About the Authors

Luisella Cianferotti
Luisella Cianferotti received her University degree (Laurea) in
Medicine and Surgery from the University of Pisa, Pisa, Italy, in 1996,
where she specialized in endocrinology and metabolism in 2002 and
got the PhD degree in endocrine and metabolic sciences in 2008.
She has been Fellow at the Imperial College School of Medicine,
Hammersmith Hospital, London, UK, and Postdoctoral Fellow at the
Massachusetts General Hospital-Harvard Medical School, MA, USA.
She is currently Research and Clinical Assistant in the Department
of Endocrinology and Metabolism, University of Pisa. She is author
of several peer-reviewed scientific papers and book chapters on
bone and mineral metabolism field. She has received several awards
and serves as a reviewer for several international scientific journals.

Maria Luisa Brandi

Maria Luisa Brandi took her MD degree in 1977 and her PhD
degree in Cell Biology in 1987. She is Full Professor of endocrinology
and metabolism diseases at the University of Florence, Florence,
Italy. Her background is in molecular endocrinology applied to
clinical medicine. She developed several novel cell biological
models used in basic research. She is responsible for a Regional
Program on Hereditary Endocrine Tumors and of the Bone
Metabolic Unit at the University of Florence. The unit is active
both in clinical and basic research for bone and mineral metabolic
disorders. She has been working in the area of genetics of
osteoporosis for approximately 10 years. Her reputation in the
area of bone and mineral metabolism is well recognized nationally
and internationally. She has been and is the main investigator for
several major applications granted from national and international
agencies and institutions. She was the President-elect of the
Italian Society of Osteoporosis, serves as a member of the
Scientific Committee of the International Osteoporosis Foundation
and is General Secretary of European Society for Clinical and
Economic Aspects of Osteoporosis and Osteoarthritis. She owns
seven patents and has published over 470 publications in peer-
reviewed journals and 200 chapters in books. She serves as a
member of the Journal of Bone and Mineral Research and is the
Editor-in-Chief of Clinical Cases in Mineral and Bone Metabolism.
For reprint orders, please contact: reprints@futuremedicine.com
6 6 © 2012 Future Medicine
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 Chapter
Failure in achieving an
optimal peak bone mass 8 Maria Luisa Brandi
Menopause- &
age-related changes in
bone remodeling &
micro­architecture
leading to bone loss 11
Systemic factors causing
secondary osteoporosis 17
Conclusion19
doi:10.2217/EBO.12.159
© 2012 Future Medicine
1
Pathogenesis of
osteoporosis
Luisella Cianferotti &
Osteoporosis is a disease characterized by a deterioration
of bone mass, architecture and quality leading to a
decreased bone strength and increased risk for fragility
fractures. Although bone mineral density (BMD) is the
major determinant for fracture risk, other factors such as
bone turnover, connectivity and mineralization contribute
to determining this risk by influencing bone quality.
Multiple pathogenetic and regulatory mechanisms are
responsible for these changes. The pathogenesis of
osteoporosis as a primary disorder is complex and is the
consequence of genetic, hormonal, dietary, lifestyle and
physical factors. Adult bone is the result of the peak bone
mass, acquired early in life, and the maintenance of bone
density and skeletal architecture in adult age. Impairment
of bone accrual during skeletal growth and/or imbalance
of factors favoring bone resorption versus bone formation
in adult bone may be responsible for skeletal fragility.
Genetics influence mainly bone accrual and the peak bone
mass, while systemic hormones (mainly parathyroid
hormone [PTH] excess and withdrawal of estrogens) or
local cytokines are mostly responsible for bone remodeling
imbalance. This chapter focuses on the principal
7
Cianferotti & Brandi

Osteoporosis consists of a deterioration in pathogenetic mechanisms in primary and

