2018 European Guidance Diagnosis and Management Osteoporosis

Osteoporosis International (2019) 30:3–44
https://doi.org/10.1007/s00198-018-4704-5
POSITION PAPER
European guidance for the diagnosis and management of osteoporosis

in postmenopausal women
J.A. Kanis 1,2 & C. Cooper 3,4 & R. Rizzoli 5 & J.-Y. Reginster 6,7 & on behalf of the Scientific Advisory Board of the European
Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and
National Societies of the International Osteoporosis Foundation (IOF)
Received: 30 May 2018 / Accepted: 12 September 2018 / Published online: 15 October 2018
# The Author(s) 2018, corrected publication 2020
Abstract
Summary Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk from
fractures due to osteoporosis.
Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of
Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2013. This manuscript
updates these in a European setting.
Methods Systematic reviews were updated.
Results The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and
assessment of fracture risk; general and pharmacological management of osteoporosis; monitoring of treatment; assessment of
fracture risk; case-finding strategies; investigation of patients; health economics of treatment. The update includes new infor-
mation on the evaluation of bone microstructure evaluation in facture risk assessment, the role of FRAX® and Fracture Liaison
Services in secondary fracture prevention, long-term effects on fracture risk of dietary intakes, and increased fracture risk on
stopping drug treatment.
Conclusions A platform is provided on which specific guidelines can be developed for national use.
Keywords Bone mineral density . Diagnosis of osteoporosis . Fracture risk assessment . FRAX . Health economics . Treatment of
osteoporosis
Summary of main recommendations
* J.A. Kanis Diagnosis of osteoporosis

[email protected]
1. The operational definition of osteoporosis is based on the
1
Centre for Metabolic Bone Diseases, University of Sheffield Medical T-score for BMD assessed by DXA at the femoral neck or
School, Beech Hill Road, Sheffield S10 2RX, UK spine and is defined as a value for BMD 2.5 SD or more
2
Mary McKillop Health Institute, Australian Catholic University, below the young female adult mean.
Melbourne, Australia 2. For clinical purposes, other sites and techniques can be
3
MRC Lifecourse Epidemiology Unit, University of Southampton, used for diagnosis.
Southampton, UK 3. Low bone mass (osteopenia) should not be considered a
4
NIHR Musculoskeletal Biomedical Research Unit, University of disease category but is intended solely for purpose of
Oxford, Oxford, UK epidemiological description.
5
University Hospitals and Faculty of Medicine of Geneva,
Geneva, Switzerland Risk factors for fragility fractures
6
Department of Public Health, Epidemiology and Health Economics,
University of Liège, Liège, Belgium 1. Several factors contribute significantly to fracture risk over
7
Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry and above that provided by bone mineral density measure-
Department, College of Science, King Saud University, ments. These include age, sex, low body mass index,
Riyadh, Kingdom of Saudi Arabia
4 Osteoporos Int (2019) 30:3–44
previous fragility fracture, parental history of hip fracture, of cases. In women intolerant to oral bisphosphonates (or in
glucocorticoid treatment, current smoking, alcohol intake of those for whom they are contraindicated), intravenous
3 or more units daily and causes of secondary osteoporosis. bisphosphonates or denosumab provide the most appropri-
2. Additional risk factors that are of use in case finding in- ate alternatives, with raloxifene, or menopause hormone
clude height loss (> 4 cm) and thoracic kyphosis. therapy as additional options. Teriparatide is preferentially
3. Bone markers (serum procollagen type I N propeptide (s- recommended for patients at high risk of fracture.
PINP) and serum C-terminal cross-linking telopeptide of 2. Treatments should be reviewed after 3–5 years treatment
type I collagen (s-CTX) as markers of bone formation and with bisphosphonate. Fracture risk should be reassessed
bone resorption, respectively) have some prognostic signifi- after a new fracture, regardless of when it occurs. The risk
cance for fracture in situations where BMD is unavailable. of new clinical and vertebral fractures increases in patients
who stop treatment.
Assessment of fracture risk 3. Withdrawal of denosumab therapy is associated with a
rebound in vertebral fracture rate. Bisphosphonate thera-
1. Country-specific FRAX® should be used to assess frac- py can be considered after discontinuation of denosumab.
ture probability in postmenopausal women who have risk 4. There is little evidence to guide decision-making beyond
factors for fracture. In individuals at intermediate risk, 10 years of treatment and management options in such
bone mineral density (BMD) measurement should be per- patients should be considered on an individual basis.
formed using dual energy X-ray absorptiometry and
FRAX fracture probability re-estimated. Intervention thresholds for pharmacological intervention
2. Where BMD testing is unavailable, FRAX can be used
without the input of BMD 1. The thresholds recommended for decision-making are
3. Trabecular bone score (TBS) may be used as an adjunct to based on probabilities of major osteoporotic and hip frac-
BMD measurements and FRAX. ture derived from FRAX. These vary in different
4. Interpretation of FRAX scores may be influenced by ex- healthcare systems with variation in ‘willingness to pay’.
posure to glucocorticoids, information on lumbar spine 2. Women aged over 65 years with a prior fragility fracture
BMD, trabecular bone score, hip axis length, falls history, can be considered for treatment without the need for fur-
immigration status and type 2 diabetes mellitus. ther assessment; BMD measurement may be felt more
5. Vertebral fracture assessment should be considered if appropriate in younger postmenopausal women.
there is a history of ≥ 4 cm height loss, kyphosis, recent 3. Age-dependent intervention thresholds provide clinically
or current long-term oral glucocorticoid therapy or a appropriate and equitable access to treatment and have
BMD T-score ≤ − 2.5. been shown to be cost-effective.
Lifestyle and dietary measures Systems of care
1. Recommendations should include a daily calcium intake 1. The utility of age-dependent FRAX thresholds in popula-
of between 800 and 1200 mg and sufficient dietary pro- tion screening approach has recently been validated as
tein, ideally achieved through dairy products. feasible, effective and health economically viable.
2. A daily dose of 800 IU cholecalciferol should be advised 2. Coordinator-based Fracture Liaison Services (FLS)
for postmenopausal women at increased risk of fracture. should be used to systematically identify men and women
3. Calcium supplementation is appropriate if the dietary in- with fragility fracture. Their effectiveness and cost-
take is below 800 mg/day, and vitamin D supplementation effectiveness have been established recently.
considered in patients at risk of, or showing evidence of,
vitamin D insufficiency.
4. Regular weight-bearing exercise should be advised, tai- Introduction
lored to the needs and abilities of the individual patient.
5. A history of falls should be obtained in individuals at In 1997 The European Foundation for Osteoporosis and Bone
increased risk of fracture with further assessment and ap- Disease (subsequently the International Osteoporosis
propriate measures undertaken in those at increased risk. Foundation; IOF) published guidelines for the diagnosis and
management of osteoporosis [1], subsequently updated in
Pharmacological intervention in postmenopausal women 2008 [2] and 2013 [3] by the IOF and European Society for
Clinical and Economic Evaluation of Osteoporosis and
1. The oral bisphosphonates (alendronate, risedronate and Osteoarthritis (ESCEO). The scope of the present guideline
ibandronate) may be used as initial treatments in the majority is to review and update the assessment and diagnosis of
Osteoporos Int (2019) 30:3–44 5
osteoporosis, the therapeutic interventions available and the contribute to fracture risk [11–13], the diagnosis of osteopo-
manner in which these can be used to develop management rosis by the use of BMD measurements is at the same time an
strategies for the prevention of fragility fracture in postmeno- assessment of a risk factor for the clinical outcome of fracture.
pausal women. The guideline is intended for all healthcare For these reasons, there is a distinction to be made between the
professionals involved in the management of osteoporosis. use of BMD for diagnosis and for risk assessment.
Where available, systematic reviews, meta-analyses and Common sites for osteoporotic fracture are the spine, hip,
randomised controlled trials have been used to provide the distal forearm and proximal humerus. The remaining lifetime
evidence base. The evidence base was updated using probability in women at the menopause of a fracture at any
PubMed to identify systematic reviews and meta-analyses one of these sites exceeds that of breast cancer (approximately
from January 2008 to December 2017. The recommendations 12%), and the likelihood of a fracture at any of these sites is
in this guideline were endorsed by the Scientific Advisory 40% or more in Western Europe [14] (Table 1), a figure close
Board of ESCEO and the Committee of Scientific Advisors to the probability of coronary heart disease.
and the Committee of National Societies of the IOF. Fragility fractures are a major cause of morbidity in the
The high societal and personal costs of osteoporosis pose population. Hip fractures cause acute pain and loss of func-
challenges to public health and physicians, particularly since tion, and nearly always lead to hospitalisation. Recovery is
most patients with osteoporosis remain untreated. There is a slow, and rehabilitation is often incomplete, with many pa-
large gap between the number of women who are treated com- tients permanently institutionalised in nursing homes.
pared to the proportion of the population that could be consid- Vertebral fractures may cause acute pain and loss of function
ered eligible for treatment based on their fracture risk. In the but may also occur without serious symptoms. Vertebral frac-
European Union (EU), it is estimated that there are and 18.44 tures often recur, however, and the consequent disability in-
million women who have a fracture probability that equals or creases with the number of fractures. Distal radial fractures
exceeds that of a woman with a prior fragility as assessed by also lead to acute pain and loss of function, but functional
FRAX® (i.e. individuals at or above a ‘fracture threshold’). On recovery is usually good or excellent.
the conservative assumption that treatments are only given to In 2010, it was estimated that 22 million women and 5.5
patients at high risk, prescription data suggest that more than million men in the EU had osteoporosis using the diagnostic
57% of women at high risk do not receive bone-specific treat- criterion of the WHO [4]. The number of new fractures in
ment [4]. Moreover, uptake of treatments for osteoporosis, 2010 in the EU was estimated at 3.5 million, comprising ap-
particularly the bisphosphonates, has declined in recent years proximately 610,000 hip fractures, 520,000 vertebral frac-
[5, 6]. In patients with fragility fractures, less than 20% of tures, 560,000 forearm fractures and 1,800,000 other fractures
patients with a fragility fracture receive therapy to reduce fu- (i.e. pelvis, rib, humerus, tibia, fibula, clavicle, scapula, ster-
ture fracture within the year following fracture [7–9]. Against num and other femoral fractures). Two thirds of all incident
this sobering background, the aim of this guidance is to stim- fractures occurred in women. Among people age 50 years or
ulate a cohesive approach to the management of osteoporosis more who were still alive in 2010, 3.3 million individuals had
in Europe. The term guidance rather than guidelines is used, to sustained a hip fracture (prevalence of prior hip fracture). The
avoid any prescriptive connotations since country- or region- corresponding number of men and women with prior clinical
specific guidelines are now widely available in many European vertebral fractures was estimated at 3.5 million. Due to chang-
countries and continue to evolve. Rather, the guidance can es in population demography, the annual number of fragility
inform the development of new guidelines or the revision of fractures will rise from 3.5 million in 2010 to 4.5 million in
existing guidelines. Whilst focussed on a European perspective 2025, corresponding to an increase of 28%.
and on postmenopausal women, the principles may be of some
assistance in other regions of the world and in men.
Table 1 Remaining lifetime probability of a major osteoporotic fracture
at the age of 50 and 80 years in men and women from Sweden [14], with
kind permission from Springer Science and Business Media
Osteoporosis in Europe
At 50 years At 80 years
Osteoporosis is defined as a systemic skeletal disease
Site Men Women Men Women
characterised by low bone mass and microarchitectural dete-
rioration of bone tissue, with a consequent increase in bone Forearm 4.6 20.8 1.6 8.9
fragility and susceptibility to fracture [10]. Although the diag- Hip 10.7 22.9 9.1 49.3
nosis of the disease relies on the quantitative assessment of Spine 8.3 15.1 4.7 8.7
bone mineral density, which is a major determinant of bone Humerus 4.1 12.9 2.5 7.7
strength, the clinical significance of osteoporosis lies in the Any of these 22.4 46.4 15.3 31.7
fractures that arise. Because a variety of non-skeletal factors
It is widely recognised that osteoporosis and the conse- strength for both cortical and trabecular bone include macro-
quent fractures are associated with increased mortality, with and microarchitecture (e.g. cross-sectional moment of inertia,
the exception of forearm fractures [15]. In the case of hip hip axis length, cortical thickness, finite element analysis, tra-
fracture, most deaths occur in the first 3–6 months following becular bone score, cortical porosity) [22–27].
the event, of which 20–30% is causally related to the fracture DXA is the most widely used bone densitometric tech-
event itself [16]. In Sweden, the number of deaths that are nique. It is versatile in the sense that it can be used to assess
causally related to hip fracture account for more than 1% of bone mineral density/bone mineral content of the whole skel-
all deaths, somewhat higher than the deaths attributed to pan- eton as well as specific sites, including those most vulnerable
creatic cancer and somewhat lower than the deaths attributed to fracture [18]. Areal density (g/cm2) rather than a true volu-
to breast cancer [16]. In 2010, the number of deaths in the EU metric density (g/cm3) is measured since the scan is two di-
that were causally related to fractures was estimated at 43,000. mensional. Areal BMD accounts for about two thirds of the
Approximately 50% of fracture-related deaths in women were variance of bone strength as determined in vitro on isolated
due to hip fractures, 28% to clinical vertebral and 22% to other bones, such as the vertebral body or proximal femur. DXA can
fractures. Corresponding proportions for men were 47, 39 and also be used to visualise lateral images of the spine from T4 to
14%, respectively [4]. L4 to detect fractures of the vertebral bodies [28–30].
The total health burden, measured in terms of lost quality- Vertebral fracture assessment (VFA) may improve fracture
adjusted life years (QALYs), was estimated at 1,180,000 risk evaluation, since many patients with vertebral fracture
QALYs for the EU. Twice as many QALYs were lost in women may not have a BMD T-score classified as osteoporosis.
compared to men. The majority of the QALYs lost were a This procedure involves less radiation and is less expensive
consequence of prior fractures. In Europe, osteoporosis than a conventional X-ray examination but performs compa-
accounted for more disability and life years lost (DALYs) than rably to traditional radiographs [31].
rheumatoid arthritis, but less than osteoarthritis. With regard to Whereas whole body bone, fat and lean mass can also be
neoplastic diseases, the burden of osteoporosis was greater than measured using DXA, these measurements are useful for re-
for all sites of cancer, with the exception of lung cancers [17]. search, but they do not assist in the routine diagnosis or as-
The cost of osteoporosis, including pharmacological interven- sessment of osteoporosis.
tion in the EU in 2010, was estimated at €37 billion. Costs of The performance characteristics of many measurement
treating incident fractures represented 66% of these costs, phar- techniques have been well documented [32, 33]. For the pur-
macological prevention 5% and long-term fracture care 29%. pose of risk assessment and for diagnosis, a characteristic of
Excluding cost of pharmacological prevention, hip fractures rep- major importance is the ability of a technique to predict frac-
resented 54% of the costs, ‘other fractures’ represented 39% and tures. This is traditionally expressed as the increase in the
vertebral and forearm fractures represented 5 and 1%, respec- relative risk of fracture per standard deviation unit decrease
tively [4]. Assigning a QALY the value of 2xGDP, the total value in bone mineral measurement—termed the gradient of risk.
of QALYs lost in 2010 was estimated at €61.4 billion.
Limitations of BMD
Bone mineral measurements There are a number of technical limitations in the general
application of DXA for diagnosis, which should be recognised
The objectives of bone mineral measurements are to provide [34, 35]. The presence of osteomalacia, a complication of poor
diagnostic criteria, prognostic information on the probability nutrition in the elderly, will underestimate total bone matrix
of future fractures, and a baseline on which to monitor the because of decreased mineralisation of bone. Osteoarthrosis or
natural history of the treated or untreated patient. Bone min- osteoarthritis at the spine or hip are common in the elderly, and
eral density (BMD) is the amount of bone mass per unit vol- contribute to the density measurement, but not necessarily to
ume (volumetric density), or per unit area (areal density), and skeletal strength. Heterogeneity of density due to
both can be measured in vivo by densitometric techniques. osteoarthrosis, previous fracture or scoliosis can often be de-
A wide variety of techniques is available to assess bone tected on the scan and in some cases excluded from the anal-
mineral that are reviewed elsewhere [18–21]. The most widely ysis. Some of these problems can be overcome with adequate-
used are based on X-ray absorptiometry in bone, particularly ly trained staff and rigorous quality control.
dual energy X-ray absorptiometry (DXA). Other techniques
include quantitative ultrasound (QUS), quantitative computed
tomography (QCT) applied both to the appendicular skeleton Diagnosis of osteoporosis
and to the spine, peripheral DXA, digital X-ray
radiogrammetry, radiographic absorptiometry and other radio- Bone mineral density is most often described as a T-score or
graphic techniques. Other important determinants of bone Z-score, both of which are units of standard deviation (SD).
The T-score describes the number of SDs by which the BMD Prevalence of osteoporosis
in an individual differs from the mean value expected in
young healthy individuals. The operational definition of oste- Because the distribution of BMD in the young healthy popula-
oporosis is based on the T-score for BMD [11, 34] assessed at tion is normally distributed and bone loss occurs with advanc-
the femoral neck and is defined as a value for BMD 2.5 SD or ing age, the prevalence of osteoporosis increases with age and
more below the young female adult mean (T-score less than or thus depends on the demography of the population. The prev-
equal to − 2.5 SD) [3, 12, 36, 37]. The Z-score describes the alence of osteoporosis in the 27 countries of the EU in men and
number of SDs by which the BMD in an individual differs women is shown in Table 2 [4]. Approximately 21% of women
from the mean value expected for age and sex. It is mostly aged 50–84 years are classified as having osteoporosis account-
used in children and adolescents [38]. ing for more than 22 million women in these countries.
The reference range recommended by the IOF, ESCEO, These data assume that the distribution of femoral neck BMD
ISCD, WHO and NOF for calculating the T-score [3, 12, 36, is the same in these index countries. There may be small differ-
37, 39] is the NHANES III reference database for femoral ences in the age- and sex-specific BMD in different European
neck measurements in women aged 20–29 years [36]. Note countries as well as within countries. If so, these differences in
that the diagnostic criteria for men use the same female refer- BMD are relatively small [48] and insufficient to account for the
ence range as that for women. This arises fortuitously because observed differences in fracture rates (see below).
for any age and BMD at the femoral neck, the risk of hip
fracture or a major osteoporotic fracture is approximately the
same in men and women [40–42]. On GE Healthcare bone Risk factors for fracture
densitometers, there is an option for T-scores for men to be
given relative to either the male or female reference range in BMD
DXA readouts. However, the T-score cannot be used inter-
changeably with different techniques and at different sites, Assessment of BMD has provided a pivotal determinant of
since the prevalence of osteoporosis and proportion of indi- fracture risk and many guidelines have used BMD thresh-
viduals allocated to any diagnostic category would vary, as olds to determine whether treatments should be recom-
does the risk of fracture [39]. mended. Intervention thresholds have ranged from T-
These considerations have led to the adoption of the femoral scores of − 3 SD to − 1.5 SD depending on the clinical con-
neck as the reference site [39], but do not preclude the use of text, the country or on health economic factors. The use of
other sites and technologies in clinical practice, though it should bone mass measurements for prognosis depends upon accu-
be recognised that the information derived from the T-score will racy. Accuracy in this context is the ability of the measure-
differ from that provided by BMD at the femoral neck. ment to predict fracture. In general, all densitometric tech-
niques have high specificity but low sensitivity, which
varies with the cutoff chosen to designate high risk.
Measurement of multiple skeletal sites
At the age of 50 years, for example, the proportion of
women with osteoporosis who will fracture their hip, spine
A number of guidelines favour the concurrent use of BMD at
or forearm or proximal humerus in the next 10 years (i.e.
the proximal femur and at the lumbar spine for patient assess-
positive predictive value) is approximately 45%. Despite this,
ment. Patients are defined as having osteoporosis on the basis of
the overall detection rate for these fractures (sensitivity) is low
the lower of two T-scores [43, 44]. The prediction of fracture is,
and 96% of fractures at the spine, hip, forearm or proximal
however, not improved overall using multiple sites [45–47].
humerus will occur in women without osteoporosis [49]. The
Selection of patients on the basis of a minimum value from
low sensitivity is one of the reasons why widespread
two or more tests will, however, increase the number of patients
population-based screening with BMD is not widely recom-
selected. The same result can be achieved by less stringent
mended in women at the time of the menopause [11].
criteria for the definition of osteoporosis, by defining osteopo-
Many cross-sectional and prospective population studies
rosis, for example, as a T-score of < − 2.0 SD rather than < − 2.5
indicate that the risk for fracture increases by a factor of 1.5
SD. Notwithstanding, the measurement of more than one site
to 3.0 for each standard deviation decrease in bone mineral
can aid in the assessment of individuals (discussed below).
density [32]. There are, however, significant differences in
the performance of different techniques at different skeletal
Low bone mass (osteopenia) sites. In addition, the performance depends on the type of
fracture that one wishes to predict [30, 32, 50]. For exam-
It is recommended that diagnostic criteria be reserved for os- ple, BMD assessments by DXA to predict hip fracture are
teoporosis and that low bone mass (osteopenia) should not be more predictive when measurements are made at the hip
considered a disease category. rather than at the spine or forearm (Table 3). For the
Table 2 Estimated number of

men and women with Age group (years) Individuals with Population at risk (000) Prevalence (%)
osteoporosis (defined as a T-score osteoporosis (000)
of − 2.5 SD or less at the femoral
neck) and prevalence in the Women Men Total Women Men Total Women Men Total
population aged over 50 years in
the EU27, 2010. From [4], with 50–54 1106 429 1535 17,556 17,152 34,708 6.3 2.5 4.4
kind permission from Springer 55–59 1578 547 2125 16,434 15,637 32,071 9.6 3.5 6.6
Science and Business Media 60–64 2188 826 3014 15,302 14,242 29,544 14.3 5.8 10.2
65–69 2523 818 3341 12,489 11,054 23,543 20.2 7.4 14.2
70–74 3409 777 4186 12,217 9967 22,184 27.9 7.8 18.9
75–79 3876 768 4644 10,335 7459 17,794 37.5 10.3 26.1
80+ 7350 1325 8675 15,573 7980 23,553 47.2 16.6 36.8
50+ 22,029 5491 27,520 99,906 83,491 183,397 22.1 6.6 15.0
prediction of hip fracture, the gradient of risk provided by Clinical risk factors
hip BMD in a meta-analysis is 2.6 [32]. In other words, the
fracture risk increases 2.6-fold for each SD decrease in hip A large number of risk factors for fracture have been identified
BMD. Thus, an individual with a Z-score of − 3 SD at the [53–55]. For the purposes of improving risk assessment, in-
hip would have a 2.63 or greater than 15-fold higher risk terest lies in those factors that contribute significantly to frac-
than an individual of the same age with a Z-score of 0. ture risk over and above that provided by bone mineral density
Where the intention is to predict any osteoporotic fracture, measurements or age [56]. A good example is age. For any
the commonly used techniques are comparable: The risk of BMD, fracture risk is much higher in the elderly than in the
fracture increases approximately 1.5-fold for each standard young [57]. This is because age contributes to risk indepen-
deviation decrease in the measurement so that an individual dently of BMD. At the threshold for osteoporosis (T-score =
with a measurement of 3 standard deviations below the − 2.5 SD), the 10-year probability of hip fracture ranges 5-fold
average value for age would have a 1.53 or greater than 3- in women from Sweden depending on age (Fig. 1) [49]. Thus,
fold higher risk than an individual with an average BMD. the consideration of age and BMD together increases the
Note that the risk of fracture in individuals with an average range of risk that can be identified.
BMD is lower than the average fracture risk, since fracture Over the past few years, a series of meta-analyses have been
risk is a convex function of BMD. undertaken to identify additional clinical risk factors that could be
The performance characteristics of quantitative ultrasound used in case-finding strategies, with or without the use of
are similar. Most studies suggest that measurements of broad- BMD [12]. There are a number of factors to be considered in
band ultrasound attenuation or speed of sound at the heel are the selection of risk factors for case finding. Of particular im-
associated with a 1.5- to 2-fold increase in risk for each stan- portance in the setting of primary care is the ease with which
dard deviation decrease in the measured variable [33, 51]. they might be used. For a globally applicable tool, the chosen
Comparative studies indicate that these gradients of risk are risk factors should also be valid in an international setting and
very similar to those provided by peripheral assessment of their predictive value documented over time. A further and
bone mineral density at appendicular sites by absorptiometric critical consideration is the reversibility of risk, i.e. is there
techniques to predict any osteoporotic fracture [32]. Unlike evidence that the risk identified by a risk factor is amenable to
DXA, however, the long-term predictive value wanes with therapeutic intervention (reversibility of risk—not reversible
time [52]. Note also that the WHO criteria for the diagnosis risk). Age is an example of an irreversible risk factor, but the
of osteoporosis cannot be applied to ultrasound results. risk of fracture identified by age has reversibility. The risk
Table 3 Age-adjusted increase in risk of fracture (with 95% confidence interval) in women for every 1 SD decrease in bone mineral density (by
absorptiometry) below the mean value for age [amended from [32], with permission from the BMJ Publishing Group
Outcome
Site of measurement Forearm fracture Hip fracture Vertebral fracture All fractures
Distal radius 1.7 (1.4–2.0) 1.8 (1.4–2.2) 1.7 (1.4–2.1) 1.4 (1.3–1.6)
Femoral neck 1.4 (1.4–1.6) 2.6 (2.0–3.5) 1.8 (1.1–2.7) 1.6 (1.4–1.8)
Lumbar spine 1.5 (1.3–1.8) 1.6 (1.2–2.2) 2.3 (1.9–2.8) 1.5 (1.4–1.7)
Fracture probability (%)

mellitus since recent evidence suggests an important indepen-
Age Women dent risk [66–68].
20 (years)
80 It should be noted that falls risk is not included in Table 4,
though it has been used in some risk engines [69, 70], since the
70 risk of fracture that is identified may not be associated with
reversibility of risk. For example, patients selected on the basis
10 of risk factors for falling may respond less to agents that preserve
60
bone mass than those selected on the basis of low BMD [71].
Biochemical assessment of fracture risk

50
0
Bone markers are increased after the menopause, and in several
-3 -2 -1 0 1
studies the rate of bone loss varies according to the marker
T-score (SD)
value [72]. Thus, a potential clinical application of biochemical
Fig. 1 Ten-year probability of hip fracture in women from Sweden
according to age and T-score for femoral neck BMD [49], with kind
indices of skeletal metabolism is in assessing fracture risk. The
permission from Springer Science and Business Media IOF and International Federation of clinical Chemistry and
Laboratory Medicine (IFCC) have proposed two of several
factors that are used for clinical assessment with FRAX are markers as reference analytes in the prediction of fracture risk;
summarised in Table 4 [12, 41, 58–64]. Each of these risk serum procollagen type I N propeptide (s-PINP) and serum C-
factors has been shown to identify reversibility of risk [65]. terminal cross-linking telopeptide of type I collagen (s-CTX) as
In the case of causes of secondary osteoporosis, the in- markers of bone formation and bone resorption, respectively
crease in fracture risk is presumed to be mediated by low [73]. A meta-analysis of prospective studies showed a signifi-
BMD. The exceptions are glucocorticoid exposure and rheu- cant association between s-PINP and the risk of fracture. The
matoid arthritis for which risks have been identified that are hazard ratio per SD increase in s-PINP (gradient of risk; GR)
independent of BMD. A further candidate is type 2 diabetes was 1.23 (95% CI 1.09–1.39) for men and women combined
unadjusted for bone mineral density. There was also a signifi-
cant association between s-CTX and risk of fracture GR = 1.18
Table 4 Clinical risk factors used for the assessment of fracture
probability [12] Centre for Metabolic Bone Diseases, University of (95% CI 1.05–1.34) unadjusted for bone mineral density. For
Sheffield Medical School, UK, University of Sheffield, UK] the outcome of hip fracture, the association between s-CTX and
risk of fracture was slightly higher, 1.23 (95% CI 1.04–1.47)
Age
[74]. Thus, there is a modest but significant association between
Sex
Low body mass index these markers and the future risk of fractures. Currently, there
Previous fragility fracture, particularly of the hip, wrist and spine are efforts by IFCC and IOF to harmonise markers of bone
including morphometric vertebral fracture in adult life turnover, which, if successful, may promote markers of bone
Parental history of hip fracture
turnover for fracture risk prediction [75].
Glucocorticoid treatment (> 5 mg prednisolone daily or equivalent for
3 months or more)
Current smoking Trabecular bone score
Alcohol intake 3 or more units daily
Causes of secondary osteoporosis
Trabecular bone score (TBS) is a recently developed analytical
Rheumatoid arthritis
Untreated hypogonadism in men and women, e.g. premature menopause, tool that performs novel grey-level texture measurements on
bilateral oophorectomy or orchidectomy, anorexia nervosa, lumbar spine DXA images, and thereby captures information
chemotherapy for breast cancer, hypopituitarism, androgen deprivation relating to trabecular microarchitecture. Low TBS is consistently
therapy in men with prostate cancer.
associated with an increase in both prevalent and incident frac-
Inflammatory bowel disease, e.g. Crohn’s disease and ulcerative colitis. It
should be noted that the risk is in part dependent on the use of tures that is partly independent of both clinical risk factors and
glucocorticoids, but an independent risk remains after adjustment for areal BMD at the lumbar spine and proximal femur [23, 76]. It
glucocorticoid exposure. can thus be used as an adjunct to BMD measurements and is a
Prolonged immobility, e.g. spinal cord injury, Parkinson’s disease, stroke,
software option for densitometers. Studies including a meta-
muscular dystrophy, ankylosing spondylitis
Organ transplantation analysis have shown an incremental improvement in fracture
Type 1 and type 2 diabetes prediction when lumbar spine TBS is used in combination with
Thyroid disorders, e.g. untreated hyperthyroidism, thyroid hormone FRAX variables [77–81]. In the meta-analysis, when additional-
suppressive therapy
ly adjusted for FRAX 10-year probability of major osteoporotic
Chronic obstructive pulmonary disease
HIV infection fracture, TBS remained a significant, independent predictor for
fracture (Gradient of risk = 1.32, 95% CI 1.24–1.41) [77]. The
adjustment of FRAX probability for TBS resulted in a small Vertebral fracture assessment should be considered in postmen-
increase in the GR (1.76, 95% CI 1.65–1.87 versus 1.70, 95% opausal women if there is a history of ≥ 4 cm height loss,
CI 1.60–1.81). A smaller change in GR for hip fracture was kyphosis, recent or current long-term oral glucocorticoid thera-
observed (FRAX® hip fracture probability GR 2.25 vs. 2.22). py, or a BMD T-score ≤ − 2.5. It should also be considered in
Thus, TBS is a predictor of fracture risk independently of FRAX individuals with a history of non-vertebral fracture [85].
and supports the use of TBS to adjust for FRAX probability.
Adjustment of FRAX probabilities [77] is available from a ded-
icated web site (https://www.sheffield.ac.uk/TBS/
CalculationTool.aspx) or via the FRAX web site (see Fig. 2).
Assessment of fracture risk
TBS may also have a role in the assessment of fracture risk
Whereas assessment guidelines have traditionally been based
in some causes of secondary osteoporosis (e.g. diabetes, hy-
on BMD, its limitations have stimulated the development of
perparathyroidism and glucocorticoid-induced osteoporosis).
risk engines that integrate several risk factors for fracture [86].
These include the Garvan fracture risk calculator [69],
Vertebral fracture assessment QFracture® [70] and FRAX® [12, 87]. Of these, FRAX has
been the most extensively used. Since its release in 2008,
The majority of vertebral fractures do not come to medical models have been made available for 64 countries in 34 lan-
attention and thus remain undiagnosed [82]. Moderate or severe guages, covering 80% of the world population. The website
vertebral fractures, even when asymptomatic, are strong risk (http://www.shef.ac.uk/FRAX) receives approximately 6
factors for subsequent fracture at the spine and other skeletal million visits annually and in 2012–2013 calculations arose
sites [83, 84]. Vertebral fracture assessment should therefore be from 173 countries [88]. This underestimates considerably the
considered in high-risk individuals, using either lateral lumbar uptake of FRAX because the website is not the sole portal for
and thoracic spine radiographs or lateral spine DXA imaging. the calculation of fracture probabilities. For example, FRAX
Fig. 2 Screen page for input of data and format of results in the UK version of the FRAX® tool (UK model, version 3.5. http://www.shef.ac.uk/FRAX).
[With permission of the Centre for Metabolic Bone Diseases, University of Sheffield Medical School, UK]
is available in BMD equipment, on smartphones, and, in some much higher risk than a single prior fracture [92]. Dose-
countries, through hand-held calculators. FRAX has been in- responses are also evident for glucocorticoid exposure [93],
corporated into more than 80 guidelines worldwide [89]. cigarette smoking [61] and alcohol intake [60]. Since it is not
possible to accommodate all such scenarios with the FRAX
Introduction to FRAX algorithm, these limitations should temper clinical judgement.
A history of falls is a significant risk factor for fracture but
FRAX® is a computer-based algorithm that calculates the 10- is not incorporated into the FRAX model. Moreover, a signif-
year probability of a major fracture (hip, clinical spine, humerus icant risk of fracture remains after adjusting for FRAX [94].
or wrist fracture) and the 10-year probability of hip fracture [12]. However, the incorporation of falls into FRAX is problematic
Fracture risk is calculated from age, body mass index and for several reasons. First, at the time of the release of FRAX,
dichotomized risk factors comprising prior fragility fracture, existing falls data were not of adequate quality, including the
parental history of hip fracture, current tobacco smoking, ever heterogeneous construct of questions on falls. Second, falls
use of long-term oral glucocorticoids, rheumatoid arthritis, risk is inherently taken into account in the algorithm, though
other causes of secondary osteoporosis and alcohol consump- not as an input variable [95]. Thus, the fracture probability
tion (Fig. 2). Femoral neck BMD can be optionally input to given for any combination of risk factors assumes that the falls
enhance fracture risk prediction [90]. Fracture probability is risk is that observed (but not documented) in the cohorts used
computed taking both the risk of fracture and the risk of death to construct FRAX. Third, the interrelationship of falls risk
into account. The use of clinical risk factors in conjunction with the other FRAX variables has been inadequately ex-
with BMD and age improves sensitivity of fracture prediction plored on an international basis. Fourth, the relationship be-
without adverse effects on specificity [90]. tween the risk variable and mortality needs to be accounted
Fracture probability differs markedly in different regions of for, but there are no data available. These technical problems
the world [91]. The heterogeneity in Europe is shown in aside, risk assessment tools are intended to identify a risk that
Fig. 3. For this reason, FRAX is calibrated to those countries is amenable to a therapeutic intervention. However, falls as a
where the epidemiology of fracture and death is known (cur- risk variable do not consistently pass the test of reversibility of
rently 64 countries). risk [71, 96–98], a necessary feature of any risk variable used
in tools to direct interventions [12, 65, 99].
Limitations of FRAX To address some of these and other limitations, relatively
simple arithmetic adjustments have been proposed, which can
The limitations of FRAX have been reviewed recently [89]. be applied to conventional FRAX estimates of probabilities of
The FRAX assessment takes no account of dose-responses for hip fracture and a major fracture to adjust the probability as-
several risk factors. For example, two prior fractures carry a sessment with knowledge of:
Fig. 3 Ten-year probability (%) Ten-year probability (%)

of a major osteoporotic fracture in
30
women from different European
countries. BMI set to 25 kg/m2.
Data from http://www.shef.ac.uk/
FRAX 25 Women aged 65 years, T-score -2.5 SD, prior fracture
20
15
10
0
high, moderate, and low exposure to glucocorticoids Assessment of risk

[100]—see below
concurrent data on lumbar spine BMD [101, 102]—see At present there is no universally accepted policy for popula-
below tion screening in Europe to identify patients with osteoporosis
trabecular bone score [77, 80, 81, 103] or those at high risk of fracture. With the increasing develop-
hip axis length [104] ment of effective agents and price reductions, this view may
falls history [105] change, particularly for elderly people [111, 112]. In the ab-
immigration status [106] sence of a screening policy, patients are identified opportunis-
type 2 diabetes [68, 107] tically using a case-finding strategy on the finding of a previ-
ous fragility fracture or the presence of significant risk factors.
With regard to glucocorticoids, Table 5 summarises the manner The risk factors that are used for clinical assessment,
in which FRAX estimates of probabilities of hip fracture and a summarised in Table 4, may be used but in principle any risk
major osteoporotic fracture can be adjusted with knowledge of factor that alerts the physician to the possibility of osteoporo-
the dose of glucocorticoids [100]. For example, a woman aged sis is a candidate. Examples are height loss (> 4 cm) [113],
60 years from the UK taking glucocorticoids for rheumatoid thoracic kyphosis and the many other less well-characterised
arthritis (no other risk factors and BMI of 24 kg/m2) has a 10- causes of secondary osteoporosis.
year probability for a major fracture of 13%. If she is on a higher A general approach to risk assessment is shown in Fig. 4
than average dose of prednisolone (> 7.5 mg daily), then the [114]. The process begins with the assessment of fracture
revised probability should be 15% (13 × 1.15). probability and the categorisation of fracture risk on the basis
Lumbar spine BMD is frequently measured by DXA and of age, sex, BMI and the clinical risk factors. On this informa-
indeed is incorporated into several clinical guidelines. It is the tion alone, some patients at high risk may be considered for
site favoured for monitoring treatment and there is thus much treatment without recourse to BMD testing. For example,
interest in the implications for FRAX of measurements at the many guidelines in Europe [1, 89, 114] recommend treatment
lumbar spine, since there are situations where there is a large in the absence of information on BMD in women with a pre-
discordance in the T-score at different skeletal sites in individ- vious fragility fracture (a prior vertebral or hip fracture in
uals for whom the use of this information will enhance the North America) [115, 116]. Many physicians would also per-
accuracy for the characterisation of risk, particularly if they lie form a BMD test, but frequently this is for reasons other than
close to an intervention threshold. The impact of spine/ to decide on intervention, for example, as a baseline to mon-
femoral neck T-score discordance has been explored in a large itor treatment. There will be other instances where the proba-
BMD-referral population from Manitoba, Canada. There was bility is so low that a decision not to treat can be made without
approximately a 10% change in fracture risk for each unit of T- BMD. Thus, not all individuals require a BMD test. The size
score discordance [101]. On this basis, the clinician may of the intermediate category in Fig. 4 will vary in different
increase/decrease FRAX estimate for a major fracture by countries. In countries that provide reimbursement for DXA,
one-tenth for each rounded T-score difference between the this will be a large category, whereas in a large number of
lumbar spine and femoral neck. countries with limited or no access to densitometry, the size
Additionally, FRAX values have been shown to be largely of the intermediate group will necessarily be small. In other
unaffected by socioeconomic status [108], variation in body countries (e.g. the UK), where provision for BMD testing is
composition [109] and a concern that treatment might invali- sub-optimal [117], the intermediate category will lie between
date the interpretation of FRAX appears misplaced [110]. the two extremes.
Table 5 Average adjustment of

10-year probabilities of a hip Dose Prednisolone equivalent (mg/day) Average adjustment over all ages
fracture or a major osteoporotic
fracture in postmenopausal Hip fracture
women and older men according Low < 2.5 0.65
to dose of glucocorticoids. Medium 2.5–7.5 No adjustment
[Adapted from [100] with kind
permission from Springer Science High ≥ 7.5 1.20
and Business Media B.V] Major osteoporotic fracture
Low < 2.5 0.8
Medium 2.5–7.5 No adjustment
High ≥ 7.5 1.15
10 year probability (%)

CRFs 25
No risk factors, no BMD
20 Prior fracture
Fracture
probability T-score = -2.5 SD
15
T-score = -1.5 SD
High Intermediate Low 10
5
Treat BMD
0
40 45 50 55 60 65 70 75 80 85 90
Age (years)
Reassess
probability Fig. 5 Ten-year probabilities (%) of a major osteoporotic fracture for
women from Kuwait at a T-score of − 2.5 SD (open triangle), − 1.5 SD
(open square) and prior fracture (open diamond). The shaded area
High Low represents fracture probabilities in women with no clinical risk factors
and average BMD. From [120] with kind permission from Springer
Science and Business Media
Treat
reimbursement issues, health economic assessment, willingness
Fig. 4 Management algorithm for the assessment of individuals at risk of
fracture [114], with kind permission from Springer Science and Business
to pay for health care in osteoporosis and access to DXA. For
Media this reason, it is not possible or desirable to recommend a uni-
fied intervention strategy. The strategy given below draws on
that most commonly applied in Europe in the context of post-
Intervention thresholds menopausal osteoporosis but takes account that access to DXA
varies markedly in different European countries [117].
Whereas BMD provides the cornerstone for the diagnosis of Since many guidelines recommend that women with a prior
osteoporosis, the use of BMD alone is less than optimal as an fragility fracture may be considered for intervention without the
intervention threshold for several reasons. Firstly, the fracture necessity for a BMD test (other than to monitor treatment), a
risk varies markedly in different countries, but the T-score prior fracture can be considered to carry a sufficient risk that
varies only by a small amount. Secondly, the significance of treatment can be recommended. For this reason, the interven-
any given T-score to fracture risk in women from any one tion threshold in women without a prior fracture can be set at
country depends on age (see Fig. 1) and the presence of clin- the age-specific fracture probability equivalent to women with a
ical risk factors. Intervention thresholds will also be deter- prior fragility fracture [114] and therefore rises with age, for
mined in part by the cost and benefits of treatment. In addition, example, from a 10-year probability of 8 to 33% in the UK
since the T-score for BMD decreases with age, a T-score of, [121]. In other words, the intervention threshold is set at the
say, − 2.5 SD becomes less significant as a risk indicator with ‘fracture threshold’. This is the approach to intervention thresh-
age [118–120]. Thus, with advancing age, the difference in the olds proposed or used in Belgium, Finland, France, Italy,
probability of fracture between the general population and Ireland, Poland, Romania, Russia, Spain, Switzerland and by
those with a T-score of − 2.5 SD diminishes and indeed, from the National Osteoporosis Guideline Group (NOGG) in the UK
the age of 78 years in the USA and 81 years onwards in [89, 122] and European guidelines for glucocorticoid-induced
Kuwait, the fracture probability becomes progressively lower osteoporosis [123]. Incidentally, the same intervention thresh-
than that of the age and sex-matched individuals (Fig. 5). In old is applied to men, since the effectiveness and cost-
other words, a T-score of − 2.5 SD becomes a diminishing risk effectiveness of intervention in men is broadly similar to that
factor with advancing age. In contrast, a prior fragility fracture in women for equivalent risk [42, 121, 124]. The approach used
is a highly significant risk factor at all ages (see Fig. 5). has been well validated and the intervention strategy shown to
The use of FRAX in clinical practice demands a consider- be cost-effective [114, 125–128].
ation of the fracture probability at which to intervene, both for Using this criterion, the intervention threshold will vary from
treatment (an intervention threshold) and for BMD testing (as- country to country because the population risks (of fracture and
sessment thresholds). Many approaches have been used to set death) vary [91, 129]. The fracture probability in women with a
intervention thresholds with FRAX [89]. The thresholds used prior fracture in the five major EU countries is shown in Fig. 6.
have varied since they depend critically on local factors such as Probabilities are highest in the UK and lowest in Spain. The
Probability (%)
Table 6 Intervention thresholds as set by FRAX-based 10-year
40
probability (%) of a major osteoporotic fracture equivalent to women
Spain with a previous fracture (no other clinical risk factors, a body mass index
of 24 kg/m2 and without BMD). The lower assessment thresholds set by
France
30 FRAX is based on the 10-year probability (%) of a major osteoporotic
Germany fracture equivalent to women without clinical risk factors (a body mass
index of 24 kg/m2 and without BMD). The upper assessment threshold is
Italy
20 set at 1.2 times the intervention threshold. Population weighted mean
UK values for the five major EU countries. From [3], with kind permission
from Springer Science and Business Media
10 Ten-year fracture probability (%)
Age range Intervention Lower assessment Upper assessment

0 (years) threshold threshold threshold
50-55 55-60 60-65 65-70 70-75 75-80 80-85 85+
Age (years) 40–44 5.2 2.3 6.2
Fig. 6 The 10-year probability of a major osteoporotic fracture by age in 45–49 5.4 2.4 6.5
women with a prior fracture and no other clinical risk factors in the five 50–54 6.3 2.9 7.6
major EU countries as determined with FRAX (version 3.5). Body mass
55–59 7.6 3.6 9.1
index set to 24 kg/m2 without BMD. From [3], with kind permission from
Springer Science and Business Media 60–64 9.9 4.9 11.9
65–69 13.4 6.9 16.1
70–74 17.6 9.7 21.5
difference between countries is most evident at younger ages 75–79 23.0 13.7 27.6
and becomes progressively less with advancing age. 80–84 29.1 18.7 34.9
For the purposes of illustration in this guidance, an ag- 85–89 31.8 20.9 38.2
gregate value is chosen. Thus, for the countries shown in 90–94 31.7 20.8 38.0
Fig. 6, the mean probability of a major fracture in women 95–99 32.2 21.1 38.6
with a prior fracture is 6.3% between the ages of 50 and 100+ 32.5 21.3 39.0
55 years. The mean is weighted for population size in each
age interval in each country. The probability rises with age
(Table 6) and can be taken as an intervention threshold. can be set to exclude a requirement for BMD testing in women
Countries with much higher or lower probabilities may wish without clinical risk factors, as given in previous European
to develop intervention thresholds based on country- guidelines [1–3, 123]. The probability equivalents are given
specific risks as has been adopted in several countries in in Table 6. In a few countries, population-based assessment
Europe and elsewhere. Note that the example in Table 6 uses with BMD is recommended (Germany and France in Europe).
the probability of a major osteoporotic fracture to determine In such cases, there would be no lower assessment threshold.
an intervention threshold fracture. In addition to the 10-year An upper threshold can be chosen to minimise the prob-
probability of a major osteoporotic fracture, intervention ability that a patient characterised to be at high risk on the
thresholds can be based on the 10-year probability of hip basis of clinical risk factors alone would be reclassified to
fracture. Either or both thresholds can be used as recom- be at low risk with additional information on BMD [125].
mended in the recent NOGG guidance [85]. In the UK, the upper assessment threshold was set at 1.2
times the intervention threshold [114]. The rationale is that
Assessment thresholds for BMD testing reclassification of risk with the addition of a BMD test
(from high risk to low risk and vice versa) is high when
The assessment strategy outlined in Fig. 4 requires the deter- fracture probabilities estimated without BMD are close to
mination of assessment thresholds for making recommenda- the intervention threshold and the likelihood of reclassifi-
tions for the measurement of BMD. There are, in principle, cation decreases the further away the probability estimate is
two assessment thresholds [114]: from the intervention threshold [125]. When patients have a
A threshold probability below which neither treatment nor a fracture probability that is 20% or more than the interven-
BMD test should be considered (lower assessment threshold). tion threshold, almost no individuals will be reclassified
A threshold probability above which treatment may be rec- (from high to low risk) when probabilities are recomputed
ommended irrespective of BMD (upper assessment threshold). with the addition of BMD to FRAX [124, 130–132]. Thus,
Most countries adopt a case-finding strategy where individ- a quotient of 1.2 is applied to the intervention, illustrated for
uals with clinical risk factors are identified for further assess- the European example in Table 6. An attraction of the ap-
ment [12]. For this scenario, the lower assessment threshold proach is that efficient use is made of BMD testing.
Ten year probability (%)

Application of probability thresholds
40
The application of these assessment thresholds depends criti-
cally on the availability (and reimbursement) of densitometry,
30 Intervention threshold
which vary from country to country. It has been estimated that
the requirements to service osteoporosis amount to approxi-
Assess with BMD
mately 11 DXA units/millions of the general population [117], 20
though this estimate probably requires updating to take ac-
count of population demography. The availability of DXA
falls above this estimate in a minority of European countries 10
(Fig. 7). The large variation in resources for BMD testing No treatment
demand the consideration of three assessment scenarios that

depend on the access to central densitometry. 0
40 50 60 70 80
Age (years)
Unrestricted access to densitometry Fig. 8 Assessment of major osteoporotic fracture risk in countries with
high access to DXA. DXA is undertaken in women with a clinical risk
factor. Assessment with DXA and/or treatment is not recommended
Where resources for BMD testing are adequate, BMD tests where the FRAX probability is lower than the lower assessment
can be undertaken in women with any clinical risk factors as threshold (green area). BMD is recommended in other women and
shown in Fig. 8. Treatment is recommended where fracture treatment recommended where the fracture probability exceeds the
intervention threshold (dotted line). The intervention threshold used is
probability exceeds the intervention threshold. Note that the that derived from Table 6. From [3], with kind permission from
lower assessment threshold is set as equivalent to women Springer Science and Business Media
without clinical risk factors (see above). In those countries
where screening of women without risk factors is recommend- Limited access to densitometry
ed, there would be no lower assessment threshold. An addi-
tional option is to recommend treatment in women with a prior Several countries must take a parsimonious approach to the use
fragility fracture without recourse to BMD (though BMD of BMD. The guidance recommends that postmenopausal wom-
might be undertaken to monitor treatment). en with a prior fragility fracture may be considered for interven-
The assessment algorithm is summarised in Box 1. BMD tion without the necessity for a BMD test. In women without a
tests are recommended in all postmenopausal women with a fragility fracture but with one or more other CRF, the intervention
clinical risk factor. threshold is set at the age-specific fracture probability equivalent
to women with a prior fragility fracture and BMD testing recom-
EU27
mended in those in whom fracture probability lies between the
Belgium
Greece
upper and lower assessment threshold as described above [114]
France
Austria
Slovenia
Portugal
Cyprus BOX 1 Assessment of fracture risk with FRAX with unlimited access to
Germany BMD*
Italy
Finland
Denmark • Fracture risk should be assessed in postmenopausal women with one or
Slovakia more clinical risk factor where assessment would influence
Netherlands
Sweden management.
Ireland • Women with a prior fragility fracture might be considered for treatment
Malta
Estonia
without the need for further risk assessment although BMD
Spain measurement may sometimes be appropriate.
UK • In women without a prior fragility fracture, the 10-year probabilities of a
Hungary
Czech major osteoporotic fracture (clinical spine, hip, forearm or humerus)
Latvia and hip fracture should be determined using FRAX without BMD. In
Poland
Lithuania
the absence of other clinical considerations, men and women with
Romania probabilities below the assessment threshold can be reassured.
Luxembourg • Those with probabilities above the assessment threshold can be
Bulgaria
considered for testing with BMD using DXA and their fracture
probability reassessed. Thereafter, women with probabilities above the
0 10 20 30 40 50
intervention threshold should be considered for treatment.
DXA (units/million)
Fig. 7 The density of central DXA equipment (units/million of the *From [3], with kind permission from Springer Science and Business
general population in the EU countries in 2010 [Kanis JA, data on file] Media
This approach, adapted to the common EU thresholds shown in BOX 2 Assessment of fracture risk with FRAX with limited access to
BMD*
Table 6, is illustrated in Fig. 9.
The assessment algorithm is summarised in Box 2. • Fracture risk should be assessed in postmenopausal women with one or
more clinical risk factor where assessment would influence
management.
• Women with a prior fragility fracture should be considered for treatment
No access or patchy access to densitometry without the need for further risk assessment although BMD
measurement may sometimes be appropriate, particularly in younger
In countries with very limited or no access to DXA, postmenopausal women.
FRAX can be used without BMD. For the purpose of risk • In women without a prior fragility fracture, the 10-year probabilities of a
major osteoporotic fracture (clinical spine, hip, forearm or humerus)
assessment, a characteristic of major importance is the and hip fracture should be determined using FRAX without BMD. In
ability of a technique to predict fractures, traditionally the absence of other clinical considerations, men and women with
expressed as the increase in relative risk per standard de- probabilities below the lower assessment threshold can be reassured
viation (SD) unit decrease in risk score—termed the gra- and those with probabilities above the upper assessment threshold can
be considered for treatment.
dient of risk. The gradient of risk with FRAX is shown in • Those with probabilities above the lower assessment threshold but
Table 7 for the use of the clinical risk factors alone, fem- below the upper assessment threshold can be considered for testing
oral neck BMD and the combination [90]. with BMD using DXA and their fracture probability reassessed.
The use of clinical risk factors alone provides a GR that lies Thereafter, women with probabilities above the intervention threshold
should be considered for treatment.
between 1.4 and 2.1, depending upon age and the type of fracture
predicted. These gradients are comparable to the use of BMD *From [3], with kind permission from Springer Science and Business
alone to predict fractures [32, 41]. For example, for the prediction Media
of any osteoporotic fracture, the GR at the age of 70 years was
1.5 with femoral neck BMD [32]. With peripheral BMD, the In several countries (Finland, Lebanon, Romania, UK),
gradient of risk is somewhat, though not significantly lower there is a link between the FRAX web site to an independent
(GR = 1.4/SD; 95% CI = 1.3–1.5/SD). These data suggest that site that plots the FRAX output against the intervention
clinical risk factors alone are of value and can be used, therefore, thresholds for that country and facilitates treatment decisions.
in the many countries where DXA facilities are insufficient The NOGG web site in the UK is widely used (https://www.
(Box 3). The rationale for the use of FRAX in the absence of sheffield.ac.uk/NOGG/) [133].
access to BMD or limited access has been recently reviewed [65,
89]. Briefly, most of the risk factors incorporated within FRAX Alternative approaches to intervention thresholds
contribute independently from BMD to fracture risk, but are not
totally independent of BMD; thus, higher risk is associated with The NOGG guidelines in the UK have recently been revised
lower underlying BMD [125, 132]. [134]. The intervention threshold up to age 70 years is set at a
risk equivalent to that associated with a prior fracture, in line
with current clinical practice, and therefore rises with age. At
Ten year probability (%) age 70 years and above, however, a fixed threshold is applied
40 [134]. The alternative thresholds equilibrate fracture risk, par-
UAT ticularly hip fracture risk, in those with or without prior frac-
IT ture selected for treatment and reduce BMD usage at older
30 Intervention threshold
ages. This modification from the age of 70 years is not neces-
Consider treatment
sarily applicable to other countries and would require the im-
20 LAT pact of changes to be evaluated.
An alternative approach to intervention thresholds has been
10
applied in Germany, which uses a country-specific algorithm to
No treatment estimate the 10-year incidence (not probability) of fracture [135].
Several guidelines in Europe that use FRAX have recom-
0
40 50 60 70 80 mended that a fixed probability threshold be used as an inter-
Age (years) vention threshold. Examples include a 20% 10-year probabil-
Fig. 9 Assessment guidelines based on the 10-year probability of a major ity of a major fracture in several European countries and a
osteoporotic fracture (%). The dotted line denotes the intervention 15% probability in Sweden [89]. Many utilise a threshold
threshold. Where assessment is made in the absence of BMD, a BMD probability of 20% for a major osteoporotic fracture many of
test is recommended for individuals where the probability assessment lies
in the orange region. The intervention threshold and BMD assessment
which also mention a hip fracture probability of 3% as an
thresholds used are those derived from Table 6. From [3], with kind alternative intervention threshold. In nearly all instances, no
permission from Springer Science and Business Media rationale is provided other than the fact that this was the
Table 7 Gradients of risk (the

increase in fracture risk per SD Gradient of risk
change in risk score) with 95%
confidence intervals with the use Age (years) BMD only Clinical risk factors alone Clinical risk factors + BMD
of BMD at the femoral neck,
clinical risk factors or the (a) Hip fracture
combination [90], with kind 50 3.68 (2.61–5.19) 2.05 (1.58–2.65) 4.23 (3.12–5.73)
permission from Springer Science
60 3.07 (2.42–3.89) 1.95 (1.63–2.33) 3.51 (2.85–4.33)
and Business Media B.V
70 2.78 (2.39–3.23) 1.84 (1.65–2.05) 2.91 (2.56–3.31)
80 2.28 (2.09–2.50) 1.75 (1.62–1.90) 2.42 (2.18–2.69)
90 1.70 (1.50–1.93) 1.66 (1.47–1.87) 2.02 (1.71–2.38)
(b) Other osteoporotic fractures
50 1.19 (1.05–1.34) 1.41 (1.28–1.56) 1.44 (1.30–1.59)
60 1.28 (1.18–1.39) 1.48 (1.39–1.58) 1.52 (1.42–1.62)
70 1.39 (1.30–1.48) 1.55 (1.48–1.62) 1.61 (1.54–1.68)
80 1.54 (1.44–1.65) 1.63 (1.54–1.72) 1.71 (1.62–1.80)
90 1.56 (1.40–1.75) 1.72 (1.58–1.88) 1.81 (1.67–1.97)
threshold used by the National Osteoporosis Foundation of Other assessment models

the USA [116]. The rationale for a fixed threshold in the
USA was based on the fracture probability at which interven- As well as the FRAX tool, other fracture risk calculators are
tion becomes cost-effective in the USA and is, therefore, not available online which include the Garvan fracture risk cal-
relevant for any other country. culator and QFracture® [69, 70]. A fundamental difference
The impact of using a fixed intervention threshold is shown between these risk models and FRAX is that the parameters
in Fig. 10 for postmenopausal women in the UK. At high of risk differ (incidence vs. probabilities) so that compara-
thresholds e.g. > 20% fracture probability 17% of postmeno- tive data are not readily interpreted [137] (Fig. 11). In
pausal women would be eligible for treatment. A problem that FRAX, fracture probability is computed taking both the
arises is that very few women under the age of 60 years would risk of fracture and the risk of death into account. This is
ever attain this threshold. On the other hand, if a less stringent important because some of the risk factors affect the risk of
threshold were chosen, say 5%, then nearly all women at the death as well as the fracture risk. Examples include increas-
age of 50 years and above would exceed this threshold. Both ing age, sex, low BMI, low BMD, use of glucocorticoids
scenarios could be justified on health economic criteria in the and smoking.
UK [128], but both are counterintuitive to clinical practice.
Critically, economic criteria should not be used to set interven- Effectiveness of risk assessment strategies
tion thresholds but, more appropriately, to validate the imple-
mentation of clinically driven intervention thresholds [136]. Until recently, the effectiveness of risk-assessment strate-
gies in which samples of the general population might be
evaluated for risk factors and BMD estimation to derive
BOX 3 Assessment of fracture risk with FRAX without BMD
individual estimates of absolute fracture risk, with targeting
• Fracture risk should be assessed in postmenopausal women with one or of anti-osteoporosis therapy on the basis of these estimates,
more clinical risk factor where assessment would influence remained uncertain. The publication of the MRC SCOOP
management.
• Women with a prior fragility fracture should be considered for treatment
trial (SCreening of Older wOmen for the Prevention of
without the need for further risk assessment. fractures) provides strong support for such a strategy
• In men, and in women without a prior fragility fracture, the 10-year [111]. This seven-centre pragmatic randomised controlled
probabilities of a major osteoporotic fracture (clinical spine, hip, trial with 5-year follow-up included 11,580 women aged
forearm or humerus) and hip fracture should be determined using
FRAX without BMD. In the absence of other clinical considerations,
70–85 years, who were randomised to receive a care algo-
men and women with probabilities below the intervention threshold rithm including FRAX and drug targeting (n = 6233) or
can be reassured. usual primary care for osteoporosis based on opportunistic
• Treatment can be considered in those in whom fracture probabilities lie case finding (n = 6250). Women were recruited from 100
above the intervention threshold.
UK general practices, and the principle outcome measures
*From [3], with kind permission from Springer Science and Business were major osteoporotic, hip and all fractures. Screening
Media reduced the incidence of hip fractures (0.72, 0.59–0.89,
Fig. 10 The impact of a fixed Identified for treatment (%)

treatment threshold in
postmenopausal women in the 100 >5% 100
UK according to threshold values 86
for the probability of a major
>10%
osteoporotic fracture. The left- 80 80
hand panel shows the proportion
of the postmenopausal population
>15%
exceeding the threshold shown at 60 60
each age. The right-hand panel 50
shows the proportion of the total >20%
postmenopausal population that 40
exceed a given threshold. From 40
>25% 29
[3], with kind permission from
Springer Science and Business >30%
20 20
17
Media 11
7
0
0
50- 60- 70- 80-
>5% >10% >15% >20% >25% >30%
Age (years) FRAX threshold
p = 0.002). The effect on hip fracture increased significant- General management

ly with baseline FRAX hip fracture probability (p = 0.021
for interaction); for example, at the 10th percentile of base- Mobility and falls
line FRAX hip probability (2.6%), hip fractures were not
significantly reduced (HR 0.93, 0.71 to 1.23), but at the Immobilisation causes of bone loss. Immobilised patients
90th percentile (16.6%), there was a 33% reduction (HR when confined to bed may lose as much bone in a week
0.67, 0.53 to 0.84) [112]. The screening algorithm resulted than they would otherwise lose in a year. Weight-bearing
in a pronounced increase in the use of anti-osteoporosis exercise forms an integral component of osteoporosis man-
medication, and greater compliance with therapy, over the agement [139–141]. The amount of weight-bearing exer-
period of follow-up. These findings strongly support a sys- cise that is optimal for skeletal health in patients with os-
tematic, community-based screening programme of frac- teoporosis is not known. Physiotherapy is an important
ture risk in older women. In addition, the strategy appears component of rehabilitation after fracture. At all times,
to be cost-effective [138]. exercises to improve muscle strength and balance may
Fig. 11 The risk of hip fracture Hip fracture risk (%)

with age in a model that considers Hip fracture probability (%)
10-year fracture risk alone (the
Garvan tool) and FRAX, which 40
computes the probability of hip
fracture from the fracture and 35
death hazards (FRAX). The T-
scores are set differently in the FRAX Garvan
30 FRAX Australia (v3.1)
two models so that the risks are Female
approximately equal at the age of T-score = -4.0 SD
60 years. Data are computed from 25 BMI = 23.9 kg/m2
the respective web sites [137]. No clinical risk factors
With kind permission from 20

Springer Science and Business Garvan Tool
Female
Media
15 T-score =-3.3 SD
No clinical risk factors
10
0
50 60 70 80 90
Age (years)
prevent falls by restoring confidence and coordination, and primary endpoints in any of the studies and the association
additionally maintain bone mass by stimulating bone for- remains the subject of some controversy [158–163].
mation and decreasing bone resorption. Overall, it can be concluded that (1) calcium and vitamin D
Such measures can be coupled with a programme to reduce supplementation may lead to a modest reduction in fracture
the likelihood of falls in those at high risk [142, 143]. risk, although population-level intervention has not been
Modifiable factors such as correcting decreased visual acuity, shown to be an effective public health strategy; (2) supple-
reducing consumption of medication that alters alertness and mentation with calcium alone does not reduce fracture risk; (3)
balance, and improving the home environment (slippery side effects of calcium supplementation include renal stones
floors, obstacles, insufficient lighting, handrails) are important and gastrointestinal symptoms; (4) vitamin D supplementa-
measures aimed at preventing falls [144]. Fall prevention ex- tion, rather than calcium, may reduce falls risk; and (5) in-
ercise interventions have been shown to reduce the risk of creased cardiovascular risk consequent to calcium supplemen-
injurious falls and of fracture [145]. Whole body vibration tation is not convincingly supported by current evidence; (6)
may be beneficial for falls risk reduction, but without effect calcium and vitamin D supplementation is recommended for
on BMD or fracture risk [146]. Some randomised trials have patients at high risk of calcium and vitamin D insufficiency,
shown that wearing hip protectors can reduce hip fracture risk, and in those who are receiving treatment for osteoporosis
particularly in the elderly living in nursing homes. A meta- [153]. This approach appears to be cost-effective [164].
analysis of well-conducted randomised controlled trials has, Vitamin D supplements alone may reduce the risk of frac-
however, cast some doubt about the anti-fracture efficacy of ture and falls provided the daily dose of vitamin D is greater
this preventive measure [147–150]. than 700 IU [165, 166]. In contrast, studies with large annual
doses of vitamin D have reported an increased risk of hip
fracture and, in one study, and also of falls [167, 168]. The
Nutrition upper limit of vitamin D dose that is beneficial on falls may be
lower than previously estimated [169, 170].
At every stage of life, adequate dietary intakes of key bone Whereas a gradual decline in caloric intake with age can be
nutrients such as calcium, vitamin D and protein contribute to considered as an appropriate adjustment to the progressive
bone health and reduce thereby the risk of osteoporosis and of reduction in energy expenditure, a parallel reduction in protein
fracture later in life [151]. Dietary sources of calcium are the intake may be detrimental for maintaining the integrity and
preferred option and calcium supplementation should only be function of several organs or systems, including skeletal mus-
targeted to those who do not get sufficient calcium from their cle and bone. Sufficient protein intakes are necessary to main-
diet and who are at high risk for osteoporosis. The tain the function of the musculoskeletal system, but they also
Recommended Nutrient Intakes are 800–1000 mg of calcium decrease the complications that occur after an osteoporotic
and 800 IU of vitamin D per day in men and women over the fracture [151, 171]. Correction of poor protein nutrition in
age of 50 years [152]. patients with a recent hip fracture has been shown to improve
Combined calcium and vitamin D supplements in a daily the subsequent clinical course by significantly lowering the
dose of 0.5–1.2 g and 400–800 IU, respectively, are generally rate of complications, such as bedsores, severe anaemia and
recommended in patients receiving bone protective therapy, intercurrent lung or renal infection. The duration of hospital
since most randomised controlled trial evidence for the effica- stay of elderly patients with hip can thus be shortened [151].
cy of interventions is based on co-administration of the agent Dairy products are a source of both protein and calcium,
with calcium and vitamin D supplements [153]. Calcium and since 1 L of milk provides 32 g of protein and 1200 mg of
vitamin D supplements may decrease secondary hyperpara- calcium. Dairy products, some being fortified with calcium or
thyroidism and reduce the risk of proximal femur fracture, vitamin D, decrease circulating PTH, increase IGF-I and de-
particularly in the elderly living in nursing homes [154, crease bone resorption markers [171–173]. Dairy products are
155]. In six trials included in the meta-analysis [155], hip associated with higher bone strength in both men and women
fracture risk was 0.61 (95% CI 0.46–0.62) with calcium and [174, 175]. In older US men and women, higher milk con-
vitamin D supplementation. In contrast, a recent meta-analysis sumption is associated with a lower hip fracture risk [176].
did not find a reduction in fracture risk in community- Fermented milk products like yogurt or soft cheese may pro-
dwelling older adults receiving calcium, vitamin D, or the vide larger amounts of these nutrients than the same volume of
combination [156]. The latter included seven trials, but only plain milk because of enrichment with milk powder to make
three among those analysed in [155]. Adding to the contro- the yogurt matrix denser [177–179]. Thus, calcium and vita-
versies over calcium, a meta-analysis has concluded that cal- min D fortified dairy products (yogurt, milk) providing at least
cium supplements without co-administered vitamin D were 40% of the RNI of calcium (400 mg) and 200 IU of vitamin D
associated with an increase in the risk of myocardial infarction per portion are valuable options for covering the needs in the
by around 30% [157]. Cardiovascular outcomes were not oldest old. Cheese consumption is associated with lower
mortality [180]. Several studies have concluded to a post hoc analysis showed a significant reduction of non-
favourable cost-effectiveness of dairy products in osteoporosis vertebral fractures [189].
management [181–184]. In the MORE study and its placebo-controlled 4-year
follow-up (CORE), the only severe (but rare) adverse event
was an increase of deep venous thromboembolism. Hot
flushes and lower limb cramps are commonly reported.
Major pharmacological interventions There was a significant and sustained decrease of the risk of
invasive breast cancer (by about 60%) [190], that has been
The most commonly used agents in Europe are raloxifene, the
subsequently confirmed in two other large cohorts, including
bisphosphonates alendronate, ibandronate, risedronate and zo-
the STAR study that showed similar breast cancer incidences
ledronic acid, agents derived from parathyroid hormone and
with raloxifene and tamoxifen in high-risk populations [191].
denosumab. They have all been shown to reduce the risk of
The RUTH study, performed in postmenopausal women at
vertebral fracture. Some have also been shown to reduce the
high risk of cardiovascular disease [192], showed that raloxi-
risk of non-vertebral fractures and, in some cases, agents have
fene had no effect on cardiovascular death, and on the inci-
been shown specifically to decrease fracture risk at the hip
dence of coronary heart disease and stroke [193]. However, an
(Table 8) [3, 85, 185, 186].
increased risk of death from stroke has been reported in wom-
en with or at risk of coronary heart disease. The efficacy of
Selective oestrogen receptor modulators raloxifene has been shown in women with osteopenia [194]
and is not dependent on the level of fracture risk assessed by
Selective oestrogen receptor modulators (SERMs) are nonste- FRAX [195]. In summary, the overall risk-benefit ratio of
roidal agents that bind to the oestrogen receptor and act as raloxifene is favourable and the drug is approved widely for
oestrogen agonists or antagonists, depending on the target the prevention and treatment of postmenopausal osteoporosis.
tissue. The concept of SERMs was triggered by the observa- Bazedoxifene is a selective oestrogen receptor modulator that
tion that tamoxifen, which is an oestrogen antagonist in breast has been approved in Europe but is only available in Spain and
tissue, is a partial agonist on bone, reducing the rate of bone Germany. In phase 3 clinical trials, bazedoxifene was shown to
loss in postmenopausal women [187]. Raloxifene is the only reduce the risk of new vertebral fracture, with favourable effects
SERM widely available for the prevention and treatment of on bone mineral density, bone turnover markers and the lipid
postmenopausal osteoporosis, but several others are in clinical profile [196, 197]. The phase III study was extended up to 7 years
development. Raloxifene prevents bone loss [188] and re- [198]. During this period, the efficacy and safety of bazedoxifene
duces the risk of vertebral fractures by 30–50% in postmeno- were sustained. Two separate network meta-analyses provided an
pausal women with low bone mass, and with osteoporosis indirect comparison of the effect of bazedoxifene versus oral
with or without prior vertebral fractures as shown in the bisphosphonates, for the prevention of vertebral [199] and non-
MORE trial [188]. There was no significant reduction of vertebral fractures [200], respectively. They concluded that
non-vertebral fractures. In women with severe vertebral frac- bazedoxifene is expected to have at least a comparable relative
tures at baseline (i.e. at highest risk of subsequent fractures), a risk reduction of vertebral [199] and non-vertebral fracture [200]
Table 8 Anti-fracture efficacy of

the most frequently used Effect on vertebral fracture risk Effect on non-vertebral fracture risk
treatments for postmenopausal
osteoporosis when given with Osteoporosis Established osteoporosisa Osteoporosis Established osteoporosisa
calcium and vitamin D, as derived
from randomised controlled trials Alendronate + + NA + (including hip)
(updated from [3]) Risedronate + + NA + (including hip)
Ibandronate NA + NA +b
Zoledronic acid + + NA +c
HRT + + + + (including hip)
Raloxifene + + NA NA
Teriparatide NA + NA +
Denosumab + +c + (including hip) +c
NA no evidence available, + effective drug

a
Women with a prior vertebral fracture
b
In subsets of patients only (post hoc analysis)
c
Mixed group of patients with or without prevalent vertebral fractures
as alendronate, ibandronate and risedronate. In a post hoc study in worldwide. In the Fracture Intervention (FIT) study, alendronate
a subgroup of women at increased risk of fracture, bazedoxifene was shown to reduce the incidence of vertebral, wrist and hip
decreased non-vertebral fracture risk. In contrast to raloxifene, the fractures by approximately half in women with prevalent verte-
efficacy of bazedoxifene is dependent on the level of fracture risk bral fractures [207–209]. In women without prevalent vertebral
assessed by FRAX [201]. In common with raloxifene, venous fractures, there was no significant decrease in clinical fractures in
thromboembolic events, primarily deep vein thromboses, leg the overall population, but the reduction was significant in the
cramps and hot flushes were more frequently reported in the active one third of patients that had a baseline hip BMD T-score lower
treatment groups compared with the placebo group [202]. than − 2.5 SD [210]. In a population of more than 90,000 men
Bazedoxifene has been combined with conjugated equine and women aged 80 years and older and who had sustained a
oestrogen to create a tissue selective oestrogen complex for prior fracture, a case-control analysis revealed that alendronate
the management of vasomotor symptoms and the prevention use was associated with a 34% decrease in hip fracture risk, and a
of osteoporosis associated with menopause [203]. A series of 12% lower mortality risk but with a 58% increase in the risk of
five phase III studies known as the Selective estrogen, mild upper gastrointestinal symptoms [211].
Menopause And Response to Therapy (SMART) trials led to Risedronate has been shown to reduce the incidence of
the approval, by the US Food and Drug Administration (FDA) vertebral and non-vertebral fractures by 40–50% and 30–
and in Europe, of a daily dose of bazedoxifene 20 mg/ 36%, respectively, in women with prevalent vertebral frac-
conjugated equine oestrogen 0.45 mg. This association im- tures [212, 213]. In a large population of elderly women,
proved vasomotor symptoms whilst opposing breast and en- risedronate decreased significantly the risk of hip fractures
dometrial proliferation, preventing bone resorption and im- by 30%, an effect that was greater in osteoporotic women
proving lipid profiles [203]. Over 12 months, this combination age 70–79 years (− 40%), and not significant in women over
product improved BMD at the spine and at the hip, reduced the age of 80 years without evidence of osteoporosis [71]. A
markers of bone turnover and significantly improved vasomo- delayed-release formulation of 35 mg risedronate weekly, giv-
tor function score in a population of European postmenopaus- en before or immediately following breakfast, showed a sim-
al women without effects on fracture risk [204]. ilar or greater effect on spine and hip BMD than traditional
immediate-release 5 mg risedronate daily. This formulation
Bisphosphonates allows osteoporotic patients to take their weekly risedronate
dose immediately after breakfast, hence offering a potential
Bisphosphonates are stable analogues of pyrophosphate for improved adherence and persistence to treatment [214].
characterised by a P-C-P bond. A variety of bisphosphonates Ibandronate given daily (2.5 mg) reduces the risk of vertebral
has been synthesised, the potency of which depends on the fractures by 50–60%. An effect on non-vertebral fractures was
length and structure of the side chain [205]. Bisphosphonates only demonstrated in a post hoc analysis of women with a base-
have a strong affinity for bone apatite, both in vitro and line of BMD T-score below − 3 SD [215–217]. Bridging studies
in vivo, which is the basis for their clinical use. They are have shown that oral ibandronate 150 mg once monthly is equiv-
potent inhibitors of bone resorption and produce their effect alent or superior to daily ibandronate in increasing BMD and
by reducing the recruitment and activity of osteoclasts and decreasing biochemical markers of bone turnover, giving rise to
increasing their apoptosis. The potency and chemical affinity its approval for the prevention of vertebral fracture in postmeno-
to bone of bisphosphonates determines their effect to inhibit pausal osteoporosis [218]. The efficacy and safety of oral month-
bone resorption and varies greatly from compound to com- ly ibandronate was confirmed for up to 5 years in women with
pound. Potency differences can range 10,000-fold in vitro, so postmenopausal osteoporosis [218, 219]. Similarly, bridging
that the doses used clinically also vary. The mechanism of studies comparing intermittent intravenous ibandronate to daily
action on osteoclasts includes inhibition of the proton vacuolar oral treatment has led to the approval of intravenous ibandronate
adenosine triphosphatase (ATPase) and alteration of the cyto- 3 mg every 3 months for the same indication [220]. A post hoc
skeleton and the ruffled border. Amino-bisphosphonates also analysis of pooled individual patient data from the studies
inhibit the farnesyl pyrophosphate synthase step in the assessing the long-term (5 years) efficacy of oral [218] and intra-
mevalonate pathway, thereby modifying the isoprenylation venous [221] ibandronate concluded that for ibandronate regi-
of guanosine triphosphate binding proteins. mens with annual cumulative exposure ≥ 10.8 mg, time-to-
Oral bioavailability of bisphosphonates is low, around 1% of fracture was significantly longer for all clinical fractures, non-
the dose ingested, and is impaired by food, calcium, iron, coffee, vertebral and clinical vertebral fractures versus placebo and that
tea and orange juice. Bisphosphonates are quickly cleared from for all fracture types, the rate of fracture appeared stable up to
plasma, about 50% being deposited in bone and the remainder 5 years [222].
excreted in urine. Their half-life in bone is very prolonged [206]. Based on the result of a phase II study [223], a large phase
Alendronate 70 mg once weekly and risedronate 35 mg once III trial in over 7700 postmenopausal osteoporotic patients
weekly are the most commonly used bisphosphonates assessed the efficacy of yearly infusion of zoledronic acid
5 mg over 3 years. As compared to the placebo group, zole- The possibility that bisphosphonate therapy is associated
dronic acid was found to reduce the incidence of vertebral with increased risk of oesophageal cancer has been raised.
fractures by 70% and that of hip fractures by 40% [224] and Two studies from the General Practice Research Database in
is now available for the treatment of postmenopausal osteopo- the UK have produced conflicting results, one failing to show
rosis. Intravenous zoledronic acid has also been shown to any association but another concluding that there was an in-
decrease the risk of fracture and mortality when given shortly creased risk with extended use over 5 years [239, 240].
after a first hip fracture [225]. The phase III trial was extended Finally, bisphosphonate use may be associated with atypical
to 6 [226] and 9 [227] years. The overall conclusion was that subtrochanteric fractures [241–243]. Likewise, associations
pursuing treatment beyond 3 years only provided marginal between bisphosphonate exposure and lower risks of mortal-
benefits [227]. Some authors even argue that an annual ad- ity and cancer also require further scrutiny [244–247]. The
ministration of 5 mg zoledronic acid might represent over risk-benefit ratio remains favourable for the use of
treatment [228]. A single dose of 5 mg zoledronic acid given bisphosphonates to prevent fractures [242].
to frail elderly women improved spine and total hip BMD over Many authors recommend that patients be reviewed after
2 years, compared to placebo but the treated group had an 3 years (IV) or 5 years (oral) treatment with bisphosphonate
increase in fractures, multiple falls and mortality [229] sug- [85, 232, 235, 237]. It is appropriate that periodic assessment
gesting that zoledronic acid may not be an appropriate treat- of fracture risk should use FRAX with femoral neck BMD
ment for such patients. [85]. Fracture risk should be reassessed after a new fracture,
regardless of when it occurs [85]. Although some advocate a
Safety of bisphosphonates ‘drug holiday’, prospective and retrospective analyses report
that the risk of new clinical fractures was 20–40% higher in
The overall safety profile of bisphosphonates is favourable. subjects who stopped treatment [248, 249] and vertebral frac-
Oral bisphosphonates are associated with mild gastrointestinal ture risk was approximately doubled [226, 250].
disturbances, and some amino-bisphosphonates (alendronate A substantial body of evidence indicates that some generic
and pamidronate) can rarely cause oesophagitis. A network formulations of alendronate are more poorly tolerated than the
meta-analysis compared the gastrointestinal safety of all oral proprietary preparations, which results in significantly poorer
and injectable bisphosphonates given to osteoporotic patients. adherence and thus effectiveness [251].
It concluded that zoledronic acid has the highest probability of
causing gastrointestinal adverse events, possibly related to Peptides of the parathyroid hormone family
nausea [230]. Intravenous amino-bisphosphonates can induce
a transient acute phase reaction with fever, bone and muscle The continuous endogenous production of parathyroid hor-
pain that ameliorates or disappears after subsequent courses mone (PTH), as seen in primary or secondary hyperparathy-
[231]. roidism, or its exogenous administration can lead to deleteri-
Osteonecrosis of the jaw has been described in cancer pa- ous consequences for the skeleton, particularly on cortical
tients receiving high doses of intravenous pamidronate or bone. However, intermittent administration of PTH (e.g. with
zoledronate. The incidence in osteoporotic patients treated daily subcutaneous injections) results in an increase of the
with oral and intravenous bisphosphonates appears to be very number and activity of osteoblasts, leading to an increase in
rare (in the order of 1/100,000 patient-year), only slightly bone mass and in an improvement in skeletal architecture at
higher than the incidence in the general population [232, both cancellous and cortical skeletal sites [252].
233]. The risk of osteonecrosis of the jaw is reported to be The 1-34 N-terminal fragment (teriparatide) is used for the
greater with a longer duration of bisphosphonate therapy [234, management of osteoporosis. The marketing authorisation for
235], but this finding is not consistent [232]. Possible expla- the 1 to 84 intact molecule has been withdrawn at the request
nations relate to the class of bisphosphonate, differences in of the marketing authorisation holder. Treatment with
potency and route of administration. The time to onset of teriparatide has been shown to reduce significantly the risk
osteonecrosis of the jaw may be shorter for intravenous zole- of vertebral fractures and also non-vertebral fractures. There
dronic acid compared to oral alendronate [236] [237]. is no convincing evidence that teriparatide reduces hip frac-
Concerns have been raised about a possible association ture, but this may reflect absence of evidence, not evidence of
between bisphosphonate therapy and atrial fibrillation. absence. Thus, the recommendation for its use in high-risk
Subsequent studies have produced conflicting results, but people is particularly strong in patients with vertebral fracture.
have not excluded the possibility of such an association in The recommended dose is 20 μg of teriparatide, given as a
people at increased risk of fracture [238]. Patients to whom subcutaneous injection [253]. Treatment with PTH has been
zoledronic acid was administered for up to 9 years had a studied when given for 18 to 24 months and beneficial effects
higher risk of cardiac arrhythmias compared to those who on non-vertebral fracture with teriparatide have been shown to
discontinued the treatment after 6 years [227]. persist for up to 30 months after stopping teriparatide [254].
The most common reported adverse events in patients treated remained stable (approximately 1.5% per year for both vertebral
withPTHorteriparatidearenausea,paininthelimbs,headacheand and non-vertebral fractures) [235, 259]. The incidence of verte-
dizziness. In normocalcaemic patients, slight and transient eleva- bral and non-vertebral fracture observed during the extension
tions of serum calcium concentrations have been observed follow- was similar to that observed in the denosumab group during
ingtheinjectionteriparatide.Serumcalciumconcentrationsreacha the first 3 years and lower than rates projected from a virtual
maximum between 4 and 6 h and return to baseline 16 to 24 h after long-term placebo cohort [259].
each dose. The change is small and routine monitoring of serum Discontinuation of denosumab is associated with a rapid
calcium during therapy is not required. PTH and teriparatide may offset of action: Markers of bone turnover increased to above
cause small increases in urine calcium excretion but the incidence baseline levels, which returned to baseline values within 1 to
of hypercalciuria does not differ from that in placebo-treated pa- 2 years after stopping treatment [261] and BMD decreased to
tients. However, these agents should be used with caution in pa- baseline values by 12–18 months, independently of the dura-
tients with active or recent urolithiasis because of their potential to tion of treatment [261]. In a sample of 1000 patients who
exacerbate the disorder. Isolated episodes of transient orthostatic discontinued denosumab during the 3-year pivotal study
hypotension are also reported. They typically resolve within mi- [258] or its extension [259], the vertebral fracture rate in-
nutes to a few hours, and do not preclude continued treatment. creased to a value similar to that observed in participants
The use of peptides of the PTH family is contraindicated in who received and then discontinued placebo [262]. The pro-
conditions characterised by abnormally increased bone turn- portion of patients developing multiple vertebral fractures af-
over (e.g. pre-existing hypercalcaemia, metabolic bone dis- ter stopping treatment was higher in the denosumab group
eases other than primary osteoporosis, including hyperpara- than in the placebo group. In addition, the odds of developing
thyroidism and Paget’s disease of bone, unexplained elevation multiple vertebral fractures after stopping denosumab was in-
of alkaline phosphatase, prior external beam or implant radi- creased in patients with prior vertebral fracture sustained be-
ation therapy to the skeleton or in patients with malignancies fore or during treatment, or in those with the longer exposure
or bone metastasis). Severe renal impairment is also a contra- to denosumab [262]. No increase in non-vertebral fracture
indication. Studies in rats have indicated an increased inci- after denosumab cessation was reported. A short duration of
dence of osteosarcoma, with long-term administration of very bisphosphonate therapy could be considered when
high doses of teriparatide [255, 256]. These findings have not discontinuing denosumab to prevent the rebound effect
been considered relevant for patients treated with very much [263]. In women transitioning from oral bisphosphonates to
smaller doses of teriparatide. injectable treatments, denosumab was associated with greater
BMD increases at all skeletal sites and greater inhibition of
Denosumab bone remodelling, compared with zoledronic acid [235, 264].
The incidence of adverse events for all individuals who
Critical molecules for the differentiation, activation and sur- received denosumab for 10 years [259] tended to decrease
vival of osteoclasts are the receptor activator of nuclear factor over time whereas serious adverse events were stable. One
NFkB (RANK), its ligand RANKL, a member of the tumour atypical femoral fracture occurred in each group during the
necrosis factor (TNF) superfamily, and osteoprotegerin extension. Seven cases of osteonecrosis of the jaw were re-
(OPG), which acts as a decoy receptor for RANKL. A fully ported in the long-term group and six cases in the cross-over
human antibody against RANKL has been developed. This group [259]. In a meta-analysis of four clinical trials, the rel-
antibody, denosumab, has been shown to specifically bind to ative risk of serious adverse events for the denosumab group
RANKL with a very high affinity, preventing its interaction compared with the placebo group was 1.33, of serious adverse
with the receptor RANK [257]. events related to infection 2.10, of neoplasm 1.11, of study
The anti-fracture efficacy of 60 mg denosumab given subcu- discontinuation due to adverse events 1.10, and of death 0.78.
taneously every 6 months has been evaluated in postmenopausal These risks were all non-significant [265].
osteoporotic women. After 3 years, there was a 68% reduction in
the incidence of new vertebral fractures. The incidence of clinical Summary of effects
vertebral fractures was similarly reduced by 69%. The incidence
of non-vertebral fractures was reduced by 20% and of hip frac- The effects of the major pharmacological interventions on
tures by 40% [258]. After completing the first 3 years of the vertebral and hip fracture risk are summarised in Table 9.
study, women from the denosumab group had 7 more years of
denosumab treatment (long-term group) and those from the pla- Combination and sequential treatments
cebo group had 7 years of denosumab exposure (cross-over
group) [259]. The yearly incidence of new vertebral fractures These treatment regimens include the concomitant or sequen-
remained low during the extension, whereas non-vertebral frac- tial use of compounds sharing the same mode of action (e.g.
tures further significantly decreased in year 4 [260] and thereafter two or more inhibitors of bone resorption) or agents with
24
Table 9 Study details and anti-fracture efficacy (relative risk (RR and 95% confidence intervals (CI)) of the major pharmacological treatments used for postmenopausal osteoporosis when given with
calcium and vitamin D, as derived from randomised controlled trials
Intervention Study Entry criteria Mean age Number of patients Fracture incidence (%)
(years) randomised over 3 yearsa
Placebo Drug RR 95% CI
a. Vertebral fracture (high risk population)

Alendronate 5–10 mg Black 1996 [207] Vertebral fractures, BMD ≤ 0.68 g/m2 71 2027 15.0 8.0 0.53 0.41–0.68
Risedronate 5 mg Harris 1999 [212] 2 vertebral fractures or 1 vertebral fracture and T-score ≤ − 2.0 69 2458 16.3 11.3 0.59 0.43–0.82
Risedronate 5 mg Reginster 2000 [213] 2 or more vertebral fractures—no BMD entry criteria 71 1226 29.0 18.0 0.51 0.36–0.73
Raloxifene 60 mg Ettinger 1999 [188] Vertebral fractures—no BMD entry criteria 66 7705 21.2 14.7 0.70 0.60–0.90
Teriparatide 20 μgb Neer 2001 [253] Vertebral fractures and FN or LS T-score ≤ − 1 if less than 2 69 1637 14.0 5.0 0.35 0.22–0.55
moderate fractures
Ibandronate 2.5 mg Chesnut 2004 [215] Vertebral fractures and LS − 5 < T-score ≤ − 2.0 69 2946 9.6 4.7 0.38 0.25–0.59
Ibandronate 20 mg Delmas 2004 [216] Vertebral fractures and LS − 5 < T-score ≤ − 2.0 70 708 9.6 4.9 0.50 0.34–0.74
Zoledronic acid 5 mg Black 2007 [224] FN T-score ≤ − 2.5, ± vertebral fracture, or T-score ≤ − 1.5 and 2+ 73 7765 10.9 3.3 0.30 0.24–0.38
mild or 1 moderate vertebral fracture
b. Vertebral fracture (low risk population)
Alendronate 5–10 mgc Cummings 1998 [210] FN T-score ≤ − 2 68 4432 3.8 2.1 0.56 0.39–0.80
Ale Alendronate 5–10 mgc Cummings 1998 [210] Subgroup of women, T-score < 2.5 NA 1631 4.0 2.0 0.50 0.31–0.82
Raloxifene 60 mg Ettinger 1999 [188] FN or LS T-score ≤ − 2.5, ± vertebral fractures 66 7705 4.5 2.3 0.50 0.40–0.80
Denosumab 60 mg Cummings 2009 [258] TH or LS ≤ − 2.5 and > − 4; 60–90 years 72 7868 7.2 2.3 0.32 0.26–0.41
c. Hip fracture
Alendronate 5–10 mg Black 1996 [207]
Vertebral fractures with BMD ≤ 0.68 g/m2 71 2027 2.2 1.1 0.49 0.23–0.99
Alendronate 5–10 mgc Cummings 1998 [210]
FN T-score ≤ − 2d 68 4432 0.8 0.7 0.79 0.43–1.44
Alendronate 5–10 mgc Cummings 1998 [210]
FN T-score ≤ − 2.5d (subgroup analysis) NA 1631 1.6 0.7 0.44 0.18–1.97
Risedronate 2.5 and 5 mg McClung 2001 [71]
T-score < − 3d or < − 2d and ≥ 1 non-skeletal risk factor for hip 77 9331 3.2 1.9 0.60 0.40–0.90
fracture (subgroup analysis osteoporotic patients 70–79 years)
Raloxifene 60 and 120 mg Ettinger 1999 [188] FN or LS T-score ≤ − 2.5, ± vertebral fractures 66 7705 0.7 0.8 1.10 0.60–1.90
Zoledronic acid 5 mg Black 2007 [224] FN T-score ≤ − 2.5 or less, ± vertebral fracture, or T-score ≤ − 1.5 73 7765 1.4 2.5 0.59 0.42–0.83
and 2+ mild or 1 moderate vertebral fracture
Denosumab 60 mg Cummings 2009 [258] TH or LS ≤ − 2.5 and > − 4; age 60–90 years 72 7868 1.2 0.7 0.60 0.37–0.97
FN femoral neck, TH total hip, LS lumbar spine, NA not available

a
Except where indicated in column 1
b
20-month study
c
4.2-year study
d
BMD adjusted to NHANES population
Osteoporos Int (2019) 30:3–44
RRR vs. placebo (%)

differing activities (e.g. an inhibitor of resorption plus an an-
abolic agent). None of the available studies has been powered 0 A
so far, to assess differences in fracture incidence between com-
bination therapy and monotherapy, but results obtained with
BMD, bone histomorphometry, finite element analysis or 20
markers of bone turnover shifted the treatment paradigm to-
Treatment B
wards a greater use of combination or sequential therapies.
Whereas the first attempts to combine alendronate and PTH 40 transition
were disappointing [266], combination of teriparatide and
denosumab generated greater increments in BMD and calcu-
lated bone strength compared to either drug alone [267], 60
supporting further investigation of this combination.
Similarly, in alendronate-treated women, 3-month teriparatide
80 C
cycles followed by 3-month off improve BMD similarly to
daily continuous treatment with teriparatide, an observation
which was not confirmed in alendronate-naive women 0 1 2 3 4
[268]. In a controlled comparison of women who switched Time (years)
from alendronate to teriparatide versus those who added Fig. 12 Schematic diagram showing the effects of a bone-forming agent
teriparatide to ongoing alendronate, the effect on hip BMD on the relative fracture risk reduction (RRR) compared with placebo. In
scenario A, treatment with a bone-forming agent induces a marked effect
and on hip strength was greater with combination therapy.
on fracture risk over an 18 months exposure compared with placebo. On
Continuing a potent anti-resorptive agent when starting a stopping the bone-forming agent, the effect on fracture wanes off over a
bone-forming agent might thus improve hip outcomes [269]. similar time interval of 18 months. In scenario C, placebo group remains
In patients at high risk of fracture, starting treatment with an untreated, whereas the group treated with a bone-forming agent is
transitioned to an inhibitor of bone turnover, which maintains the
anabolic agent seems most appropriate to promptly reduce the
efficacy up to 4 years. In scenario B, both the treatment and the placebo
fracture risk [186]. Given that treatments with anabolic agents are groups are treated after the exposure with an inhibitor of bone turnover
limited to 18–24 months and that efficacy will wane once treat- [270]. With kind permission from Springer Science and Business Media
ment is stopped, the real potential of the anabolic treatments is
whether their greater effect on BMD and fracture can be main-
tained with the inhibitors of bone turnover once treatment is cohort of postmenopausal women in their 60s, the combined
stopped (Fig. 12) [270]. In the absence of a subsequent prescrip- use of conjugated oestrogen and medroxyprogesterone acetate
tion of an anti-resorptive agent, the benefits obtained during was originally associated with a 30% increased risk of coronary
treatment with teriparatide progressively disappear [271], where- heart disease (CHD), and breast cancer and with a 40% increase
as they are maintained when denosumab [267] is prescribed, as in stroke [276–278]. There was also a slight increase in the risk of
soon as possible after stopping the anabolic intervention. dementia [279], and no clinically meaningful effect on health-
related quality of life such as sleep disturbance or vasomotor
symptoms [280]. In a subsequent analysis, the increase in breast
Other pharmacological interventions cancer risk was much less in women not previously exposed to
MHT [278]. In hysterectomized women receiving conjugates
Menopausal hormone therapy oestrogen alone, there was also an increase in stroke, but not of
CHD and breast cancer, suggesting a deleterious effect of
Oestrogens reduce the accelerated bone turnover induced by medroxyprogesterone acetate [281]. It has been postulated that
the menopause and prevent bone loss at all skeletal sites re- the benefits of HRT outweigh the risks in younger postmeno-
gardless of age and duration of therapy. Results from obser- pausal women [282, 283], but so far there is no placebo-
vational studies and randomised placebo-controlled trials have controlled study showing the long-term safety of such ap-
shown that estrogens decrease the risk of vertebral and non- proaches. However, in a recent publication, re-assessing the
vertebral fractures (including hip fracture) by about 30%, re- long-term outcomes of the WHI, MHT with conjugated
gardless of baseline BMD [272, 273]. When hormone replace- oestrogen and medroxyprogesterone acetate for a median of
ment therapy is stopped, bone loss resumes at the same rate as 5.6 years or with conjugated oestrogen alone for a median of
after the menopause, but fracture protection may persist argu- 7.2 years was not associated with an increased risk of all-cause,
ably for several years [274, 275]. cardiovascular, or cancer mortality during a cumulative follow-
The original analyses of the Women’s Health Initiative (WHI) up of 18 years [284]. This may challenge the current recommen-
suggested, however, that the long-term risks of menopausal hor- dation to use HRT only for climacteric symptoms, at a dose as
mone therapy (MHT) outweighed the benefits. In this large small as possible and for a limited period of time [285].
Vitamin D derivatives Vertebroplasty and kyphoplasty
Alfacalcidol is a synthetic analogue of the vitamin D metabolite In patients with recent vertebral fracture in whom pain persists for
calcitriol (1,25-dihydroxyvitamin D3) and it is metabolised to 2 to 3 weeks despite a well-conducted analgesic programme, in-
calcitriol by its 25-hydroxylation in the liver. It is somewhat less jection of cement in the fractured vertebral body without
potent than calcitriol. Both alfacalcidol and calcitriol are used in (vertebroplasty) or with preceding balloon inflation
some countries for the treatment of osteoporosis. Several but not (kyphoplasty) may lead to reduction of pain and positive function-
all studies show decreases in vertebral fracture risk [286, 287]. A al outcomes [296, 297]. Whether pain relief is related to the cement
meta-analysis suggested that combined treatment with itself or to local anaesthetic is still unclear [298, 299].
alendronate and alfacalcidol prevented all osteoporotic fractures Heterogeneity in treatment recommendations is, in part, explained
more than alfacalcidol or alendronate alone [288]. The effects on by an insufficient clinical evidence base for vertebral augmenta-
bone mineral density have been less extensively studied. A few tion and heterogeneity of patients, leading to undue reliance on
reports have suggested that alfacalcidol and calcitriol exert a expert opinion [300, 301]. An increase in new vertebral fracture
direct action on muscle strength and decreases the likelihood of rates at non-treated levels, especially those adjacent to the treated
falling in elderly subjects [289, 290]. vertebrae, has been reported [297, 302] but not consistently [303]
The major problem with the use of the vitamin D deriva- following both vertebroplasty and kyphoplasty.
tives is the risk of hypercalcaemia and hypercalciuria. Adverse
effects of prolonged hypercalcaemia include impairment of
renal function and nephrocalcinosis. The narrow therapeutic Fracture liaison services
window demands the frequent surveillance of serum and pos-
sibly urine calcium in patients exposed to these agents. Fracture liaison services (FLS), also known as osteoporosis
Calcium supplementation of the diet should be avoided or coordinator programmes and care manager programmes, pro-
used with care. vide a system for the routine assessment and management of
postmenopausal women and older men who have sustained a
Clodronate fragility fracture [304–306]. Since the majority of patients
presenting with fragility fracture do not receive appropriate
Clodronate is a relatively weak bisphosphonate, but has been assessment and treatment, fracture liaison services address this
shown to decrease the risk of vertebral and non-vertebral frac- need through a systematic approach to identify cases, assess
tures in randomised controlled studies [291, 292]. It is widely risk of further fractures and the need for treatment. Most frac-
available for the treatment of neoplastic bone disease but li- ture liaison services are based in secondary care although
censed for use in osteoporosis in only a few countries. models in primary care have also been described. A dedicated
coordinator, often a nurse, working closely with the patient,
primary care physician, orthopaedic and trauma department
Local osteo-enhancement procedure and osteoporosis and falls service is central to the develop-
ment of a successful service. An example of the structure of a
Local osteo-enhancement procedure (LOEP) is a local treat- fracture liaison service is shown in Fig. 13.
ment, which requires a minimally invasive injection in the The IOF has launched a global campaign (‘Capture the frac-
femoral neck of a resorbable synthetic bone graft substitute, ture®’) to promote this approach for the prevention of a second
containing a proprietary triphasic calcium sulphate/calcium fracture [308, 309]. This initiative aims to set internationally
phosphate implant [293]. In postmenopausal women with endorsed standards for best practice by facilitating the implemen-
low hip BMD (mean T-score = − 3.1), femoral neck BMD in tation of fracture liaison services involving best practice frame-
treated hips increased by 58% compared to contralateral con- works, multidisciplinary models and FLS questionnaires.
trol hips, during 5–7 years of follow-up [293]. X-ray and QCT The benefits of coordinator-based systems to ensure appro-
analyses demonstrated that the implant material was priate management of patients following a fracture are well
completely resorbed in all patients and replaced with bone that established [7, 308–315]. Use of a systematic coordinator ap-
integrated with the surrounding trabecular and cortical bone proach in the Kaiser Permanente Healthy Bones Program was
[294]. QCT scans were used to conduct patient-specific, non- associated with a 40% reduction in hip fractures [314]. Recent
linear finite element analysis to estimate hip strength in simu- studies from the UK [316–318] reported that the initiation of
lated sideways fall and stance loading conditions. Femoral FLS reduced the 30-day and 1-year mortality rates following
strength in sideway fall was 36% higher in treated than control hip fracture, led to a significant reduction in second fracture
femurs 5–7 years after the procedure [295]. No safety issues rate and increased the utilisation of anti-osteoporosis treatment
were reported during the study [293–295]. Data on fracture by 15%. Although the health economic analyses that have
outcomes are not yet available. been published so far have shown that osteoporosis
Fig. 13 Schema of a Fracture

Casualty , inpaent
Liaison Service (FLS) integrated
and outpaent
with post-fracture falls risk
assessment [after [307]]
Idenﬁcaon of
fracture paents
FLS assessment
Falls risk Exercise Bone-speciﬁc

Educaon
assessment* programme intervenon
Recommended management plan to GP
management programmes are a cost-effective intervention for even redeem their prescription. Overcoming non-adherence pre-
the prevention of fractures [314, 315, 319–321], larger and sents particular challenges in asymptomatic bone diseases and
longer-term studies will be needed to further quantify the ef- other chronic, asymptomatic conditions. In such settings, the
fect of FLS care on subsequent fracture risk [322]. level of perceived threat to health does not motivate the patient
to adhere to therapy. In addition, risk of non-adherence with any
therapy increases with increased duration of treatment [324].
Adherence and monitoring of treatment Poor adherence to medication is associated with adverse ef-
fects on outcomes in osteoporosis or osteopenia, and non-
Adherence to treatment adherent patients have smaller decreases in rates of bone turn-
over, smaller gains in BMD and a significantly greater risk of
When discussing adherence, there is a need to define the ter- fracture [325–327]. Partial adherence also has a significant im-
minology [323], since a wide variety of definitions is used in pact on cost-effectiveness [328]. Further research is required to
the literature. optimise thresholds of compliance and persistence, the impact of
gap length, offset times, and fraction of benefit [329].
1. Adherence is a general term encompassing the aspects Improving adherence to osteoporosis therapy requires effec-
mentioned below. tive patient/provider communication and close patient monitor-
2. Persistence describes for how long the medication is taking for the early identification of declining adherence. Patients’
en. Persistence could be expressed as number of days until belief in a medication contributes to better adherence and can be
discontinuation or the proportion of the cohort still on the improved by firmly associating treatment with expected benefits
medication after a given time since first prescription. Non- such as reduced risk of fracture and thereby an improved quality
persistence is assumed to be the same as discontinuation if of life. Patients may be encouraged to adhere when presented
a treatment gap is longer than a set number of days. with measurements of biochemical markers of bone turnover or
3. Compliance denotes the proximity to the treatment recom- their BMD results together with an explanation of how these
mendation as given in the official product information measures relate to risk reduction. Another primary component
(SPC). It is often simplified to mean the number of doses of improving adherence is to use simplified or user-friendly treat-
taken divided by the number of prescribed doses. This sim- ment programmes [330, 331]. Frequency of dosing is another
plification does not include some important aspects of com- determinant of adherence [332, 333]. A recent IOF and ECTS
pliance, such as taking medication with food (for the oral taskforce suggested that screening to detect a lack of adherence
bisphosphonates), at the correct time of the day, too large with oral bisphosphonates should involve the measurement of
doses to compensate for forgotten doses, pill dumping, etc. P1NP and CTX at baseline and 3 months after starting therapy. In
4. Primary non-adherence is when the patient is prescribed a the absence of a decrease above the least significant change (i.e.
drug and then never fills the prescription. − 38% for P1NP and − 56% for CTX), a low adherence should
be suspected [334].
Non-adherence to medical therapy is a widespread public It should be noted that inadequate adherence can also take
health problem. It is estimated that only half of the patients com- the form of improper drug administration, even when doses
ply with long-term therapy of which a substantial minority do not are not missed. An example is the malabsorption of oral
bisphosphonates when taken with food. Such non-adherence Monitoring of treatment with biochemical markers
poses the potential problems of decreased drug absorption and of bone turnover
increased risk of adverse effects [335].
The most informative biochemical markers of bone turnover
Monitoring of treatment with densitometry for the monitoring of osteoporosis are procollagen I N-
terminal extension peptide (P1NP) for assessing bone forma-
The goal of bone-targeted drug therapy in a patient with oste- tion, and C-telopeptide breakdown products (especially serum
oporosis is to increase bone strength, in order to decrease the CTX) to assess bone resorption [72–74].
risk of fracture. In untreated men and women, BMD is one of Treatment-induced changes in bone markers are more rapid
the major determinants of bone strength, and low BMD is an than changes in BMD and are typically measured 3–6 months
important predictor of fracture. Whether the long-term anti- or so after starting treatment when treatment-induced changes
fracture efficacy of anti-osteoporotic drugs depends on the are expected to be most evident. In a research setting, a sig-
extent to which treatment can increase or maintain BMD is nificant association has been reported between the short-term
controversial [336]. Meta-regressions, based on summary sta- decrease in markers of bone turnover with the use of anti-
tistics, demonstrate a stronger correlation between the change resoptive agents and gains in BMD [345, 346]. More impor-
in BMD and fracture risk reduction than results based on the tantly, significant associations have been reported between the
individual patient data [337, 338]. short-term decrease in markers of bone turnover and the re-
Whereas 16% of vertebral fracture risk reduction after duction in risk of vertebral and non-vertebral fractures with
treatment with alendronate was attributed to an increase in the use of anti-resorptive agents (raloxifene and
BMD at the lumbar spine [339], larger increases in BMD at bisphosphonates). For the bisphosphonates, a screening strat-
both the spine and hip, observed with alendronate, were asso- egy has been proposed by the IOF based on the response of
ciated with greater reductions in the risk of non-vertebral frac- P1NP and CTX after 3 months of therapy [334]. If no change
tures. However, for patients treated with risedronate or ralox- is observed, the clinician should reassess the adherence to the
ifene, changes in BMD predict even more poorly the degree of treatment and also other potential issues with the drug. More
reduction in vertebral (raloxifene) or non-vertebral research is required using standardised analytes before robust
(risedronate) fractures. Twelve percent and 7% of the effects evidence-based recommendations can be given [73].
of risedronate to reduce non-vertebral fractures were attributed Despite limited evidence, failure of treatment may be in-
to changes in the spine and femoral neck BMD, respectively ferred when two or more incident fractures have occurred
[340]. For raloxifene, the percentage changes in BMD during treatment, when serial measurements of bone turnover
accounted for 4% of the observed vertebral fracture risk re- markers are not suppressed by anti-resorptive therapy and
duction [341]. Percent changes in total hip BMD at month 36 where bone mineral density continues to decrease [347].
explained up to 35% of the effect of denosumab to reduce new
or worsening vertebral fractures and up to 84% of the reduc-
tion in non-vertebral fracture risk [342]. It is reasonable to Investigation of patients with osteoporosis
conclude, however, that early monitoring of BMD has limited
value in the prediction of treatment responses with inhibitors Diagnostic work up
of bone resorption.
For bone-forming agents, increases in BMD account for The same diagnostic approach should be undertaken in all
approximately one third of the vertebral fracture risk reduction patients with osteoporosis irrespective of the presence or ab-
with teriparatide [343]. Further data are needed on the role of sence of fragility fractures. However, the range of clinical and
BMD monitoring patients treated with bone-forming agents biological tests will depend on the severity of the disease, the
but appears to be of greater value than their use with inhibitors age at presentation and the presence or absence of vertebral
of bone resorption. fractures. The aims of the clinical history, physical examina-
In postmenopausal osteoporosis, treatment-induced incre- tion and clinical tests are as follows:
ments in BMD with inhibitors of bone turnover are modest
(typically 2% per year) in comparison to the precision error of & To exclude a disease which can mimic osteoporosis (e.g.
repeat measurements (typically 1–2%) so that the time interval osteomalacia, myelomatosis);
of repeat estimates must be sufficiently long in order to deter- & To elucidate causes of osteoporosis and contributory
mine whether any change is real [344]. In the absence of other factors;
clinical imperatives, a 5-year interval may be appropriate. For & To assess the severity of osteoporosis to determine the
other agents such as and PTH derivatives, the treatment- prognosis of the disease, i.e. the risk of subsequent
induced increment is much more rapid and more frequent fractures;
BMD tests may be considered. & To select the most appropriate form of treatment;
& To perform baseline measurements for subsequent moni- Other causes include impaired phosphate transport or the
toring of treatment. chronic use of some drugs such as aluminium salts (and other
The procedures that may be relevant to the investiga- phosphate binding antacids), high doses of fluoride or etidro-
tion of osteoporosis are shown in Table 10. These inves- nate, and the chronic use of some anticonvulsants. In most
tigations may be used to: cases, the diagnosis of osteomalacia is suspected by the clin-
& Establish the diagnosis of osteoporosis (e.g. DXA or X- ical history and by abnormalities in biochemical tests such as
rays); low values of serum and urinary calcium, serum phosphate
& Establish the cause (e.g. thyroid function tests for hyper- and 25-hydroxyvitamin D, and high values for alkaline phos-
thyroidism, and urinary free cortisol for Cushing phatase and parathyroid hormone. A transiliac bone biopsy
syndrome); after double tetracycline labelling may be necessary to dem-
& Establish differential diagnosis (e.g. protein electrophore- onstrate unequivocally a defect in mineralisation.
sis for myeloma, and serum calcium and alkaline phos- Diffuse osteoporosis with or without pathological fracture is
phatase for osteomalacia). common in patients with multiple myeloma, a condition
suspected by the severity of bone pain, increased sedimentation
rate and Bence Jones proteinuria and identified by marrow aspi-
Investigations commonly conducted in secondary care in- rate, and serum and urine (immuno-) electrophoresis of proteins.
clude a full blood count, ESR, serum calcium and phosphate, Similarly, pathological fractures resulting from metastatic malig-
liver function tests and tests of renal function. Additional mea- nancies can mimic osteoporosis and can be excluded by clinical
surements include the biochemical indices of bone turnover, and radiological examination, biological tests such as tumour
serum parathyroid hormone, serum 25-hydroxyvitamin D, se- markers, and scintigraphy or other imaging techniques.
rum or urine protein electrophoresis, fasting and 24-h urinary Vertebral fractures in osteoporosis should be differentiated from
calcium, urinary free cortisol, thyroid function tests, IgA anti- vertebral deformities attributable to other disorders such as sco-
tissue transglutaminase antibody or IgA endomysial antibody, liosis, osteoarthrosis and Scheuermann’s disease.
tryptase and (rarely) transiliac bone biopsy. Free testosterone,
gonadotrophin and prolactin measurements may be of value in
men. Assessment is guided by the clinical findings, and some Health economics
patients who apparently have primary osteoporosis are subse-
quently found to have mild hyperparathyroidism or hyperthy- There is an increasing need for management strategies to be
roidism, systemic mastocytosis, the late appearance of osteo- placed in an appropriate health economic perspective for
genesis imperfecta or osteomalacia. guideline development and for reimbursement. The type of
evaluation used is principally cost-utility analysis as a measure
of cost-effectiveness. In the context of evaluating treatments,
Differential diagnosis of osteoporosis this takes account, not only of fractures avoided, but also of
any change in morbidity and mortality from both beneficial
Osteomalacia and malignancy commonly induce bone loss and unwanted effects. QALYs are the accepted unit of mea-
and fractures. Osteomalacia is characterised by a defect of surement in health economic assessment of interventions
mineralisation of bone matrix most commonly attributable to using cost-utility analysis. In order to estimate QALYs, each
impaired intake, production or metabolism of vitamin D. year of life is valued according to its utility to the patient.
Values range from 0, the least desirable health state, to 1, or
Table 10 Routine procedures proposed in the investigation of perfect health. The decrement in utility associated with frac-
osteoporosis. From [2], with kind permission from Springer Science tures is the cumulative loss of utility over time. There is at
and Business Media present little international consensus as to when treatment can
Routine be considered to be cost-effective [348, 349]. One approach is
History including the FRAX clinical risk factors to base the threshold value on a measure of a country’s eco-
Examination including height and weight nomic performance and a value of about 2 times GDP/capita
Blood cell count, sedimentation rate, serum calcium, albumin, has been suggested as a threshold that can be applied to
creatinine, phosphate, alkaline phosphatase and liver transaminases Western economies [350]. On this basis, threshold values
Lateral radiograph of lumbar and thoracic spine would be about €32,000 in the UK, close to the recommenda-
Bone densitometry (dual energy X-ray absorptiometry at hip and spine) tion of the National Institute for Health and Clinical
Other procedures Excellence [351]. Although the GDP per capita provides an
Lateral imaging DXA for vertebral fracture assessment (VFA) index of affordability, there is also a marked heterogeneity in
Markers of bone turnover, when available the proportion of GDP that countries are willing to devote to
health care, and in the proportion of the population at risk from
osteoporotic fracture (i.e. elderly people). In a systematic re- The advent of probability-based assessment has prompted the
view, the ratio between WTP per QALY and GDP per capita cost-effectiveness of interventions as a function of fracture prob-
varies widely from 0.05 to 5.40, depending on scenario out- ability. Several studies have examined the cost-effectiveness of
comes. The average ratio of WTP per QALY and GDP per intervention thresholds expressed in terms of fracture probability
capita for extending life or saving life was 2.03 [352]. [123, 127, 130, 360, 361]. In studies from the UK [114, 127],
generic alendronate was shown to be cost-effective in the pre-
vention and treatment of fractures in postmenopausal women
Studies of intervention with a 10-year fracture probability for a major fracture that
exceeded 7.5% (Fig. 14). It is interesting that in the different
There has been a rapid expansion of research in Europe on the European countries where such studies have been performed,
cost-utility of interventions in osteoporosis, which has been the the probabilities of major fractures selected as making generic
subject of several reviews [124, 128, 353–357]. A useful tabular alendronate a cost-effective intervention are quite similar: 7.5%
summary of studies up to April 2012 is provided in Brandão et al. in the UK [127], 8.8% in Portugal [363], 13.8% in Switzerland
[358]. Despite the use of different models, different settings and [361] and 10–15%, depending on age, in Greece [362]. This is
payer perspectives, analyses suggest that there are cost-effective quite remarkable, given the disparities in the clinical and eco-
scenarios that can be found in the context of the management of nomic epidemiology of factures and, especially, the willingness
osteoporosis for all but the most expensive interventions to pay adopted for each country: the UK €27,786, Switzerland
(Table 11) [127]. A pan-European study from 2004 estimated €115,000, Portugal €32,000 and Greece €30,000.
the cost-effectiveness of branded alendronate in nine countries The recent appraisal by NICE [128] indicated that all oral
[359]. Alendronate was shown to be cost-saving compared to no bisphosphonates were cost-effective in women with a 10-year
treatment in women with osteoporosis (with and without previ- probability of 1% or more. Thus, the all treatment scenarios
ous vertebral fracture) from the Nordic countries (Norway, with alendronate can be considered as cost-effective (see
Sweden and Denmark). The cost-effectiveness of alendronate Table 6 and Fig. 9). This raises an important issue in that the
compared to no treatment was also within acceptable ranges in health economic thresholds espoused by NICE simply demar-
Belgium, France, Germany, Italy, Spain, Switzerland and the cate a level of risk above which the respective oral and IV
UK. However, with the markedly decrease in price of generic bisphosphonate treatments are cost-effective but that the
bisphosphonates, analyses based on a branded drug price have thresholds used to decide treatment should be based on clini-
become obsolete. For example, the cost of alendronate (70 mg cal appropriateness [136, 364].
weekly) assumed in Table 11 was £95 per annum (2007) and in A special need for the incorporation of FRAX into health
2017 had fallen to a yearly cost of £8.64 in the UK. NICE have economic models arises from studies that have examined the
recently reappraised the cost-effectiveness of oral and intrave- interaction between FRAX-based probabilities with
nous bisphosphonates [128]. Treatment with oral
bisphosphonates was cost-effective of women with a 10-year Cost/QALY gained (£000)
probability of a major osteoporotic fracture of 1% or more. For
intravenous bisphosphonates, the threshold for cost-effectiveness 40
was a 10-year probability of 10%.
30
Table 11 Comparison of the cost-effectiveness (£/QALY gained) of
alendronate with other interventions in women aged 70 years from the
UK [data for treatments other than alendronate from [127], with 20
permission from Elsevier]
T-score = − 2.5 SD No BMD 10
Intervention No prior Prior Prior

0
fracture fracture fracture
0 20 40 60 80
Alendronate 6225 4727 6294 Probability of major osteoporotic fracture (%)
Etidronate 12,869 10,098 9093 Fig. 14 Correlation between the 10-year probability of a major fracture
Ibandronate daily 20,956 14,617 14,694 (calculated with BMD) and cost-effectiveness of generic alendronate at
the age of 50 years in women (BMI set to 26 kg/m2). Each point
Ibandronate intermittent 31,154 21,587 21,745
represents a particular combination of BMD and clinical risk factors (all
Raloxifene 11,184 10,379 10,808 possible combinations of CRFs at BMD T-scores between 0 and − 3.5 SD
Raloxifene without breast 34,011 23,544 23,755 in 0.5 SD steps—512 combinations) with a BMI set to 26 kg/m2. The
cancer horizontal line denotes the threshold for cost-effectiveness (a willingness
Risedronate 18,271 12,659 13,853 to pay of £20,000/QALY gained). From [114], with kind permission from
Springer Science and Business Media
effectiveness. Interventions studied include raloxifene [195, treatment’ a relevant comparator. Notwithstanding,
201], bazedoxifene [201], clodronate [365], daily and weekly alendronate has been considered as a first line intervention.
teriparatide [366, 367], denosumab [368], alendronate [369], The view arises, not because of apparent differences in effica-
as well as a basket of interventions used by general practi- cy between treatments, but because of cost. However, the poor
tioners in the UK [111]. Most of these were post hoc but, in effectiveness and side effect profile of many generic formula-
the case of denosumab, was a pre-planned analysis. In addition, tions challenge this view [251].
the ‘screening for prevention of fractures in older women’ The advent of new anabolic agents given for relatively
(SCOOP) study was a prospective randomised study that dem- short periods followed by maintenance with sequential inhib-
onstrated efficacy for hip fracture in women selected on the basis itors of bone resorption will offer new challenges for health
of hip fracture probability assessed using FRAX [111]. economic appraisal.
Several of these studies have shown greater efficacy
against fracture in individuals at higher risk treated with Acknowledgements We are grateful to the IOF Committee of Scientific
Advisors and the Committee of National Societies to the ESCEO
clodronate, bazedoxifene, denosumab and in the SCOOP
Scientific Advisory Board for their review of this paper and its endorse-
study. This FRAX-dependency has marked economic conse- ment. The paper updates the earlier guidance of 2013 [3] ‘European
quences, illustrated when comparing the cost-effectiveness of guidance for the diagnosis and management of osteoporosis in postmen-
the two selective oestrogen receptor modulators, raloxifene opausal women’ and many sections of text are reproduced with kind
permission of from Springer Science and Business Media B.V. The sum-
and bazedoxifene. The overall effectiveness of these two
mary and recommendations are in close accord with those established by
agents on vertebral fracture risk is rather comparable but the the UK National Osteoporosis Guideline Group [85] of which JAK and
efficacy of bazedoxifene increases in women with the higher CC are members.
the baseline fracture probability. In contrast, the relative risk
reduction with raloxifene is constant over the range of fracture Compliance with ethical standards
probabilities studied. As a consequence, raloxifene has better
cost-effectiveness at low fracture probabilities whereas Conflict of interests JAK reports grants from Amgen, Eli Lilly and
Radius Health; non-financial support from Medimaps, and Asahi; and
bazedoxifene has the better cost-effectiveness at high baseline
other support from AgNovos. JAK is the architect of FRAX® but has
fracture probabilities [370, 371]. The contrasting effect of no financial interest. CC reports personal fees from Alliance for Better
FRAX-dependent and FRAX-independent interactions with Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer,
efficacy on fractures averted is shown in Table 12. Roche, Servier, Takeda and UCB. RR has received consulting fees or
advisory board fees from Radius Health, Labatec, Danone, Nestlé,
Despite differences in apparent cost-effectiveness, there is,
CNIEL and Sandoz. J-YR has received advisory board or consulting fees
however, no proven difference in efficacy between the major- from IBSA-Genévrier, Pierre Fabre, Radius Health, TEVA and Mylan;
ity of treatments shown in Table 11 and head to head compar- and lecture fees from Anovos, IBSA-Genévrier, Mylan, CNIEL, Dairy
isons of interventions with fracture outcomes are few and Research Council (DRC) and Theramex; and institutional grant support
from IBSA-Genévrier, Mylan, CNIEL and Radius Health.
recent [372]. For these reasons, the value of an incremental
analysis between the individual treatments is questionable, Open Access This article is licensed under a Creative Commons
since any resulting hierarchy of treatments is dependent large- Attribution-NonCommercial 4.0 International License, which permits
ly on price, but otherwise meaningless in clinical terms. In any non-commercial use, sharing, adaptation, distribution and reproduc-
tion in any medium or format, as long as you give appropriate credit to the
addition, the large number of untreated patients makes ‘no original author(s) and the source, provide a link to the Creative Commons
licence, and indicate if changes were made. The images or other third
Table 12 Contrasting effects on the number of fractures saved with an party material in this article are included in the article’s Creative
intervention, the efficacy of which the relative risk reduction (RRR) is Commons licence, unless indicated otherwise in a credit line to the ma-
independent or dependent on FRAX (average RRR set at 40%) terial. If material is not included in the article’s Creative Commons licence
and your intended use is not permitted by statutory regulation or exceeds
FRAX independent FRAX dependent the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this licence, visit http://
Fracture RRR Fractures RRR Fractures creativecommons.org/licenses/by-nc/4.0/.
probability (%) (%) saved (%) saved
0 40 0 0 0
5 40 2 0.14 1
10 40 4 0.27 3 References
15 40 6 0.40 6
20 40 8 0.54 11 1. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D (1997)
Guidelines for diagnosis and management of osteoporosis. The
25 40 10 0.68 17 European Foundation for Osteoporosis and Bone Disease.
30 40 12 0.80 24 Osteoporos Int 7:390–406
Total 42 62 2. Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY,
Borgstrom F, Rizzoli R (2008) European guidance for the
diagnosis and management of osteoporosis in postmenopausal metabolism, 8th edition. Ed Rosen CJ, Chapter 30, pp 249–263.
women. Osteoporos Int 19:399–428 John Wiley & Sons,
3. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, 19. Glüer CC (2013) Quantitative computed tomography in children
Reginster J-Y, on behalf of the Scientific Advisory Board of the and adults. Primer on the metabolic bone diseases and disorders of
European Society for Clinical and Economic Aspects of mineral metabolism, 8th edition. Ed Rosen CJ, Chapter 31, pp
Osteoporosis and Osteoarthritis (ESCEO) and the Committee of 264–276. John Wiley & Sons,
Scientific Advisors of the International Osteoporosis Foundation 20. Majumdar S (2013) Magnetic resonance imaging of bone. Primer
(IOF) (2013) European guidance for the diagnosis and manage- on the metabolic bone diseases and disorders of mineral metabo-
ment of osteoporosis in postmenopausal women. Osteoporos Int lism, 8th edition. Ed Rosen CJ, Chapter 32, pp 277–282. John
24:23–57 Wiley & Sons,
4. Hernlund E, Svedbom A, Ivergård M, Ivergård M, Compston J, 21. Gary JR, Cook G, Gnanasegaran G, Fogelman I (2013)
Cooper C, Stenmark J, McCloskey EV, Jönsson B, Kanis JA Radionuclide scintigraphy in metabolic bone disease. In: Primer
(2013) Osteoporosis in the European Union: medical manage- on the metabolic bone diseases and disorders of mineral metabo-
ment, epidemiology and economic burden. A report prepared in lism, 8th edition. Ed Rosen CJ, chapter 33, pp. John Wiley &
collaboration with the International Osteoporosis Foundation Sons, pp 283–288
(IOF) and the European Federation of Pharmaceutical Industry 22. Johannesdottir F, Thrall E, Muller J, Keaveny TM, Kopperdahl
Associations (EFPIA). Archives of Osteoporosis 8:136. https:// DL, Bouxsein ML (2007) Comparison of non-invasive assess-
doi.org/10.1007/s11657-013-0136-1. Access: http://www. ments of strength of the proximal femur. Bone 105:93–102
iofbonehealth.org/data-publications/regional-audits/osteoporosis- 23. Silva BC, Leslie WD, Resch H, Lamy O, Lesnyak O, Binkley N,
european-union-medical-management-epidemiology-and McCloskey EV, Kanis JA, Bilezikian JP (2014) Trabecular bone
Accessed 4 Jan 2018 score: a non-invasive analytical method based upon the DXA
5. Kanis JA, Svedbom A, Harvey N, McCloskey EV (2014) The image. J Bone Miner Res 29:518–530
osteoporosis treatment gap. J Bone Miner Res 29:1926–1928 24. Edmondson CP, Schwartz EN (2017) Non-BMD DXA measure-
6. Kim SC, Kim DH, Mogun H, Eddings W, Polinski JM, Franklin ments of the hip. Bone 104:73–83
JM, Solomon DH (2016) Impact of the U.S. Food and Drug
25. Leslie WD, Lix LM, Majumdar SR, Morin SN, Johansson H,
Administration’s safety-related announcements on the use of
Odén A, McCloskey EV, Kanis JA (2017) Total hip bone area
bisphosphonates after hip fracture. J Bone Miner Res 31:1536–
affects fracture prediction with FRAX in Canadian white women.
1540
J Clin Endocrinol Metab 102:4242–4249
7. Elliot-Gibson V, Bogoch ER, Jamal SA, Beaton DE (2004)
26. Bala Y, Zebaze R, Ghasem-Zadeh A, Atkinson EJ, Iuliano S,
Practice patterns in the diagnosis and treatment of osteoporosis
Peterson JM, Amin S, Bjørnerem Å, Melton LJ 3rd, Johansson
after a fragility fracture: a systematic review. Osteoporos Int 15:
H, Kanis JA, Khosla S, Seeman E (2014) Cortical porosity iden-
767–778
tifies women with osteopenia at increased risk for forearm frac-
8. Giangregorio L, Papaioannou A, Cranney A, Zytaruk N, Adachi
tures. J Bone Miner Res 26:1356–1362
JD (2006) Fragility fractures and the osteoporosis care gap: an
27. Zebaze R, Ghasem-Zadeh A, Mbala A, Seeman E (2013) A new
international phenomenon. Semin Arthritis Rheum 35:293–305
method of segmentation of compact-appearing, transitional and
9. Haaland DA, Cohen DR, Kennedy CC, Khalidi NA, Adachi JD,
trabecular compartments and quantification of cortical porosity
Papaioannou A (2009) Closing the osteoporosis care gap: in-
from high resolution peripheral quantitative computed tomograph-
creased osteoporosis awareness among geriatrics and rehabilita-
ic images. Bone 54:8–20
tion teams. BMC Geriatr 9:28
10. Consensus Development Conference (1993) Diagnosis, prophy- 28. Schousboe JT, Ensrud KE, Nyman JA, Kane RL, Melton LJ, 3rd
laxis, and treatment of osteoporosis. Am J Med 94:646–650 (2006) Cost-effectiveness of vertebral fracture assessment to de-
11. World Health Organization (1994) Assessment of fracture risk and tect prevalent vertebral deformity and select postmenopausal
its application to screening for postmenopausal osteoporosis. women with a femoral neck T-score >−2.5 for alendronate thera-
Report of a WHO Study Group. World Health Organ Tech Rep py: a modeling study. J Clin Densitom 9:133–143
Ser 843:1–129 29. McCloskey EV, Vasireddy S, Threlkeld J, Eastaugh J, Parry A,
12. Kanis JA on behalf of the WHO Scientific Group (2008) Bonnet N, Beneton M, Kanis JA, Charlesworth D (2008)
Assessment of osteoporosis at the primary health-care level. Vertebral fracture assessment (VFA) with a densitometer predicts
WHO Collaborating Centre, University of Sheffield, Sheffield, future fractures in elderly women unselected for osteoporosis. J
UK, Technical Report Bone Miner Res 23:1561–1568
13. Nguyen T, Sambrook P, Kelly P, Jones G, Lord S, Freund J, 30. Lee JH, Lee YK, Oh SH, Ahn J, Lee YE, Pyo JH, Choi YY, Kim
Eisman J (1993) Prediction of osteoporotic fractures by postural D, Bae SC, Sung YK, Kim DY (2016) A systematic review of
instability and bone density. BMJ 307:1111–1115 diagnostic accuracy of vertebral fracture assessment (VFA) in
14. Kanis JA, Johnell O, Odén A, Sembo I, Redlund-Johnell I, postmenopausal women and elderly men. Osteoporos Int 27:
Dawson A, De Laet C, Jonsson B (2000) Long-term risk of oste- 1691–1699
oporotic fracture in Malmo. Osteoporos Int 11:669–674 31. Lewiecki EM (2010) Bone densitometry and vertebral fracture
15. Cooper C, Atkinson EJ, Jacobsen SJ, O’Fallon WM, Melton LJ, assessment. Curr Osteoporos Rep 8:123–130
3rd (1993) Population-based study of survival after osteoporotic 32. Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well
fractures. Am J Epidemiol 137:1001–1005 measures of bone mineral density predict occurrence of osteopo-
16. Kanis JA, Odén A, Johnell O, De Laet C, Jonsson B, Oglesby AK rotic fractures. BMJ 312:1254–1259
(2003) The components of excess mortality after hip fracture. 33. Gluer CC (1997) Quantitative ultrasound techniques for the as-
Bone 32:468–473 sessment of osteoporosis: expert agreement on current status. The
17. Johnell O, Kanis JA (2006) An estimate of the worldwide preva- International Quantitative Ultrasound Consensus Group. J Bone
lence and disability associated with osteoporotic fractures. Miner Res 12:1280–1288
Osteoporos Int 17:1726–1733 34. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev
18. Blake G, Adams JE, Bishop N (2013) DXA in adults and children. N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:
Primer on the metabolic bone diseases and disorders of mineral 1137–1141
35. Watts NB (2004) Fundamentals and pitfalls of bone densitometry Predictive ability of heel quantitative ultrasound for incident frac-
using dual-energy X-ray absorptiometry (DXA). Osteoporos Int tures: an individual-level meta-analysis. Osteoporos Int 26:1979–
15:847–854 1987
36. Looker AC, Wahner HW, Dunn WL Calvo MS, Harris TB, Heyse 53. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM,
SP, Johnston CC, Jr., Lindsay R (1998) Updated data on proximal Ensrud KE, Cauley J, Black D, Vogt TM (1995) Risk factors for
femur bone mineral levels of US adults. Osteoporos Int 8: 468– hip fracture in white women. Study of Osteoporotic Fractures
489 Research Group. N Engl J Med 332:767–773
37. Kanis JA, McCloskey EV, Johansson H, Odén A, Melton LJ, 3rd, 54. Ribot C, Pouilles JM, Bonneu M, Tremollieres F (1992)
Khaltaev N (2008) A reference standard for the description of Assessment of the risk of post-menopausal osteoporosis using
osteoporosis. Bone 42: 467–475 clinical factors. Clin Endocrinol 36:225–228
38. Ferrari S, Bianchi ML, Eisman JA, Foldes AJ, Adami S, Wahl 55. Poor G, Atkinson EJ, O’Fallon WM, Melton LJ 3rd (1995)
DA, Stepan JJ, de Vernejoul MC, Kaufman JM (2012) Predictors of hip fractures in elderly men. J Bone Miner Res 10:
Osteoporosis in young adults: pathophysiology, diagnosis, and 1900–1907
management. Osteoporos Int 23:2735–2748 56. Kanis JA (2002) Diagnosis of osteoporosis and assessment of
39. Kanis JA, Gluer CC (2000) An update on the diagnosis and as- fracture risk. Lancet 359:1929–1936
sessment of osteoporosis with densitometry. Committee of 57. Hui SL, Slemenda CW, Johnston C (1988) Age and bone mass as
Scientific Advisors, International Osteoporosis Foundation. predictors of fracture in a prospective study. J Clin Invest 81:
Osteoporos Int 11:192–202 1804–1809
40. De Laet CEDH, Van Hout BA, Burger H, Hofman A, Weel AE, 58. Kanis JA, Johansson H, Odén A, Johnell O, De Laet C, Eisman
Pols H (1998) Hip fracture prediction in elderly men and women: JA, McCloskey EV, Mellstrom D, Melton LJ 3rd, Pols HA, Reeve
validation in the Rotterdam study. J Bone Miner Res 13: 1587– J, Silman AJ, Tenenhouse A (2004) A family history of fracture
1593 and fracture risk: a meta-analysis. Bone 35: 1029–1037
41. Johnell O, Kanis JA, Odén A, Johansson H, De Laet C, Delmas P, 59. Kanis JA, Johansson H, Odén A, Johnell O, de Laet C, Melton LJ
Eisman JA, Fujiwara S, Kroger H, Mellstrom D, Meunier PJ, III, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA,
Melton LJ 3rd, O’Neill T, Pols H, Reeve J, Silman A, McCloskey EV, Mellstrom D (2004) A meta-analysis of prior
Tenenhouse A (2005) Predictive value of BMD for hip and other corticosteroid use and fracture risk. J Bone Miner Res 19:893–899
fractures. J Bone Miner Res 20: 1185–1194 60. Kanis JA, Johansson H, Johnell O, Odén A, De Laet C, Eisman
42. Kanis JA, Bianchi G, Bilezikian JP, Kaufman JM, Khosla S, JA, Pols H, Tenenhouse A (2005) Alcohol intake as a risk factor
Orwoll E, Seeman E (2011) Towards a diagnostic and therapeutic for fracture. Osteoporos Int 16:737–742
consensus in male osteoporosis. Osteoporos Int 22:2789–2798 61. Kanis JA, Johnell O, Odén A, Johansson H, De Laet C, Eisman J
43. Lewiecki EM, Watts NB, McClung MR, Petak SM, Bachrach LK, (2005) Smoking and fracture risk: a meta-analysis. Osteoporos Int
Shepherd JA, Downs RW, Jr. (2004) Official positions of the in- 16:155–162
ternational society for clinical densitometry. J Clin Endocrinol 62. De Laet C, Kanis JA, Odén A, Johanson H, Johnell O, Delmas P,
Metab 89:3651–3655 Eisman JA, Kroger H, Fujiwara S, Garnero P, McCloskey EV,
44. Binkley N, Bilezikian JP, Kendler DL, Leib ES, Lewiecki EM, Mellstrom D, Melton LJ 3rd, Meunier PJ, Pols HA, Reeve J,
Petak SM (2006) Official positions of the International Society for Silman A, Tenenhouse A (2005) Body mass index as a predictor
Clinical Densitometry and Executive Summary of the 2005 of fracture risk: a meta-analysis. Osteoporos Int 16:1330–1338
Position Development Conference. J Clin Densitom 9:4–14 63. Klotzbuecher CM, Ross PD, Landsman PD, Abbott TA, Berger M
45. Blake GM, Patel R, Knapp KM, Fogelman I (2003) Does the (2000) Patients with prior fractures have an increased risk of future
combination of two BMD measurements improve fracture dis- fractures: a summary of the literature and statistical synthesis. J
crimination? J Bone Miner Res 18:1955–1963 Bone Miner Res 15:721–739
46. Kanis JA, Johnell O, Odén A, Johansson H, Eisman JA, Fujiwara 64. Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P,
S, Kroger H, Honkanen R, Melton LJ 3rd, O’Neill T, Reeve J, Eisman J, Fujiwara S, Garnero P, Kroger H, McCloskey EV,
Silman A, Tenenhouse A (2006) The use of multiple sites for the Mellstrom D, Melton LJ, Pols H, Reeve J, Silman A,
diagnosis of osteoporosis. Osteoporos Int 17: 527–534 Tenenhouse A (2004) A meta-analysis of previous fracture and
47. Leslie WD, Lix LM, Tsang JF, Caetano PA (2007) Single-site vs subsequent fracture risk. Bone 35:375–382
multisite bone density measurement for fracture prediction. Arch 65. Kanis JA, McCloskey E, Johansson H, Odén A, Leslie WD (2012)
Intern Med 167:1641–1647 FRAXwith and without bone mineral density. Calcif Tissue Int 90:
48. Odén A, McCloskey EV, Johansson H, Kanis JA (2013) 1–13
Assessing the impact of osteoporosis on the burden of hip frac- 66. Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES,
tures. Calcif Tissue Int 92:42–49 Ensrud KE, Donaldson MG, Cauley JA, Harris TB, Koster A,
49. Kanis JA, Johnell O, Odén A, Dawson A, De Laet C, Jonsson B Womack CR, Palermo L, Black DM (2011) Association of
(2001) Ten-year probabilities of osteoporotic fractures according BMD and FRAX score with risk of fracture in older adults with
to BMD and diagnostic thresholds. Osteoporos Int 12:989–995 type 2 diabetes. JAMA 305:2184–2192
50. Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, 67. Giangregorio LM, Leslie WD, Lix LM, Johansson H, Odén A,
Ensrud K, Genant HK, Palermo L, Scott J, Vogt TM (1993) McCloskey E, Kanis JA (2012) FRAX underestimates fracture
Bone density at various sites for prediction of hip fractures. The risk in patients with diabetes. J Bone Miner Res 27:301–308
Study of Osteoporotic Fractures Research Group. Lancet 341:72– 68. Leslie WD, Rubin MR, Schwartz AZ, Kanis JA (2012)
75 Perspective: diabetes and bone. J Bone Miner Res 27:2231–2237
51. Moayyeri A, Adams JE, Adler RA, Krieg MA, Hans D, Compston 69. Nguyen ND, Frost SA, Center JR, Eisman JA, Nguyen TV (2008)
J, Lewiecki EM (2012) Quantitative ultrasound of the heel and Development of prognostic nomograms for individualizing 5-year
fracture risk assessment: an updated meta-analysis. Osteoporos Int and 10-year fracture risks. Osteoporos Int 19:1431–1444
23:143–153 70. Hippisley-Cox J, Coupland C (2009) Predicting risk of osteopo-
52. McCloskey EV, Kanis JA, Odén A, Harvey NC, Bauer D, rotic fracture in men and women in England and Wales: prospec-
González-Macias J, Hans D, Kaptoge S, Krieg MA, Kwok T, tive derivation and validation of QFractureScores. BMJ 339:
Marin F, Moayyeri A, Orwoll E, Gluёr C, Johansson H (2015) b4229
71. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Selby P, Thompson F, Thurston A, Vine N (2017) UK clinical
Roux C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier guideline for the prevention and treatment of osteoporosis. Arch
PJ, Reginster JY (2001) Effect of risedronate on the risk of hip Osteoporos 12:43
fracture in elderly women. Hip Intervention Program Study 86. Kanis JA, Harvey NC, Johansson H, Odén A, McCloskey EV,
Group. N Engl J Med 344:333–340 Leslie WD (2017) Overview of fracture prediction tools. J Clin
72. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J (2000) The Densitom 20:360–367
use of biochemical markers of bone turnover in osteoporosis. 87. Kanis JA, Johnell O, Odén A, Johansson H, McCloskey E (2008)
Committee of Scientific Advisors of the International FRAX and the assessment of fracture probability in men and
Osteoporosis Foundation. Osteoporos Int 11(Suppl 6):S2–17 women from the UK. Osteoporos Int 19:385–397
73. Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, 88. Kanis JA, Johansson H, Odén A, Cooper C, EV l MC (2014)
Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Worldwide uptake of FRAX. Arch Osteoporos 9:166. https://doi.
Wahl DA, Cooper C, Kanis JA (2011) Markers of bone turnover org/10.1007/s11657-013-0166-8
for the prediction of fracture risk and monitoring of osteoporosis 89. Kanis JA, Harvey NC, Cooper C, Johansson H, Odén A,
treatment: a need for international reference standards. Osteoporos McCloskey EV (2016) A systematic review of intervention
Int 22:391–420 thresholds based on FRAX. Arch Osteoporos 11(1):25
74. Johansson H, Odén A, Kanis JA, McCloskey EV, Morris HA, 90. Kanis JA, Odén A, Johnell O, Johansson H, De Laet C, Brown J,
Cooper C, Vasikaran S (2014) A meta-analysis of reference Burckhardt P, Cooper C, Christiansen C, Cummings S, Eisman
markers of bone turnover for prediction of fracture. Calcif Tissue JA, Fujiwara S, Glüer C, Goltzman D, Hans D, Krieg MA, La
Int 94:560–567 Croix A, McCloskey E, Mellstrom D, Melton LJ 3rd, Pols H,
75. Morris HA, Eastell R, Jorgensen NR, Cavalier E, Vasikaran S, Reeve J, Sanders K, Schott AM, Silman A, Torgerson D, van
Chubb SAP, Kanis JA, Cooper C, Makris K (2017) Clinical use- Staa T, Watts NB, Yoshimura N (2007) The use of clinical risk
fulness of bone turnover marker concentrations in osteoporosis. factors enhances the performance of BMD in the prediction of hip
Clin Chim Acta 467:34–41 and osteoporotic fractures in men and women. Osteoporos Int 18:
76. Harvey NC, Glüer CC, Binkley N, McCloskey EV, Brandi ML, 1033–1046
Cooper C, Kendler D, Lamy O, Laslop A, Camargos BM, 91. Kanis JA, Johnell O, De Laet C, Jonsson B, Odén A, Ogelsby AK
Reginster JY, Rizzoli R, Kanis JA (2015) Trabecular bone score (2002) International variations in hip fracture probabilities: impli-
(TBS) as a new complementary approach for osteoporosis evalu- cations for risk assessment. J Bone Miner Res 17:1237–1244
ation in clinical practice. A consensus report of a European 92. Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N,
Society for Clinical and Economic Aspects of Osteoporosis and Cauley JA, Compston JE, Dawson-Hughes B, El-Hajj Fuleihan G,
Osteoarthritis (ESCEO) Working Group. Bone 78:216–224 Johansson H, Leslie WD, Lewiecki EM, Luckey M, Odén A,
77. McCloskey EV, Odén A, Harvey NC, Leslie WD, Hans D, Papapoulos SE, Poiana C, Rizzoli R, Wahl DA, McCloskey EV
Johansson H, Barkmann R, Boutroy S, Brown J, Chapurlat R, (2011) Interpretation and use of FRAX in clinical practice.
Elders PJ, Fujita Y, Glüer CC, Goltzman D, Iki M, Karlsson M, Osteoporos Int 22:2395–2411
Kindmark A, Kotowicz M, Kurumatani N, Kwok T, Lamy O, 93. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C
Leung J, Lippuner K, Ljunggren Ö, Lorentzon M, Mellström D, (2000) Use of oral corticosteroids and risk of fractures. J Bone
Merlijn T, Oei L, Ohlsson C, Pasco JA, Rivadeneira F, Rosengren Miner Res 15:993–1000
B, Sornay-Rendu E, Szulc P, Tamaki J, Kanis JA (2016) A meta- 94. Harvey NC, Odén A, Orwoll E, Lapidus J, Kwok T, Karlsson MK,
analysis of trabecular bone score in fracture risk prediction and its Rosengren BE, Ljunggren Ö, Cooper C, McCloskey E, Kanis JA,
relationship to FRAX. J Bone Miner Res 31:940–948 Ohlsson C, Mellström D, Johansson H (2018) Falls predict frac-
78. Martineau P, Leslie WD, Johansson H, Odén A, McCloskey EV, tures independently of FRAX probability: a meta-analysis of the
Hans D, Kanis JA (2017) Clinical utility of using lumbar spine Osteoporotic Fractures in Men (MrOS) Study. J Bone Miner Res
trabecular bone score to adjust fracture probability: the Manitoba 33:510–516
BMD cohort. J Bone Miner Res 32:1568–1574 95. Harvey NC, Johansson H, Odén A, Karlsson MK, Rosengren BE,
79. Leslie WD, Aubry-Rozier B, Lix LM, Morin SN, Majumdar SR, Ljunggren Ö, Cooper C, McCloskey E, Kanis JA, Ohlsson C,
Hans D (2014) Spine bone texture assessed by trabecular bone Mellström D (2016) FRAX predicts incident falls in elderly
score (TBS) predicts osteoporotic fractures in men: the Manitoba men. Findings from MrOs Sweden. Osteoporos Int 27:267–274
Bone Density Program. Bone 67:10–14 96. Oliver D, Connelly JB, Victor CR, Shaw FE, Whitehead A, Genc
80. McCloskey EV, Odén A, Harvey NC, Leslie WD, Hans D, Y, Vanoli A, Martin FC, Gosney MA (2007) Strategies to prevent
Johansson H, Kanis JA (2015) Adjusting fracture probability by falls and fractures in hospitals and care homes and effect of cog-
trabecular bone score. Calcif Tissue Int 96:500–509 nitive impairment: systematic review and meta-analyses. BMJ
81. Leslie WD, Johansson H, Kanis JA, Lamy O, Odén A, 334:82
McCloskey EV, Hans D (2014) Lumbar spine texture enhances 97. Kayan K, Johansson H, Odén A, Vasireddy S, Pande K, Orgee J,
10-year fracture probability assessment. Osteoporos Int 25:2271– Kanis JA, McCloskey EV (2009) Can fall risk be incorporated
2277 into fracture risk assessment algorithms: a pilot study of respon-
82. Fink HA, Milavetz DL, Palermo L, Nevitt MC, Cauley JA, Genant siveness to clodronate. Osteoporos Int 20:2055–2061
HK (2005) What proportion of incident radiographic vertebral 98. Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates
deformities is clinically diagnosed and vice versa? J Bone Miner S, Clemson LM, Lamb SE (2009) Interventions for preventing
Res 20:1216–1222 falls in older people living in the community. Cochrane Database
83. Melton LJ 3rd, Atkinson EJ, Cooper C, O’Fallon WM, Riggs BL Syst Rev 2:CD007146
(1999) Vertebral fractures predict subsequent fractures. 99. Michael YL, Whitlock EP, Lin JS, Fu R, O’Connor EA, Gold R
Osteoporos Int 10:214–221 (2010) Primary care-relevant interventions to prevent falling in
84. Johansson H, Odén A, McCloskey EV, Kanis JA (2014) Mild older adults: a systematic evidence review for the U.S.
morphometric vertebral fractures predict vertebral fractures but Preventive Services Task Force. Ann Intern Med 153:815–825
not non-vertebral fractures. Osteoporos Int 25:235–241 100. Kanis JA, Johansson H, Odén A, McCloskey EV (2011) Guidance
85. Compston J, Cooper A, Cooper C, Gittoes N, Gregson C, Harvey for the adjustment of FRAX according to the dose of glucocorti-
N, Hope S, Kanis JA, McCloskey EV, Poole KES, Reid DM, coids. Osteoporos Int 22:809–816
101. Leslie WD, Lix LM, Johansson H, Odén A, McCloskey E, Kanis 115. Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP,
JA (2011) Spine-hip discordance and fracture risk assessment: a Feldman S, Hanley DA, Hodsman A, Jamal SA, Kaiser SM,
physician-friendly FRAX enhancement. Osteoporos Int 22:839– Kvern B, Siminoski K, Leslie WD; Scientific Advisory Council
847 of Osteoporosis Canada (2010) 2010 Clinical practice guidelines
102. Johansson H, Kanis JA, Odén A, Leslie WD, Fujiwara S, Glüer for the diagnosis and management of osteoporosis in Canada:
CC, Kroger H, LaCroix AZ, Lau E, Melton LJ 3rd, Eisman JA, summary. CMAJ 182: 1864–1873
O’Neill TW, Goltzman D, Reid DM, McCloskey E (2014) Impact 116. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B,
of femoral neck and lumbar spine BMD discordances on FRAX Randall S, Lindsay R (2014) Clinician’s guide to prevention and
probabilities in women: a meta-analysis of international cohorts. treatment of osteoporosis. Osteoporos Int 25:2359–2381
Calcif Tiss Int 95: 428–435 117. Kanis JA, Johnell O (2005) Requirements for DXA for the man-
103. Leslie WD, Shevroja E, Johansson H, McCloskey EV, Harvey agement of osteoporosis in Europe. Osteoporos Int 16:229–238
NC, Kanis JA, Hans D (2018) Risk-equivalent T-score adjustment 118. Kanis JA, McCloskey EV, Harvey NC, Johansson H, Leslie WD
using lumbar spine trabecular bone score (TBS): the Manitoba (2015) Intervention thresholds and the diagnosis of osteoporosis. J
BMD Registry. Osteoporos Int 29:751–758 Bone Miner Res 30:1747–1753
104. Leslie WD, Lix LM, Morin SN, Johansson H, Odén A, 119. Grigorie D, Sucaliuc A, Johansson H, Kanis JA, McCloskey E
McCloskey EV, Kanis JA (2015) Adjusting hip fracture probabil- (2013) Incidence of hip fracture in Romania and the development
ity in men and women using hip axis length: the Manitoba Bone of a Romanian FRAX model. Calcif Tissue Int 92:429–436
Density Database. J Clin Densitom 19:326–331 120. Johansson H, Azizieh F, Al Ali N, Alessa T, Harvey NC,
105. Masud T, Binkley N, Boonen S, Hannan MT. on behalf of the McCloskey E, Kanis JA (2017) FRAX- vs. T-score-based inter-
FRAX Position Conference members (2011) Can falls and frailty vention thresholds for osteoporosis. Osteoporos Int 28:3099–
be used in FRAX? J Clin Densitom 14: 194–204 3105
106. Johansson H, Odén A, Lorentzon M, McCloskey E, Kanis JA, 121. Compston J, Cooper A, Cooper C, Francis R, Kanis JA, Marsh D,
Harvey NC, Karlsson MK, Mellstrom D (2015) Is the Swedish McCloskey EV, Reid DM, Selby P, Wilkins M (2009) Guidelines
FRAX model appropriate for immigrants to Sweden? Osteoporos for the diagnosis and management of osteoporosis in postmeno-
Int 26:2617–2622 pausal women and men from the age of 50 years in the UK.
107. Leslie WD, Johansson H, McCloskey EV, Harvey NC, Kanis JA, Maturitas 62:105–108
Hans D (2018) Comparison of methods for improving fracture risk 122. Tarantino U, Iolascon G, Cianferotti L, Masi L, Marcucci G,
assessment in diabetes: the Manitoba BMD Registry. J Bone Giusti F, Marini F, Parri S, Feola M, Rao C, Piccirilli E, Zanetti
Miner Res https://doi.org/10.1002/jbmr.3538 [Epub ahead of EB, Cittadini N, Alvaro R, Moretti A, Calafiore D, Toro G,
print] Gimigliano F, Resmini G, Brandi ML (2017) Clinical guidelines
108. Brennan SL, Leslie WD, Lix LM, Johansson H, Odén A, for the prevention and treatment of osteoporosis: summary state-
McCloskey E, Kanis JA (2014) FRAX provides robust fracture ments and recommendations from the Italian Society for
prediction regardless of socioeconomic status. Osteoporos Int 25: Orthopaedics and Traumatology. J Orthop Traumatol 18(Suppl
61–69 1):3–36
109. Leslie WD, Orwoll EW, Nielson CM, Morin SN, Majumdar SR, 123. Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S,
Johansson H, Odén A, McCloskey EV, Kanis JA (2014) Estimated Borgström F, Cooper C, Diez Perez A, Eastell R, Hofbauer LC,
lean mass and fat mass differentially affect femoral bone density Kanis JA, Langdahl BL, Lesnyak O, Lorenc R, McCloskey E,
and strength index but are not FRAX independent risk factors for Messina OD, Napoli N, Obermayer-Pietsch B, Ralston SH,
fracture. J Bone Miner Res 29:2511–2519 Sambrook PN, Silverman S, Sosa M, Stepan J, Suppan G, Wahl
110. Leslie WD, Lix LM, Johansson H, Odén A, McCloskey E, Kanis DA, Compston JE (2012) A framework for the development of
JA (2012) Does osteoporosis therapy invalidate FRAX for fracture guidelines for the management of glucocorticoid-induced osteo-
prediction? J Bone Miner Res 27:1243–1251 porosis. Osteoporos Int 23:2257–2276
111. Shepstone L, Lenaghan E, Cooper C, Clarke S, Fong-Soe-Khioe 124. Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M
R, Fordham R, Gittoes N, Harvey I, Harvey N, Heawood A, (2007) Glucocorticoid-induced osteoporosis: a systematic review
Holland R, Howe A, Kanis J, Marshall T, O’Neill T, Peters T, and cost-utility analysis. Health Technol Assess 11:1–256
Redmond N, Torgerson D, Turner D, McCloskey E (2018) A 125. Johansson H, Odén A, Johnell O, Jonsson B, de Laet C, Oglesby
randomized controlled trial of screening in the community to re- A, McCloskey EV, Kayan K, Jalava T, Kanis JA (2004)
duce fractures in older women—the SCOOP Study. Lancet 391: Optimization of BMD measurements to identify high risk groups
741–747 for treatment—a test analysis. J Bone Miner Res 19:906–913
112. McCloskey E, Johansson H, Harvey NC, Shepstone L, Lenaghan 126. Johansson H, Kanis JA, Odén A, Johnell O, McCloskey E (2009)
E, Fordham R, Harvey I, Howe A, Cooper C, Clarke S, Gittoes N, BMD, clinical risk factors and their combination for hip fracture
Heawood A, Holland R, Marshall T, O’Neill TW, Peters TJ, prevention. Osteoporos Int 20:1675–1682
Redmond N, Torgerson D, Kanis JA (2018) Management of pa- 127. Kanis JA, Adams J, Borgstrom F, Cooper C, Jönsson B, Preedy D,
tients with high baseline hip fracture risk by FRAX reduces hip Selby P, Compston J (2008) The cost-effectiveness of alendronate
fractures—a post hoc analysis from the SCOOP Study. J Bone in the management of osteoporosis. Bone 42:4–15
Miner Res 33:1020–1026 128. National Institute for Health and Care Excellence (2017) TA 464:
113. Ismail AA, Cooper C, Felsenberg D, Varlow J, Kanis JA, Silman bisphosphonates for treating osteoporosis. Technology appraisal
AJ, O’Neill TW (1999) Number and type of vertebral deformities: guidance 464. National Institute for Health and Care Excellence,
epidemiological characteristics and relation to back pain and London. nice.org.uk/guidance/ta464
height loss. European Vertebral Osteoporosis Study Group. 129. Shiroiwa T, Sung YK, Fukuda T, Lang HC, Bae SC, Tsutani K
Osteoporos Int 9:206–213 (2010) International survey on willingness-to-pay (WTP) for one
114. Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F, additional QALY gained: what is the threshold of cost effective-
Odén A (2008) Case finding for the management of osteoporosis ness? Health Econ 19:422–437
with FRAX—assessment and intervention thresholds for the UK. 130. Tosteson AN, Melton LJ, 3rd, Dawson-Hughes B, Baim S, Favus
Osteoporos Int 19:1395–1408 MJ, Khosla S, Lindsay RL (2008) Cost-effective osteoporosis
treatment thresholds: the United States perspective. Osteoporos Int injuries in community dwelling older adults: systematic review
19:437–447 and meta-analysis of randomised controlled trials. BMJ 347:f6234
131. Leslie WD, Morin S, Lix LM, Johansson H, Odén A, McCloskey 146. Jepsen DB, Thomsen K, Hansen S, Jørgensen NR, Masud T, Ryg J
E, Kanis JA (2012) Fracture risk assessment without bone density (2017) Effect of whole-body vibration exercise in preventing falls
measurement in routine clinical practice. Osteoporos Int 23:75–85 and fractures: a systematic review and meta-analysis. BMJ Open
132. Leslie WD, Majumdar SR, Lix LM, Johansson H, Odén A, 7(12):e018342
McCloskey E, Kanis JA (2012) High fracture probability with 147. Sawka AM, Boulos P, Beattie K, Thabane L, Papaioannou A,
FRAX usually indicates densitometric osteoporosis: implications Gafni A, Cranney A, Zytaruk N, Hanley DA, Adachi JD (2005)
for clinical practice. Osteoporos Int 23:391–397 Do hip protectors decrease the risk of hip fracture in institutional
133. McCloskey EV, Johansson H, Harvey NC, Compston J, Kanis JA and community-dwelling elderly? A systematic review and meta-
(2017) Access to fracture risk assessment by FRAX® and linked analysis of randomized controlled trials. Osteoporos Int 16:1461–
National Osteoporosis Guideline Group (NOGG) guidance in the 1474
UK—an analysis of anonymous website activity. Osteoporos Int 148. Parker MJ, Gillespie WJ, Gillespie LD (2006) Effectiveness of hip
28:71–76 protectors for preventing hip fractures in elderly people: system-
134. McCloskey E, Kanis JA, Johansson H, Harvey N, Odén A, atic review. BMJ 332:571–574
Cooper A, Cooper C, Francis RM, Reid DM, Marsh D, Selby P, 149. Kiel DP, Magaziner J, Zimmerman S, Ball L, Barton BA, Brown
Thompson F, Hewitt S, Compston J (2015) FRAX-based assess- KM, Stone JP, Dewkett D, Birge SJ (2007) Efficacy of a HIP
ment and intervention thresholds—an exploration of thresholds in protector to prevent HIP fracture in nursing home residents: the
women aged 50 years and older in the UK. Osteoporos Int 26: HIP PRO randomized controlled trial. JAMA 298:413–422
2091–2099 150. Gillespie WJ, Gillespie LD, Parker MJ (2010) Hip protectors for
135. Neuerburg C, Stumpf U, Schmidmaier R, Kammerlander C, preventing hip fractures in older people. Cochrane Database Syst
Pfeilschifter J, Mutschler W, Bocker W (2017) Investigation and Rev CD001255
management of osteoporosis in aged trauma patients: a treatment 151. Rizzoli R (2014) Nutritional aspect of bone health. Best Pract Res
algorithm adapted to the German guidelines for osteoporosis. J Clin Endocrinol Metab 28:795–808
Orthop Surg Res 12:86. https://doi.org/10.1186/s13018-017-
152. Food and Agricultural Organization of the United Nations/World
0585-0
Health Organization (2001) Human vitamin and mineral require-
136. Harvey NC, McCloskey E, Kanis JA, Compston J, Cooper C
ments. Report of a joint FAO/WHO expert consultation. Bangkok,
(2018) Cost-effective but clinically inappropriate: new NICE in-
Thailand. Washington, DC
tervention thresholds in osteoporosis (Technology Appraisal 464).
153. Harvey NC, Biver E, Kaufman JM, Bauer J, Branco J, Brandi ML,
Osteoporos Int 29:1511–1513
Bruyère O, Coxam V, Cruz-Jentoft A, Czerwinski E, Dimai H,
137. Kanis JA, Odén A, Johansson H, McCloskey E (2012) Pitfalls in
Fardellone P, Landi F, Reginster JY, Dawson-Hughes B, Kanis
the external validation of FRAX. Osteoporos Int 23:423–431
JA, Rizzoli R, Cooper C (2017) The role of calcium supplemen-
138. Turner DA, Khioe RFS, Shepstone L, Lenaghan E, Cooper C,
tation in healthy musculoskeletal ageing: an expert consensus
Gittoes N, Harvey NC, Holland R, Howe A, McCloskey E,
meeting of the European Society for Clinical and Economic
O’Neill TW, Torgerson D, Fordham R (2018) The cost-
Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal
effectiveness of screening in the community to reduce osteoporot-
Diseases (ESCEO) and the International Foundation for
ic fractures in older women in the UK: economic evaluation of the
Osteoporosis (IOF). Osteoporos Int 28:447–462
SCOOP study. J Bone Miner Res 33:845–851
154. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A (2007)
139. Howe TE, Shea B, Dawson LJ, Downie F, Murray A, Ross C,
Use of calcium or calcium in combination with vitamin D supple-
Harbour RT, Caldwell LM, Creed G (2011) Exercise for
mentation to prevent fractures and bone loss in people aged 50
preventing and treating osteoporosis in postmenopausal women.
years and older: a meta-analysis. Lancet 370:657–666
Cochrane Database Syst Rev CD000333
140. Sañudo B, de Hoyo M, Del Pozo-Cruz J, Carrasco L, Del Pozo- 155. Weaver CM, Alexander DD, Boushey CJ, Dawson-Hughes B,
Cruz B, Tejero S, Firth E (2017) Systematic review of the exercise Lappe JM, LeBoff MS, Liu S, Looker AC, Wallace TC, Wang
effect on bone health: the importance of assessing mechanical DD (2016) Calcium plus vitamin D supplementation and risk of
loading in perimenopausal and postmenopausal women. fractures: an updated meta-analysis from the National
Menopause 24: 1208–1216, Osteoporosis Foundation. Osteoporos Int 27:367–376
141. McMillan LB, Zengin A, Ebeling PR, Scott D (2017) Prescribing 156. Zhao JG, Zeng XT, Wang J, Liu L (2017) Association between
physical activity for the prevention and treatment of osteoporosis calcium or vitamin D supplementation and fracture incidence in
in older adults. Healthcare (Basel) 6;5(4). pii: E85. https://doi.org/ community-dwelling older adults: a systematic review and meta-
10.3390/healthcare5040085 analysis. JAMA 318:2466–2482
142. Howe TE, Rochester L, Neil F, Skelton DA, Ballinger C (2011) 157. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR (2011)
Exercise for improving balance in older people. Cochrane Calcium supplements with or without vitamin D and risk of car-
Database Syst Rev 11:CD004963 diovascular events: reanalysis of the Women’s Health Initiative
143. Sherrington C, Michaleff ZA, Fairhall N, Paul SS, Tiedemann A, limited access dataset and meta-analysis. BMJ 342:d2040
Whitney J, Cumming RG, Herbert RD, Close JCT, Lord SR 158. Nordin BE, Lewis JR, Daly RM, Horowitz J, Metcalfe A, Lange
(2017) Exercise to prevent falls in older adults: an updated sys- K, Prince RL (2011) The calcium scare—what would Austin
tematic review and meta-analysis. Br J Sports Med 51:1750–1758 Bradford Hill have thought? Osteoporos Int 22:3073–3077
144. Tricco AC, Thomas SM, Veroniki AA, Hamid JS, Cogo E, Strifler 159. Bolland MJ, Grey A, Reid IR (2011) Re: The calcium scare: what
L, Khan PA, Robson R, Sibley KM, MacDonald H, Riva JJ, would Austin Bradford Hill have thought? Osteoporos Int 22:
Thavorn K, Wilson C, Holroyd-Leduc J, Kerr GD, Feldman F, 3079–3080 author reply 3081-3073
Majumdar SR, Jaglal SB, Hui W, Straus SE (2017) Comparisons 160. Bolland MJ, Grey A, Reid IR (2012) Misclassification does not
of interventions for preventing falls in older adults: a systematic explain increased cardiovascular risks of calcium supplements. J
review and meta-analysis. JAMA 318:1687–1699 Bone Miner Res 27:959 author reply 960-951
145. El-Khoury F, Cassou B, Charles MA, Dargent-Molina P (2013) 161. Lewis JR, Calver J, Zhu K, Flicker L, Prince RL (2011) Calcium
The effect of fall prevention exercise programmes on fall induced supplementation and the risks of atherosclerotic vascular disease
in older women: results of a 5-year RCT and a 4.5-year follow-up. Research Group (2018) High dairy protein intake is associated
J Bone Miner Res 26:35–41 with greater bone strength parameters at the distal radius and tibia
162. Lewis JR, Zhu K, Prince RL (2012) Adverse events from calcium in older men: a cross-sectional study. Osteoporos Int 29:69–77
supplementation: relationship to errors in myocardial infarction 176. Feskanich D, Meyer HE, Fung TT, Bischoff-Ferrari HA, Willett
self-reporting in randomized controlled trials of calcium supple- WC (2018) Milk and other dairy foods and risk of hip fracture in
mentation. J Bone Miner Res 27:719–722 men and women. Osteoporos Int 29:385–396
163. Lewis JR, Zhu K, Prince RL (2012) Response to: 177. Laird E, Molloy AM, McNulty H, Ward M, McCarroll K, Hoey L,
Misclassification does not explain increased cardiovascular risks Hughes CF, Cunningham C, Strain JJ, Casey MC (2017) Greater
of calcium supplements. J Bone Miner Res 27:960–961 yogurt consumption is associated with increased bone mineral
164. Hiligsmann M, Ben Sedrine W, Bruyère O, Evers SM, Rabenda V, density and physical function in older adults. Osteoporos Int 28:
Reginster JY (2015) Cost-effectiveness of vitamin D and calcium 2409–2419
supplementation in the treatment of elderly women and men with 178. Rizzoli R, Biver E (2018) Effects of fermented milk products on
osteoporosis. Europ J Public Health 25:20–25 bone. Calcif Tissue Int 102:489–500
165. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, 179. Biver E, Durosier-Izart C, Merminod F, Chevalley T, van
Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J Rietbergen B, Ferrari SL, Rizzoli R (2018) Fermented dairy prod-
(2009) Fall prevention with supplemental and active forms of ucts consumption is associated with attenuated cortical bone loss
vitamin D: a meta-analysis of randomised controlled trials. BMJ independently of total calcium, protein, and energy intakes in
339:b3692 healthy postmenopausal women. Osteoporos Int 29:1771–1782
166. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, 180. Chen GC, Wang Y, Tong X, Szeto IMY, Smit G, Li ZN, Qin LQ
Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA, Meyer HE, (2017) Cheese consumption and risk of cardiovascular disease: a
Pfeifer M, Sanders KM, Stähelin HB, Theiler R, Dawson-Hughes meta-analysis of prospective studies. Eur J Nutr 56:2565–2575
B (2012) Pooled analysis of vitamin D dose requirements for 181. Ethgen O, Hiligsmann M, Burlet N, Reginster JY (2015) Public
fracture prevention. N Engl J Med 367:40–49 health impact and cost-effectiveness of dairy products supple-
167. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C mented with vitamin D in prevention of osteoporotic fractures.
(2007) Effect of annual intramuscular vitamin D on fracture risk in Arch Public Health 2015(14):73–48
elderly men and women—a population-based, randomized, dou- 182. Ethgen O, Hiligsmann M, Burlet N, Reginster JY (2016) Cost-
ble-blind, placebo-controlled trial. Rheumatol (Oxford) 46:1852– effectiveness of personalized supplementation with vitamin D-rich
1857 dairy products. Osteoporos Int 27:301–308
168. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz 183. Hiligsmann M, Neuprez A, Buckinx F, Locquet M, Reginster JY
MA, Young D, Nicholson GC (2010) Annual high-dose oral vita- (2017) A scoping review of the public health impact of vitamin D-
min D and falls and fractures in older women: a randomized con- fortified dairy products for fracture prevention. Arch Osteoporos
trolled trial. JAMA 303:1815–1822 12:57. https://doi.org/10.1007/s11657-017-0352-1
169. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, 184. Hiligsmann M, Reginster JY (2017) The projected public health
Meyer OW, Theiler R, Dick W, Willett WC, Egli A (2016) and economic impact of vitamin D fortified dairy products for
Monthly high-dose vitamin D treatment for the prevention of func- fracture prevention in France. Expert Rev Pharmacoecon
tional decline: a randomized clinical trial. JAMA Intern Med 176: Outcomes Res 7:1–5
175–183 185. Saito T, Sterbenz JM, Malay S, Zhong L, MacEachern MP, Chung
170. Smith LM, Gallagher JC, Suiter C (2017) Medium doses of daily KC (2017) Effectiveness of anti-osteoporotic drugs to prevent sec-
vitamin D decrease falls and higher doses of daily vitamin D3 ondary fragility fractures: systematic review and meta-analysis.
increase falls: a randomized clinical trial. J Steroid Biochem Mol Osteoporos Int 28:3289–3300
Biol 173:317–322 186. Kanis JA, Cooper C, Rizzoli R, Abrahamsen B, Al-Daghri NM,
171. Rizzoli R, Biver E, Bonjour J-P, Coxam V, Goltzman D, Kanis JA, Brandi ML, Cannata-Andia J, Cortet B, Dimai HP, Ferrari S, Hadji
Lappe J, Rejnmark L, Sahni S, Weaver C, Weiler H, Reginster JY P, Harvey NC, Kraenzlin M, Kurth A, McCloskey E, Minisola S,
(2018) Benefits and safety of dietary protein for bone health. A Thomas T, Reginster JY (2017) Identification and management of
position paper from the International Osteoporosis Foundation and patients at increased risk of osteoporotic fracture: outcomes of an
from the European Society for Clinical and Economical Aspects of ESCEO expert consensus meeting. Osteoporos Int 28:2023–2034
Osteopororosis, Osteoarthritis and Musculoskeltal Diseases. 187. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA,
Osteoporos Int May 8. https://doi.org/10.1007/s00198-018-4534- Jordan VC, Carbone PP, DeMets DL (1992) Effects of tamoxifen
5. [Epub ahead of print] on bone mineral density in postmenopausal women with breast
172. Rizzoli R (2014) Dairy products, yogurts, and bone health. Am J cancer. N Engl J Med 326:852–856
Clin Nutr 99(5 Suppl):1256S–1262S 188. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen
173. Rozenberg S, Body JJ, Bruyère O, Bergmann P, Brandi ML, T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR,
Cooper C, Devogelaer JP, Gielen E, Goemaere S, Kaufman JM, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud
Rizzoli R, Reginster JY (2016) Effects of dairy products con- KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of verte-
sumption on health: benefits and beliefs—a commentary from bral fracture risk in postmenopausal women with osteoporosis
the Belgian Bone Club and the European Society for Clinical treated with raloxifene: results from a 3-year randomized clinical
and Economic Aspects of Osteoporosis, Osteoarthritis and trial. Multiple Outcomes of Raloxifene Evaluation (MORE)
Musculoskeletal Diseases. Calcif Tissue Int 98:1–17 Investigators. JAMA 282:637–645
174. Durosier-Izart C, Biver E, Merminod F, van Rietbergen B, 189. Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E,
Chevalley T, Herrmann FR, Ferrari SL, Rizzoli R (2017) Adachi JD (2003) Severity of prevalent vertebral fractures and the
Peripheral skeleton bone strength is positively correlated with risk of subsequent vertebral and nonvertebral fractures: results
total and dairy protein intakes in healthy postmenopausal women. from the MORE trial. Bone 33:522–532
Am J Clin Nutr 105:513–525 190. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ,
175. Langsetmo L, Shikany JM, Burghardt AJ, Cawthon PM, Orwoll Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M,
ES, Cauley JA, Taylor BC, Schousboe JT, Bauer DC, Vo TN, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC (1999)
Ensrud KE, Osteoporotic Fractures in Men (MrOS) Study The effect of raloxifene on risk of breast cancer in postmenopausal
women: results from the MORE randomized trial. Multiple management of vasomotor symptoms and osteoporosis prevention
Outcomes of Raloxifene Evaluation. JAMA 281:2189–2197 associated with menopause. Pharmacotherapy 36:548–561
191. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini 204. Hadji P, Ryan KA, Yu CR, Mirkin S, Komm BS (2016) CE/BZA
RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL effects on bone and quality of life in European postmenopausal
3rd, Robidoux A, Margolese RG, James J, Lippman SM, women: a pooled analysis. Climacteric 19:482–487
Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford 205. Rizzoli R (2011) Bisphosphonates for post-menopausal osteopo-
LG, Jordan VC, Wolmark N (2006) Effects of tamoxifen vs ral- rosis: are they all the same? Quart J Med 104:281–300
oxifene on the risk of developing invasive breast cancer and other 206. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK,
disease outcomes: the NSABP Study of Tamoxifen and McCloskey EV, Beneton MN, Gertz BJ, Sciberras DG, Holland
Raloxifene (STAR) P-2 trial. JAMA 295:2727–2741 SD, Orgee J, Coombes GM, Rogers SR, Porras AG (1997)
192. Mosca L, Barrett-Connor E, Wenger NK, Collins P, Grady D, Elimination and biochemical responses to intravenous alendronate
Kornitzer M, Moscarelli E, Paul S, Wright TJ, Helterbrand JD, in postmenopausal osteoporosis. J Bone Miner Res 12:1700–1707
Anderson PW (2001) Design and methods of the Raloxifene Use 207. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE,
for The Heart (RUTH) study. Am J Cardiol 88:392–395 Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott
193. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996)
Kornitzer M, McNabb MA, Wenger NK (2006) Effects of ralox- Randomised trial of effect of alendronate on risk of fracture in
ifene on cardiovascular events and breast cancer in postmenopaus- women with existing vertebral fractures. Fracture Intervention
al women. N Engl J Med 355:125–137 Trial Research Group. Lancet 348:1535–1541
194. Kanis JA, Johnell O, Black DM, Downs RW Jr, Sarkar S, Fuerst T, 208. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C
Secrest RJ, Pavo I (2003) Effect of raloxifene on the risk of new (2002) Meta-analyses of therapies for postmenopausal osteoporo-
vertebral fracture in postmenopausal women with osteopenia or sis. IX: summary of meta-analyses of therapies for postmenopaus-
osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene al osteoporosis. Endocr Rev 23:570–578
Evaluation trial. Bone 33:293–300
209. Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley
195. Kanis JA, Johansson H, Odén A, McCloskey EV (2010) A meta-
J (2005) A systematic review and economic evaluation of
analysis of the efficacy of raloxifene on all clinical and vertebral
alendronate, etidronate, risedronate, raloxifene and teriparatide
fractures and its dependency on FRAX. Bone 47:729–735
for the prevention and treatment of postmenopausal osteoporosis.
196. Silverman SL, Christiansen C, Genant HK, Vukicevic S,
Health Technol Assess 9:1–160
Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA
210. Cummings SR, Black DM, Thompson DE, Applegate WB,
(2008) Efficacy of bazedoxifene in reducing new vertebral frac-
Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin
ture risk in postmenopausal women with osteoporosis: results
SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998)
from a 3-year, randomized, placebo-, and active-controlled clini-
Effect of alendronate on risk of fracture in women with low bone
cal trial. J Bone Miner Res 23:1923–1934
density but without vertebral fractures: results from the Fracture
197. Silverman SL, Chines AA, Kendler DL, Kung AW, Teglbjaerg
Intervention Trial. JAMA 280:2077–2082
CS, Felsenberg D, Mairon N, Constantine GD, Adachi JD
211. Axelsson KF, Wallander M, Johansson H, Lundh D, Lorentzon M
(2012) Sustained efficacy and safety of bazedoxifene in
(2017) Hip fracture risk and safety with alendronate treatment in
preventing fractures in postmenopausal women with osteoporosis:
the oldest-old. J Intern Med 282:546–559
results of a 5-year, randomized, placebo-controlled study.
Osteoporos Int 23:351–363 212. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T,
198. Palacios S, Silverman SL, de Villiers TJ, Levine AB, Goemaere S, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS,
Brown JP, De Cicco Nardone F, Williams R, Hines TL, Mirkin S, Axelrod DW, Miller PD (1999) Effects of risedronate treatment on
Chines AA, Bazedoxifene Study Group (2015) A 7-year random- vertebral and nonvertebral fractures in women with postmeno-
ized, placebo-controlled trial assessing the long-term efficacy and pausal osteoporosis: a randomized controlled trial. Vertebral
safety of bazedoxifene in postmenopausal women with osteopo- Efficacy with Risedronate Therapy (VERT) Study Group.
rosis: effects on bone density and fracture. Menopause 22:806– JAMA 282:1344–1352
813 213. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C,
199. Ellis AG, Reginster JY, Luo X, Bushmakin AG, Williams R, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R
Sutradhar S, Mirkin S, Jansen JP (2014) Indirect comparison of (2000) Randomized trial of the effects of risedronate on vertebral
bazedoxifene vs oral bisphosphonates for the prevention of verte- fractures in women with established postmenopausal osteoporo-
bral fractures in postmenopausal osteoporotic women. Curr Med sis. Vertebral Efficacy with Risedronate Therapy (VERT) Study
Res Opin 30:1617–1626 Group. Osteoporos Int 11:83–91
200. Ellis AG, Reginster JY, Luo X, Cappelleri JC, Chines A, Sutradhar 214. McClung MR, Balske A, Burgio DE, Wenderoth D, Recker RR
S, Jansen JP (2014) Bazedoxifene versus oral bisphosphonates for (2013) Treatment of postmenopausal osteoporosis with delayed-
the prevention of nonvertebral fractures in postmenopausal wom- release risedronate 35 mg weekly for 2 years. Osteoporos Int 24:
en with osteoporosis at higher risk of fracture: a network meta- 301–310
analysis. Value Health 17:424–432 215. Chesnut IC, Skag A, Christiansen C, Recker R, Stakkestad JA,
201. Kanis JA, Johansson H, Odén A, McCloskey EV (2009) Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC,
Bazedoxifene reduces vertebral and clinical fractures in postmen- Delmas PD (2004) Effects of oral ibandronate administered daily
opausal women at high risk assessed with FRAX. Bone 44:1049– or intermittently on fracture risk in postmenopausal osteoporosis. J
1054 Bone Miner Res 19:1241–1249
202. de Villiers TJ, Chines AA, Palacios S, Lips P, Sawicki AZ, Levine 216. Delmas PD, Recker RR, Chesnut CH, 3rd, Skag A, Stakkestad JA,
AB, Codreanu C, Kelepouris N, Brown JP (2011) Safety and Emkey R, Gilbride J, Schimmer RC, Christiansen C (2004) Daily
tolerability of bazedoxifene in postmenopausal women with oste- and intermittent oral ibandronate normalize bone turnover and
oporosis: results of a 5-year, randomized, placebo-controlled provide significant reduction in vertebral fracture risk: results from
phase 3 trial. Osteoporos Int 22:567–576 the BONE study. Osteoporos Int 15: 792–798
203. Umland EM, Karel L, Santoro N (2016) Bazedoxifene and con- 217. Harris ST, Blumentals WA, Miller PD (2008) Ibandronate and the
jugated equine estrogen: a combination product for the risk of non-vertebral and clinical fractures in women with
postmenopausal osteoporosis: results of a meta-analysis of phase 229. Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM
III studies. Curr Med Res Opin 24:237–245 (2015) Efficacy and safety of single-dose zoledronic acid for os-
218. Reginster JY, Adami S, Lakatos P, Greenwald M, Stepan JJ, teoporosis in frail elderly women: a randomized clinical trial.
Silverman SL, Christiansen C, Rowell L, Mairon N, Bonvoisin JAMA Intern Med 175:913–921
B, Drezner MK, Emkey R, Felsenberg D, Cooper C, Delmas PD, 230. Tadrous M, Wong L, Mamdani MM, Juurlink DN, Krahn MD,
Miller PD (2006) Efficacy and tolerability of once-monthly oral Levesque LE, Cadarette SM (2014) Comparative gastrointestinal
ibandronate in postmenopausal osteoporosis: 2 year results from safety of bisphosphonates in primary osteoporosis: a network me-
the MOBILE study. Ann Rheum Dis 65:654–661 ta-analysis. Osteoporos Int 25:1225–1235
219. Miller PD, Recker RR, Reginster JY, Riis BJ, Czerwinski E, 231. Rizzoli R, Reginster JY, Boonen S, Breart G, Diez-Perez A,
Masanauskaite D, Kenwright A, Lorenc R, Stakkestad JA, Felsenberg D, Kaufman JM, Kanis JA, Cooper C (2011)
Lakatos P (2012) Efficacy of monthly oral ibandronate is Adverse reactions and drug-drug interactions in the management
sustained over 5 years: the MOBILE long-term extension study. of women with postmenopausal osteoporosis. Calcif Tissue Int
Osteoporos Int 23:1747–1756 89:91–104
220. Delmas PD, Adami S, Strugala C, Stakkestad JA, Reginster JY, 232. Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke
Felsenberg D, Christiansen C, Civitelli R, Drezner MK, Recker BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ,
RR, Bolognese M, Hughes C, Masanauskaite D, Ward P, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE (2016)
Sambrook P, Reid DM (2006) Intravenous ibandronate injections Managing osteoporosis in patients on long-term bisphosphonate
in postmenopausal women with osteoporosis: one-year results treatment: report of a task force of the American Society for Bone
from the dosing intravenous administration study. Arthritis and Mineral Research. J Bone Miner Res 31: 16–35
Rheum 54:1838–1846 233. Khan AA, Morrison A, Kendler DL, Rizzoli R, Hanley DA,
221. Bianchi G, Czerwinski E, Kenwright A, Burdeska A, Recker RR, Felsenberg D, McCauley LK, O’Ryan F, Reid IR, Ruggiero SL,
Felsenberg D (2012) Long-term administration of quarterly IV Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T,
ibandronate is effective and well tolerated in postmenopausal os- Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan
teoporosis: 5-year data from the DIVA study long-term extension. SL, Obermayer-Pietsch B, Langdahl BL, Dabagh RA, Davison
Osteoporos Int 23:1769–1778 KS, Sándor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz
DD, Sulimani R, Saunders DP, Brown JP, Compston J (2017)
222. Miller PD, Recker RR, Harris S, Silverman S, Felsenberg D,
Case-based review of osteonecrosis of the jaw (ONJ) and appli-
Reginster J, Day BM, Barr C, Masanauskaite D (2014) Long-
cation of the international recommendations for management from
term fracture rates seen with continued ibandronate treatment:
the international task force on ONJ. J Clin Densitom 20:8–24
pooled analysis of DIVA and MOBILE long-term extension stud-
234. Fung P, Bedogni G, Bedogni A Petrie A, Porter S, Campisi G,
ies. Osteoporos Int 25:349–357
Bagan J, Fusco V, Saia G, Acham S, Musto P, Petrucci MT, Diz P,
223. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P,
Colella G, Mignogna MD, Pentenero M, Arduino P, Lodi G,
Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P,
Maiorana C, Manfredi M, Hallberg P, Wadelius M, Takaoka K,
Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR,
Leung YY, Bonacina R, Schiødt M, Lakatos P, Taylor T, De Riu
Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H,
G, Favini G, Rogers SN, Pirmohamed M, Nicoletti P; GENVABO
Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G,
Consortium, Fedele S (2017) Time to onset of bisphosphonate-
Verbruggen L, Meunier PJ (2002) Intravenous zoledronic acid in
related osteonecrosis of the jaws: a multicentre retrospective co-
postmenopausal women with low bone mineral density. N Engl J
hort study. Oral Dis 23: 477–483
Med 346:653–661
235. Meier C, Uebelhart B, Aubry-Rozier B, Birkhäuser M, Bischoff-
224. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Ferrari HA, Frey D, Kressig RW, Lamy O, Lippuner K, Stute P,
Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink Suhm N, Ferrari S (2017) Osteoporosis drug treatment: duration
P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue and management after discontinuation. A position statement from
TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly the SVGO/ASCO. Swiss Med Wkly 147:w14484
zoledronic acid for treatment of postmenopausal osteoporosis. N 236. Rizzoli R, Burlet N, Cahall D, Delmas PD, Eriksen EF, Felsenberg
Engl J Med 356:1809–1822 D, Grbic J, Jontell M, Landesberg R, Laslop A, Wollenhaupt M,
225. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper Papapoulos S, Sezer O, Sprafka M, Reginster JY (2008)
CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore Osteonecrosis of the jaw and bisphosphonate treatment for osteo-
KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams porosis. Bone 42:841–847
K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) Zoledronic 237. Anagnostis P, Paschou SA, Mintziori G, Ceausu I, Depypere H,
acid and clinical fractures and mortality after hip fracture. New Lambrinoudaki I, Mueck A, Pérez-López FR, Rees M, Senturk
Engl J Med 357:1–11 LM, Simoncini T, Stevenson JC, Stute P, Trémollieres FA, Goulis
226. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, DG (2017) Drug holidays from bisphosphonates and denosumab
Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung in postmenopausal osteoporosis: EMAS position statement.
PC, Man Z, Martinez RL, Tan M, Ruzycky ME, Su G, Eastell R Maturitas 101:23–30
(2012) The effect of 3 versus 6 years of zoledronic acid treatment 238. Pazianas M, Compston J, Huang CL (2010) Atrial fibrillation and
of osteoporosis: a randomized extension to the HORIZON-Pivotal bisphosphonate therapy. J Bone Miner Res 25:2–10
Fracture Trial (PFT). J Bone Miner Res 27:243–254 Erratum in: J 239. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ (2010)
Bone Miner Res. 2012 Dec;27(12):2612 Exposure to oral bisphosphonates and risk of esophageal cancer.
227. Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, JAMA 304:657–663
Lippuner K, Cummings SR, Hue TF, Mukhopadhyay A, Tan M, 240. Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V (2010)
Aftring RP, Eastell R (2015) The effect of 6 versus 9 years of Oral bisphosphonates and risk of cancer of oesophagus, stomach,
zoledronic acid treatment in osteoporosis: a randomized second and colorectum: case-control analysis within a UK primary care
extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone cohort. BMJ 341:c4444
Miner Res 30:934–944 241. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown
228. Grey A (2016) Intravenous zoledronate for osteoporosis: less TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D,
might be more. Ther Adv Musculoskelet Dis 8:119–123 Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K,
Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, parathyroid hormone (1-34) for 2 years and relevance to human
Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte safety. Toxicol Pathol 30:312–321
M, American Society for Bone and Mineral Research (2010) 256. Jolette J, Wilker CE, Smith SY, Doyle N, Hardisty JF, Metcalfe
Atypical subtrochanteric and diaphyseal femoral fractures: report AJ, Marriott TB, Fox J, Wells DS (2006) Defining a noncarcino-
of a task force of the American Society for Bone and Mineral genic dose of recombinant human parathyroid hormone 1-84 in a
Research. J Bone Miner Res 25:2267–2294 2-year study in Fischer 344 rats. Toxicol Pathol 34:929–940
242. Rizzoli R, Akesson K, Bouxsein M, Kanis JA, Napoli N, 257. Lecart MP, Reginster JY (2011) Current options for the manage-
Papapoulos S, Reginster JY, Cooper C (2011) Subtrochanteric ment of postmenopausal osteoporosis. Expert Opin Pharmacother
fractures after long-term treatment with bisphosphonates: a 12:2533–2552
European Society on Clinical and Economic Aspects of 258. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R,
Osteoporosis and Osteoarthritis, and International Osteoporosis Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S,
Foundation Working Group Report. Osteoporos Int 22:373–390 Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C
243. Meier RP, Perneger TV, Stern R, Rizzoli R, Peter RE (2012) (2009) Denosumab for prevention of fractures in postmenopausal
Increasing occurrence of atypical femoral fractures associated women with osteoporosis. N Engl J Med 361:756–765
with bisphosphonate use. Arch Intern Med 172:930–936 259. Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R,
244. Chlebowski RT, Chen Z, Cauley JA, Anderson G, Rodabough RJ, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler
McTiernan A, Lane DS, Manson JE, Snetselaar L, Yasmeen S, DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN,
O’Sullivan MJ, Safford M, Hendrix SL, Wallace RB (2010) Oral Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW,
bisphosphonate use and breast cancer incidence in postmenopaus- Papapoulos S (2017) 10 years of denosumab treatment in post-
al women. J Clin Oncol 28:3582–3590 menopausal women with osteoporosis: results from the phase 3
245. Pazianas M, Abrahamsen B, Eiken PA, Eastell R, Russell RG randomised FREEDOM trial and open-label extension. Lancet
(2012) Reduced colon cancer incidence and mortality in postmen- Diabetes Endocrinol 5:513–523
opausal women treated with an oral bisphosphonate-Danish 260. Ferrari S, Adachi JD, Lippuner K, Zapalowski C, Miller PD,
National Register Based Cohort Study. Osteoporos Int 23:2693– Reginster JY, Törring O, Kendler DL, Daizadeh NS, Wang A,
2701 O’Malley CD, Wagman RB, Libanati C, Lewiecki EM (2015)
246. Hartle JE, Tang X, Kirchner HL, Bucaloiu ID, Sartorius JA, Further reductions in nonvertebral fracture rate with long-term
Pogrebnaya ZV, Akers GA, Carnero GE, Perkins RM (2012) denosumab treatment in the FREEDOM open-label extension
Bisphosphonate therapy, death, and cardiovascular events among and influence of hip bone mineral density after 3 years.
female patients with CKD: a retrospective cohort study. Am J Osteoporos Int 26:2763–2771
Kidney Dis 59:636–644 261. Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD,
247. Bondo L, Eiken P, Abrahamsen B (2013) Analysis of the associ- Yang YC, Grazette L, San Martin J, Gallagher JC (2011) Effects
of denosumab treatment and discontinuation on bone mineral den-
ation between bisphosphonate treatment survival in Danish hip
sity and bone turnover markers in postmenopausal women with
fracture patients-a nationwide register-based open cohort study.
low bone mass. J Clin Endocrinol Metab 96:972–980
Osteoporos Int 24:245–252
262. Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB,
248. Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG (2008) Risk
McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP
of hip fracture after bisphosphonate discontinuation: implications
(2018) Vertebral fractures after discontinuation of denosumab: a
for a drug holiday. Osteoporos Int 19:1613–1620
post hoc analysis of the randomized placebo-controlled
249. Mignot MA, Taisne N, Legroux I, Cortet B, Paccou J (2017)
FREEDOM Trial and its extension. J Bone Miner Res 33:190–
Bisphosphonate drug holidays in postmenopausal osteoporosis:
198
effect on clinical fracture risk. Osteoporos Int 28:3431–3438
263. Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen
250. Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer EF, Guanabens N, Obermayer-Pietsch B, Ralston SH, Eastell R,
DC, Suryawanshi S, Feldstein A, Haskell WL, Hochberg MC, Zillikens MC (2017) Discontinuation of denosumab therapy for
Torner JC, Lombardi A, Black DM (2004) Randomized trial of osteoporosis: a systematic review and position statement by
effect of alendronate continuation versus discontinuation in wom- ECTS. Bone 105:11–17
en with low BMD: results from the Fracture Intervention Trial 264. Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard
long-term extension. J Bone Miner Res 19:1259–1269 BS, Bolognese MA, Malouf J, Bone HG, Reginster JY, Singer A,
251. Kanis JA, Reginster JY, Kaufman JM, Ringe JD, Adachi JD, Wang C, Wagman RB, Cummings SR (2016) Denosumab or zo-
Hiligsmann M, Rizzoli R, Cooper C (2012) A reappraisal of ge- ledronic acid in postmenopausal women with osteoporosis previ-
neric bisphosphonates in osteoporosis. Osteoporos Int 23:213– ously treated with oral bisphosphonates. J Clin Endocrinol Metab
221 101:3163–3170
252. Kraenzlin ME, Meier C (2011) Parathyroid hormone analogues in 265. von Keyserlingk C, Hopkins R, Anastasilakis A, Toulis K, Goeree
the treatment of osteoporosis. Nat Rev Endocrinol 7:647–656 R, Tarride JE, Xie F (2011) Clinical efficacy and safety of
253. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, denosumab in postmenopausal women with low bone mineral
Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant density and osteoporosis: a meta-analysis. Semin Arthritis
HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone Rheum 41:178–186
(1-34) on fractures and bone mineral density in postmenopausal 266. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA,
women with osteoporosis. N Engl J Med 344:1434–1441 Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ
254. Prince R, Sipos A, Hossain A, Syversen U, Ish-Shalom S, (2003) The effects of parathyroid hormone and alendronate alone
Marcinowska E, Halse J, Lindsay R, Dalsky GP, Mitlak BH or in combination in postmenopausal osteoporosis. N Engl J Med
(2005) Sustained nonvertebral fragility fracture risk reduction af- 349:1207–1215
ter discontinuation of teriparatide treatment. J Bone Miner Res 20: 267. Leder BZ, Tsai JN, Neer RM, Uihlein AV, Wallace PM, Burnett-
1507–1513 Bowie SA (2016) Response to therapy with teriparatide,
255. Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt denosumab, or both in postmenopausal women in the DATA
JA, Westmore MS, Linda Y, Nold JB (2002) Skeletal changes in (Denosumab and Teriparatide Administration) study randomized
rats given daily subcutaneous injections of recombinant human controlled trial. J Clin Densitom 19:346–351
268. Cosman F, Nieves JW, Zion M, Garrett P, Neubort S, Dempster D, J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL,
Lindsay R (2015) Daily or cyclical teriparatide treatment in wom- Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML,
en with osteoporosis on no prior therapy and women on Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller
alendronate. J Clin Endocrinol Metab 100:2769–2776 S (2004) Effects of conjugated equine estrogen in postmenopausal
269. Cosman F, Nieves JW, Dempster DW (2017) Treatment sequence women with hysterectomy: the Women’s Health Initiative ran-
matters: anabolic and antiresorptive therapy for osteoporosis. J domized controlled trial. JAMA 291: 1701–1712
Bone Miner Res 32:198–202 282. Fenton A, Panay N (2012) The Women’s Health Initiative—a
270. Kanis JA, Cooper C, Rizzoli R, Reginster J-Y (2018) Review of decade of progress. Climacteric 15:205
the guideline of the American College of Physicians on the treat- 283. Langer RD, Manson JE, Allison MA (2012) Have we come full
ment of osteoporosis. Osteoporos Int 29:1505–1510 circle—or moved forward? The Women’s Health Initiative 10
271. Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, years on. Climacteric 15:206–212
Hue T, Lang TF, McGowan JA, Rosen CJ (2005) One year of 284. Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice
alendronate after one year of parathyroid hormone (1-84) for os- RL, LaCroix AZ, Chlebowski RT, Howard BV, Thomson CA,
teoporosis. N Engl J Med 353:555–565 Margolis KL, Lewis CE, Stefanick ML, Jackson RD, Johnson
272. Torgerson DJ, Bell-Syer SE (2001) Hormone replacement therapy KC, Martin LW, Shumaker SA, Espeland MA, Wactawski-
and prevention of nonvertebral fractures: a meta-analysis of ran- Wende J (2017) Menopausal hormone therapy and long-term all-
domized trials. JAMA 285:2891–2897 cause and cause-specific mortality: the Women’s Health Initiative
273. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, randomized trials. JAMA 318:927–938
LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, 285. Langer RD, Simon JA, Pines A, Lobo RA, Hodis HN, Pickar JH,
Pettinger M, Stefanick ML, Wactawski-Wende J, Watts NB Archer DF, Sarrel PM, Utian WH (2017) Menopausal hormone
(2003) Effects of estrogen plus progestin on risk of fracture and therapy for primary prevention: why the USPSTF is wrong.
bone mineral density: the Women’s Health Initiative randomized Climacteric 20:402–413
trial. JAMA 290:1729–1738 286. Richy F, Ethgen O, Bruyère O, Reginster JY (2004) Efficacy of
274. Sornay-Rendu E, Garnero P, Munoz F, Duboeuf F, Delmas PD alphacalcidol and calcitriol in primary and corticosteroid-induced
(2003) Effect of withdrawal of hormone replacement therapy on osteoporosis: a meta-analysis of their effects on bone mineral den-
bone mass and bone turnover: the OFELY study. Bone 33:159– sity and fracture rate. Osteoporos Int 15:301–310
166 287. Richy F, Schacht E, Bruyère O, Ethgen O, Gourlay M, Reginster
275. Bagger YZ, Tanko LB, Alexandersen P, Hansen HB, Mollgaard JY (2005) Vitamin D analogs versus native vitamin D in
A, Ravn P, Qvist P, Kanis JA, Christiansen C (2004) Two to three preventing bone loss and osteoporosis-related fractures: a compar-
years of hormone replacement treatment in healthy women have ative meta-analysis. Calcif Tissue Int 76:176–186
long-term preventive effects on bone mass and osteoporotic frac- 288. Tilyard MW, Spears GF, Thomson J, Dovey S (1992) Treatment of
tures: the PERF study. Bone 34:728–735 postmenopausal osteoporosis with calcitriol or calcium. N Engl J
276. Roussow JE, Anderson GL, Prentice RL, LaCroix A, Kooperberg Med 326:357–362
C, Stefanick ML (2002) Risks and benefits of estrogen plus pro- 289. Gallagher JC, Rapuri PB, Smith LM (2007) An age-related de-
gestin in healthy postmenopausal women: principal results from crease in creatinine clearance is associated with an increase in
the Women’s Health Initiative randomized controlled trial. JAMA number of falls in untreated women but not in women receiving
288:321–333 calcitriol treatment. J Clin Endocrinol Metab 92:51–58
277. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, 290. Shao HB, Yao YM, Wang ZY, Zhang QF, Wei W (2015) Effects of
Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, combined alendronate and alfacalcidol on prevention of fractures
Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, in osteoporosis patients: a network meta-analysis. Int J Clin Exp
Mysiw WJ (2003) Effect of estrogen plus progestin on stroke in Med 8:12935–12941
postmenopausal women: the Women’s Health Initiative: a ran- 291. McCloskey E, Selby P, Davies M, Robinson J, Francis RM,
domized trial. JAMA 289:2673–2684 Adams J, Kayan K, Beneton M, Jalava T, Pylkkänen L, Kenraali
278. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, J, Aropuu S, Kanis JA (2004) Clodronate reduces vertebral frac-
Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, ture risk in women with postmenopausal or secondary osteoporo-
Khandekar J, Petrovitch H, McTiernan A (2003) Influence of es- sis: results of a double-blind, placebo-controlled 3-year study. J
trogen plus progestin on breast cancer and mammography in Bone Miner Res 19:728–736
healthy postmenopausal women: the Women’s Health Initiative 292. McCloskey EV, Beneton M, Charlesworth D, Kayan K, deTakats
Randomized Trial. JAMA 289:3243–3253 D, Dey A, Orgee J, Ashford R, Forster M, Cliffe J, Kersh L,
279. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene Brazier J, Nichol J, Aropuu S, Jalava T, Kanis JA (2007)
JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen Clodronate reduces the incidence of fractures in community-
JM, Wassertheil-Smoller S, Wactawski-Wende J (2003) Estrogen dwelling elderly women unselected for osteoporosis: results of a
plus progestin and the incidence of dementia and mild cognitive double-blind, placebo-controlled randomized study. J Bone Miner
impairment in postmenopausal women: the Women’s Health Res 22:135–141
Initiative Memory Study: a randomized controlled trial. JAMA 293. Howe J, Huber B, Favell D, Hill R, Bouxsein M, Engelke K,
289: 2651–2662 Genant H (2017) Long-term prospective cohort study of a local
280. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, osteo-enhancement procedure (LOEP) to treat proximal femurs of
Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix post-menopausal osteoporotic women. Osteoporos Int 28(S1):S75
AZ, Granek IA, Valanis BG (2003) Effects of estrogen plus pro- 294. Engelke K, Favell D, Hill R, Fuerst T, Huber B, Howe J, Genant H
gestin on health-related quality of life. N Engl J Med 348:1839– (2017) QCT demonstrates long-term proximal femur trabecular
1854 density increases in osteoporotic women following treatment with
281. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, a minimally invasive local osteo-enhancement procedure involv-
Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, ing injection of a resorbable triphasic calcium based implant ma-
Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, terial. J Bone Miner Res 32(suppl 1):S11
Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller 295. Keaveny T, Lee D, Favell D, Hill R, Howe J, Huber B, Bouxsein
L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson M (2017) FEA-estimated proximal femur strength increases
through 5-7 year follow-up in osteoporotic women treated with a 310. Marsh D, Akesson K, Beaton DE, Bogoch ER, Boonen S, Brandi
local osteo-enhancement procedure involving injection of a re- ML, McLellan AR, Mitchell PJ, Sale JE, Wahl DA (2011)
sorbable, triphasic calcium-based implant material. J Bone Miner Coordinator-based systems for secondary prevention in fragility
Res 32:S11 fracture patients. Osteoporos Int 22:2051–2065
296. Boonen S, Van Meirhaeghe J, Bastian L, Cummings SR, Ranstam 311. Davis JC, Guy P, Ashe MC, Liu-Ambrose T, Khan K (2007)
J, Tillman JB, Eastell R, Talmadge K, Wardlaw D (2011) Balloon HipWatch: osteoporosis investigation and treatment after a hip
kyphoplasty for the treatment of acute vertebral compression frac- fracture: a 6-month randomized controlled trial. J Gerontol A
tures: 2-year results from a randomized trial. J Bone Miner Res 26: Biol Sci Med Sci 62:888–891
1627–1637 312. Gardner MJ, Flik KR, Mooar P, Lane JM (2002) Improvement in
297. Wang H, Sribastav SS, Ye F, Yang C, Wang J, Liu H, Zheng Z the undertreatment of osteoporosis following hip fracture. J Bone
(2015) Comparison of percutaneous vertebroplasty and balloon Joint Surg Am 84-A:1342–1348
kyphoplasty for the treatment of single level vertebral compres- 313. Majumdar SR, Beaupre LA, Harley CH, Hanley DA, Lier DA,
sion fractures: a meta-analysis of the literature. Pain Physician 18: Juby AG, Maksymowych WP, Cinats JG, Bell NR, Morrish DW
209–222 (2007) Use of a case manager to improve osteoporosis treatment
298. Papanastassiou ID, Phillips FM, Van Meirhaeghe J, Berenson JR, after hip fracture: results of a randomized controlled trial. Arch
Andersson GB, Chung G, Small BJ, Aghayev K, Vrionis FD Intern Med 167:2110–2115
(2012) Comparing effects of kyphoplasty, vertebroplasty, and non- 314. Dell R (2011) Fracture prevention in Kaiser Permanente Southern
surgical management in a systematic review of randomized and California. Osteoporos Int 22(Suppl 3):457–460
non-randomized controlled studies. Eur Spine J 21:1826–1843 315. Majumdar SR, Lier DA, Rowe BH, Russell AS, McAlister FA,
299. Firanescu CE, de Vries J, Lodder P, Venmans A, Schoemaker MC, Maksymowych WP, Hanley DA, Morrish DW, Johnson JA (2011)
Smeet AJ, Donga E, Juttmann JR, Klazen CAH, Elgersma OEH, Cost-effectiveness of a multifaceted intervention to improve qual-
Jansen FH, Tielbeek AV, Boukrab I, Schonenberg K, van Rooij ity of osteoporosis care after wrist fracture. Osteoporos Int 22:
WJJ, Hirsch JA, Lohle PNM (2018) Vertebroplasty versus sham 1799–1808
procedure for painful acute osteoporotic vertebral compression 316. Drew S, Judge A, May C, Farmer A, Cooper C, Javaid MK,
fractures (VERTOS IV): randomised sham controlled clinical trial. Gooberman-Hill R (2015) Implementation of secondary fracture
BMJ 360:k1551. https://doi.org/10.1136/bmj.k1551 prevention services after hip fracture: a qualitative study using
300. Beall DP, Tutton SM, Murphy K, Olan W, Warner C, Test JB extended normalization process theory. Implement Sci 10:57.
(2017) Analysis of reporting bias in vertebral augmentation. Pain https://doi.org/10.1186/s13012-015-0243-z
Physician 20:E1081–E1090 317. Hawley S, Javaid MK, Prieto-Alhambra D, Lippett J, Sheard S,
301. Luthman S, Widén J, Borgström F (2018) Appropriateness criteria Arden NK, Cooper C, Judge A (2016) Clinical effectiveness of
for treatment of osteoporotic vertebral compression fractures. orthogeriatric and fracture liaison service models of care for hip
Osteoporos Int 29:793–804 fracture patients: population-based longitudinal study. Age
302. Bae JS, Park JH, Kim KJ, Kim HS, Jang IT (2017) Analysis of risk Ageing 45:236–242
factors for secondary new vertebral compression fracture follow- 318. Hawley S, Leal J, Delmestri A, Prieto-Alhambra D, Prieto-
ing percutaneous vertebroplasty in patients with osteoporosis. Alhambra D, Arden NK, Cooper C, Javaid MK, Judge A (2016)
World Neurosurg 99:387–394 Anti-osteoporosis medication prescriptions and incidence of sub-
303. Zhang H, Xu C, Zhang T, Gao Z, Zhang T (2017) Does percuta- sequent fracture among primary hip fracture patients in England
neous vertebroplasty or balloon kyphoplasty for osteoporotic ver- and Wales: an interrupted time-series analysis. J Bone Miner Res
tebral compression fractures increase the incidence of new verte- 31:2008–2015
bral fractures? A meta-analysis. Pain Physician 20:E13–E28 319. McLellan AR, Wolowacz SE, Zimovetz EA, Beard SM, Lock S,
304. Chevalley T, Hoffmeyer P, Bonjour JP, Rizzoli R (2002) An oste- McCrink L, Adekunle F, Roberts D (2011) Fracture liaison ser-
oporosis clinical pathway for the medical management of patients vices for the evaluation and management of patients with osteo-
with low-trauma fracture. Osteoporos Int 13:450–455 porotic fracture: a cost-effectiveness evaluation based on data col-
305. McLellan AR, Gallacher SJ, Fraser M, McQuillian C (2003) The lected over 8 years of service provision. Osteoporos Int 22:2083–
fracture liaison service: success of a program for the evaluation 2098
and management of patients with osteoporotic fracture. 320. Cooper MS, Palmer AJ, Seibel MJ (2012) Cost effectiveness of
Osteoporos Int 14:1028–1034 the Concord minimal trauma Fracture Liaison service, a prospec-
306. Ganda K, Puech M, Chen JS, Speerin R, Bleasel J, