dose of vitamin D is greater than 700 IU [30]. In con-
trast, studies with large annual doses of vitamin D have
reported an increased risk of falls and hip fracture [46]. Thus,
a yearly regimen of vitamin D high-dose supplementation
should be avoided.
4.5 Conclusion
For the management of osteoporosis, protein intake of 1.0–
1.2 g/kg BW/d, calcium intake of 1000 mg/day, and vitamin D
supplements of 800–1000 IU/d are associated with higher
muscle strength and improved bone health [37]. The positive
effect of physical activity on muscle protein synthesis and
function is augmented by protein intake [12, 13].
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9. Kelley GA, Kelley KS, Kohrt WM. Exercise and bone mineral
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10. Karlsson MK, Nordqvist A, Karlsson C. Physical activity, muscle
function, falls and fractures. Food Nutr Res. 2008;52:1920.
11. Chilibeck PD, Vatanparast H, Cornish SM, Abeysekara S,
Charlesworth S. Evidence-based risk assessment and recommen-
dations for physical activity: arthritis, osteoporosis, and low back
pain. Appl Physiol Nutr Metab. 2011;36(Suppl 1):S49–79.
12. Cermak NM, Res PT, de Groot LC, Saris WH, van Loon
LJ. Protein supplementation augments the adaptive response
of skeletal muscle to resistance-type exercise training: a meta-
analysis. Am J Clin Nutr. 2012;96:1454–64.
13. Finger D, Goltz FR, Umpierre D, Meyer E, Rosa LH, Schneider
CD. Effects of protein supplementation in older adults undergo-
ing resistance training: a systematic review and meta-analysis.
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14. Nelson ME, Rejeski WJ, Blair SN, et al. Physical activity
and public health in older adults: recommendation from the
American College of Sports Medicine and the American Heart
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15. Panel on Prevention of Falls in Older Persons, American
Geriatrics Society and British Geriatrics Society. Summary of
the Updated American Geriatrics Society/British Geriatrics
Society clinical practice guideline for prevention of falls in older
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16. Woolcott JC, Richardson KJ, Wiens MO, et al. Meta-analysis of
the impact of 9 medication classes on falls in elderly persons.
Arch Intern Med. 2009;169:1952–60.
17. Harwood RH, Foss AJ, Osborn F, Gregson RM, Zaman A,
Masud T. Falls and health status in elderly women following
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first eye cataract surgery: a randomised controlled trial. Br J

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19. Sherrington C, Tiedemann A. Physiotherapy in the prevention of
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20. Trombetti A, Hars M, Herrmann FR, Kressig RW, Ferrari S,
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22. Low S, Ang LW, Goh KS, Chew SK. A systematic review of the
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falls and fractures in hospitals and care homes and effect of cog-
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effect of fall prevention exercise programmes on fall induced
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Clin Endocrinol Metab. 2014;28:795–808.
26. Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, et al. Dietary
calcium and serum 25-hydroxyvitamin D status in relation to
BMD among U.S. adults. J Bone Miner Res. 2009;24:935–42.
27. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on
dietary reference intakes for calcium and vitamin D from the
Institute of Medicine: what clinicians need to know. J Clin
Endocrinol Metab. 2011;96:53–8.
28. Mithal A, Wahl DA, Bonjour JP, et al. Global vitamin D sta-
tus and determinants of hypovitaminosis D. Osteoporosis Int.
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29. Rizzoli R, Stevenson JC, Bauer JM, et al. The role of dietary pro-
tein and vitamin D in maintaining musculoskeletal health in post-
menopausal women: a consensus statement from the European
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Osteoarthritis (ESCEO). Maturitas. 2014;79:122–32.
30. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analy-
sis of vitamin D dose requirements for fracture prevention. N
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31. Gaffney-Stomberg E, Insogna KL, Rodriguez NR, Kerstetter
JE. Increasing dietary protein requirements in elderly people
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57:1073–9.
32. Castaneda C, Gordon PL, Fielding RA, Evans WJ, Crim
MC. Marginal protein intake results in reduced plasma IGF-I
levels and skeletal muscle fiber atrophy in elderly women. J Nutr
Health Aging. 2000;4:85–90.
33. Kerstetter JE, O'Brien KO, Caseria DM, Wall DE, Insogna
KL. The impact of dietary protein on calcium absorption and
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34. Darling AL, Millward DJ, Torgerson DJ, Hewitt CE, Lanham-
New SA. Dietary protein and bone health: a systematic review
and meta-analysis. Am J Clin Nutr. 2009;90:1674–92.
35. Munger RG, Cerhan JR, Chiu BC. Prospective study of dietary
protein intake and risk of hip fracture in postmenopausal
women. Am J Clin Nutr. 1999;69:147–52.
36. Bauer J, Biolo G, Cederholm T, et al. Evidence-based recom-
mendations for optimal dietary protein intake in older people:
a position paper from the PROT-AGE Study Group. J Am Med
Dir Assoc. 2013;14:542–59.
37. Rizzoli R, Branco J, Brandi ML, et al. Management of osteopo-
rosis of the oldest old. Osteoporosis Int. 2014;25:2507–29.
38. Feldblum I, German L, Castel H, Harman-Boehm I, Shahar
DR. Individualized nutritional intervention during and after
hospitalization: the nutrition intervention study clinical trial. J
Am Geriatr Soc. 2011;59:10–7.
39. Schurch MA, Rizzoli R, Slosman D, Vadas L, Vergnaud P,
Bonjour JP. Protein supplements increase serum insulin-like
growth factor-I levels and attenuate proximal femur bone loss
in patients with recent hip fracture. A randomized, double-blind,
placebo-controlled trial. Ann Intern Med. 1998;128:801–9.
40. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of
calcium or calcium in combination with vitamin D supplementa-
tion to prevent fractures and bone loss in people aged 50 years
and older: a meta-analysis. Lancet. 2007;370:657–66.
42 R. Rizzoli
41. Rizzoli R. Dairy products, yogurts, and bone health. Am J Clin

Nutr. 2014;99:1256S–62S.
42. Kanis JA, McCloskey EV, Johansson H, et al. European guid-
ance for the diagnosis and management of osteoporosis in post-
menopausal women. Osteoporosis Int. 2013;24:23–57.
43. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium
supplements on risk of myocardial infarction and cardiovascular
events: meta-analysis. BMJ. 2013;c3691:341.
44. Prentice RL, Pettinger MB, Jackson RD, et al. Health risks and
benefits from calcium and vitamin D supplementation: Women's
Health Initiative clinical trial and cohort study. Osteoporosis Int.
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45. Paik JM, Curhan GC, Sun Q, et al. Calcium supplement intake
and risk of cardiovascular disease in women. Osteoporosis Int.
2014;25:2047–56.
46. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose
oral vitamin D and falls and fractures in older women: a random-
ized controlled trial. JAMA. 2010;303:1815–22.
Chapter 5
Efficacy and Safety
of Osteoporosis
Treatment
Michael R. McClung
5.1 Introduction
For postmenopausal women with osteoporosis, pharmaco-
logical therapy compliments adequate nutrition, regular
physical activity, and, when appropriate, strategies to prevent
falls, alleviate pain, and optimize function. The objective of
drug therapy is to reduce the incidence of serious fragility
fractures that can impair function, degrade quality of life, and
even increase the risk of death. Several drugs with different
mechanisms of action are available for clinical use. This chap-
ter will review the effectiveness, important safety issues, and
practical considerations in choosing among the most impor-
tant treatment options. Salmon calcitonin (limited evidence
of efficacy and no longer available in Europe) and strontium
ranelate (modest evidence of efficacy, significant restrictions
on use in Europe, and never available in the United States)
will not be discussed.
M. R. McClung (*)
Oregon Osteoporosis Center, Portland, OR, USA

44 M. R. McClung
5.2 Bisphosphonates
Nitrogen-containing bisphosphonates, congeners of pyro-
phosphate, are the most studied and most commonly used
drugs for the treatment of osteoporosis. Four members of this
class of drugs are in clinical use (Tables 5.1 and 5.2).
These organic compounds bind tightly but variably to
bone matrix. Upon endocytosis into osteoclasts, important
synthetic pathways are interrupted, resulting in decreased
osteoclast function, reduction in bone resorption, and, sec-
ondarily, decreased bone formation [10]. Drug not bound to
the bone is rapidly excreted and unmetabolized via the uri-
nary tract. Poor absorption of orally administered bisphos-
phonates, blunted even more in the presence of food, requires
strict oral dosing rules: the drug should be taken after an
overnight fast at least 30–60 min before food or beverages
other than water.
After 3 years of treatment, bone mineral density (BMD)
increases of 5–7% and 1.6–5% are noted in the spine and
femoral neck, respectively [1, 2, 4, 5]. BMD in the proximal
femur does not increase further with treatment after 5 years
(Fig. 5.1).
Reductions in vertebral fracture risk of 60–70% are
observed within the first year of treatment. Significant reduc-
tions in non-vertebral fractures (20–30%) and hip fractures
(40–50%) have been reported with each drug except ibandro-
nate [1–3, 5]. The effects of treatment on indices of bone
remodeling persist as long as treatment is administered with-
out evidence of pharmacological resistance [11–13]. The
reduction in fracture risk also persists but does not improve
with long-term therapy. Upon stopping treatment after sev-
eral years, bone turnover markers return to baseline values
within 12 months of stopping risedronate but remain below
baseline for several years upon stopping alendronate or zole-
dronic acid [14–16]. Protection from vertebral fracture is at
least partially lost within 3–5 years after stopping alendronate
or zoledronic acid [15, 16].
Bisphosphonates have been well-tolerated in clinical trials.
In clinical practice, upper gastrointestinal (GI) intolerance
Table 5.1 Effects of therapies on fracture risk in postmenopausal women with osteoporosis
Vertebral fracture Non-vertebral fracture Hip fracture
Incidence (%) Relative risk Incidence (%) Relative risk Incidence (%) Relative risk
Chapter 5
Drug References Years Placebo Treatment reduction Placebo Treatment reduction Placebo Treatment reduction
Alendronate [1] 3 15 8 47% 14.7 11.9 20% 2.2 1.1 51%
Risedronate [2, 3] 3 16.3 11.8 41% 8.4 5.2 40% 3.2 1.9 40%
Ibandronate [4] 3 9.6 4.7 62% 8.2 9.1 NS Not reported
Zoledronic [5] 3 10.9 3.3 70% 10.8 8 25% 2.5 1.4 41%
acid
Denosumab [6] 3 7.2 2.3 68% 8.0 6.5 20% 1.2 0.7 40%
Teriparatide [7] 1.6 14 5 65% 9.7 6.3 35% Not reported
a a a 0.8 NS
Raloxifene [8] 3 4.5 2.3 50% 9.3 8.5 NS 0.7
21.2b 14.7b 30%b
Bazedoxifene [9] 3 4.1 2.3 42% 6.3 5.7 NS Not reported
Because data are from individual clinical trials, direct comparisons of efficacy cannot be made
a
In patients without prior vertebral fractures
Efficacy and Safety of Osteoporosis Treatment
b
In patients with prior vertebral fractures; NS not significant
45
Table 5.2 Osteoporosis drugs: dosing, contraindications, and precautions
46
Route of
Drug Dose administration Contraindicationsa Important warnings or precautionsa
Bisphosphonates
Alendronate 10 mg daily Oral Hypocalcemia Not recommended in patients with
70 mg weekly Esophageal stricture eGFR <30–35 cc/min
or dysfunction
Risedronate 5 mg daily Oral
M. R. McClung
Inability to remain
35 mg weekly
upright after dosing
150 mg
patients at increased
monthly
risk of aspiration
Ibandronate 150 mg Oral
monthly Intravenous
3 mg Q
3 months
Zoledronic 5 mg Q Intravenous Hypersensitivity Severe incapacitating bone, joint,
acid 12 months Hypocalcemia and/or muscle pain may occur
eGFR <35 cc/min
Denosumab 60 mg Q Subcutaneous Hypersensitivity –
6 months Hypocalcemia
Chapter 5
Pregnancy
Teriparatide 20 ugm daily Subcutaneous Hypersensitivity At risk for osteosarcomab
Active or recent urolithiasis
Patients with bone metastases,
history of skeletal malignancies,
metabolic bone diseases other than
osteoporosis, or hypercalcemic
disorders
Estrogen agonists/antagonists
Raloxifene 60 mg daily Oral Active or past Hepatic impairment
history of venous Hypertriglyceridemia
thromboembolism Risk of death from stroke in patients
Pregnancy at increased risk for major coronary
Nursing mothers events
(continued)
Efficacy and Safety of Osteoporosis Treatment
47
Table 5.2 (continued)
48
Route of
Drug Dose administration Contraindicationsa Important warnings or precautionsa
Bazedoxifene 20 mg daily Oral Hypersensitivity Hypertriglyceridemia
Active or past Hepatic or severe renal impairment
history of venous
thromboembolic
M. R. McClung
events
Women of child-
bearing potential
Unexplained uterine
bleeding
Evidence of
endometrial cancer
a
According to the US Food and Drug Administration prescribing information for each drug except European
Medicines Agency prescribing information for bazedoxifene
b
Patients with Paget’s disease of bone, pediatric and young adult patients with open epiphyses, and patients with prior
external beam or implant radiation involving the skeleton
Chapter 5 Efficacy and Safety of Osteoporosis Treatment 49
8
7 Denosumab
% change from baseline
6 Zoledronic acid
5
4 Alendronate
3
2
1 Raloxifene
0
0 1 2 3 4 5 6 7 8 9
Years
Figure 5.1 Percentage change in bone mineral density (BMD) from

baseline in response to treatment with raloxifene [8], alendronate
[1], zoledronic acid (femoral neck BMD [5]), and denosumab (total
hip BMD [6])
occurs with oral dosing, and flu-like symptoms occur with

initial intravenous doses [17]. Osteonecrosis of the jaw occurs
commonly in patients receiving high doses of bisphospho-
nates for treatment of cancer-related bone disease but occurs
very rarely with osteoporosis doses. Femoral shaft fractures
with atypical features are observed with long-term bisphos-
phonate therapy, and the risk appears to increase with longer
duration of treatment. In patients with osteoporosis, the
reduction in the incidence of vertebral and hip fracture far
exceeds the risk of atypical femoral fracture, even after
10 years of treatment. Based on the limited evidence avail-
able, temporary interruption of therapy is recommended
after 3–5 years in patients at modest risk for fractures, while
the benefit/risk ratio remains favorable for patients at high
risk, at least up to 10 years [18]. Rare cases of hypersensitivity
and of inflammatory eye disease have been reported.
Concerning signals about atrial fibrillation with intravenous
zoledronic acid and esophageal cancer with oral bisphospho-
nates have not been confirmed [17]. No impairment of frac-
50 M. R. McClung
ture healing has been observed in clinical studies.

Hypocalcemia upon starting therapy can occur in patients
with vitamin D deficiency, and adequate intake of calcium
and vitamin D should be assured before treatment begins
[19–22]. Mortality after hip fracture is reduced with alendro-
nate or zoledronic acid therapy [23, 24].
Few patients with impaired renal function were included
in clinical trials, and no renal safety issues were noted in those
studies [25]. In clinical practice, renal failure has been
reported with intravenous zoledronic acid therapy, and this
drug is contraindicated in patients with glomerular filtration
rate (GFR) <35 mL per minute (Table 5.2) [22]. Alendronate
and risedronate are not recommended in patients with esti-
mated GFR <30 or 35 mL/min [20, 21].
5.3 Estrogen Agonist/Antagonists

Estrogen agonist/antagonists (previously selective estrogen
receptor modulators or SERMs) are weak activators of the
estrogen receptor in skeletal tissue while inhibiting the
effects of estrogen in reproductive tissues. Raloxifene is
approved for treating women with postmenopausal osteopo-
rosis in both North America and Europe, while bazedoxifene
is approved for the same indication only in Europe. Treatment
with both drugs induces modest reduction in markers of bone
turnover and increases in bone mineral density [8, 9]. In
women with postmenopausal osteoporosis, raloxifene for
3 years decreased the incidence of vertebral fracture by
30–50% [8]. No effect was observed on the risk of non-
vertebral or hip fracture. In a head-to-head study, bazedoxi-
fene and raloxifene were similar in their effects on fracture
risk [9]. By antagonizing estrogen in breast tissue, raloxifene
decreases the risk of invasive breast cancer by 70% [26]. No
effect of bazedoxifene on breast cancer risk was observed [9].
Both drugs are associated with an estrogen-like two- to three-
fold increase in the risk of venous thrombotic events [27, 28].
In women at high risk for cardiovascular disease, raloxifene
was associated with a twofold increase in the risk of death

from stroke although the incidence of stroke or cardiac
arrhythmias was not increased with therapy [29].
5.4 Denosumab
Denosumab, a fully human monoclonal antibody, binds specifi-
cally to receptor activator of nuclear factor kappa-B (RANK)
ligand. By inactivating RANK ligand, the proliferation and
activation of osteoclasts are inhibited, resulting in substantial
reduction in bone turnover. Subcutaneous dosing with 60 mg
provides substantial inhibition of bone turnover for 6 months
[30]. BMD progressively increases with therapy, achieving after
average increments of 21.7% and 9.2% in dual-energy X-ray
absorptiometry (DXA) measurements of the spine and hip,
respectively, over 10 years [31]. In the FREEDOM pivotal
fracture trial, the risk of vertebral, hip, and spinal fracture was
reduced by 68%, 40%, and 20%, respectively, with denosumab
therapy over 3 years [6]. These effects on fracture risk were
observed as early as 12 months and appear to persist for at
least 10 years. Switching from a bisphosphonate to denosumab
results in slightly greater gains in BMD than if the patient
remains on the bisphosphonate [32].
No major safety issues have been observed in clinical trials.
A modest increase frequency of skin rash and cellulitis, not
associated with injection site, was noted during the first
3 years of the FREEDOM study [6]. The incidence of these
skin affects did not increase with therapy over 10 years and
was not increased in patients who had received placebo dur-
ing years 1–3 of the FREEDOM study but who then took
denosumab during years 4–10 in the extension study [31]. A
theoretical risk of immune dysfunction has not been observed.
Rare cases of atypical femoral fracture and osteonecrosis of
the jaw were observed in the FREEDOM extension study,
but the number of cases is much too low to know if this is
truly a consequence of treatment or if the risk of this possible
side effect is related to the duration of treatment [31]. Rare
52 M. R. McClung
cases of anaphylaxis, usually following the first dose, have

been reported [33].
As with all potent anti-remodeling agents, hypocalcemia
can occur when denosumab treatment is initiated, especially
in patients who have vitamin D deficiency, severe renal
impairment, or hypoparathyroidism [33]. Adequate intake of
calcium and vitamin D should be provided before treatment
begins.
Because denosumab is not cleared by the kidney and is not
nephrotoxic, its use is not contraindicated in patients with
severe renal impairment. The effect of denosumab on BMD
and vertebral fracture risk is similar in patients with chronic
kidney disease stage III and IV compared to patients with
normal renal function [34]. The benefits and risks of deno-
sumab therapy in patients on dialysis have not been evalu-
ated thoroughly.
There is no limit to the duration of denosumab therapy.
Upon discontinuing denosumab, markers of bone turnover
return to or rise above baseline values within 9 months of the
last dose, BMD gradually returns toward baseline values, and
protection from vertebral fracture risk is lost within a few
months [35, 36]. Multiple and severe vertebral fractures have
been reported in patients who stop denosumab, and transition
to another anti-remodeling drug should be considered [7].
5.5 Teriparatide
Teriparatide (recombinant human parathyroid hormone
1–34), when administered daily by subcutaneous injection,
activates bone remodeling with bone formation exceeding
bone resorption leading to progressive increases in BMD and
improved trabecular microarchitecture [37]. Estimated
strength of cortical bone (proximal femur or hip region)
increases despite an increase, at least transiently, in cortical
porosity [38].
In the Pivotal Fracture Trial, women with established
osteoporosis therapy were treated with teriparatide 20 μg or
40 μg daily for an average of 19 months [39]. With the 20 μg
daily dose, spine and hip BMD by DXA increased by 9.1%

and 5%, respectively. This was associated with a 65% reduc-
tion in the incidence of vertebral fracture and a 35% decrease
in non-vertebral fracture risk. Too few hip fractures occurred
in the study to evaluate the effect of therapy on hip fracture
risk. In postmenopausal women with previous vertebral frac-
tures, teriparatide was more effective than risedronate in
reducing the risk of vertebral fractures within 12 months and
of non-vertebral fracture within 24 months [40].
Adverse effects, usually mild and self-limited, included
hypercalcemia, nausea, and light-headedness. Because high-
dose, lifelong teriparatide therapy in rats induced a dose-
related increase in osteosarcoma, teriparatide is
contraindicated in patients at risk for osteosarcoma including
children and adolescents (Table 5.1) [38]. Therapy is also lim-
ited by regulatory authorities to 18 months in Europe and to
24 months in the United States.
5.6 Choosing Among Therapies

In the absence of contraindications, bisphosphonates and
denosumab are first-line therapies for all women with post-
menopausal osteoporosis. For patients with upper GI tract
abnormalities (e.g., gastrectomy, celiac disease, and Crohn’s
disease) or in whom concern exists about adherence to
therapy, intravenous zoledronic acid or subcutaneous deno-
sumab ensures absorption and compliance. Denosumab is an
appropriate choice in patients who cannot take bisphospho-
nates because of impaired renal function. Raloxifene and (in
Europe) bazedoxifene are excellent options in younger post-
menopausal women with osteoporosis who are at high risk
for spinal fracture but low risk for hip fracture, especially in
those with risk factors for breast cancer. Teriparatide is
appropriate for patients at high risk for vertebral fracture,
including patients with previous vertebral fractures and low
spine BMD. It is also used in patients who are intolerant of
or who have poor or inadequate responses to anti-resorptive
drugs.
54 M. R. McClung
5.7 Conclusion
Several drugs are effective in reducing the risks of important
fractures. The classes of drugs differ in their mechanisms of
action, potency, and side effect profiles, but among drugs
within a particular class, the effects appear to be similar.
Serious side effects are possible with each class of drug, but
these risks can be reduced by avoiding treatment in patients
at risk for a side effect and educating patients to notify their
physician upon the appearance of symptoms of possible side
effects such as calf pain with raloxifene or thigh pain with
bisphosphonates. When patients at high risk of fracture are
treated, the benefits of fracture reduction far outweigh the
risk of a serious adverse event.
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treatment on vertebral and nonvertebral fractures in women
with postmenopausal osteoporosis: a randomized controlled
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on the risk of hip fracture in elderly women. N Engl J Med.
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acid for treatment of postmenopausal osteoporosis. N Engl J
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8. Ettinger B, Black DM, Mitlak BH, et al. Reduction of verte-

bral fracture risk in postmenopausal women with osteoporosis
treated with raloxifene: results from a 3-year randomized clinical
trial. JAMA. 1999;282:637–45.
9. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of
bazedoxifene in reducing new vertebral fracture risk in post-
menopausal women with osteoporosis: results from a 3-year,
randomized, placebo-, and active-controlled clinical trial. J Bone
Miner Res. 2008;23:1923–34.
10. Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular
mechanisms of action of bisphosphonates: current status. Clin
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with alendronate for osteoporosis in postmenopausal women. N
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TD, Chines AA. Seven years of treatment with risedronate in
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(PFT). J Bone Miner Res. 2015;30:934–44.
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remains reduced one year after discontinuation of risedronate.
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16. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6
years of zoledronic acid treatment of osteoporosis: a random-
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56 M. R. McClung
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double-dummy, randomised controlled trial. Lancet. 2017.; pii:
S0140-6736(17)32137-2
Chapter 6
Management of Patients
with Increased Fracture
Risk
Felicia Cosman
6.1 Introduction
Osteoporosis is often diagnosed in women and men in the
sixth decade of life, resulting in up to 40 years during which
bone loss progresses and fracture risk increases. Therefore,
treatment decisions for osteoporosis should consider not just
whether to treat but also what is the most rational approach
to long-term control of the disease, with the goals of minimiz-
ing fracture risk while also minimizing risk of adverse events.
Different medications are more appropriate at different ages
and severity of the disease. Furthermore, proof of efficacy for
any therapy beyond 5 years is limited, and some adverse
events with potent anti-resorptive medication might be
associated with duration of treatment. No osteoporosis medi-
cation should be used forever, and sequential monotherapy,
rotating effective agents, is the most logical approach for
most individuals.
F. Cosman (*)
Helen Hayes Hospital, West Haverstraw, NY, USA

60 F. Cosman
This chapter provides a rationale for treatment decisions

at different ages and stages of osteoporosis and discusses
treatment sequences that are most likely to achieve the great-
est therapeutic margin. The chapter will also cover a rationale
for consideration of stopping therapy (and how to determine
when and if to restart therapy). Finally, the chapter discusses
the circumstances in which combination therapy should be
considered.
6.2 reatment for Younger Women

T
(Early 50s to Mid or Late 60s)
with Osteoporosis by Bone Mineral
Density But No Fractures
Most logical for this group of women is a hormone regimen
or tissue-selective estrogen complex (TSEC; conjugated
estrogen/bazedoxifene), especially in women with active hot
flashes, or an estrogen agonist/antagonist agent (EAA; ral-
oxifene) in women without active hot flashes. Fracture risk in
these younger individuals is low (especially in the absence of
a history of fractures), and hip fracture is particularly rare [1].
Although younger individuals with a bone mineral density
(BMD) diagnosis of osteoporosis have substantial lifelong
risk, the short-term risk (over the ensuing decade) is in fact
low. The major fractures of concern are vertebrae and wrist in
this age group. All therapies, including hormone and EAA
regimens, maintain and/or increase BMD and reduce risk of
vertebral fractures [2–4]. Hormone therapy (HT) or TSEC
therapies can be followed sequentially by an EAA in some
individuals, once hot flashes and night sweats are no longer
an issue, without worry about long-term adverse events in the
skeleton. Furthermore, breast cancer risk reduction is an
added benefit of EAA use [5]. If patients have fractures, lose
bone, or simply reach an age where HT/estrogen therapy
(ET), TSEC, and EAA therapies are no longer desirable
(based on other risks such as venous thrombosis), a switch to
more potent bone-specific anti-resorptive therapies should
be considered (see below). Furthermore, fracture risk, includ-
Chapter 6 Management of Patients with Increased... 61
ing hip fracture risk, increases with age, so agents with known
efficacy against fractures throughout the skeleton, and spe-
cifically the hip (see Chap. 5), would be required for most
individuals with osteoporosis in their 70s and beyond.
6.3 reatment for Older Women (Late 60s

T
and Beyond) with Osteoporosis by Bone
Mineral Density or an Isolated Fracture
(Especially if More Remote)
As patients age, agents with efficacy across the skeleton
(beyond the spine only), including TPTD, oral and i.v.
bisphosphonates, and/or denosumab, are required. In older
women with a recent hip fracture, yearly infusions of zole-
dronic acid have been demonstrated to reduce the incidence
of second clinical fractures and to reduce mortality [6].
Denosumab may be preferable to bisphosphonates for
patients who require more substantial increments in BMD,
since with denosumab, BMD continues to increase in both
the spine and hip after the first 3 years of treatment [7],
whereas BMD plateaus in patients taking bisphosphonates
after 3 years [8]. Therefore, patients with low BMD are more
likely to achieve BMD goals (T-score at least > −2.5) when
taking long-term denosumab compared with
bisphosphonates.
6.4 atients with Severe Osteoporosis at

P
High Risk for Fractures
Anabolic therapy (i.e., teriparatide, TPTD, or abaloparatide)
should be considered for patients who are at high risk of frac-
ture (highest risk is in those patients with multiple fractures
[9] and/or recent fractures [10–13]). Although anabolic ther-
apy is more expensive than other therapies, the concept that
it should be used only after “failing” a previous therapy is not
logical. The only data that confirm efficacy against fractures
62 F. Cosman
are from patients who had not been on prior osteoporosis

therapy [14]. Furthermore, in high-risk patients, teriparatide
reduces fractures significantly compared to risedronate over
a period of 24 months [12]. Patients who are transitioned
from bisphosphonates or denosumab to TPTD or PTH have
different BMD and bone turnover marker responses com-
pared with treatment-naive patients [10, 11, 14–20]. This is
particularly problematic for the hip and likely to be problem-
atic in other cortical-predominant sites. Total hip and femoral
neck BMD levels actually decline during the first year after
the transition from bisphosphonates (alendronate and rise-
dronate) or denosumab (where the decline is particularly
marked) [21]. For patients who are being switched to anabolic
therapy because of a recent fracture, declining BMD, or a
stable but persistently low BMD, a decline in hip BMD is
obviously not a desirable outcome. It is in these patients that
combination therapy has the greatest potential.
6.5 Combination Therapy

Combination therapy with two anti-resorptive drugs is not
justified. Although it is infrequently used, combination of an
anti-resorptive with a bone-forming agent has some rationale.
Combination therapy was formally tested in 102 women on
prior alendronate who were randomized to continue or stop
their anti-resorptive when TPTD was initiated [22]. This
study was therefore a direct randomized comparison of
TPTD monotherapy versus TPTD combination therapy in
treatment-experienced patients. Although an anabolic
response was seen, both biochemically and densitometrically
in all groups, there was a greater increase in all biochemical
turnover markers in those randomized to TPTD monother-
apy. Of particular note was the early increase in the bone
resorption marker, cross-linked C-telopeptide (CTX), which
was already significantly elevated at 1 month in the patients
assigned to TPTD monotherapy, suggesting that withdrawal
of bisphosphonates results in exaggerated bone resorption
upon exposure to TPTD. As a result, BMD declined in the

first 6 months in the hip (consistent with all TPTD or PTH
monotherapy studies in bisphosphonate-experienced
patients). The BMD increments at both 6 and 18 months in
both the spine and hip were greater in those patients random-
ized to the TPTD/alendronate combination compared with
TPTD monotherapy, and at no time point did hip BMD
decline in the combination therapy group [23]. This trial also
formally evaluated a cohort of women on prior raloxifene
treatment randomized to a TPTD/raloxifene combination
versus TPTD monotherapy. Differences in BMD accrual
were minimal between these groups.
Consistent with the DXA findings in patients on prior
alendronate, volumetric BMD of the hip did not change in
women who switched from alendronate to TPTD monother-
apy but increased significantly at both 6 and 18 months in
those who received combination TPTD/alendronate [24].
Furthermore, volumetric BMD of the cortical compartment
of the hip declined significantly in those randomized to
TPTD monotherapy. Strength of the hip, assessed by finite
element analysis, did not decline with TPTD monotherapy
implying that the decline in cortical BMD was not in an area
critical for strength. However, hip strength increased signifi-
cantly only with combination therapy.
Similar observations were made from a group of patients
who were transitioned from denosumab (after 2 years) to
TPTD. However, the effect of the transition from denosumab
to TPTD monotherapy on hip BMD was far more prominent
compared with the transition from bisphosphonates to TPTD
[21]. Combination therapy has not been formally tested in
women on prior denosumab (where TPTD is later added),
but combination denosumab/TPTD has been investigated in
women who were treatment-naive. In these patients, both
spine and hip BMD increased more in the combination group
than TPTD monotherapy, especially in the first year [25]. By
analogy, this combination might be more effective than
TPTD monotherapy in those previously treated with
denosumab.
64 F. Cosman
The findings from these studies have important implica-

tions for the clinical use of TPTD in patients who have
received prior bisphosphonates or denosumab and are at
high risk for fractures of the hip and other skeletal sites that
are rich in cortical bone (e.g., a patient on bisphosphonate or
denosumab who sustains a hip fracture). It may be that the
withdrawal of the bisphosphonate or denosumab actually
facilitates an exaggerated bone resorption response to TPTD
and offsets the expected positive bone balance, particularly in
the cortical skeleton, creating cortical porosity. In this case
continuing the anti-resorptive while adding the bone-forming
agent may therefore be a better option. The lack of substan-
tial impact of prior raloxifene use on the subsequent use of
TPTD is also important clinically because it provides a ratio-
nale for the use of raloxifene (and likely other EAA and
TSEC agents) as a bridge to maintain BMD in younger
patients who may need TPTD or abaloparatide later in life.
There are relatively few indications for combination ther-
apy in patients who have not been on prior potent anti-
resorptive treatment. Patients with recent hip and vertebral
fractures could be considered for combination treatment with
TPTD and denosumab. If this path is chosen, after combina-
tion treatment for up to 2 years, denosumab should be contin-
ued until BMD goals are achieved and patients remain free
of fracture (at least for several years, including no new verte-
bral fractures documented by repeat spine imaging).
Denosumab is also probably the agent of choice after
treatment with TPTD monotherapy until BMD goals (T-score
above −2.5) are achieved.
6.6 hen Is Stopping Osteoporosis