bone mass and microarchitecture, leading to secondary osteoporosis, with special
decreased bone strength and increased fracture risk.
attention to genetics and estrogen
The pathogenesis of osteoporosis is multifactorial and deprivation during menopause as the main
takes into account genetics, systemic factors such as
factors contributing to bone loss.
deficiency or excess of certain hormones and
environmental factors and their interaction.
Failure in achieving an optimal peak
Perturbations in peak bone mass acquisition
predisposes to osteoporosis later in life. bone mass
Osteoporosis later in life may result from
failure in achieving an optimal skeletal
health during development and growth. It is estimated that 60% of adult
bone mass depends on peak acquisition.
Several hormonal, heritable and environmental factors influence both
the acquisition of peak bone mass and the maintenance of skeletal
homeostasis throughout life. Certain hormone deficiencies do not only
elicit bone resorption in adults, but also impair bone consolidation and
growth during infancy and adolescence. Both the timing and the quantity
of sex hormones (estrogens and testosterone), and the growth hormone/
IGF-1 secreted during puberty are critical for bone formation and accrual,
especially during the latter stages. In males who experienced late-onset
puberty or adolescents with low IGF-1 levels, adult BMD is significantly
lower than in controls. Exogenous administration of glucocorticoids or
other calciotropic drugs during infancy and adolescence, as well as
nutritional deficiencies or lifestyle factors, such as smoking and alcohol
consumption, can blunt the genetically determined peak bone mass.

Genetic determinants of peak bone mass (BMD & fracture risk)

Genetics is the major factor influencing peak bone mass and strength, but
also bone mass maintenance, interaction with environmental factors and
response to therapy. Studies in monozygotic and dizygotic twins have
proved an up to 60–80% heritability of bone mass.
Several studies have demonstrated that at
least 50% of bone mass is genetically
Bone mineral density: representative of the
amount of mineral in a specific area of bone.
determined and it is clear that bone mass
is inherited as a polygenic trait.
Peak bone mass: amount of bone mass achieved at
the end of skeletal maturation; it is generally acquired In the past decade, insights into genetic
between 12 and 16 years of age; it is sustained mainly determinants of osteoporosis have derived
by surges of sex hormones and growth hormone/IGF1 from monogenic bone diseases or phenotypes
and it is characterized by a positive calcium balance,
with increased bone formation, increased linear
characterized by increased bone mass. These
growth and consolidation of trabecular and cortical studies have initially underlined the key role
components.

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 Pathogenesis of osteoporosis

of effectors of the canonical Wnt signaling in Osteoblasts: also referred to as bone-forming

skeletal homeostasis (Figure 1.1). Subsequent cells, are specialized bone cells of mesenchymal
origin, which deposit bone matrix that is needed for
in vitro studies and animal models have
the development of new bone.
confirmed that this universal pathway is also
critical for osteoblast differentiation and
plays a key role in the regulation of bone accrual in postnatal life [1].
Independent studies in humans, subsequently confirmed by gain- or loss-of-
function animal models, have documented a key role of Lrp5 (Wnt coreceptor)

Figure 1.1. Canonical Wnt signaling.

AMG-785
Wnt
BHQ-880
WIF1 Sclerostin
sFRP
Wnt Dkk1
Sclerostin
Dkk1 Wnt
LRP5/6

LRP5/6
Kremen

Frizzled Frizzled

APC Axin Axin

APC
GSK-3β
P β-catenin
LRP5 GSK-3β
degradation
β-catenin
β-catenin
Proteosomal β-catenin
degradation

Nucleus Nucleus
β-catenin Osteoblast gene
TCF/LEF transcription and
bone formation
Cytoplasm Cytoplasm

(A) Canonical Wnt signaling promotes osteoblast differentation. Several secreted proteins can modulate
canonical Wnt signaling: Wnt inhibitors (sFRPs or WIF1) can prevent Wnt binding to Wnt coreceptor; scle-
rostin (SOST) or Dkk1 disrupt Wnt-LRP5/6 interaction. In the absence of Wnt binding to LRP5/6, b-catenin
is phosphorylated and targeted to degradation. (B) When sclerostin and/or Dkk1 are neutralized by specific
monoclonal antibodies (AMG-785 and BHQ-880, respectively) or in the absence of other Wnt inhibitors, Wnt
can bind to the specific receptor. This inhibits the phosphorilating complex, so that b-catenin accumulates
and translocates into the nucleus where upon binding to TCF/LEF transcription factors it drives transcription
of osteoblast-specific target genes.
WIF1: Wnt inhibitory factor 1.

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Cianferotti & Brandi

and sclerostin (Wnt inhibitor) in postnatal bone formation. Gain-of-function

mutations in Lrp5 are responsible for the high bone mass phenotype
appearing in adolescence and persisting throughout adulthood, due to
hyperactivation of the canonical Wnt-signaling pathway. Conversely,
loss-of-function mutations in Lrp5 were shown to cause osteoporosis
pseudoglioma, a disease characterized by bone loss appearing earlier in life
and blindness at birth. Mutations in sclerostin, a Wnt-inhibitor, cause in
humans the severe van Buchem disease, characterized by high bone mass,
skeletal overgrowth, hyperosteosis and hearing loss.
In parallel with these findings, in the last decade an association of osteoporosis
and osteoporotic fractures with a large number of candidate genes has been
reported. However, this number has been refined in recent years taking
advantage of large-scale association studies, meta-analyses, genome-wide
approaches (testing single-nucleotide polymorphisms and copy-number
variations) and studies testing candidate genes [2]. Studies of polymorphisms
of several genes have identified candidate loci, although they have shown
contradictory results. Variations in the DNA sequences in these regions confer
either risk or protection from osteoporosis. Polymorphisms of genes codifying
effectors of the vitamin D pathway, such as the vitamin D receptor and the
vitamin D-binding protein, polymorphisms of genes codifying for collagen Ia1,
and polymporphisms of genes codifying effectors of the estrogen endocrine
pathway (e.g., the estrogen receptors [mainly ESR1] or key enzymes in the
metabolism of androgens and estrogens [CYP19A1 and CYP17A1]) have been
associated with lower BMD and/or increased risk for osteoporotic fractures.
Recently, the largest genome-wide analysis to date has found an association
between 56 genetic loci with vertebral and femoral BMD and between a subset
of 14 loci with fracture risk [3]. This important study underlines the highly
polygenic nature of BMD variation and the critical role of various biological
pathways (e.g., Wnt factors, Wnt inhibitors, RANK/RANKL/osteoprotegerin
system) influencing osteoporosis and fracture risk.

Nutritional determinants of peak bone mass

During puberty, a positive calcium balance is realized, since intestinal
calcium absorption is increased and calcium excretion is reduced, with
specific racial and sex differences. The relative excess of calcium and
phosphate is necessary for adequate mineralization of the fast-growing
skeletal tissue. A dietary calcium deficiency, a vitamin D deficiency
(i.e., vitamin D <20 ng/ml or 50 mmol/l) blunts the peak bone mass and
can be responsible for fragile bones later in life [4]. An excess of dietary salt
increases urinary calcium loss. Physical weight-bearing activity can
positively influence bone geometry and final BMD.

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 Pathogenesis of osteoporosis

In addition, external environmental Osteoclasts: also referred to as bone-resorbing

factors such as maternal vitamin D status cells, are large multinucleated bone cells of
hematopoietic origin, which resorb mineralized bone.
and placental calcium transfer can be
responsible for modulation of peak bone Bone remodeling: a lifelong skeletal process where
mature mineralized bone is replaced by newly formed
mass acquisition and maintenance through
bone by the coordinated activities of osteoclasts
epigenetic mechanisms [5]. (bone resorption) and osteoblasts (bone formation).
Osteocytes: the most numerous cells in adult bone,
Menopause- & age-related changes are branched cells embedded in mineralized bone
in bone remodeling & micro­ matrix, networked with each other and with cells on
architecture leading to bone loss the bone surface, capable of sensing fluid shear stress
Adult skeleton is maintained through the and releasing factors into the surrounding canaliculi.
opposite still tightly coupled activities of
bone-forming osteoblasts and bone-resorbing osteoclasts, arising from
different progenitors (Figure 1.2). This remodeling process allows the bone
to grow, to shape and model, to adapt to multiple physiological needs and
to repair microfractures. Osteoblasts are driven by systemic factors such
as hormones (i.e., PTH, growth hormone/IGF-1 and sex hormones), and
interleukins (i.e., IL-1 and IL-6) [6]. Osteoclasts, in turn, require specific
signals from osteoblasts to differentiate into mature resorbing cells, such
as multicolony stimulating factor and RANKL [7]. RANKL plays a key role in
osteoclast activation. The RANKL-dependent osteoclast activation is
counter-balanced by osteoprotegerin (OPG), a decoy receptor for RANKL
also produced by osteblasts [8]. A complete bone remodeling cycle occurs
at the level of the basic multicellular unit (BMU), which also includes
osteocytes, fully mature osteoblasts embedded in bone mineralized matrix
capable of sensing mechanical stimuli and producing biochemical signals
towards the other bone cells (Figure 1.3) [9]. Osteocytes are important
either in the initiation and termination of the remodeling process and
mineralization, in that they secrete factors able to recruit osteoclasts in
response to mechanical loading or stress and they secrete sclerostin, a
Wnt and bone morphogenetic protein inhibitor that act paracrinally to
inhibit osteoblast activity. The relatively short period (3 weeks) of bone
resorption sustained by osteoclasts is followed by a longer period
(3–6 months) of bone formation sustained by osteoblasts, which secrete
bone matrix that eventually becomes mineralized. While the concerted
activities of osteocytes, osteoclasts and osteoblasts in bone remodeling
serve as supply of mineral for the extracellular space, they also confer
elasticity and strength to the skeleton
throughout life [10]. For most of the time,
An imbalance/uncoupling of bone remodeling,
bone resorption equals bone formation.
with a relative prevalence of bone resorption
However, there are some periods in which over formation, is critical in the development of
postmenopausal or age-related osteoporosis.

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Cianferotti & Brandi

Figure 1.2. Bone marrow niche, differentiation of bone cells and principal mechanisms of
osteoclast activation.

C/EBPβ/δ+→PPARγ+
C/EBPα+ Adipocyte
differentiation

Apoptotic
SOX9+ COL2+ Chondrocyte
osteoblast
differentiation

Mesenchymal
stem cell
RUNX2+ Lining cells
COL1a+ RUNX2+ Preosteoblast Mature osteoblast
COL1a+ RUNX2+ ALP+→BSP+→OC+
OSX+

OPG RANKL
RANKL M-CSF Osteocyte
M-CSF M-CSF Sclerostin

PU.1

Hematopoietic Preosteoclast Osteoclast Active osteoclast Apoptotic

stem cell c-Fms-→c-Fms+ c-Fms+ NF-κB+ c-Src+ cathepsin K+ osteoclast
NF-κB-→NF-κB+ c-Src+ αvβ3+ TRAP+
Bone marrow niche c-jun+ c-fos+
TNF-α, IL-1, IL-6, IL-7

Mesenchymal stem cells enclosed within the bone marrow niche contain progenitors that give rise to differ-
ent cell lineages (osteoblast, chondrocytes and adipocytes). Each lineage is characterized by the sequential
expression of different factors. Differentiation into the adipocyte lineage is driven by C/EBP factors and PPARg.
Differentiation into the chondrocyte lineage is driven by the transcription factor SOX9 and, subsequenty, the
expression of COL2. Differentiation into the osteoblast lineage is primarily driven by the transcription factor
Runx2 (or Cbfa1), OSX (osterix) and is characterized by the early expression of COL1a. Bone matrix-producing
mature osteoblast, expressing specific markers such as ALP, BSP and OC, express the osteoclast-activating
factor, RANKL, and secrete a decoy receptor for RANKL, OPG, able to neutralize it. Osteoblasts can undergo
apoptosis, or terminally differentiate into lining cells or osteocytes. Osteocytes are cells embedded within the
bone matrix, able to sense mechanical stimuli via dendritic processes and secrete sclerostin, which, in turn,
inhibits osteoblast differentiation. Progenitor cells belonging to hematopoietic precursors differentiate into
osteoclasts, characterized by the early expression of c-Fms (receptor for M-CSF), followed by the expression
of NFkB (or RANK) along with transcription factors, such as c-jun and c-fos, which drive polarized cells to fully
differentiated bone-resorbing cells, expressing TRAP, avb3 integrin and cathepsin K.
ALP: Alkaline phosphatase; BSP: Bone sialoprotein; Col2: Type 2 collagen; M-CSF: Multicolony
stimulating factor; OC: Osteocalcin; OPG: Osteoprotegerin; OSX: Osterix; PPARg: Peroxisomal proliferator-
activated receptor g; RANK: Receptor activator for NFkb; RANKL: Receptor activator for NFkB ligand;
TRAP: Tartate-resistant acid phosphatase.

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 Pathogenesis of osteoporosis

Figure 1.3. Bone-remodeling cycle at the level of a single basic multicellular unit and
modifications during active bone loss.

Bone marrow capillary

Mineralized bone matrix

Osteoid

Bone Bone
resorption formation

Osteoclast precursors Osteoclasts Osteocytes

Osteoblast precursors Osteoblasts Lining cells

(A) Bone marrow progenitors give rise to bone cells; during remodeling old bone is removed by the
multinucleated osteoclasts (bone resorption), then replaced by new bone matrix produced by osteoblasts
(bone formation), which eventually becomes mineralized; the concerted activity of osteoclasts, osteoblasts
and osteocytes are coordinated by several growth factors that act paracrinally and couple bone resorption
to bone formation. (B) An increased bone resorption and/or a deficient bone formation and/or impaired
mineralization lead to bone loss.

one of the two mechanisms physiologically prevails on the other. Thus,

during development and the first decades of life (linear growth), the
remodeling rate is rapid and bone formation exceeds bone resorption
leading to bone growth in size and density. Subsequently, bone formation
declines throughout adulthood because of a decrease in recruitment,
differentiation, activity, and/or life span of osteoblasts [11]. With aging and
sex hormone deprivation the rate of bone remodeling increases, so that
bone resorption easily prevails on bone formation and bone deterioration
occurs. At the tissue level, the slower bone formation on the periosteal
surface does not compensate for the greater endosteal and intracortical
resorption, leading to cortical thinning and porosity, and trabecular

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Cianferotti & Brandi

resorption leading to loss of trabeculae and connectivity. If peak bone

mass was inadequate and/or the entity of resorption was relatively greater
than expected or bone formation was further inhibited, osteoporosis is
likely to occur [12]. Any systemic or local factor that potentially affects one
of the phases of the remodeling cycle (recruitment, proliferation,
differentiation, function or apoptosis) will lead to disequilibrium in bone
remodeling (Figure 1.4).

Postmenopausal osteoporosis
The key role of estrogen deficiency in postmenopausal osteoporosis has
been well ascertained. Menopausal estrogen deprivation induces an
increase in remodeling rate and the net result is an uncoupling of the two
opposite activities of bone remodeling favoring resorption over formation,
thus leading to bone loss [11,13] . After
Figure 1.4. Systemic and local factors in the menopause, the levels of circulating
pathogenesis of bone loss. estrogens positively correlate with BMD so
that the lowest estradiol levels in post­
↓ Vitamin D–calcium ↑ Thyroid hormones menopausal women are associated with the
↑ PTH ↓ Estrogens lowest BMD and the greatest risk for
↑ Glucocorticoids ↓ Testosterone
fracture. Moreover, alterations in aromatase
activity both in women and in men leading
to a decrease in estradiol levels are
associated with low BMD and increased
fracture risk. The decrease in circulating
estrogens promotes osteoclast recruitment
to sites of active remodeling and increases
BMU activation frequency and resorption
depth, thus exacerbating the process of
Normal bone Osteoporosis bone resorption. In addition, estrogen
deficiency also reduces the lifespan of
↑ T-lymphocyte activation ↑ IL-1, IL-6 and IL-7 osteoblasts, thus reducing the volume of
↑ M-CSF ↑ TNF-α bone formed at the level of the single BMU,
↑ RANKL ↓ IFN-γ contributing to the negative BMU balance.
↑ ROS ↑ Prostaglandins Indeed, in animal models (ovariectomized
mice), after estrogen withdrawal the initial
Modification of various systemic factors (A) or local rapid phase of bone loss either at trabecular
factors in specific microenvironements (B) elicit and cortical sites due to increased osteoclast
bone resorption and/or inhibit bone formation,
thus leading to deterioration in bone strength and activity is generally followed by a slower but
micoarchitecture. extensive period of defective bone formation
M-CSF: Multicolony stimulating factor; PTH: Para- due to inadequate osteoblast function.
thyroid hormone; RANKL: Receptor activator for During estrogen deficiency, the enhanced
NFkB ligand; ROS: Reactive oxygen species.

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 Pathogenesis of osteoporosis

osteoblast apoptosis in the face of An overactivation of the immune system is at

increased osteoclast lifespan favors bone least, in part, responsible for the postmenopausal
bone loss.
resorption over bone formation. One of the
most critical mechanisms that become
unbalanced during estrogen-deprivation (or in response to increased PTH,
growth hormone or IL-1), is the RANKL/OPG system. Animal studies and
in vitro studies have demonstrated that the system RANKL/OPG and
several cytokines (e.g.,  IL-1, IL-6, TNF and IL-11) are activated during
estrogen deprivation [14]. Results from human studies are conflicting. While
there is a general consensus that circulating levels of both OPG and RANKL
are increased after menopause, the correlation of these two markers with
BMD and fracture risk is faint. However, studies in bone biopsies have
shown that the RANKL/OPG mRNA ratio is increased in bone (proximal
femur) from patients who suffered a fracture relative to controls with
osteoarthritis [8].
Recent studies have shown that an activation of the immune system is a
major determinant in the enhancement of bone resorption induced by
estrogen withdrawal [15]. Activated T cells secrete TNF in the bone marrow,
which is able to elicit osteoclastogenesis and osteoclast function. Indeed,
ovariectomy fails to cause bone loss in nude mice, in TNF-knockout mice
or in mice in which T-cell activation was blocked pharmacologically.
Estrogen withdrawal also causes other mineral disturbances. Indeed, the
intestinal calcium absorption is decreased and urinary calcium excretion
is increased, thus leading to an increased calcium loss, negative calcium
balance and secondary hyperparathyroidism. In the setting of vitamin D
deficiency (i.e., serum 25-OH vitamin D <20 ng/ml or <50 mmol/l) and/or
poor calcium intake (<800–1000 mg/day), PTH levels increase further, thus
favoring high bone turnover and bone loss, especially in older women.
Indeed, elders with calcium and/or vitamin D deficiency experience greater
degrees of bone impairment and an increased risk for nonvertebral
fractures [16]. If vitamin D deficiency is prolonged, the defect in mineralization
(i.e., osteomalacia) can compromise bone strength to a greater extent.
Continuous elevation of PTH causes an uncoupling in bone remodeling,
favoring bone resorption over formation, affecting mainly cortical sites [17].
Several studies have shown that high levels of PTH cause a rise in sclerostin
levels, thus leading to an inhibition of the canonical Wnt signaling.
Moreover, secondary hyperparathyroidism during calcium/vitamin D
insufficiency/deficiency is associated with
an increase in insulin-like growth factor
binding protein-4 and a downregulation of Bone marrow: soft, vascular tissue filling the
cavities of bones, containing vessels and
IGF-1 activity on osteoblasts. stromal and hematopoietic precursors of bone cells.

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Cianferotti & Brandi

Involutional (age-related) osteoporosis

After completion of growth and throughout adulthood bone mass declines
in both sexes because of a decrease in bone formation. However, since
the remodeling rate is slow, bone loss mainly depends on trabecular
thinning rather than on loss of connectivity and periosteal apposition still
compensate for endocortical resorption, bone strength is usually only
partially compromised. With aging, as with the lack of sex hormones, the
rate of remodeling gradually increases. Initially, trabecular bone will be
the most affected since it has the greater number of remodeling surfaces
per unit bone volume and remodeling occurs on remodeling surfaces. This
will lead to trabecular thinning and perforation and, ultimately, loss of
trabeculae. Remodeling, then, becomes predominant on endosteal and
intracortical surfaces producing cortical thinning and intracortical porosity,
thus reducing bone resistance and strength.
One of the major mechanisms of the reduced bone formation in the aging
bone is the inhibition of the canonical Wnt signaling pathway. As
previously described, Wnt signaling increases bone mass through
different ways. Multipotent mesenchymal stem cells in the bone marrow
have the ability to give rise to different cell lineages, such as osteoblast
and adipocyte lineages, which are believed to be reciprocally related.
With aging, there is a progressive accumulation of adipocytes in the bone
marrow. It has been demonstrated that the activation of canonical Wnt
signaling enhances osteoblastogenesis and decreases adipogenesis. In
transgenic mice overexpressing Wnt10b in the bone marrow or in mice
lacking Wnt inhibitors such as Dkk1 or sclerostin in osteoblasts, bone
mass is increased [18].

Emerging concepts in the pathogenesis of osteoporosis

Sex hormones, and estrogens in particular, have been always attributed a
central role in the development of osteoporosis [19]. However, there are
several evidences that other mechanisms can play a key role in the
development of fragile bones.
An increase in oxidative stress with aging, starting from the third decade
of life, is a key pathogenetic mechanism leading to a decrease in osteoblast
lifespan and bone formation and an increase in osteoblast and osteocyte
apoptosis, independently of the decrease in sex hormones [20]. Age-
related oxidative stress drives mesenchymal stem cells into the adipogenic
lineage at the expenses of the osteoblast lineage mainly by shifting
b-catenin, the principal effector of the Wnt-signaling pathway, to the
antioxidant FoxO-mediated pathway. Indeed, mice lacking FoxOs, which
are transcription factors defending against oxidative stress, display a

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 Pathogenesis of osteoporosis

prominent bone loss similar to that Several drugs commonly used as adjuvant
observed with aging but at younger age. therapy in cancer or other chronic diseases can
induce or worsen skeletal fragility.
Conversely, mice overexpressing FoxO3
display an increased bone mass. In this The increase in oxidative stress occurring during aging
is detrimental to skeletal homeostasis.
setting, estrogen deficiency accelerates
bone loss, at least in part, compromising
the defense to oxidative stress.
Recent studies have attributed roles of regulation of bone mass to
serotonin [21]. The hormone serotonin, which is peripherally synthesized,
inhibits bone formation, while the neurotrasmitter serotonin, which is
centrally synthesized, promotes bone formation and inhibits bone
resorption by decreasing sympathetic tone and other indirect
mechanisms, which are not entirely defined. Central serotonin itself is
inhibited by leptin, a master regulator of energy metabolism, integrating
the model of a central neuroregulation of skeletal homeostasis.
Pituitary glycoprotein hormones, such as follicle-stimulating hormone
and thyroid-stimulating hormone, may play a role in the regulation of
remodeling by acting on the specific receptors expressed on bone
cells [22]. In particular, thyroid-stimulating hormone would inhibit bone
turnover, while follicle-stimulating hormone would enhance bone
resorption by indirect action on osteoclasts through osteoblasts.
The role and weight of these latter proposed different mechanisms of
control of skeletal homeostasis, mainly assessed in rodents, and their
precise role in the development of menopausal- and age-related
osteoporosis have still to be fully proven and characterized in humans.

Systemic factors causing secondary osteoporosis

Secondary osteoporosis can be the result of various conditions, including
endocrinopathies, systemic diseases, malabsorption syndromes and
treatment regimens with drugs such as corticosteroids, aromatase
inhibitors, chemoterapeutic agents or immunosuppressants (Box 1.1) [23].
High levels of glucocorticoids compromise peak bone mass acquisition
and maintenance of skeletal homeostasis [24]. Long-term exogenous
administration of glucocorticoids or endogenous excess of cortisol
(Cushing syndrome) cause profound abnormalities in bone turnover,
inhibiting bone formation and stimulating bone resorption. Osteoblast
and osteocyte apoptosis, along with the stimulation of osteoclastogenesis,
is responsible for the acute rapid bone loss
observed during the first months of Sex hormones play a key role in bone accrual
systemic corticoisteroid therapy, which is and maintenance and their deficiency is
associated with various degrees of bone loss.

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Cianferotti & Brandi

Box 1.1. Main causes in the pathogenesis generally followed by a more gradual
of secondary osteoporosis. decrease in bone mass and deterioration
Endocrine diseases in bone microarchitecture because of
ƒƒ Primary or secondary hypogonadism osteoblast and osteocyte apoptosis.
Moreover, glucocorticoid excess promotes
ƒƒ Primary hyperparathyroidism
urinary loss of calcium and inhibits calcium
ƒƒ Hyperthyroidism
absorption, thus leading to a negative
ƒƒ Glucocorticoid excess calcium balance that causes a secondary
ƒƒ Diabetes mellitus (Type 1) increase in PTH levels, which elicits bone
Chronic diseases resorption.
ƒƒ Sarcoidosis
Hypogonadism is also an important cause
ƒƒ Amyloidosis of osteoporosis in men. In congenital
ƒƒ Rheumatoid arthritis hypogonadism, such as Klinefelter
ƒƒ Lupus syndrome (primary hypogonadism) or
Gastrointestinal diseases Kallman syndrome (hypogonadotropic
ƒƒ Malabsorption hypogonadism), there is an uncoupling in
ƒƒ Inflammatory bowel disease bone turnover mainly due to a defective
ƒƒ Celiac disease
bone formation, with a major effect on
cortical bone. Conversely, in age-related
ƒƒ Gastric bypass
testosterone deficiency or late-onset
Hematologic diseases hypogonadism, resorption that prevails
ƒƒ Multiple myeloma over formation and trabecular bone is
ƒƒ Lymphoma/leukemia mostly affected. Estrogens are also
ƒƒ Systemic mastocytosis critically important in men, since defects
Inherited disorders in androgen aromatization are associated
ƒƒ Osteogenesis imperfecta with decreased BMD and increased risk for
ƒƒ Hypophosphatasia skeletal fractures.
ƒƒ Idiopathic hypercalciuria In primary hyperparathyroidism, the chronic
ƒƒ Cystic fibrosis excess of PTH increases bone turnover and
ƒƒ Hemocromatosis the activation frequency of new remodeling
ƒƒ Homocystinuria
units, with a parallel increase in bone
resorption and bone formation (coupling).
Drugs
However, since resorption is faster than
ƒƒ Glucocorticoids
formation, the remodeling space is
ƒƒ Immunosuppressants increased. Cortical bone is mainly
ƒƒ Aromatase inhibitors compromised, while cancellous bone is
ƒƒ Gonadotropin releasing hormone analogs relatively spared, particularly in cases of mild
ƒƒ Anticonvulsants disease. In hyperthyroidism, the excess of
ƒƒ Supraphysiologic thyroxine doses thyroid hormones stimulates bone
ƒƒ Barbiturates resorption over formation (uncoupling),
ƒƒ Selective serotonin reuptake inhibitors leading to cortical and trabecular bone loss.

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 Pathogenesis of osteoporosis

In both these endocrinopathies, the bone Box 1.1. Main causes in the pathogenesis
loss is, at least in part, reversible after of secondary osteoporosis (cont.).
successful treatment, since with the Others
normalization of bone turnover the increased ƒƒ Alcoholism
remodeling space is rapidly refilled. ƒƒ Tobacco
Bone loss induced by cancer treatment is ƒƒ Eating/nutritional disorders
usually more rapid and severe than ƒƒ Organ transplant
menopausal- or age-related bone loss [25]. ƒƒ Immobilization
Aromatase inhibitors, a common endocrine ƒƒ Chronic kidney disease
adjuvant therapy in the management of
ƒƒ Liver disease
estrogen receptor-positive breast cancer,
inhibit the peripheral conversion of
androgens to estrogens. Treatment with these drugs or the induction of
ovarian failure with gonadotropin releasing hormone agonists in patients
with breast cancer results in bone loss due to estrogen deficiency, with
the same mechanisms described above, but at a faster pace. Similarly,
androgen deprivation therapy in prostate cancer induces bone loss at
an accelerated pace than that occurring during aging, reducing BMD by
7–8% per year and increasing the risk for skeletal fractures by 13 and
33% at 5 and 10 years, respectively.

Conclusion
The pathogenesis of osteoporosis is complex and various mechanisms
contribute to altering bone turnover. During the first phase of sex-hormone
withdrawal, the enhancement in bone resorption is surely the key
mechanism of bone loss. The rapidity and the final degree of bone loss will
be influenced by genetic and epigenetic background, nutrition and other
systemic factors that can contribute to modify bone turnover. The classic
view of defective bone formation has nowadays been revisited and it is
now considered the main mechanism responsible for sustained bone
impairment during age. Further studies are necessary to establish in
humans the role of the different pathways proposed for the regulation of
skeletal homeostasis, as demonstrated in animal models.

Financial & competing interests disclosure

ML Brandi has received honoraria or grants from Servier, MSD, Amgen, Novartis,
Eli Lilly, Roche, NPS and Stroder. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

www.futuremedicine.com 19
Cianferotti & Brandi

Summary.

ƒƒ Osteoporosis is a disease characterized by reduced bone strength leading to increased risk for
fragility fractures.
ƒƒ Alterations in hormonal and nutritional factors, which are critical for mineral homeostasis,
prevent the achievment of an optimal peak bone mass and strength predisposing to
osteoporosis later in life.
ƒƒ An imbalance in bone turnover with a prevailing bone resorption over formation leads to bone
loss and deterioration in microarchitecture, thus reducing bone strength.
ƒƒ Sex hormones influence bone metabolism throughout life and estrogen or testosterone
deprivation results in a rapid bone loss.
ƒƒ Dietary calcium and vitamin D deficiency induce a state of secondary hyperparathyroidism,
which is detrimental to bone accrual and maintenance.
ƒƒ Besides the estrogen-centric theory of bone loss, oxidative stress is an important, newly
identified pathogenetic mechanism in the development of age-related osteoporosis.
ƒƒ Exogenous or endogenous excess of glucocorticoids cause profound effects in bone cells and
turnover, with a rapid deterioration of skeletal tissue.

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