PRIMER

Postmenopausal osteoporosis
Richard Eastell1, Terence W. O’Neill2, Lorenz C. Hofbauer3, Bente Langdahl4, Ian R. Reid5,
Deborah T. Gold6 and Steven R. Cummings7
Abstract | Osteoporosis is a metabolic bone disorder that is characterized by low bone mass and
micro-architectural deterioration of bone tissue. Fractures of the proximal femur, the vertebrae
and the distal radius are the most frequent osteoporotic fractures, although most fractures in the
elderly are probably at least partly related to bone fragility. The incidence of fractures varies greatly
by country, but on average up to 50% of women >50 years of age are at risk of fractures. Fractures
severely affect the quality of life of an individual and are becoming a major public health problem
owing to the ageing population. Postmenopausal osteoporosis, resulting from oestrogen deficiency,
is the most common type of osteoporosis. Oestrogen deficiency results in an increase in bone turnover
owing to effects on all types of bone cells. The imbalance in bone formation and resorption has effects
on trabecular bone (loss of connectivity) and cortical bone (cortical thinning and porosity).
Osteoporosis is diagnosed using bone density measurements of the lumbar spine and proximal femur.
Preventive strategies to improve bone health include diet, exercise and abstaining from smoking.
Fractures may be prevented by reducing falls in high-risk populations. Several drugs are licensed to
reduce fracture risk by slowing down bone resorption (such as bisphosphonates and denosumab) or
by stimulating bone formation (such as teriparatide). Improved understanding of the cellular basis
for osteoporosis has resulted in new drugs targeted to key pathways, which are under development.

Osteoporosis has been defined as a systemic ­skeletal
disease that is characterized by low bone mass and
micro-architectural deterioration of bone tissue, with
a consequent increase in bone fragility and susceptibil­
ity to fracture1. The most frequent osteoporotic frac-
tures are fractures of the hip, wrist and spine (FIG. 1),
although most fractures in the elderly are probably at
least partly related to osteoporosis. Osteoporosis is more
common in women and, in this Primer, we focus on
postmenopausal osteoporosis.
Bone mineral density (BMD) is a key tool in identify­
ing osteoporosis and its introduction into clinical prac-
tice 30 years ago was a major step forward. A working
group of the WHO has defined osteoporosis oper­
ationally as a BMD that is 2.5 standard deviations below
the peak bone mass for adult women, or lower 2. The
­number of standard deviations from average is defined
by the T-score, and a T-score of ≤–2.5 is thus defined
Correspondence to R.E. as osteoporosis. The limitation of this approach is that
Metabolic Bone Centre, it increases a risk factor to the status of a diagnostic
Northern General Hospital, ­criterion and so ignores the other determinants of bone
Herries Road, Sheffield,
strength and fracture propensity. In the same way that
S5 7AU, UK.
r.eastell@sheffield.ac.uk we estimate the risk of cardiovascular disease from key
risk factors, there has been a move to use BMD along
Article number: 16069
doi:10.1038/nrdp.2016.69 with key risk factors for fracture (particularly age,
Published online 29 Sep 2016 weight and prior fracture) to predict fracture in the next
10 years; the most widely used tool is the WHO Fracture
Risk Assessment Tool (FRAX) score3.
These approaches of characterizing osteoporosis
prove helpful in explaining individual risk and can help
with deciding whom to treat. When we make a diagno-
sis of osteoporosis in our clinical practice, we take into
account the level of BMD, the presence of a fracture
strongly linked to osteoporosis (such as proximal femur
or spine) or a high 10‑year fracture risk4. Osteoporosis
is a treatable condition and yet many people with this
condition remain undiagnosed and untreated5. This
Primer examines the epidemiology and pathophysiology
of postmenopausal osteoporosis and considers its diag-
nosis, prevention and treatment and its effect on quality
of life, as well as looks to the future.
Epidemiology
Incidence and prevalence
Osteoporosis is a considerable clinical and public health
burden because of its association with age-related
fractures. In the United States, 10 million individuals
>50 years of age are estimated to have osteoporosis
of the hip (based on a T-score of ≤–2.5), with about
1.5 million osteoporotic fractures each year. In Europe,
27.6 million people are estimated to have age-related
osteoporosis and >3.5 million fragility fractures are

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PRIMER

Author addresses data from non-western populations, although there is

1
Academic Unit of Bone Metabolism, and Mellanby Centre
for Bone Research, University of Sheffield, Sheffield, UK.
2
Arthritis Research UK Centre for Epidemiology, Centre for
Musculoskeletal Research, Manchester Academic Health
Science Centre (MAHSC), The University of Manchester,
Manchester, UK.
3
Division of Endocrinology, Diabetes, and Bone Diseases
and Centre for Healthy Aging, Technische Universität
Dresden Medical Center, Dresden, Germany.
4
Department of Endocrinology and Internal Medicine,
Aarhus University Hospital, Aarhus, Denmark.
5
Department of Medicine, University of Auckland,
Auckland, New Zealand.
6
Departments of Psychiatry & Behavioral Sciences,
Sociology, and Psychology & Neuroscience, Duke
University Medical Center, Durham, North Carolina, USA.
7
San Francisco Coordinating Center, California Pacific
Medical Center Research Institute and the University of
California, San Francisco, San Francisco, California, USA.
observed each year 6,7. The economic cost of these frac-
tures is high with an annual cost of US$17 billion in the
United States in 2005 and €37 billion in Europe based on
data from 2010 (REFS 7,8).
From an individual perspective, the lifetime risk for
sustaining an osteoporotic fracture from 50 years of
age is estimated to be one in two for women and one in
five for men based on data from the United Kingdom
General Practice Research Database9. The incidence
of osteoporotic fractures increases with age and is
approximately twice as high in women as in men at all
ages (FIG. 2). The preferential location of fractures also
varies with age. In women, the incidence of wrist and
spine fractures begins to rise considerably from around
50 years of age, whereas hip fractures occur later in life.
In general, the pattern of fracture incidence with age
is similar in men, although, in contrast to women, the
incidence of wrist fracture in men remains low until
later life9.
Globally, the frequency of the major osteoporotic
fractures (including fractures of the spine, hip, wrist
and shoulder) varies substantially, being highest in
Scandinavia and lowest in Africa10,11. The variation is
most marked for hip fracture, with rates in women vary­
ing by >200‑fold. This may partly reflect ethnic influ-
ences on fracture: higher fracture risk is seen in white
women than in black women. However, there is variation
also within geographical regions. For example, hip frac-
ture rates vary in Europe by a factor of approximately
11‑fold: the highest rates are in northern Europe and the
lowest rates are in the Mediterranean area12.
Since the early-to-mid-twentieth century, the
age-specific incidence of hip fractures has increased
in many western countries. In most countries, rates
stabil­ized towards the end of the twentieth century
and in some areas, particularly northern Europe and
North America, the incidence has begun to decline13–15.
This decline in hip fractures has been associated with
higher BMD in the elderly, which might be attributed
to an increased prevalence of obesity. There are fewer
evidence that hip fracture rates may be continuing to
rise in some Asian countries. For example, the age-­
specific rate of hip fractures rose threefold to fourfold in
Beijing, China, from 1990–1992 to 2002–2006 (REF. 16).
The risk might be due to westernization of lifestyle that
includes using cars instead of bikes and chairs instead of
­squatting. The number of fractures globally is expected
to rise considerably over the next 30 years because of
ageing; the number of people in the world ≥65 years
of age is expected to double between 2010 and 2040
(REF. 17). The increase in the number of old people will
be most marked in Asia where it is estimated that half of
all hip fractures will occur by 2050 (REF. 18).
Genetics factors
Genetic factors have an important role in the develop­
ment of osteoporosis. Twin and family studies have
shown that the heritability of bone mass is 50–70%19,20.
The heritability estimates for fracture strongly depend
on age. The heritability of, for example, hip fractures
in individ­uals <69 years of age was 70%, whereas it
was almost negligible in individuals >79 years of age21.
Variants in the genes encoding factors known to regu-
late bone mass (such as oestrogen receptor-α (ERα)22,
vitamin D receptor 23, transforming growth factor-β
(TGFβ)24, low-density lipoprotein receptor-related pro-
tein 5 (LRP5) and LRP6 (both involved in WNT sig-
nalling))25 and bone matrix components (for example,
collagen type I α1 (REF. 26)) were found to be associated
with bone mass and fracture risk, but these variants could
be used to explain only very little of the inter-­individual
variation. A study in 2015 suggested that at least 500
different genetic variants influence bone mass and/or
fracture risk27. After the discovery of the importance of
the WNT pathway in bone bio­logy, genetic vari­ants in
some of the genes related to this pathway have also been
shown to affect bone mass and fracture risk. In addition
to LRP5 and LRP6, variants in WNT1 (REF. 28), WNT16
(REF. 29) and SOST (encoding ­s clerostin)30 have been
found to affect bone mass. Large international collabor­
ative efforts are ongoing to unravel more of the under-
lying genetic variance. Genome-wide association studies
including >200,000 individuals have identified 56 loci
associated with BMD and 14 of these were also associ­
ated with fracture risk31. However, before these vari-
ants can be included in risk assessment of i­ ndividuals,
a ­functional effect will have to be established.
Mechanisms/pathophysiology
Bone remodelling — the constant and coordinated
turnover of mineralized bone matrix in response to
mechanical and endocrine stimuli — is accomplished
by two specialized cells: bone-resorbing osteoclasts
and bone-forming osteoblasts (FIG. 3). Osteocytes sense
mechanical strain and regulate bone remodelling. About
95% of the body’s calcium is incorporated into the bone
matrix by the action of osteoblasts, which produce
type I collagen as the main bone matrix protein. The
absorption and distribution of calcium to the skeleton
is under endocrine control of, for example, vitamin D,