W
Treatment Reasonable?
BMD on osteoporosis therapy is a predictor of future frac-
ture risk, just as BMD predicts fracture risk in treatment-
naive individuals. Three large-scale osteoporosis treatment
studies confirm this relationship. Two were randomized

extensions of large pivotal fracture trials with alendronate
and zoledronic acid [8, 26, 27], and one is an observational
study of long-term use of denosumab [7]. These studies show
that future fracture risk is dependent on the hip BMD level
achieved during treatment. Those patients who still have
osteoporosis after an initial treatment period have a future
fracture risk similar to those with that BMD who have not yet
been treated. This suggests that hip BMD above osteoporosis
range (T-score > −2.5) should be a goal of osteoporosis ther-
apy. It is critical to realize, however, that when non-
bisphosphonate osteoporosis medications are stopped bone
density declines quickly. This is true of all estrogen-containing
agents, TPTD (and presumably abaloparatide), and deno-
sumab. Moreover the rapid loss of bone mass after discon-
tinuation of a medication such as denosumab is associated
with structural deterioration and an increase in risk of (mul-
tiple) vertebral fractures [28]. Therefore, it is inadvisable to
stop these agents. Non-bisphosphonate medications must be
continued, or switched to a bisphosphonate, at least tempo-
rarily [29]. Because of the residual persistent effect of
bisphosphonates after treatment discontinuation, therapy can
be stopped after bisphosphonate use. During the off-treatment
period after use of a bisphosphonate, maintenance of BMD
or a much slower BMD loss after discontinuation can be
expected (compared with all non-bisphosphonate com-
pounds) [30, 31].
Therefore, it is possible to use non-bisphosphonate thera-
pies to achieve a BMD target and then switch to bisphospho-
nate treatment to help maintain BMD. Patients who have not
had recent fractures and who have BMD above the osteopo-
rosis range, especially in the absence of multiple prevalent
vertebral fractures, after 3–5 years of osteoporosis therapy or
therapy sequences, are good candidates for temporary cessa-
tion of treatment. Table 6.1 provides a summary of the overall
principles concerning switching and stopping osteoporosis
medications.
66 F. Cosman
Table 6.1 Key principles of stopping and switching osteoporosis

medication
Key principles: stopping and switching osteoporosis medications
Stopping osteoporosis medications:
BMD loss will occur after stopping any non-bisphosphonate
medications:
Most rapid loss occurs after stopping denosumab
BMD is maintained or lost slowly after stopping BPs:
BMD loss may be more rapid after stopping risedronate
versus other BPs
BMD most likely to remain stable for several years after
stopping zoledronic acid
If medication withdrawal is desirable after treatment with
a non-bisphosphonate medication (especially denosumab,
TPTD, or abaloparatide), switch to BP first, preferably
zoledronic acid, for at least 1 year
Switches that are advisable:
From HT to EAA
From HT or EAAs to any other agent (TPTD/abaloparatide,
denosumab, or BP).
From denosumab to BP
From BP to denosumab is ok but may increase BMD less
than sequence of denosumab first followed by BP
From TPTD/abaloparatide to denosumab or BP
Switches that are not optimal:
From BP to TPTD/abaloparatide – expect some hip BMD
loss or at least no gain for up to 18 months
From denosumab to TPTD/abaloparatide – expect dramatic
hip BMD loss
BMD bone mineral density, BP bisphosphonate, EAA estrogen
agonist/antagonist agent, HT hormone therapy, PTH parathyroid
hormone, TPTD teriparatide
6.7 Resumption of Treatment After

Medication Holiday
There is variability among the BPs regarding the duration of
action after cessation of therapy (risedronate probably has
the shortest and zoledronic acid probably has the longest
duration of action) and substantial interindividual variability
as well. Serum biochemical markers (yearly) and BMD (at

least every 2 years) can be used to help determine when the
effect of the bisphosphonate is diminishing. There is no evi-
dence base upon which to make decisions about treatment
resumption. Clinical logic suggests that a new fracture and/or
a decline in BMD (greater than 4–5% which represents least
significant change for BMD and a BMD T-score that is now
again at ≤−2.5) would be a rationale for resumption of treat-
ment. An increase in biochemical marker level more than
double the nadir level and resulting in a level in the upper
normal premenopausal range might also be a rationale for
resuming osteoporosis treatment or at least watching BMD
closely (maybe annually) as this marker level might be a sign
of incipient active bone loss.
After a medication holiday, if treatment resumption is
required, similar principles can be used regarding the selec-
tion of best medications or medication sequences as were
used to select initial therapy.
6.8 Conclusion
When osteoporosis treatment is initiated, long-term treatment
plans should be considered. Sequential monotherapy, rotating
agents, is the best approach for most patients. Treatment
sequence is of critical importance to maximize benefit and
minimize risk. In general, anabolic agents should be used prior
to potent anti-resorptive agents, and the latter should be
reserved for individuals in their late 60s and beyond.
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tinue treatment? J Clin Endocrinol Metab. 2014;99(12):4546–54.
28. Brown JP, Roux C, Torring O, Ho PR, Beck Jensen JE, Gilchrist
N, et al. Discontinuation of denosumab and associated fracture
incidence: analysis from the Fracture Reduction Evaluation of
Denosumab in Osteoporosis Every 6 Months (FREEDOM)
trial. J Bone Miner Res. 2013;28(4):746–52.
29. Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios
D, Siddhanti S, et al. Final results of the DAPS (Denosumab
Adherence Preference Satisfaction) study: a 24-month, random-
ized, crossover comparison with alendronate in postmenopausal
women. Osteoporos Int. 2012;23(1):317–26.
30. Boonen S, Ferrari S, Miller PD, Eriksen EF, Sambrook PN,
Compston J, et al. Postmenopausal osteoporosis treatment with
antiresorptives: effects of discontinuation or long-term continu-
ation on bone turnover and fracture risk--a perspective. J Bone
Miner Res. 2012;27(5):963–74.
31. Reid IR, Black DM, Eastell R, Bucci-Rechtweg C, Su G, Hue
TF, et al. Reduction in the risk of clinical fractures after a single
dose of zoledronic Acid 5 milligrams. J Clin Endocrinol Metab.
2013;98(2):557–63.
Chapter 7
Management of Male
Osteoporosis
Piet Geusens and Joop van den Bergh
7.1 Introduction
After middle age, osteoporosis-related fractures are more
common in women than in men [1]. As a result, fracture pre-
vention has been most extensively studied in postmenopausal
women. However, between 30% and 40% of fractures due to
osteoporosis occur in men, and the lifetime risk of fracture
for men aged 50 or older is between 13% and 30% [2–4].
During aging, fracture risk rises exponentially in both sexes,
but the increase occurs about a decade later in men than in
women [1].
The mortality rate of patients with hip fractures older than
70 years is two to three times higher in men than in women
[1]. In contrast to the risk of a first fracture after the age of
50 years, which is higher in women than in men, the risk of a
subsequent fracture after a first fracture is the same for both
sexes [5]. Therefore, men older than 50 years deserve atten-
tion for fracture risk evaluation and fracture prevention in
high-risk patients.
P. Geusens (*) · J. van den Bergh

Department of Internal Medicine, Maastricht University Medical
Center, Maastricht, The Netherlands

72 P. Geusens and J. van den Bergh
Case finding Risk evaluation Differential diagnosis Therapy Follow up
Recent vertebral General measures:

fracture* Adequate calcium
and vitamin D
Smoking cessation
Recent hip Alcohol limitation
Tolerance
Assessment of Adherence
fracture* secondary osteoporosis Weight-bearing
Persistence
and other metabolic exercise
Efficacy
Recent T-score ≤–2.5 bone diseases Duration of therapy
and fall risk
non-vertebral- Medications:
Drug holiday
based on medical history,
non-hip T-score –1.0 to –2.5 physical examination and Alendronate
DXA
fracture laboratory testing Risedronate
Bone markers
Zoledronic acid
DXA Denosumab
VFA/RX Teriparatide
FRAX Testosterone therapy
Other clinical
risk factors Vertebral Fall risk prevention
fracture
Other indications
for high fracture
risk
Long-term
glucocorticoids*
Figure 7.1 Fracture prevention algorithm in men: a five-step deci-

sion plan. In green, recommendations according to Watts et al. [9].
*DXA not strictly necessary for therapeutic decisions, but helpful
for follow-up. (Adapted from Ref. [9])
Fracture prevention consists of a systematic multistep

approach that starts with clinical case finding, followed by
evaluation, differential diagnosis, treatment, and follow-up [6].
There is a wealth of evidence for the efficacy of each of these
steps in women, but the evidence for efficacy in men is less well
documented. As a result, most of the current fracture preven-
tion guidelines are for women at high risk of fractures [7].
Fracture prevention can be summarized in a five-step
evaluation and treatment plan as presented in Fig. 7.1 based
on recommendations from the American Endocrine Society
review in 2012 [8, 9] and a review paper of a European expert
panel in 2013 [10].
7.2 Case Finding

The first step is clinical case finding, which means that men at
risk for future fractures should be recognized. We propose
two patient risk profiles: men older than 50 years with a his-
tory of fracture after 50 years of age and men with no history
of fractures but with clinical risk factors for fracture [9].
Chapter 7 Management of Male Osteoporosis 73
7.2.1 Men with a History of Fracture
In men with a history of fracture, the risk of subsequent frac-

tures is increased and is highest in the first years after a frac-
ture. Evaluation of fracture risk and underlying diseases is
therefore advocated as soon as possible after a recent fragility
fracture. In this context, the fracture liaison service (FLS) with
a specialized osteoporosis nurse under supervision of a special-
ist (surgeon, endocrinologist, rheumatologist, geriatrician) is
considered as the most effective case finding strategy [11, 12].
7.2.2 Men Without a History of Fracture
In men without a history of fracture, clinical case finding

takes into account age, body mass index (BMI), parent with
hip fracture, a fall in the past year, inability to complete a
walking test, diseases/conditions related to loss of bone min-
eral density (BMD), or increased risk of fractures such as
delayed puberty, hypogonadism, hyperparathyroidism, hyper-
thyroidism, chronic obstructive pulmonary disease, drugs
such as glucocorticoids or GnRH agonists, and lifestyle
choices such as alcohol abuse and smoking [9, 13].
7.3 Risk Evaluation

To evaluate fracture risk, clinical risk factors, assessment of
BMD using dual-energy X-ray absorptiometry (DXA), and
imaging of the spine by radiography or vertebral fracture
assessment (VFA) using DXA technology are available. VFA
has the advantage of low radiation dose, and it has a high
negative predictive value [14].
7.3.1 Men with a History of Fracture
The presence of a low-trauma vertebral or hip fracture is

generally considered a sufficiently high risk of subsequent
fractures for pharmaceutical treatment to be recommended
without the requirement for using DXA. However, a baseline

DXA and imaging of the full spine may be useful for
decision-making during follow-up.
In men with a non-vertebral non-hip fracture, measure-
ment of BMD using DXA is recommended, and if osteoporo-
sis is diagnosed (T-score ≤ −2.5), pharmacological treatment
should be initiated. VFA and prediction of fracture risk using
the Fracture Risk Assessment (FRAX®) calculator are rec-
ommended for men with a non-vertebral non-hip fracture
and osteopenia (T-score between −1 and −2.5). In these men,
pharmacological treatment is recommended if a vertebral
fracture is present or, in the USA, if the FRAX risk for major
fractures is ≥20% and/or the FRAX risk for hip fracture is
≥3% [9]. In a European expert review, it was stated that treat-
ment is widely recommended in men after any fragility frac-
ture [10].
7.3.2 Men Without a History of Fracture
In men older than 70 years, measurement of BMD using

DXA is suggested, whereas in men aged 50–69 years, DXA of
the spine and hip is suggested if fracture risk factors are
present. Fracture risk calculators such as FRAX® (www.shef.
ac.uk) and the Garvan fracture risk calculator (www.garvan.
org.au) can aid patient evaluation.
Treatment is advocated if the patient has osteoporosis or
osteopenia, if VFA indicates the presence of a previously
undiagnosed vertebral fracture, or, in the USA, if the patient’s
10-year FRAX risk is ≥20% for major fractures or ≥3% for
hip fracture. Regardless of DXA result, pharmaceutical treat-
ment is recommended for men who receive ≥7.5 mg/day long-
term prednisone or an equivalent glucocorticoid therapy.
7.4 Differential Diagnosis

The next step in the evaluation and treatment plan is the dif-
ferential diagnosis. A complete history and physical examina-
tion is suggested for men who are being evaluated for
osteoporosis or considered for pharmacological treatment.

The aim is to gather information regarding evidence of causes
of secondary osteoporosis or other metabolic bone diseases,
fall risk, and overall frailty. Laboratory evaluation with mea-
surement of serum calcium, phosphate, creatinine (with esti-
mated glomerular filtration rate), alkaline phosphatase, liver
function, 25 hydroxy vitamin D, total testosterone, thyroid-
stimulating hormone (TSH), complete blood count, and
24hour urinary calcium (creatinine and sodium) excretion is
suggested [9, 15]. Additional laboratory testing should be car-
ried out if the patient’s medical history or the results of the
physical examination suggest a specific cause of osteoporosis.
Such testing might include, but is not limited to, analysis of
the level of sex hormone-binding globulin, tissue transgluta-
minase antibodies (for diagnosis of celiac disease) or parathy-
roid hormone, serum protein electrophoresis (with free κ and
λ light chains) and/or urine protein electrophoresis, and addi-
tional thyroid function tests [9, 15].
7.5 Treatment
Following differential diagnosis, treatment should be initiated
in men at high risk of fracture. A daily total calcium intake of
1000–1200 mg and cessation of smoking are recommended,
and weight-bearing exercises, limiting alcohol intake to
<3 units/day, and vitamin D supplementation (if serum levels
are <75 nmol/l) are suggested for men with, or at increased
risk of, osteoporosis and fractures [9].
Regulatory agencies accept studies for reimbursement
when surrogate endpoints, such as changes in BMD, are com-
parable to changes that are attained in women (in studies
with fracture endpoint). The antiresorptive drugs alendronate
[16, 17], risedronate [18], ibandronate [19], zoledronic acid
[20–22], strontium ranelate [23], and denosumab [24, 25] have
been investigated in male populations with low BMD. All
studies had BMD as the primary endpoint and demonstrated
a significant BMD increase [16–25]. In terms of BMD, zole-
dronic acid was not inferior compared to alendronate but
also not superior [20]. Strontium ranelate increases BMD as
in women [23], but its mechanism of action is still unclear

[26]. Two studies reported fracture reduction as a secondary
outcome [16, 18]. In other studies, the number of fractures
was too small to allow for statistical analyses.
Only one intervention study with reduction of vertebral
fractures as primary endpoint is available in men: zoledronic
acid significantly reduced the risk of vertebral fractures com-
pared with placebo (primary endpoint) [22]. In the study by
Lyles et al. [21], a post recent hip fracture study, zoledronic
acid decreased second subsequent clinical fractures in a
population with both males and females by 35% and mortal-
ity from any cause by 28%. Therefore, treatment with zole-
dronate is suggested for men with a recent hip fracture [9].
In men receiving androgen deprivation therapy for non-
metastatic prostate cancer, denosumab was associated with a
reduction in the incidence of new vertebral fractures [27] and
is recommended for men with prostate cancer who are receiv-
ing androgen deprivation therapy [9].
Teriparatide increased BMD in men compared with pla-
cebo [28, 29], and men who received teriparatide and who may
have received follow-up antiresorptive therapy had a
decreased risk of moderate and severe vertebral fractures [30].
Initiation of testosterone therapy instead of anti
osteoporosis medication is suggested for men with a border-
line high risk of fracture who have serum testosterone levels
<6.9 nmol/l on more than one determination and signs or
symptoms of androgen deficiency. Testosterone therapy is
also suggested for men at high risk of fracture with testoster-
one levels <6.9 nmol/l who lack standard indications for tes-
tosterone therapy but have contraindications to approved
pharmacological agents for osteoporosis [9]. An agent with
proven anti-fracture efficacy, such as a bisphosphonate or
teriparatide, is suggested for men at high risk of fracture who
are receiving testosterone therapy [9].
7.6 Follow-Up
The final stage of the evaluation and treatment plan is fol-
low-
up to evaluate tolerance, adherence, persistence, and
efficacy of therapy and to decide about duration of therapy,

drug holiday, and switching of therapy. Monitoring BMD
using DXA of the spine and hip, bone resorption markers,
such as levels of serum Ctelopeptide or urine Ntelopeptide
of type I collagen, can be used to monitor antiresorptive
therapy responses, and bone formation markers, such as
serum procollagen I Npropeptide, can be used to monitor
responses to anabolic therapy. However, appropriate values
for bone markers to indicate optimal response to treatment
remain unclear [9]. No studies are available on the duration
of treatment and eventual drug holiday. A man of 75 years of
age with a fracture still has a mean lifetime expectancy of
8 years; thus long-term treatment decisions are necessary
[31]. As proposed in women, re-evaluation after 5-year
therapy using clinical risk factors and DXA would allow
physicians to identify patients at low fracture risk (e.g., BMD
above a T-score of −1.0 or −2.5), in whom treatment could be
temporarily interrupted, and patients at high risk, in whom
treatment should continue [32].
7.7 Conclusion
Based on the available literature, recommendations for multi-
step fracture prevention in men can be formulated [8, 9].
However, high-quality evidence is not available to support any
of the recommendations or suggestions. Further studies are,
therefore, required to increase the level of evidence for optimal
fracture prevention in men to a level comparable to that in
women. In the context of gendered medicine and innovations,
fracture prevention in men deserves more attention [33].
References
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and disability associated with osteoporotic fractures. Osteoporos
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2. Cooper C, Melton LJ 3rd. Epidemiology of osteoporosis. Trends
3. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center
JR. Mortality risk associated with low-trauma osteoporotic
fracture and subsequent fracture in men and women. JAMA.
2009;301:513–21.
4. van Helden S, van Geel AC, Geusens PP, Kessels A,
Nieuwenhuijzen Kruseman AC, Brink PR. Bone and fall-related
fracture risks in women and men with a recent clinical fracture.
J Bone Joint Surg Am. 2008;90:241–8.
5. van Geel TA, van Helden S, Geusens PP, Winkens B, Dinant
GJ. Clinical subsequent fractures cluster in time after first frac-
tures. Ann Rheum Dis. 2009;68:99–102.
6. van den Bergh JP, van Geel TA, Geusens PP. Osteoporosis,
frailty and fracture: implications for case finding and therapy.
Nat Rev Rheumatol. 2012;8:163–72.
7. Leslie WD, Schousboe JT. A review of osteoporosis diagnosis
and treatment options in new and recently updated guide-
lines on case finding around the world. Curr Osteoporos Rep.
2011;9:129–40.
8. Geusens PP, Bone v d BJP. New guidelines for multistep fracture
prevention in men. Nat Rev Rheumatol. 2012;8:568–70.
9. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an
Endocrine Society clinical practice guideline. J Clin Endocrinol
Metab. 2012;97:1802–22.
10. Kaufman JM, Reginster JY, Boonen S, et al. Treatment of osteo-
porosis in men. Bone. 2013;53:134–44.
11. Akesson K, Marsh D, Mitchell PJ, et al. Capture the fracture: a
best practice framework and global campaign to break the fragil-
ity fracture cycle. Osteoporos Int. 2013;24:2135–52.
12. McLellan AR, Gallacher SJ, Fraser M, McQuillian C. The frac-
ture liaison service: success of a program for the evaluation and
management of patients with osteoporotic fracture. Osteoporos
Int. 2003;14:1028–34.
13. Lewis CE, Ewing SK, Taylor BC, et al. Predictors of non-spine
fracture in elderly men: the MrOS study. J Bone Miner Res.
2007;22:211–9.
14. Chapurlat RD, Duboeuf F, Marion-Audibert HO, Kalpakcioglu
B, Mitlak BH, Delmas PD. Effectiveness of instant vertebral
assessment to detect prevalent vertebral fracture. Osteoporos
Int. 2006;17:1189–95.
15. Bours SP, van den Bergh JP, van Geel TA, Geusens PP. Secondary
osteoporosis and metabolic bone disease in patients 50 years and
older with osteoporosis or with a recent clinical fracture: a clini-

cal perspective. Curr Opin Rheumatol. 2014;26:430–9.
16. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treat-
ment of osteoporosis in men. N Engl J Med. 2000;343:604–10.
17. Gonnelli S, Cepollaro C, Montagnani A, et al. Alendronate treat-
ment in men with primary osteoporosis: a three-year longitudi-
nal study. Calcif Tissue Int. 2003;73:133–9.
18. Boonen S, Orwoll ES, Wenderoth D, Stoner KJ, Eusebio R,
Delmas PD. Once-weekly risedronate in men with osteoporosis:
results of a 2-year, placebo-controlled, double-blind, multicenter
study. J Bone Miner Res. 2009;24:719–25.
19. Orwoll ES, Binkley NC, Lewiecki EM, Gruntmanis U, Fries MA,
Dasic G. Efficacy and safety of monthly ibandronate in men with
low bone density. Bone. 2010;46:970–6.
20. Orwoll ES, Miller PD, Adachi JD, et al. Efficacy and safety
of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a
once-weekly 70-mg oral alendronate in the treatment of male
osteoporosis: a randomized, multicenter, double-blind, active-
controlled study. J Bone Miner Res. 2010;25:2239–50.
21. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic
acid and clinical fractures and mortality after hip fracture. N
Engl J Med. 2007;357:1799–809.
22. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and
zoledronic acid therapy in men with osteoporosis. N Engl J Med.
2012;367:1714–23.
23. Kaufman JM, Audran M, Bianchi G, et al. Efficacy and safety
of strontium ranelate in the treatment of osteoporosis in men. J
Clin Endocrinol Metab. 2013;98:592–601.
24. Orwoll E, Teglbjaerg CS, Langdahl BL, et al. A random-
ized, placebo-controlled study of the effects of denosumab for
the treatment of men with low bone mineral density. J Clin
25. Langdahl BL, Teglbjaerg CS, Ho PR, et al. A 24-month study
evaluating the efficacy and safety of denosumab for the treat-
ment of men with low bone mineral density: results from the
ADAMO trial. J Clin Endocrinol Metab. 2015;100:1335–42.
26. Chavassieux P, Meunier PJ, Roux JP, Portero-Muzy N, Pierre M,
Chapurlat R. Bone histomorphometry of transiliac paired bone
biopsies after 6 or 12 months of treatment with oral strontium
ranelate in 387 osteoporotic women: randomized comparison to
alendronate. J Bone Miner Res. 2014;29:618–28.
27. Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in

men receiving androgen-deprivation therapy for prostate cancer.
N Engl J Med. 2009;361:745–55.
28. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide
[human parathyroid hormone (1-34)] therapy on bone density in
men with osteoporosis. J Bone Miner Res. 2003;18:9–17.
29. Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R,
Bilezikian JP. Parathyroid hormone as a therapy for idiopathic
osteoporosis in men: effects on bone mineral density and bone
markers. J Clin Endocrinol Metab. 2000;85:3069–76.
30. Kaufman JM, Orwoll E, Goemaere S, et al. Teriparatide effects on
vertebral fractures and bone mineral density in men with osteo-
porosis: treatment and discontinuation of therapy. Osteoporos
Int. 2005;16:510–6.
31. Abrahamsen B, Osmond C, Cooper C. Life expectancy in
patients treated for osteoporosis: observational cohort study
using national Danish prescription data. J Bone Miner Res.
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32. McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy
for osteoporosis: benefits, risks, and drug holiday. Am J Med.
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33. Schiebinger L, Klinge I, Sánchez de Madariaga I, Paik HY,
Schraudner M, Stefanick M (eds). Osteoporosis research in
men: rethinking standards and reference models. Gendered
Innovations in Science, Health & Medicine, Engineering and
Environment (2011–2015). https://genderedinnovations.stan-
ford.edu/case-studies/osteoporosis.html. Accessed 14 Jan 2016.
Chapter 8
Management
of Glucocorticoid-
Induced Osteoporosis
Christian Roux
8.1 Introduction
Glucocorticoid-induced osteoporosis (GIOP) is the most
common cause of secondary osteoporosis, the first cause
before 50 years, and the first iatrogenic cause of the disease.
There is a huge variability of side effects of glucocorticoids
(GCs) among individuals for largely unknown reasons.
However, in the context of the use of GCs, bone fragility is
characterized by the rapidity of bone loss and the occurrence
of fractures within the first months of use of GCs, indicating
the need for appropriate early management of the patients.
The main effect of the use of GCs on bone is the impair-
ment in bone formation, related to the decrease in osteoblast
differentiation, the increase in osteoblast and osteocyte apop-
tosis, and the anti-anabolic effects such as a decrease in
insulin-like growth factor 1 (IGF1) [1]. This reduced bone
formation occurs in a situation of abnormal bone turnover:
C. Roux (*)
Department of Rheumatology, Paris Descartes University, Cochin
Hospital, Paris, Paris, France

82 C. Roux
inflammation by itself is responsible for enhanced osteoclas-

togenesis and osteoclast activity through the production of
receptor activator of nuclear factor-kappaB (RANK) ligand
by activated lymphocytes. Expression of sclerostin (inhibitor
of formation) is also increased in models of inflammation.
Thus, the introduction of GCs is associated with an uncou-
pling between high bone resorption and low bone formation
[2]. Taking GCs also has indirect effects of reduced produc-
tion of sexual steroids and myopathy and muscle weakness,
responsible in turn for an increased risk of falls.
8.2 Fracture Risk

The risk of fractures is increased twofold in patients receiving
GCs and is even higher for vertebral fractures (VFs).
Asymptomatic VFs are frequent in patients receiving long-
term GCs because of the analgesic effect of the treatment.
Patient height must be measured at the initiation of GCs, and
height loss must be checked in the follow-up for diagnosis of
incident vertebral fractures. The increase in risk is immediate
and occurs as early as 3 months after the initiation of therapy;
thus primary prevention is highly recommended.
The assessment of fracture risk [3] is based on:
• Classical risk factors of osteoporosis – age, female gender,
low body mass index, history of falls, previous fractures,
duration of menopause, and smoking.
• Characteristics of GC therapy – the risk is mainly associ-
ated with recent and prolonged GC use rather than remote
and short-term use.
• Characteristics of the underlying inflammatory disease
including the potential previous deleterious effect of
chronic inflammation.
Thus the Fracture Risk Assessment (FRAX) tool may help
in GIOP, in order to take into account the whole list of risk
factors. Adjustment of FRAX has been proposed for post-
menopausal women and men aged ≥50 years with lower or
Chapter 8 Management of Glucocorticoid-Induced... 83
higher doses than 2.5–7.5 mg/day: a factor of 0.8 for low-dose

exposure and 1.15 for high-dose exposure for major osteopo-
rotic fractures and 0.65 and 1.20 for hip fracture probability.
For very high doses of GCs, greater upward adjustment of
fracture probability may be required.
The interpretation of bone mineral density (BMD) is diffi-
cult in patients with GC treatment, as there is an unmatched
data between BMD and fracture data. BMD can be normal and
the bone fragility being high, because of alteration of bone
quality. The threshold (in T-score) below which patients with
GCs are at risk is unknown. A practical approach is to consider
that a low BMD at the initiation of GCs, or underlying osteo-
porosis, is by itself a strong risk factor for immediate fractures.
8.3 Management of Patients

with Glucocorticoid-Induced
Osteoporosis
The first step for treatment is to review the daily dose of GCs.
Physicians should consider reducing the dose to the lowest
active dose, the use of immunosuppressive drugs as GCs spar-
ing agents, and local (i.e., intra-articular) administration of
the treatment.
The second step is the use of anti-osteoporotic treatment
such as bisphosphonates, denosumab, and teriparatide, which
have been assessed in both the prevention and treatment of
GIOP. At the initiation of GCs, bisphosphonates (alendro-
nate, risedronate, and zoledronate) prevent the bone loss,
which in contrast is observed in the placebo groups (although
appropriately treated by calcium and vitamin D). These drugs
can increase BMD in patients with established GIOP. The
efficacy on fractures is not a direct evidence from studies; it is
mainly based on bridging data between the short-term
change in BMD in patients with GCs and the long-term
change in BMD and reduction of fracture risk in patients with
postmenopausal osteoporosis.
84 C. Roux
Teriparatide is the first-choice therapy in patients with

established GIOP, as the principal cause of bone fragility is
reduction in bone formation. Moreover, in a prospective
comparative study, the use of teriparatide was associated with
fewer VFs than the use of alendronate.
There are a number of guidelines on the use of pharmaco-
logical treatment in GIOP, published by different national
societies and colleges, which vary somewhat [4, 5]. However,
all of them stress the early increase in the risk of fracture at
the initiation of GCs and the importance of recognition of
patients at high risk of fracture. For such patients (elderly
subjects, patients who already have osteoporosis, and patients
on high doses of GCs), primary prevention is always
recommended.
There is no recommendation for the duration of treatment
in GIOP. It must be prolonged if an individual has underlying
osteoporosis and other risk factors for osteoporosis. Whether
the treatment can be stopped in some individuals with nor-
mal BMD, absence of prevalent fractures, and quiescent
underlying inflammatory disease is a research question.
References
1. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-
induced osteoporosis: pathophysiology and therapy. Osteoporos
Int. 2007;18:1319–28.
2. Roux C. Osteoporosis in inflammatory joint diseases. Osteoporos
Int. 2011;22:421–33.
3. van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper
C. Clinical assessment of the long-term risk of fracture in patients
with rheumatoid arthritis. Arthritis Rheum. 2006;54:3104–12.
4. Grossman JM, Gordon R, Ranganath VK, et al. American College
of Rheumatology 2010 recommendations for the prevention and
treatment of glucocorticoid-induced osteoporosis. Arthritis Care
Res (Hoboken). 2010;62:1515–26.
5. Lekamwasam S, Adachi JD, Agnusdei D, et al. A framework for the
development of guidelines for the management of glucocorticoid-
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Chapter 9
New Bone-Forming
Agents
Socrates E. Papapoulos
9.1 Introduction
Pharmacological interventions for patients with osteoporosis
aim at decreasing the risk of fractures and associated clinical
consequences by correcting the imbalance between bone
resorption and bone formation that constitutes the patho-
physiological basis of the disease. Despite the availability of
efficacious treatments for fracture reduction, there are still
unmet needs requiring a broader range of therapeutics. In
particular, there is a need for agents capable of replacing
already lost bone and of drastically reducing the risk of non-
vertebral fractures, the most frequent fragility fractures. In
recent years, new molecules and therapeutic targets have
been identified, and many were investigated as potential
treatments for osteoporosis [1]. This chapter briefly reviews
newly developed bone-forming agents.
S. E. Papapoulos (*)
Center for Bone Quality, Leiden University Medical Center,
Leiden, The Netherlands
86 S. E. Papapoulos
9.2 Parathyroid Hormone-Related Peptides

Parathyroid hormone (PTH) peptides (e.g., teriparatide) bind
to PTH/PTHrP type 1 receptor (PTH1R) in osteoblasts and
osteocytes and stimulate bone formation but also bone
resorption in patients with osteoporosis [2]. PTHrP, a protein
with homology to PTH at the amino terminus that also binds
to PTHR1, was hypothesized to increase bone formation with
less increase in bone resorption than teriparatide making it
an attractive bone-forming treatment for osteoporosis.
Abaloparatide, a novel 34 aa synthetic peptide analog of
PTHrP given by daily sc injections, increased BMD at the
spine and the hip, in the latter at a level significantly higher
than teriparatide (Fig. 9.1). In addition, abaloparatide
increased biochemical markers of bone formation and
resorption to a lesser extent than teriparatide despite being
administered at a higher dose (80 μg/d vs 20 μg/d) [3].
The efficacy of abaloparatide in the prevention of frac-
tures was evaluated in a phase III clinical trial of 2463 women
with osteoporosis randomized to receive abaloparatide
8 PBO ABL TPTD

% Change BMD from baseline
0
Lumbar spine Total hip
Figure 9.1 Percentage changes of bone mineral density (BMD) of

postmenopausal women with osteoporosis after 24 weeks of treat-
ment with subcutaneous injections of placebo (PBO), abaloparatide
(ABL) 80 μg/d, and teriparatide (TPTD) 20 μg/d. (Adapted from
Leder et al. [3])
Chapter 9 New Bone-Forming Agents 87
80 μg/d sc, placebo sc, or open-label teriparatide 20 μg/d sc for

18 months [4]. Compared with placebo, abaloparatide reduced
the risk of new vertebral fractures by 86% and of non-
vertebral fractures by 43%; the decreases with teriparatide
were 80% and 28% (ns), respectively. Abaloparatide was well
tolerated – the most frequently reported adverse events were
back pain, arthralgia, upper respiratory tract infection, hyper-
calciuria, and dizziness. The incidence of hypercalcemia 4 h
after the injection was 0.37%, 3.41%, and 6.36% for the pla-
cebo, abaloparatide, and teriparatide groups, respectively.
9.3 Sclerostin Inhibitors

The role of sclerostin in bone metabolism was identified in stud-
ies of patients with sclerosteosis and van Buchem disease, two
rare sclerosing bone dysplasias characterized by progressive
generalized overgrowth and thickening of bone that is resistant
to fracture. The two disorders are due to different defects of the
SOST gene, located on chromosome 17q12–21, and result in
impaired production of sclerostin. Sclerostin, a glycoprotein pro-
duced in the skeleton exclusively by osteocytes, is transported to
the bone surface where it inhibits bone formation by antagoniz-
ing the canonical Wnt signaling pathway in osteoblasts [5, 6];
sclerostin also upregulates RANKL synthesis by osteocytes
thereby stimulating osteoclastogenesis [7] (Fig. 9.2).
The restricted expression of sclerostin in the skeleton, and
the lack of abnormalities in organs other than the skeleton in
humans and animals with sclerostin deficiency, made this
protein a target of new bone-building therapies for osteopo-
rosis [9]. A number of sclerostin inhibitors have been investi-
gated in preclinical and early clinical studies, but only one
humanized monoclonal antibody, romosozumab, was tested
in phase III clinical studies of women with postmenopausal
osteoporosis. Romosozumab stimulated trabecular and corti-
cal bone formation and increased bone mass and strength in
animal models [10–12]. Importantly, the majority of new bone
formation induced by romosozumab was modeling-based,
occurring at quiescent surfaces, which is a clear anabolic
88 S. E. Papapoulos
Wnt
LRP4 Scl LRP5/6
RANKL
Sclerostin
Loading
PTH
Estrogen
Sclerostin AB
Figure 9.2 Schematic representation of sclerostin actions. Osteocyte-

produced sclerostin inhibits the proliferation, differentiation, and
survival of osteoblasts and reduces bone formation. It also stimu-
lates the production of RANKL by neighboring osteocytes and
bone resorption. In osteoblasts, sclerostin binds to LRP5/LRP6 and
inhibits the Wnt signaling pathway, an action facilitated by LRP4.
Production of sclerostin is decreased by mechanical loading, PTH,
estrogens, and other factors. LRP4/LRP5/LRP6 low-density lipopro-
tein receptor-related protein 4/low density lipoprotein receptor-
related protein 5/low density lipoprotein receptor-related protein 6,
PTH parathyroid hormone, RANKL receptor activator of nuclear
factor kappa-B ligand, Scl sclerostin. (Reproduced from Appelman-
Dijkstra and Papapoulos [8])
response [13]. The effect of sclerostin inhibition on bone for-

mation decreased with prolongation of treatment and was
reversible upon its discontinuation.
Romosozumab given by monthly sc injections rapidly
increased areal and volumetric BMD at the spine and the hip
to levels clearly higher than daily teriparatide in treatment-
naïve women as well as in osteoporotic women previously

treated with bisphosphonate [14–17]. Adverse events were
similar between placebo and romosozumab-treated patients
with the exception of mild reactions at the injection sites [15].
Changes of biochemical markers and histological parameters
of bone turnover in animals and humans during treatment
with romosozumab were different from those observed dur-
ing treatment with PTH or PTHrP peptides (Fig. 9.3) and
suggested a functional uncoupling between bone formation
and bone resorption.
There was an early rapid increase in bone formation fol-
lowed by a progressive decline with time, which was not due to
the development of neutralizing antibodies. The increase in
bone formation was associated with a decrease of bone resorp-
tion, possibly through an inhibitory effect of the antibody on
the production of RANKL by osteocytes. Treatment prolong-
ing, however, appears to modestly reduce bone resorption but
also bone turnover. It may thus be that while romosozumab
acts as a pure anabolic agent in the beginning of treatment its
Bone formation Bone resorption
TPTD %100 ROMO

%250
200
50
150
100
0
50
0 –50
0 1M 3M 6M 9M 12M 0 1Wk 1M 2M 3M 6M 9M 12M
Figure 9.3 Schematic representation of changes in the levels of

biochemical markers of bone turnover during treatment with subcu-
taneous injections of teriparatide (TPTD, 20 μg daily) or romoso-
zumab (ROMO, 210 mg once monthly) for 1 year. Bone formation
and bone resorption were assessed by measuring serum levels of
procollagen type 1 aminoterminal propeptide (P1NP) and carboxy-
terminal collagen cross-linking (CTX), respectively. (Reproduced
from Papapoulos [14])
90 S. E. Papapoulos
continued administration results in mild inhibition of bone

resorption and reduction of the remodeling space.
In one phase III clinical trial (FRAME) 7180 postmeno-
pausal women aged between 55 and 90 years with BMD
T-scores between −2.5 and −3.5 at the total hip or femoral
neck were randomized to once-monthly sc injections of
romosozumab (ROMO) 210 mg or placebo for 1 year fol-
lowed by open-label denosumab (DMab) 60 mg sc every
6 months for a further 12 months; all women received vitamin
D and calcium supplements [18]. Compared with placebo,
ROMO treatment decreased the incidence of vertebral frac-
tures by 73% at 12 months and by 75%, after transition to
DMab, at 24 months. The risk of clinical fractures decreased
significantly by 36% at 12 months while that of non-vertebral
fractures by 25%, a nonsignificant result, probably due to lack
of an effect in patients from Latin America with very low
fracture risk. In study sites from the rest of the world, a 42%
significant reduction in the incidence of non-vertebral frac-
tures was observed. Adverse events, including serious cardio-
vascular events, osteoarthritis, and cancer, were balanced
between the two groups. One case adjudicated as atypical
femoral fracture was observed 3.5 months after the first
ROMO injection in a patient with prodromal symptoms
before starting treatment and two cases of osteonecrosis of
the jaw after 12-month ROMO and 12-month ROMO and
one dose DMab, respectively.
In the other phase III clinical trial (ARCH), 4039 women,
mean age 74.3 years, with severe postmenopausal o steoporosis
at high risk of fractures were randomized to receive sc
ROMO 210 mg once monthly or oral alendronate (ALN)
70 mg once weekly for 12 months; thereafter, all patients
received ALN until the end of the trial with maintenance of
blinding to the initial treatment assignment; all women
received daily calcium and vitamin D [19]. A superior anti-
fracture efficacy of ROMO treatment was already evident at
12 months, and the incidence of all osteoporotic fractures,
including those of the hip, decreased significantly in women
treated with ROMO/ALN compared with those treated with
ALN/ALN. Adverse events and serious adverse events were
balanced between the two groups. However, during the first

year of the study, positively adjudicated serious cardiovascu-
lar events were observed more often with ROMO than with
ALN (50 vs 38 patients, respectively). Whether this imbalance
was a chance finding, as it was not observed in the placebo-
controlled FRAME study, or whether it was due to inhibition
of sclerostin in the vasculature or to a protective effect of
ALN need to be clarified [20]. During the second year of
open-label ALN treatment two cases of osteonecrosis of the
jaw (one in each group) and six cases of adjudicated atypical
femoral fractures (two in the ROMO/ALN group and four in
the ALN/ALN group) were observed.
The Wnt signaling pathway, a key regulator of bone forma-
tion, provided a number of targets for the development of
bone anabolic therapies to fulfill an unmet need of patients
with severe osteoporosis. Of these, sclerostin emerged as the
preferred target due to its bone specificity and dual action on
bone formation and resorption. Of the different sclerostin
inhibitors developed, romosozumab was extensively investi-
gated in adequately designed and performed preclinical and
clinical studies. Results showed superior efficacy of romoso-
zumab compared with existing therapies, and the magnitude of
the rapid, pronounced gains of bone mass on treatment super-
seded those of other therapeutics. Thus, sclerostin inhibition
met expectations of an efficacious anabolic therapy to fulfill a
currently unmet need in the management of patients with
severe osteoporosis. The imbalance, however, of serious cardio-
vascular events in the ARCH study, needs to be clarified.
9.4 Conclusion
The two components of bone remodeling resorption and for-
mation constitute the primary target of pharmacological
interventions for the management of the disease. It is now
clear that bone resorption and formation can be differently
modulated by new classes of anti-osteoporotic medications
[8] that provide a novel, personalized perspective for the
management of patients in clinical practice.
92 S. E. Papapoulos
References
1. Appelman-Dijkstra NM, Papapoulos SE. Novel approaches to
the treatment of osteoporosis. Best Pract Res Clin Endocrinol
Metab. 2014;28:843–57.
2. Compston JE. Skeletal actions of intermittent parathyroid
hormone: effects on bone remodelling and structure. Bone.
2007;40:1447–52.
3. Leder BZ, O’Dea LS, Zanchetta JR, et al. Effects of abalopara-
tide, a human parathyroid hormone-related peptide analog, on
bone mineral density in postmenopausal women with osteopo-
rosis. J Clin Endocrinol Metab. 2015;100:697–706.
4. Miller PD, Hattersly G, Riis BJ, et al. Effect of abaloparatide
vs placebo on new vertebral fractures in postmenopausal
women with osteoporosis: a randomized clinical trial. JAMA.
2016;316:722–33.
5. Moester MJ, Papapoulos SE, Lowik CW, van Bezooijen
RL. Sclerostin: current knowledge and future perspectives.
Calcif Tissue Int. 2010;87:99–107.
6. van Lierop AH, Appelman-Dijkstra NM, Papapoulos SE.
Sclerostin deficiency in humans. Bone. 2017;96:51–62.
7. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay
DM, Atkins GJ. Sclerostin stimulates osteocyte support of
osteoclast activity by a RANKL-dependent pathway. PLoS One.
2011;6:e25900.
8. Appelman-Dijkstra NM, Papapoulos SE. Modulating bone
resorption and bone formation in opposite directions in the treat-
ment of postmenopausal osteoporosis. Drugs. 2015;75:1049–58.
9. Appelman-Dijkstra NM, Papapoulos SE. Sclerostin inhibi-
tion in the management of osteoporosis. Calcif Tissue Int.
2016;98:370–80.
10. Li X, Warmington KS, Niu QT, et al. Inhibition of scleros-
tin by monoclonal antibody increases bone formation, bone
mass, and bone strength in aged male rats. J Bone Miner Res.
2010;25:2647–56.
11. Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin
antibody in cynomolgus monkeys increases bone formation,
bone mineral density, and bone strength. J Bone Miner Res.
2010;25:948–59.
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bodies in animal models of osteoporosis. Bone. 2017;96:63–75.
13. Ominsky MS, Niu QT, Li C, Li X, Ke HZ. Tissue-level mechanisms

responsible for the increase in bone formation and bone volume
by sclerostin antibody. J Bone Miner Res. 2014;29:1424–30.
14. Papapoulos SE. Anabolic bone therapies in 2014: new bone-
forming treatments for osteoporosis. Nat Rev Endocrinol.
2015;11:69–70.
15. McClung MR, Grauer A, Boonen S, et al. Romosozumab in
postmenopausal women with low bone mineral density. N Engl
J Med. 2014;370:412–20.
16. Genant HK, Engelke K, Bolognese MA, et al. Effects of romo-
sozumab compared with teriparatide on bone density and mass
at the spine and hip in postmenopausal women with low bone
mass. J Bone Miner Res. 2017;32:181–7.
17. Langdahl BL, Libanati C, Crittenden DB, et al. Romosozumab
(sclerostin monoclonal antibody) versus teriparatide in post-
menopausal women with osteoporosis transitioning from oral
bisphosphonate therapy: a randomised, open-label, phase 3 trial.
Lancet. 2017;390:1585–94.
18. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab
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19. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alen-
dronate for fracture prevention in women with osteoporosis. N
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Index
A dual-energy X-ray
Aerobic activity, 33 absorptiometry, 21
Anabolic therapy, 61, 62, 77, 91 quantitative computed
Androgen-deprivation therapy, tomography, 22
76 quantitative ultrasound, 22
x-ray dose, 22
Bone mineral density (BMD),
B 11–13, 24, 25, 27, 44, 49,
Bazedoxifene, 50, 53 60, 83
Biconcavity, 16 Bone modeling, 2
Bisphosphonates, 83 Bone multicellular unit (BMU),
bone mineral density, 44, 49 1
clinical use, 44 Bone remodeling, 1, 3, 44
dosing, contraindications, Bone resorption, 3–5, 24, 32, 44,
and precautions, 52, 64, 77, 82, 86, 88–91
46–48 Bone turnover markers (BTM),
femoral shaft fractures, 49 24
fracture risk Bone-specific anti-resorptive
in postmenopausal therapies, 60
women, 45 Burden of disease, 17, 18
vertebral, 44
hypersensitivity, 49
hypocalcemia, 50 C
impaired renal function, 50 Calcium, 1, 6, 32, 35, 37, 50, 52, 75,
inflammatory eye disease, 49 83, 90
Paget’s disease, 48 Carboxy-terminal collagen
upper gastrointestinal crosslinking (CTX), 89
intolerance, 44 Cervical fracture, 14
Bone macrostructure and Colony-stimulating factor-1
microstructure, 23, 24 (CSF-1 or M-CSF), 4
Bone mass Crush fracture, 16

https://doi.org/10.1007/978-3-319-26757-9
96 Index
D bone mineral density, 83

Denosumab therapy, 51, 52 fracture risk, 82
Diagnosis, 11 initiation, 84
Dietary proteins, 33, 35 sclerostin expression, 82
Distal forearm fracture, 16, 17 teriparatide, 84
Dual-energy X-ray Glucocorticoids (GCs), 81
absorptiometry
(DXA), 21
H
High-resolution peripheral
E QCT, 24
Estrogen agonist/antagonists, 50 Hip fracture, 14, 15
Estrogen control cytokines Hormone therapy (HT), 60
production, 5 Hypocalcemia, 50
F I
Fall prevention Immobilization, 32
environmental (extrinsic) Insulin-like growth factor 1
factors, 34, 35 (IGF-1), 7
intrinsic factors, 34 Interleukin-6, 7
Femoral shaft fractures, 49 Intravenous zoledronic acid
Fracture risk assessment therapy, 50
(FRAX)
anabolic therapy, 61, 62
BMD, 24, 25, 27 L
characteristics, 25, 26 Lipoprotein receptor-related
combination therapy, 62–64 protein 5 (LRP5), 7
effect of therapies, 45 Low energy, 13
FRAX® tool, 26, 27 Low trauma’ fractures, 31
GIOP, 82
in older women, 61
switching and stopping M
osteoporosis Male osteoporosis
medications, 65, 66 differential diagnosis, 74, 75
treatment resumption, 67 follow-up, 76, 77
in younger women, 60 fracture prevention, 71, 72
FRAX® calculation tool, 26, 27 risk evaluation, 71, 73–74
treatment, 75, 76
with history of fracture, 73
G without history of
Glucocorticoid-induced fracture, 73
osteoporosis (GIOP) Malnutrition, 35
bisphosphonates, 83 Mechanical overload, 31
Index 97
Mixed loading exercise, 32 P

Multi-task music-based Paget’s disease, 48
training, 35 Parathyroid hormone
(PTH), 5, 87
Parathyroid hormone-related
N peptides (PTHrP), 86
Non-bisphosphonate therapies, Pathophysiological bases, 2, 3
65 Pelvic fracture, 17
Non-invasive skeletal Physical activity, 32, 33
assessments Physiotherapy, 32
bone macrostructure and Preventive measures, 31, 32
microstructure, 23, 24 Procollagen type 1
bone mass aminoterminal
bone turnover markers, 24 propeptide (P1NP), 89
dual-energy X-ray Protein, 35, 36
absorptiometry, 21 Proximal humeral fracture, 17
quantitative computed Proximal tibial fractures, 17
tomography, 22
quantitative ultrasound, 22
X-ray dose, 22 Q
Nutrition Quantitative computed
calcium, 37 tomography
protein, 35, 36 (QCT), 22
vitamin D, 37, 38 Quantitative ultrasound
(QUS), 22
O
Osteoblasts (OB), 6 R
Osteoclast (OC), 3 Raloxifene, 50
Osteoporosis-pseudoglioma RANKL/RANK/OPG system, 2
syndrome (OPPG), 7 Receptor activator of nuclear
Osteoporotic fracture factor-kappaB
distal forearm fracture, 16, 17 (RANK) ligand, 4, 82
high energy trauma, 13 Recommended dietary
hip, 14, 15 allowance, 35
incidence rates, 15 Recommended nutrient intakes
low energy trauma, 13 (RNI), 37
pelvic, 17 Resistance exercise training, 33
proximal humeral, 17
proximal tibial, 17
spine, 14 S
vertebral fracture, 15, 16 Scheuermann’s disease, 16
wrist, 14 Sclerostin inhibitors
Osteoprotegerin (OPG), 4 anabolic therapy, 91
98 Index
Sclerostin inhibitors (cont.) U

bone formation and Upper gastrointestinal (GI)
resorption, 91 intolerance, 44
preclinical and clinical studies,
87
production, 88 V
restricted expression, 87 Vertebral deformities, 15, 16
romosozumab, 87–91 Vertebral fracture (VFs), 15, 16,
teriparatide, 89 18, 23, 31, 44, 50, 52, 53,
Wnt signaling pathway, 87, 91 60, 64, 65, 82, 90
Sclerostin production, 7 Vertebral fracture assessment
Spine fracture, 14 (VFA), 23, 73, 74, 76
Standard deviation (SD), 12 Vitamin D, 6, 32, 35, 37, 38, 50, 52,
75, 83, 90
T
Teriparatide therapy, 52, 53 W
glucocorticoid-induced Wedge fracture, 16
osteoporosis, 84 Weight bearing exercise, 32
male osteoporosis, 76 Wingless (Wnt) canonical
Testosterone therapy, 76 signaling, 7
Tissue non-specific alkaline Wnt/LRP5/beta-catenin
phosphatase (TNAP), canonical signaling
6 pathway, 2, 87, 91
Tissue selective estrogen Wrist fracture, 14
complex (TSEC), 60
Trabecular bone score (TBS), 24
Trochanteric fracture, 14 Z
T-score, 12 Z-score, 12

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Serge Livio Ferrari

Christian Roux Editors

ISBN 978-3-319-26755-5 ISBN 978-3-319-26757-9 (eBook)

Library of Congress Control Number: 2018964428

© Springer Nature Switzerland AG 2019

This Springer imprint is published by the registered company Springer

Every few seconds, a patient is admitted to a hospital with a

Geneva, Switzerland Serge Livio Ferrari

2 Diagnosis and Clinical Aspects of Osteoporosis��������� 11

3 Evaluation of Fracture Risk ����������������������������������������� 21

4 Prevention of Osteoporosis and Fragility

5 Efficacy and Safety of Osteoporosis Treatment������������� 43

6 Management of Patients with Increased

7 Management of Male Osteoporosis����������������������������� 71

9 New Bone-Forming Agents������������������������������������������� 85

Felicia Cosman, MD Helen Hayes Hospital, West Haverstraw,

Serge Livio Ferrari, MD Division of Bone Diseases, Geneva

Piet Geusens, MD Department of Internal Medicine,

John A. Kanis, MD Center for Metabolic Bone Diseases,

Eugene V. McCloskey, MD Center for Metabolic Bone

Michael R. McClung, MD Oregon Osteoporosis Center,

Socrates E. Papapoulos, MD Center for Bone Quality,

René Rizzoli, MD Division of Bone Diseases, Geneva

Christian Roux, MD Department of Rheumatology, Paris

Jopp van den Bergh, MD, PhD Department of Internal

© Springer Nature Switzerland AG 2019 1

bone formation (i.e., without prior resorption), a process

Increased bone loss

Figure 1.1 Increased bone remodeling causes bone loss

canonical signaling pathway [6] and the RANKL/RANK/

1.3 The Role of Osteoclasts

Osteoclastogenesis is activated by a number of pro-­

Figure 1.2 Osteoprotegerin (OPG), the natural antagonist of

development of a human monoclonal antibody against

1.3.1 Control of Bone Resorption

Because the production of RANKL as well as other cyto-

Figure 1.3 Estrogen controls cytokine production in bone and bone

elevated, such as during poor calcium intake, vitamin D defi-

1.4 The Role of Osteoblasts

1.4.1 Control of Bone Formation

Several signaling molecules play major roles in controlling dif-

insulin-like growth factor 1 (IGF-1) and other growth factors

Figure 1.4 Sclerostin produced by osteocytes inhibits bone formation

with aging and contributes directly to osteoporosis remains

8. Bruzzaniti A, Baron R. Molecular regulation of osteoclast activ-

21. Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a

2.2 Diagnosing Osteoporosis

© Springer Nature Switzerland AG 2019 11

2.3 Osteoporotic Fractures

Osteoporosis Low bone Normal

Figure 2.1 The distribution of bone mineral density in young healthy

from low energy trauma as being osteoporotic. “Low energy”

Figure 2.2 Typical sites of osteoporotic fracture: wrist (left), spine

femoral fractures. Under this schema, the fracture sites that

2.3.1 Hip Fracture

Hip fracture is the most serious osteoporotic fracture.

Annual Incidence (rate/1,000)

Figure 2.3 Incidence (rate/1000 per annum) by age of fractures at

Geneva, Switzerland Serge Livio Ferrari

2 Diagnosis and Clinical Aspects of Osteoporosis�� 11

3 Evaluation of Fracture Risk �� 21

4 Prevention of Osteoporosis and Fragility

5 Efficacy and Safety of Osteoporosis Treatment�� 43

6 Management of Patients with Increased

7 Management of Male Osteoporosis�� 71

9 New Bone-Forming Agents�� 85

1.3 The Role of Osteoclasts

Osteoclastogenesis is activated by a number of pro-

1.3.1 Control of Bone Resorption

1.4 The Role of Osteoblasts

1.4.1 Control of Bone Formation

2.2 Diagnosing Osteoporosis

2.3 Osteoporotic Fractures

2.3.1 Hip Fracture

2.3.2 Vertebral Fracture

2.3.3 Distal Forearm Fracture

2.3.4 All Fractures

2.4 Burden of Disease

3.2 Non-invasive Skeletal Assessments

3.2.1 Measurements of Bone Mass

3.2.2 Measurements of Bone Structure

3.2.3 Measurements of Bone Turnover

3.3 Assessment of Fracture Risk

4.2 Physical Activity

4.3 Prevention of Falls

4.3.1 Intrinsic Factors

4.3.2 Environmental (Extrinsic) Risk Factors

4.4.1 Calcium and Vitamin D

5.3 Estrogen Agonist/Antagonists

5.6 Choosing Among Therapies

6.2 reatment for Younger Women