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 PRIMER

In addition, bone geometry of long bones differs sub-

a b c
stantially between women and men. This partly explains
why women are more prone to developing osteoporotic
bone fractures39 (FIG. 4). In the process of bone model-
ling during puberty, boys experience a greater periosteal
apposition rate at the outer cortical surface under the
influence of testosterone, leading to wider bones and
a higher cortical thickness. During puberty, girls have
enhanced periosteal apposition, but mainly endocortical
thickening of their cortical bone. Starting from young
d e f g adulthood and extending just before perimenopause,
cortical remodelling in women involves endocortical
resorption, which is almost compensated for by peri-
osteal apposition40. When oestrogen levels decline after
menopause in women, endocortical resorption is further
enhanced, whereas periosteal apposition is decreased,
translating into a thinner cortex. Oestrogen replacement
Figure 1 | Osteoporotic bone. a–c | Radiographs showing fractures
Nature (arrows)
Reviews of thePrimers
| Disease
therapy can prevent, but not reverse, cortical bone loss40.
proximal femur (part a), distal radius (part b) and vertebra (part c). d–g | High resolution Apart from thinning of the cortex, an additional struc-
quantitative CT allows study of the trabecular (the sponge-like interior compartment tural basis for impaired bone quality has been identified:
of bone) and cortical (the compact, outer layer of bone) components of the radius (part d increased cortical porosity 41. Swiss cheese-like pores
and part f) and the tibia (part e and part g). Compared with controls (part d and part e), (FIG. 4) have been observed in the cortex of women with
osteoporosis (part f and part g) is characterized by thinning of the cortex and reduced postmenopausal osteoporosis41, aged men and patients
trabecular bone mass with a loss of trabecular connectivity.
with type 2 diabetes mellitus42, and have been linked to
increased fragility.
parathyroid hormone (PTH) and sex steroids, including
oestrogens. The levels of PTH increase with age, which Oestrogens and osteoporosis
might partly be because of vitamin D insufficiency, and Reduced ovarian production of oestrogens after meno­
contribute to the increase in bone turnover with ageing. pause is the cause for an initial phase of rapid bone loss
in women, with an annual bone loss rate of 3–5% for
Bone structure and remodelling in osteoporosis 5–10 years, which mainly affects trabecular bone. This
A consistent feature of postmenopausal women is phenomenon, sex-specific differences in bone geo­
the concurrent increase of bone resorption and bone metry (FIG. 4) and the lack of a bona fide male equiva-
formation at the tissue level, termed high bone turn­ lent of meno­pause contribute to a higher incidence of
over. However, at the cellular level — the multicellular osteoporotic fractures in postmenopausal women than
bone-remodelling unit — there is a negative imbalance in age-matched men34,43. The onset and the severity of
in bone remodelling, with bone resorption outpacing postmenopausal osteoporosis are modulated by genetic
bone formation. Bone resorption on the basis of bio- factors, the degree of weight-bearing physical activity,
chemical markers of bone turnover is increased by 90% nutrition, smoking, body mass index (BMI), concurrent
after menopause, but bone formation is only increased diseases and medications, and ageing.
by 45%, thus resulting in net bone loss with each The effect of fat mass and oestrogen on BMD is
remodel­ling cycle32. Mechanisms that contribute to this explained by the fact that residual oestrogens are prod­
negative remodelling imbalance in osteoporosis include uced by conversion of adrenal androgens (for example,
the increased number of multicellular bone-remodelling androstenedione and dehydroepiandrosterone sulfate) by
units, when bone is remodelled with a prolongation of the enzyme aromatase (also known as CYP19A1), which
the resorption period and a concurrent shortening of the is highly expressed in white adipose tissue44. Thus, obese
formation period33–36, thus favouring sustained loss. women tend to have higher circulating levels of oestro-
Bone loss in postmenopausal women occurs in two gen throughout their lifetime but especially after meno-
phases: an initial shorter phase lasting 3–5 years with pause than age-matched individuals with a normal BMI,
rapid loss of mainly trabecular bone (menopause-­ which confer partial protection against osteoporosis45.
related bone loss) and a second longer phase of slower In circumstances in which this peripheral androgen-to‑­
loss lasting 10–20 years that occurs in women and men oestrogen conversion is blocked, for example, by the use
(age-related bone loss) and involves both cortical (the of aromatase inhibitors as in hormone receptor-positive
outer shell) and trabecular compartments37,38 (FIG. 4). breast cancer, bone loss is further enhanced45. The pro-
This explains why fracture incidence in men increases tective effect of oestrogens on the female skeleton also
about a decade later than in women and why fragility becomes apparent in transient periods of oestrogen
fractures of the spine occur earlier than fractures at deficiency, such as post-partum and during lactation46.
other skeletal sites (FIG. 2). Vertebral bodies are mainly In these circumstances, increased bone resorption is
(approximately 80%) composed of trabecular bone, thought to mobilize calcium from the maternal skele-
whereas long bones and hip consist mainly of cortical ton to ensure calcium transfer to the offspring via breast
bone (80% and 40%, respectively). milk, underscoring the evolutionary importance of

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 PRIMER

350
Women
350
Men increasing the secretion of IL‑1, IL‑6 and tumour necro-
sis factor (TNF) (FIG. 5). The net result is enhanced bone
300 300 turnover with increased bone resorption and subse-
Incidence per 10,000 per year

Incidence per 10,000 per year

quently increased bone formation, with a net effect of
250 250
resorption exceeding formation. The increase in bone
200 200
turnover is augmented by a pro-inflammatory cytokine
milieu and immune cell activation induced by oestrogen
150 150 deficiency 49. In principle, these alterations are reversed by
oestrogen replacement. Oestrogens and oestrogen defi-
100 100 ciency affect all three bone cell types and immune cells
50 50
in a distinct manner, which is highlighted in the sections
below (FIG. 5).
0 0
Osteoblasts and bone formation. Osteoblast function
55 4
60 9
65 4
70 9
75 4
80 9
85 4
90 9
4

55 4
60 9
65 4
70 9
75 4
80 9
85 4
90 9
4
–5
–5
–6
–6
–7
–7
–8
–8
–9

–5
–5
–6
–6
–7
–7
–8
–8
–9
50

50 and bone formation require the activation of bone

Age groups (years) Age groups (years)
morpho­genetic protein (BMP), TGFβ and particularly
Vertebral fracture Forearm fracture Femur and hip fractures the canonical WNT signalling pathway. WNT signal-
ling is under negative control by WNT inhibitors such
Figure 2 | Fracture incidence with increasing age. Incidence of radiographic vertebral,
Nature Reviews | Disease Primers as sclerostin, Dickkopf 1 and secreted Frizzled-related
forearm, and femur and hip fractures in women and men are shown. Data from
REFS 197,198.
protein 1, all of which are secreted by osteoblasts and
osteocytes52,53 (FIG. 3).
Oestrogens are crucial regulators of osteoblast differ-
a dynamic bone metabolism. Of note, oestrogen is also entiation and activity. Oestrogens enhance osteogenic
crucial for bone health in men, as men with inactive ERα differentiation of cultured mesenchymal stem cells
have severe osteoporosis47, and bone loss in men is more (MSCs), promote differentiation from pre-osteoblasts to
closely corre­lated to serum o ­ estradiol levels rather than osteoblasts and prolong osteoblast and osteocyte lifespan
to serum testosterone levels48. by suppressing apoptosis54. Moreover, oestrogens stim-
ulate the production of IGF1 and TGFβ by osteoblasts
Altered oestrogen signalling. ERs with a high affinity as well as procollagen synthesis55 (FIG. 5). These marked
for oestrogens have been detected in osteoblasts, osteo­ in vitro effects have been confirmed in humans follow-
clasts and osteocytes; these receptors include ERα and ing dermal oestrogen application to postmenopausal
ERβ isoforms, which bind to different ligands, mediate women for 6 years, which leads to increased trabecular
different effects and have different spatial distributions37. thickness of 12% and increased trabecular bone volume
ERα mediates most effects of natural oestrogen ligands of 61%, as a result of enhanced bone formation56. The
and is mainly expressed in bone cells that reside in cor- bone-forming effects of oestrogens in humans depend
tical bone, whereas ERβ mediates the effects of phyto-­ on the p ­ reparation, dose and mode of administration.
oestrogens (for example, found in soy products) on bone
and is predominantly expressed in bone cells present in Osteoclasts and bone resorption. Oestrogens function
trabecular bone38,49. ERs are nuclear receptors and ligand as anti-resorptive hormones that limit bone resorption
binding induces conformational changes that result in ER and bone loss (FIG. 5). Oestrogens regulate the receptor
dimerization and subsequent interactions with coactiv­ activator of NF‑κB (RANK; also known as TNFRSF11A)
ator or co-repressor proteins to either stimulate or inhibit ligand (RANKL; also known as TNFRSF11), RANK and
the expression of oestrogen target genes encoding pro- osteoprotegerin (OPG; also known as TNFRSF11B)
teins such as IL‑1, insulin-like growth factor 1 (IGF1) and pathway (FIG. 3) at several levels. Oestrogens upregulate
TGFβ. These effects are referred to as classical or genomic the expression of RANKL in the osteoblastic cell lineage
ER effects of ER activation. However, ERs can also bind to and induce the expression of OPG, a naturally occur-
transcription factors such as nuclear factor-κβ (NF‑κβ), ring antagonist of RANKL, in vitro57. Moreover, oestro-
which prevents their action, for example, the inhibition gens interfere with osteoclast signalling downstream of
of IL6 expression49. Moreover, membrane receptor-­ RANK, thereby preventing osteoclast differentiation and
mediated effects have been reported for certain types of promoting osteoclast apoptosis via increased produc-
oestrogens in which these compounds induce rapid non- tion of TGFβ by osteoblasts. Under conditions of acute
genomic effects, for example, phosphorylation of extra- oestro­gen deficiency, osteoclast differentiation and activ-
cellular signal-regulated kinase (ERK) kinases and other ity are increased by a higher expression of RANKL49,58
enzymes50. The relative contribution of genomic versus and other pro-osteoclastic cytokines, including TNF,
non-genomic effects on the skeleton in health and disease IL‑1 and IL‑6, by MSCs and lymphocytes. These effects
is unclear and requires further investigation51. are partially suppressed by oestrogen administration in
Lack of oestrogen affects all bone cells either directly ­postmenopausal women58.
by regulating cellular differentiation, activity and apop-
tosis or indirectly via altered expression of oestrogen-­ Osteocytes and mechanosensing. Osteocytes control
responsive target genes; proteins encoded by these genes bone remodelling and mineralization and function as
might function in an autocrine or paracrine manner by endocrine cells. Among the key molecules produced by

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 PRIMER

osteocytes are RANKL59, inhibitors of the WNT signalling
pathway (including sclerostin and Dickkopf 1) and fibro-
blast growth factor 23 (FGF23), a regulator of phosphate
homeostasis (FIG. 3). Oestrogen deficiency is associated
with impaired mechanosensing by osteocytes; oestro-
gens were shown to inhibit the production of sclerostin
by osteoblastic lineage cells, thus providing a rationale
for the bone-forming ability of oestrogens60,61 (FIG. 5).
In mice that systemically lack ERα, mechanical load-
ing did not evoke an adequate bone-anabolic response,
indicating that functioning ER signalling is required for
mechanosensing and mechano­transduction62. Of note,
structural abnormalities in the osteocytic network have
MSC HSC
RANK
Pre-osteoblast Pre-osteoclast
been observed in women with osteoporosis, which
suggests that there is decreased c­ onnectivity between
­adjacent osteocytes52.
Immune response and microenvironment. Several
inflammatory pathways are negatively controlled by
oestrogens and contribute to a pro-inflammatory milieu
in the acute phase of oestrogen deficiency 49. Extensive
characterization of the RANKL–RANK pathway 57 and
identification of the role of activated T cells and their
prominent cytokine TNF on osteoclast biology 49 have
led to the emerging concept of osteoimmunology — the
mutual interactions between the immune system and
bone metabolism. Rodents without appropriate T cell
activation, or defective RANKL or TNF production or
action fail to enhance osteoclastic bone resorption and
are protected against bone loss after ovariectomy 38,49,57.
Most of these findings are based on ovariectomy models
of inbred mouse strains and thus need to be cautiously
interpreted. In humans, RANKL levels are upregulated in
MSCs and T cells as well as in B cells immediately after
menopause and these levels return to ­premenopausal
­levels with oestrogen replacement therapy 49,58.

Alternative mechanisms. The oestrogen-centric para­

RANKL
M-CSF
Osteoclast
Osteoblast
OPG
Cathepsin K
Cl–
H+
Cl–
H+
Sclerostin
Bone formation Bone resorption
Osteocyte
Bone
Figure 3 | Bone remodelling. In the adult skeleton, bone is constantly
Nature Reviewsremodelled at
| Disease Primers
multiple sites by the coordinated and sequential actions of bone-resorbing osteoclasts
and bone-forming osteoblasts to repair microdamage and to adapt bone structure to
the mechanical and metabolic needs. Osteocytes represent >95% of all bone cells, are
embedded in the mineral, function as mechanosensors and fine-tune bone remodelling
by osteoblasts and osteoclasts. Osteoblasts are derived from mesenchymal stem cells
(MSCs) and are specialized to produce an extracellular bone matrix, including type I
collagen, and non-collagenous proteins, including osteocalcin, osteonectin and
osteopontin. The bone matrix is subsequently mineralized and stiffened by deposition
of calcium hydroxyapatite. WNT signalling, and its inhibitors, has an important role in
osteoblast differentiation. Osteoclasts are derived from haematopoietic stem cells
(HSCs) of the macrophagic and monocytic lineage. Differentiation from precursor cells
towards activated multinucleated cells is crucially dependent on receptor activator of
nuclear factor‑κB (RANK) ligand (RANKL) that acts on osteoclastic RANK, and
permissive levels of macrophage colony-stimulating factor (M‑CSF). Osteoprotegerin
(OPG; also known as TNFRSF11B) functions as a decoy to block this interaction. RANKL
is mainly produced by osteoblastic lineage cells (MSCs, osteoblasts and osteocytes) and
lymphocytes57. Mature bone-resorbing osteoclasts are large multinucleated cells. Using
a sealing zone to attach at the bone surface and augmenting their surface with a ruffled
border, mature osteoclasts secrete HCl to create an acidic microenvironment where
enzymes such as cathepsin K, which degrades type I collagen, are most active.
digm of bone loss in postmenopausal osteoporosis
has recently been challenged and ageing and oxidative
stress have been proposed as alternative mechanisms
based on experiments in animal models35. These con-
cepts are not mutually exclusive. In fact, some of the
non-genomic effects of the ER on osteoblast apoptosis
have been linked to the attenuation of reactive oxygen
species (ROS) production in mice63. In line with this,
inhib­ition of NADPH oxidase 4 (NOX4), an enzyme
that generates ROS, protected mice from ovariectomy-­
induced trabecu­lar bone loss64. In summary, oestro­gen
deficiency contributes to a pro-inflammatory milieu,
with enhanced activities of osteoclastogenic cytokines,
­activated T cells and higher levels of ROS.
Diagnosis, screening and prevention
Diagnosis
Postmenopausal women or men >50 years of age who
are at risk of having osteoporosis should be assessed.
The risk is evaluated in the individual based on the
presence of clinical risk factors, which include previ-
ous fragility fracture, genetic predisposition, smoking,
>14 units of alcohol per week, early-onset menopause
(<45 years of age), low BMI (<19 kg per m2) or other fac-
tors involved in secondary osteoporosis (BOX 1). General
screening of populations for osteoporosis is not recom-
mended because the risk of fractures in postmeno­pausal
women without clinical risk factors with a T-score of
≤–2.5 is lower than in women with the same T-score
who have risk factors65–67.
Osteoporosis is defined by BMD at the lumbar spine,
total hip or femoral neck of 2.5 standard deviations or
more below the population mean for young healthy
adults (peak bone mass); the difference in standard
deviations is defined as the T-score68. BMD is measured
by dual-energy X‑ray absorptiometry (DXA). DXA is

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an X‑ray-based technique that quantifies bone mineral
content (BMC) by using two X‑ray sources of different
energies allowing subtraction of the attenuation of radi-
ation by soft tissues from the total attenuation to deter-
mine the attenuation caused by bone mineral. By adding
information about the area of the bone investig­ated, areal
BMD can be calculated as BMC divided by bone area.
The technique is very precise, fairly fast and exposes the
patient to very low doses of radiation. These character­
istics in combination with the fact that BMD is the single
best predictor of fracture risk69,70 are the main reasons
for choosing BMD as the diagnostic criterion for osteo­
porosis. There have been discussions whether the diag-
nostic criteria should be expanded to reflect treatment
indications and reimbursements4, but as these vary
worldwide, the above-mentioned definition is still valid.
A prerequisite for the definition of osteoporosis on the
basis of BMD is that other modifiable causes of low BMD
are excluded. Secondary osteoporosis (BOX 1) should be
investigated and any underlying disorder treated. Renal
osteodystrophy can be difficult to exclude in patients
with chronic kidney disease (stage 4 and stage 5), as bio­
chemical markers of bone turnover are more difficult to
interpret in these patients. A bone biopsy might therefore
be needed to diagnose the patient correctly. As part of the
diagnostic work‑up, it is important to take the full patient
Men Phase 2
Periosteal surface
Endocortical surface
Age
18 50 60 75 (years)
Menopause
(only in women)
Women Phase 1 Phase 2
Figure 4 | Sex-specific differences in bone modelling (and remodelling).
Nature Reviews | Disease Primers
a | Bone modelling (and remodelling) in men. During puberty, androgens promote a
marked periosteal apposition, leading to an outwards displacement with wider bone and
thicker cortices. Despite some endocortical resorption during adulthood, bone strength
is mostly maintained during ageing, until cortical thinning and cortical porosity develop.
b | Bone modelling (and remodelling) in women. During puberty, women have more
endocortical rather than periosteal bone apposition, yielding more gracile bones, than
men do. In the first phase of bone loss after menopause, oestrogen deficiency markedly
stimulates endocortical resorption and mitigates periosteal apposition, thus causing
rapid cortical thinning. The effects on trabecular bone loss during this phase are even
greater. In a second phase, endocortical resorption continues at a slower rate and
cortical porosity develops, rendering the bone more prone to fragility fractures.
history into account, including clinical and laboratory
investigations. For example, in patients with back pain,
loss of height and a difference in BMD between adjacent
vertebrae of >1 standard deviation, the presence of a
verte­bral fracture should be assessed. Prevalent vertebral
fractures can be investigated either by a radiograph of the
spine or by assessment of vertebral fractures using DXA
with similar diagnostic accuracy.
The level of bone turnover can be determined by
measuring bone turnover markers. The recommended
markers are serum procollagen type I amino‑terminal
propeptide, which is a marker of bone formation, and
serum carboxy‑terminal collagen crosslinks, which
are markers of bone resorption71. The bone turnover
markers are not used for diagnosis but are helpful in the
monitor­ing of treatment response and the identifi­cation
of failure to respond72. The greater the reduction in bone
turnover markers with anti-resorptive treatment, the
greater the fracture risk reduction71. The characterization
of the disease will enable more relevant treatment deci-
sions. If bone turnover is high, a greater BMD response
can be expected to both anti-resorptive and anabolic
treatments than if bone turnover is low (in which case
observation without treatment might be appropriate).
Prevention
Prevention of osteoporosis comprises primary and
secondary prevention. Primary prevention is directed
towards the general population, whereas secondary
prevention focuses on individuals who are at increased
risk of developing osteoporosis because of the presence
of clinical risk factors. Treatment of patients with estab-
lished osteoporosis is sometimes referred to as tertiary
prevention (discussed below).
Prevention of osteoporosis can generally be achieved
through distinct mechanisms. One mechanism to pre-
vent osteoporosis is to augment bone gain during child-
hood and adolescence and the peak bone mass that the
individual is genetically determined to achieve. This
is important as modelling suggests that the onset of
osteo­porosis will be delayed by 13 years by increasing
peak bone mass by 10%73. The other mechanism to
prevent osteoporosis is by minimizing the menopause-­
related and age-related bone loss. In addition to meas-
ures that affect BMD, osteoporotic fractures can be
prevented by reducing the risk of falls. Nutritional
­interventions, maintenance of a BMI of >20 kg per m2,
regular physical activity, moderation of alcohol intake,
falls prevention and smoking cessation are all impor-
tant in the p
­ revention of osteoporosis and osteoporotic
fractures (BOX 2).
Nutrition and/or supplementation. Nutrition includes
an endless number of components of which many are
likely to be important for bone mass and quality. Calcium
and vitamin D supplementation have been researched
the most. The suggestion that calcium supplementation
may prevent osteoporosis is based on the underlying
physiology: calcium insufficiency leads to secondary
hyperparathyroidism, which again leads to increased
bone resorption. However, evidence for a preventive

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a With oestrogen b Oestrogen deficiency

MSC HSC ↑ Activated
Oestrogen T cells

Active
Pre-osteoblast T cell Pre-osteoclast

Oestrogen
Oestrogen
WNT WNT
Osteoblast Sclerostin RANKL ↑ Sclerostin ↑ RANKL
Apoptosis

Bone ↑ Bone formation

Osteoclast ↑↑ Bone resorption

Osteocyte ↓ Mechanosensing

Oestrogen Oestrogen Bone loss

Figure 5 | Role of oestrogens in bone remodelling. a | Physiological bone remodelling. Oestrogens enhance bone
formation by stimulating osteoblast differentiation and function and suppress osteoclast differentiation
Nature Reviewsand activityPrimers
| Disease
through direct cellular effects and reduced production of receptor activator of nuclear factor‑κB ligand (RANKL) by
activated T cells, mesenchymal stem cells (MSCs), osteoblasts and osteocytes. In addition, oestrogens are required for
adequate mechanosensing and mechanotransduction by the osteocytes. b | Oestrogen deficiency. RANKL production is
upregulated translating into a higher osteoclast number and activity. Concurrently, the function of individual osteoblasts
is suppressed, partly by upregulation of the WNT inhibitor sclerostin, whereas the total number of osteoblasts increases.
The role of osteocytes in mechanosensing is also impaired. HSC, haematopoietic stem cell.

effect of calcium supplementation on the development
of osteoporosis is weak. Calcium intake either as dairy
products or supplements has in some studies been
found to be positively associated with bone gain dur-
ing childhood and adolescence74,75; however, this has
not been confirmed in a meta-analysis of randomized
clinical trials in children76. A population-based study in
the United States showed an association between cal-
cium intake and bone mass in adults with vitamin D
insufficiency (serum 25‑hydroxy vitamin D (25‑OH
vitamin D) levels of <50 nmol per l), but not in those
with normal vitamin D levels (>50 nmol per l)77, but
a meta-analysis of randomized clinical trials in adults
found that calcium supplementation was associated with
increases in BMD78. Increased calcium intake or sup-
plementation cannot prevent menopause-related bone
loss but has, in some studies, been shown to reduce age-­
related bone loss79. Finally, meta-analyses of the effect
of calcium supplementation in adults have not shown
any effect on fracture prevention78,80. In addition, cal-
cium supplementation might be associated with adverse
effects. Calcium supplementation might increase the risk
of myocardial infarction81, but meta-analyses82,83 produce
inconsistent results depending on how the data from
the Women’s Health Initiative (WHI) study are treated.
In the WHI study, calcium and vitamin D supplemen­
tation were associated with a 17% increased risk of
nephro­lithiasis84; the same is not seen in ­individuals with
a high-calcium diet 85.
Vitamin D deficiency (serum 25‑OH vitamin D lev-
els of <30 nmol per l) leads to rickets in children and
osteomalacia in adults and should therefore be avoided.
In population-based studies, vitamin D insufficiency
(serum 25‑OH vitamin D levels of <50 nmol per l) has
been shown to lead to increases in PTH secretion and
it is therefore recommended to ensure sufficient intake
of vitamin D to reach a serum level of vitamin D that is
>50 nmol per l. However, it is probably not a vitamin D
level of <50 nmol per l that has a risk for osteoporosis
and fracture, but the secondary increase in the levels of
PTH. A meta-analysis showed an approximately 20%
reduction in non-vertebral and hip fractures in individ­
uals and patients who were supplemented with vit­
amin D alone or in combination with calcium86. A dose
dependency of the effects was observed; only studies
providing a daily dose of >20 μg (800 IU) showed preven-
tion of fractures and a serum level of 25‑OH vitamin D
of >75 nmol per l was needed to prevent hip fractures.
Another meta-analysis, which included postmenopausal
women as well as older men (mean or median popula-
tion of >65 years of age) concluded that supplementation
with vitamin D alone is unlikely to prevent fractures, but
supplementation with vitamin D in combination with
calcium is likely to do so87. The underlying mechanism
is probably a combination of effects of vitamin D on
bone metabolism and muscle function. Vitamin D defi-
ciency leads to reduced muscle strength as a result of a
­reduction in type IIa muscle fibres88.

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Box 1 | Drugs and diseases associated with increased fracture risk

• Drugs • Rheumatological diseases
-- Glucocorticoids -- Rheumatoid arthritis
-- Aromatase inhibitors -- Ankylosing spondylitis
-- Proton pump inhibitors • Haematological diseases
-- Glitazones (also known as thiazolidinediones) -- Multiple myeloma
-- Anti-epileptics -- Systemic mastocytosis
-- Loop-acting diuretics -- Leukaemia
-- Heparin and warfarin
• Neurological diseases
-- Antidepressants
-- Stroke
• Endocrine diseases -- Immobilization
-- Anorexia nervosa -- Parkinson disease
-- Hypogonadism
• Other diseases
-- Cushing syndrome
-- Congestive cardiac failure
-- Vitamin D deficiency
-- Chronic obstructive lung disease
-- Hyperparathyrodism
-- Chronic renal insufficiency
-- Hyperthyroidism
-- Osteogenesis imperfecta
-- Diabetes mellitus (type 1 and type 2)
-- Marfan syndrome
• Gastrointestinal diseases -- Ehlers–Danlos syndrome
-- Malabsorption -- Human immunodeficiency virus infection
-- Inflammatory bowel diseases (and its treatment)

Observational studies have shown that other nutri-
ents might influence calcium metabolism and therefore
potentially the risk of osteoporosis. Intake of vegetables
and fruits leads to alkalization of the urine owing to the
high content of potassium and thereby decreases cal-
cium excretion, whereas intake of meat and fish acid-
ifies the urine via the sulfur-rich amino acids and can
cause hypercalcuria89,90. However, the effects might only
be minimal as it has been shown that these effects on
urinary calcium excretion are balanced by changes in
calcium absorption91. High protein intake accompanied
by low calcium intake is associated with an increased risk
of fractures, whereas a high protein intake accompanied
by a high calcium intake is associated with a reduced risk
of fracture92,93.
BMI. Body weight and body composition is also of rel-
evance in the prevention of osteoporosis. Weight loss
in older women is associated with a general increased
fracture risk94, whereas weight gain is associated with
reduced risk of hip fractures but increased risk of other
peripheral fractures95,96. Sarcopaenia is associated with
increased risk of fractures97, although sarcopaenia is
very poorly defined. According to some definitions, it is
defined as poor muscle function, either because of low
muscle mass or impaired function of the muscles.
Physical activity. The bone cells, especially osteocytes,
respond to mechanical strains or absence of such98,99
(FIG. 3). Clinical studies investigating the effect of physical
training have shown that it is possible to increase BMD,
especially in younger individuals (<25 years of age)100–102.
Although some evidence suggests that the skeleton
responds less well to physical activity with increasing
age103, some studies show an effect of exercise on BMD in
postmenopausal women104–106. However, positive effects
on BMD are lost if the exercise programme is stopped.
Evidence that physical training prevents fractures is
still lacking. Whole-body vibration has in some stud-
ies been shown to reduce falls and improve BMD, but
not ­consistently 107,108, and no effect on fracture risk has
been shown.
Smoking. Smoking, current as well as past, has in a
meta-analysis been shown to be associated with increased
risk of fractures, including hip fractures109. Smoking is
associated with impaired intestinal calcium absorption
and increased age-related bone loss110. Smoking impairs
the effects of postmenopausal hormone replacement on
bone mass, probably through liver induction of metab-
olizing enzymes and thereby increased metabolism
of oestrogen111. Smoking cessation has been found to
improve BMD in postmenopausal women, probably
through changes in sex hormone levels and thereby
bone turnover 112.
Fall prevention. The main complication of osteoporo-
sis is fractures. The risk of hip fracture and other non-­
vertebral fractures is closely associated with the risk
of falling 95,113. It is therefore relevant to investigate the
risk of falling in patients with osteoporosis. Often, an
increased risk of falling is part of more general frailty.
However, sometimes the risk of falling is associated with
specific pathologies, such as reduced vision, cardiac
arrhythmias or medical treatments (for example, anti-
hypertensives and sedatives). The risk of falling may be
improved considerably by addressing these conditions.
Even in individuals without these conditions, recurrent
falls may be prevented by multifactorial approaches114.
Although, a considerable reduction in falls would be
expected to reduce fractures, this association remains to
be proven for the majority of fall prevention strat­egies.
Two strategies have been shown to prevent both falls and
fractures. Cataract surgery has been shown to reduce
falls by 34% and fractures by 46% in elderly, mainly
white, women115. Randomized clinical trials investigating

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 PRIMER

the effects of vitamin D supplementation on the risk
of falls and fractures and meta-analyses of these have
shown that vitamin D supplementation decreases the
risk of falling and non-vertebral fractures, including
hip fractures, by approximately 20%86,116; these effects
were only seen with doses of vitamin D of >17.5–20 μg
(700–800 IU) per day. Later analyses of the same clinical
studies have come to different conclusions regarding the
consistency of the above-mentioned findings; the dif-
ferences are mainly caused by a difference in the criteria
for inclusion or exclusions of studies, as some analyses
included all studies, whereas others only included studies
using medium-dose or high-dose supplementation, good
adherence and high-quality assessment of falls117–120.
Management
Patient selection
Following the practice established in cardiovascular
disease, it is now common to make treatment decisions
for osteoporosis on the basis of estimated event risk, in
this case, the risk of a fracture. This strategy acknow­
ledges that several factors, including age, determine
fracture risk, not just BMD or previous fracture history.
Two widely used fracture risk calculators are WHO
FRAX3 and that from the Garvan Institute121 (TABLE 1).
As they use different clusters of risk factors, they dif-
fer in treatment recommendation in approximately
25% of patients122. In patients with borderline fracture
risk, the use of more than one calculator may permit a
more comprehensive appreciation of their real risk. The
choice of threshold for intervention should be based on
a cost-effectiveness analysis, which is influenced not
only by fracture risk but also by the cost and the safety
of each intervention. The use of a single intervention
criterion is not appropriate for agents of widely different
cost. A 10‑year hip fracture risk of 3% has been advo-
cated as a criterion for treatment123, although it should be
noted that this will result in the treatment of individuals
whose BMD and fracture history would not have quali-
fied them for entry to most of the pivotal phase III trials
of the agents we are using, so this practice is not strictly
evidence-based.
Management
When considering pharmaceutical intervention, gen-
eral preventive measures (as discussed above) should
be implemented. Vitamin D (800 IU daily) should be
prov­ided for those at risk of osteomalacia (for example,
the frail elderly who are housebound or institutional-
ized). The issue of whether to give calcium supplements
to patients along with an anti-resorptive drug remains
controversial and may be more suitable for those with
low habitual dietary calcium intake. Calcium supple-
ments have traditionally been provided when anti-­
resorptive drugs are prescribed, but fracture prevention
has been shown in the absence of calcium and calcium
does not seem to influence the effects of these agents
on BMD124.
Although there are a range of agents available for
treating osteoporosis, only the potent bisphospho-
nates (alendronate, risedronate and zoledronate) and
denosumab have been shown to have broad anti-fracture
efficacy (for vertebral, non-vertebral and hip fractures)
and are approved for use. Generally, bisphosphonates are
used as a first-line treatment, because they are less expen-
sive than denosumab and their efficacy is comparable.
Some bisphosphonates are available as generics, which
increases ease of access. Thus far, the only approved
agent that stimulates bone formation is teriparatide and
intact PTH; the others are anti-resorptive agents.
Bisphosphonates. Bisphosphonates (including oral alen-
dronate, oral risedronate, oral or intravenous ibandro-
nate, and intravenous zoledronate) have been the most
widely used agents for managing osteoporosis over the
past two decades. They bind avidly to bone mineral
and are subsequently ingested by osteoclasts, the bone-­
resorbing activity of which is suppressed through the
inhibition of a crucial enzyme in the mevalonate path-
way 125. Their efficacy in fracture prevention is shown
in FIG. 6, along with that of other agents. Although the
reduction in non-vertebral fractures is only small, they
typically reduce hip fracture risk by about 50%126 and
vertebral fracture risk by 40–70%127. Cost, convenience,
compliance and adverse-effect profiles usually guide the
choice between intravenous and oral bisphosphonates.
Oral bisphosphonates cause gastrointestinal disturb­
ance in about 20% of users, which probably contributes
to poor long-term compliance with these drugs in some
reports. About one-third of patients having their first infu-
sion of an intravenous bisphosphonate will experience a
transient, flu-like illness. In addition, intravenous bis-
phosphonates carry a risk of acute renal failure in patients
with severe pre-existing kidney disease (glomer­ular fil-
tration rate of <35 ml/min). Adequate renal ­function is
necessary for use of intravenous bisphosphonates.
The occurrence of osteonecrosis of the jaw in patients
with cancer receiving high doses of intravenous bisphos­
phonates has caused concern that this may also be a
consequence of the lower doses used in osteoporosis
treatment with these agents. Although osteo­necrosis has
been described in patients with osteoporosis, its inci-
dence is very low 128 and in some studies does not seem
to be greater in those who receive bisphosphonates
than in patients with osteoporosis who are not taking
these drugs129–131.
Box 2 | Prevention strategies for at‑risk women
Recommendations for postmenopausal women with
documented osteoporosis or increased risk of
developing osteoporosis:
• Sufficient daily intake of calcium (800–1,000 mg per day),
preferentially through diet
• Vitamin D supplementation in those who are likely
to be deficient in vitamin D; dosage to achieve serum
25‑hydroxy vitamin D3 levels of >50 nmol per l
• Avoid weight loss and low body mass index
• Daily physical activity (weight-bearing, such as
skipping, steps and walking)
• Cessation of smoking

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However, atypical femoral fractures are a concern.
These seem to develop initially as stress fractures in the
lateral cortex of the femoral shaft, often spontaneously
progressing to transverse fractures132,133. Bisphosphonate
use is more common in patients with these fractures
(78%) than in those with ‘typical’ fractures of the fem-
oral shaft (10%), and incidence increases with time
on these drugs132. Atypical femoral fractures might be
more common with alendronate than with risedron­
ate or zoledronate134 and Asian patients may be more
susceptible135. Incidence seems to drop dramatically in
the 1–2 years after drug discontinuation132. However,
atypical femoral fractures represent a small minority
of total femoral fractures132, so bisphosphonates are
believed to prevent many more fractures than they
might cause in those with increased fracture risk.
It is important to periodically review the need for
continued bisphosphonate therapy, to consider drug
discontinuation in patients whose T‑score has risen
to >–2.5 and to consider temporary drug h ­ olidays
in those who have been on treatment for >5 years.
However, effective interventions must continue to be
provided for patients with osteoporosis who have a high
fracture risk.
Denosumab. Denosumab is a monoclonal antibody
directed against RANKL, administered as 6‑monthly,
subcutaneous injections for osteoporosis treatment.
It markedly reduces bone turnover, results in sustained
and substantial increases in BMD and achieves a similar
fracture reduction as seen with zoledronate136,137 (FIG. 6).
Osteonecrosis of the jaw and atypical femoral fractures
have been reported in patients treated for osteoporosis
with denosumab and the low incidences are compar­
able to those seen with bisphosphonates137. There is
a rebound in bone turnover and a rapid loss of BMD
within months of a 6‑monthly injection being missed138
and there have been case reports of increased vertebral
fracture risk following denosumab cessation139. BMD
studies have shown additive effects when denosumab
is combined with teriparatide140, although the effect of
the combination on fractures is not known.
Teriparatide. Teriparatide, the N‑terminal 34 amino
acids of PTH, stimulates both bone formation and
bone resorption. Daily or weekly subcutaneous injec-
tions result in progressive increases in spine BMD, with
smaller increases in the hip141. Teriparatide at a dose of
20 μg per day reduced the risk of vertebral fractures by
70% and non-vertebral fractures by 50% over a median
treatment period of 21 months142, and weekly dosing with
56.5 μg over 72 weeks reduced vertebral but not non-­
vertebral fractures (relative non-vertebral fracture risk:
0.98 (95% CI: 0.47–2.07))143. Teriparatide and intact PTH
have not been shown to reduce hip fracture risk. Nausea,
headache and hypercalcaemia have caused withdrawals
from clinical trials of teriparatide and intact PTH, and
there are post-marketing anecdotes of musculoskeletal
pain. Despite concern from rat studies that parathyroid
peptides increase the incidence of osteosarcoma, there
is no evidence of this from 10 years of human use144.
Combinations of teriparatide with bisphosphonates or
with denosumab are additive in their BMD effects145,146.
Strontium. Strontium is a divalent cation with chemical
and biological properties similar to those of calcium.
Its ranelate salt is used to treat osteoporosis, adminis-
tered daily in powder form. It produces large increases
in BMD, which are at least in part an artefact of imag-
ing owing to heavier strontium ions replacing calcium
in hydroxyapatite. It has a weak anti-resorptive effect
based on results of bone turnover markers147. A study
of 170 paired biopsy samples before and after stron-
tium treatment showed reductions in several ­formation
­indices at 6 and 12 months (including bone forma-
tion rate), no consistent changes in resorption and
reduced bone volume at 12 months148. Vertebral fracture
­numbers were decreased by 40%149 and non-vertebral
fractures by 16%150, but hip fracture was only decreased
in a post-hoc subgroup analysis150.

Table 1 | Comparison of FRAX and Garvan tools

Parameters FRAX tool* Garvan tool‡
Clinical risk • Age (40–90 years) • Age (60–96 years)§
factors • Sex • Sex
• Weight • Fractures since 50 years of age (up to 3)
• Previous fracture in adulthood (yes or no) • Falls over the past 12 months (up to 3)
• Family history of hip fractures
• Current smoking
• Glucocorticoid use
• Rheumatoid arthritis
• Secondary osteoporosis
• Alcohol
Other • Incorporates competing risk of mortality • No competing risk of mortality
considerations • Different algorithms can be used for different • No different algorithms for different
ethnicities and countries ethnicities
• Probably involves interactions between variables • No interactions between individual variables
Types of fracture • Hip fracture at 10 years • Hip fracture at 5 and 10 years
predicted • Major osteoporotic fracture at 10 years • Any fragility fracture at 5 and 10 years
FRAX, Fracture Risk Assessment Tool. *See REF. 3. ‡See REF. 121. §Since the time of data collection and analyses, the Garvan
calculator has expanded its eligible age range to include individuals 50–59 years of age. Reproduced with permission from
REF. 122, Maturitas–Elsevier.

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Non-vertebral fracture Hip fracture Vertebral fracture

Calcium
Vitamin D
Calcium and vitamin D
Alendronate
Risedronate
Bisphosphonates
Ibandronate
Zoledronate
Denosumab
Teriparatide
PTH1–84
Strontium
Raloxifene
Odanacatib

0.2 0.5 1 2 0.6 0.2 0.5 1 2 4 8 0.1 0.2 0.5 1 2

Favours Favours Favours Favours Favours Favours
treatment control treatment control treatment control
Figure 6 | Fracture prevention by osteoporotic agents. Summary of trial data documenting Naturethe efficacy| Disease
Reviews of treatments
Primers
for the prevention of non-vertebral hip fractures and vertebral fractures. The results for strontium150, odanacatib199
and parathyroid hormone (PTH) 1–84 (REF. 200) are relative risks. Other data are odds ratios and from REF. 126. Values are
shown with 95% confidence intervals201.

Considerable safety concerns are associated with
strontium treatment. It causes rare severe dermato­
logical reactions 151, but more concern relates to a
60% increase in the risk of myocardial infarction in
the original pivotal trials152. This finding caused the
Pharmaco­v igilance Risk Assessment Committee of
the European Medicines Agency to recommend suspen-
sion of the medicine because of its cardiovascular risk,
but the Agency subsequently continued availability of
the med­icine, restricting its use to patients who ­cannot
be treated with other medicines that are approved for
osteoporosis, subject to their regular screening and
monitoring to exclude cardiovascular disease153. The
combination of limited efficacy, low compliance and
major safety concerns results in low enthusiasm for its
use in osteoporosis treatment.
Oestrogen replacement therapy. Oestrogen replace-
ment has been shown to prevent postmenopausal bone
loss and to reduce fracture risk154–156. However, oestro­
gen has effects on many tissues, some positive and
some negative, creating a complex risk–benefit situ­
ation. In the WHI study, beneficial effects on fractures
and colon cancer incidence were counterbalanced by
changes in cardiovascular, cerebrovascular and venous
thromboembolic events155,156. This balance is likely to
be different for oestrogen alone and for oestrogen plus
progestins and may also vary between specific oestro-
gens and progestins. This complexity has caused many
patients and physicians to lose enthusiasm for oestrogen
as a bone-protective therapy, even though its efficacy
is beyond question. A reappraisal of the literature on
this topic suggests that, in the small number of women
who have increased fracture risk in the decade follow-
ing menopause, the balance of benefit versus risk is
­probably positive157.
Selective oestrogen receptor modulators. Selective ER
modulators (SERMs; for example, raloxifene, bazedox­
ifene and lasofoxifene) are compounds that inter-
act with ERs and that show a range of tissue-specific
agonist and antagonist effects. Raloxifene has been
widely used in osteoporosis, but its effects on BMD are
consider­ably less than those of oestrogen158. Although
raloxifene reduces vertebral fracture numbers, it has
no effect on hip and other non-vertebral fractures159.
It is well tolerated but has been shown to increase the
risk of thromboembolic disease in two different studies,
with a relative risk of 3.1 (95% CI: 1.5–6.2) found in
one159 and a hazard ratio of 1.44 (95% CI: 1.06–1.95)
found in another 160. In addition, the risk of fatal
stroke was increased in one study (hazard ratio: 1.49
(95% CI: 1–2.24))160.
Bazedoxifene is marketed in combination with con-
jugated oestrogens. This preparation has been shown to
improve vasomotor symptoms, vulvovaginal ­atrophy
and BMD, without adverse effects on the breast and
endo­metrium161,162. It has positive effects on BMD,
which are less than those of potent anti-resorptives163,
but its anti-fracture efficacy is unknown. Bazedoxifene
alone has been shown to reduce vertebral fracture risk
by about 40%164. Lasofoxifene is the only SERM that
has been shown to reduce the risk of non-vertebral
­fractures165, but it is not yet marketed.
Quality of life
Osteoporosis is often a silent disease; loss of BMD by
itself rarely affects quality of life. However, the effect of
fractures associated with osteoporosis on health-­related
quality of life (HRQOL) is typically profound166. HRQOL
reflects the following dimensions of well-­being: physi-
cal, psychological, social and financial167. Research has
shown that low-trauma fractures initiate the downward

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 PRIMER

a 3,500 b 20
18
3,000
Incidence rate per 100,000

16
2,500 14

Prevalence (%)
2,000 12
10
1,500 8

1,000 6
4
500
2
0 0
86
87
88

19 9
90

19 1
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19 3
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19 5
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20 9
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00

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02

20 3
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05

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8

0
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19

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19

19

20

20

20

19
19
19
19
20
20
20
20
20
20
20
20
20
20
20
20
20
Year Year
65–74 years 75–84 years >84 years Women Men

Figure 7 | Evolution of fracture incidence and bisphosphonate use. a | Evolution of hipNature

fractureReviews | Disease
incidence by agePrimers
for men and women in the United States. b | Prevalence of bisphosphonate use among men and women ≥55 years of age.
Values are shown with 95% confidence intervals. Part a is reproduced with permission from JAMA, 2009, 302 (14):
1573–1579. Copyright © (2009) American Medical Association. All rights reserved. Part b is reproduced with permission
from REF. 181, American Society for Bone and Mineral Research.

spiral of quality of life that leads to worsen­ing prob-
lems in all four domains. All fractures have undesir­
able physical consequences; however, the physical and
quality-­of-life consequences associated with spine
and hip fractures are marked. Vertebral fracture out-
comes include deformity, fear of falling, chronic pain
and mortality, whereas hip fractures often cause activ-
ities of daily living limitations, dysmobility, excessive
morbidity and excess mortality, especially in the first
year post-fracture168.
The physical and functional outcomes of osteoporo-
tic fractures have been well studied, especially those
associated with a hip fracture169 and/or two or more
spinal fractures170. However, psychosocial and financial
consequences of these fractures are less well identified.
In short, HRQOL is compromised in the psychological
realm by feelings of anxiety (for example, fear of falling
and fear of fractures) and depression. In fact, comorbid
anxiety and depression occurs in patients with osteo-
porosis171. Reduced self-esteem and self-image can also
occur with increasing numbers of fractures167.
The social consequences of osteoporosis are even
less well understood and studied than the psycho­logical
consequences. Perhaps the most serious is the loss of
social roles; that is, the inability to continue to enact
roles associated with employment, family leisure and
self-care activities, including hobbies, athletics, sexual
intimacy, bathing and dressing. Such limitations can take
away independence and feelings of self-worth and can
breed hopelessness. The interaction between these social
factors (such as loneliness and isolation) and psycho­
logical factors (such as anxiety and depression) leads to
an ever-deepening downward spiral172.
Finally, the financial cost of osteoporotic fractures
adds yet another way in which HRQOL is impaired.
Although there are few in‑depth studies of individual
costs, evaluations of societal cost suggest that the eco-
nomic burden of osteoporosis is substantial8. Current
and projected direct costs of fractures of which the
majority is covered by health care systems worldwide
increase steadily 8,173. However, osteoporosis also has
indirect costs that are borne by individuals with frac-
tures. These costs include lost wages, the need to hire
people to complete home chores and other expenditures
that are not directly related to medical care. Estimates
suggest that indirect costs account for half of the total
costs of osteoporosis174.
Overall, osteoporotic fractures compromise HRQOL
in all domains. As the number of fractures increase,
HRQOL decreases, with hip and spine fractures having
the biggest negative effect on HRQOL. Prevention of
fractures through screening and appropriate and rapid
treatment of fractures when they occur might preserve
HRQOL and slow the downward spiral that can begin
with a single atraumatic fracture175.
Outlook
Trends in incidence
Since about 1976, the rates of hip fracture have been
declining by about 20% per decade in the United States
(FIG. 7a), Canada and in most countries in Europe176,177.
Effective treatment can only account for a small fraction
of this trend owing to the low prevalence of use of drugs
for osteoporosis178. Femoral neck BMD has also been
increasing in the United States during that period such
that the prevalence of osteoporosis has decreased by
more than half between 2002 and 2010 (REF. 179). Some
of the effect might be attributable to the rise in BMI,
but the reasons are not clear 180. Despite these trends, the
global number of fractures will continue to rise rapidly
owing to the ageing population.
Trends in management
Since about 2005, prescriptions of drug treatments in the
United States have declined by 25–50% even in patients
with hip fracture and particularly among women with
lower levels of education (FIG.  7b) . The decline is
probably mostly due to publicity about the occur-
rence of atypical femoral fractures and ­osteonecrosis
of the jaw with bisphosphonates and denosumab,

12 | 2016 | VOLUME 2 www.nature.com/nrdp

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 PRIMER

although the absolute risk in osteoporosis treatment
remains low 181. All bisphosphonates have become
generic, which is associated with reductions in price
that means that treatment to prevent fractures is now
more cost-effective and, therefore, should be more
widely used. Efforts to better target the prescription of
treatments have included institution of ‘fracture liaison’
services in some hospitals to initiate drug treatments, or
to measure BMD and risk, in patients who are admit-
ted for fracture182. This promising approach has had
mixed results because of the expense of employing a
clinical specialist to identify patients and because most
patients who start treatments after fracture discontinue
them within a year. This is a particular concern with
denosumab, as there is an accelerated bone loss138 and
probable increase of multiple vertebral fractures after
stopping therapy 139.
New treatments
The ultimate aim in osteoporosis management would
be to develop a treatment that reduces fracture risk,
­especially non-vertebral and hip fractures, by improving
bone mass, muscle strength and endurance. This would
reduce the risk of injurious falls, shorten rehabilitation
time and reduce disability due to fractures. Although
we are not there yet, several treatments with novel
­mechanisms of action are due to make their debut soon.
The anti-sclerostin antibody romosozumab has been
shown to markedly increase bone formation for up to
6 months after the initial dose and the highest dose
increases spine and hip BMD by about 11% and 4%,
respectively, over just 12 months of monthly sub­cutaneous
administration183. Preliminary reports from the FRAME
study indicate that 1 year of treatment reduces the risk
of vertebral fracture by 75% but with no significant
reduction in risk of non-vertebral fractures184. Complete
results from ongoing trials will determine whether
short-term treatment with an anti-­sclerostin antibody
offers greater anti-fracture efficacy than ­denosumab
or zoledronate.
Abaloparatide, an analogue of PTH-related pro-
tein, functions similarly to teriparatide. Treatment for
18 months with the doses intended for use in practice
tended to increase BMD of the spine and hip to a greater
degree than teriparatide185. The ACTIVE trial showed
an 86% reduction in the risk of vertebral fractures and
a 43% decrease in the risk of non-vertebral fractures186.
Full details about its safety have not been published, but,
if approved for use, abaloparatide might be a new option
for treatment of patients at high risk of fracture.
Odanacatib, a cathepsin K inhibitor, suppresses
resorption of collagen matrix while allowing the forma-
tion of bone. It might permit a more favourable balance
of a small decrease in resorption with less inhibition of
formation187. The LOFT trial found a 47% decrease in the
risk of hip fracture and a 54% decrease in the risk of verte­
bral fractures188. The safety profile has resulted in halting
of drug development as there was an excess incidence of
stroke189; there were also rare instances of ­atypical femur
fractures and morphoea-like skin lesions188.
Guidelines for treatment and screening
The National Osteoporosis Foundation (United States)
guidelines have been updated with a new emphasis on
screening for vertebral fractures using vertebral imag-
ing by DXA or radiograph in patients who are at risk
of vertebral fractures as a result of older age, low BMD,
≥2 cm height loss or history of a fracture along with the
measurement of BMD190; treatment is recom­mended
with T‑scores of ≤–2.5 at any skeletal site independent
of age, a vertebral fracture, or a BMD T‑score between
–1 and –2.5 along with an increased risk of fracture
by the FRAX algorithm. By contrast, the National
Osteoporosis Guideline Group (United Kingdom) guide-
lines e­ mphasize the assessment of risk using the FRAX
algor­ithm and treating on the basis of risks that are spe-
cific to age groups191. Besides these, there are guidelines
of the International Osteoporosis Foundation192 and
>60 available national guidelines193 that take account of
local practices.
Goal-directed treatment
It has been proposed to treat patients with the aim to
reach target levels of BMD, for example, a T‑score of
≥–2.5 at any skeletal site or a fracture risk that is lower
than the level that would indicate starting treatment 194.
In this scheme, the choice of drug would be based on
the likelihood of a patient reaching this goal using the
treatment options. Achievement of BMD goals dur-
ing treatment could guide when to pause or switch treat-
ment. For denosumab and zoledronate, improvement in
BMD is accompanied by a decrease in fracture risk195,196;
this would support using changes in BMD as a goal to
advise management choices. However, the association
between BMD and fracture risk is not strong for other
treatments and the change in BMD will not be so pre-
cise as to predict changes in the risk of fracture. Thus,
goal-directed treatment would be best if both improve-
ments in BMD and data about how treatments reduce
risk were considered.

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Acknowledgements
R.E. was supported by a Senior Investigator Award from
the National Institute of Health Research. L.C.H. was
funded by Deutsche Forschungsgemeinschaft, SFB‑655 and
Transregio‑67.
Author contributions
Introduction (R.E.); Epidemiology (T.W.O.); Mechanisms/
pathophysiology (L.C.H.); Diagnosis, screening and prevention
(B.L.); Management (I.R.R.); Quality of life (D.T.G.); Outlook
(S.R.C.); Overview of Primer (R.E.).
Competing interests
R.E. has received consulting fees from Amgen, AstraZeneca,
GlaxoSmithKline (GSK), Immunodiagnostic Systems, Ono
Pharma, Lilly and Roche Diagnostics, and grant support from
Amgen, Immunodiagnostic Systems, Lilly and AstraZeneca.
L.C.H. has received honoraria for serving on the advisory
board and for giving lectures from Amgen, Eli Lilly, Merck,
Novartis and UCB. B.L. has received consulting fees from
Amgen, Merck, Eli Lilly and UCB, and grant support from
Novo Nordisk, Eli Lilly and Orkla Health. I.R.R. has received
research funding and honoraria from Merck, Amgen and
Novartis. S.R.C. serves as a consultant to Amgen, Radius,
Merck and Eli Lilly about the design of studies and
interpretation of results, and has received grant support from
Amgen for systematic review of medical risk factors for hip
fracture. He has not received funds for lectures or other
promotional activities. D.T.G. and T.W.O. have no conflicts of
interest or competing interests to report.

16 | 2016 | VOLUME 2 www.nature.com/nrdp

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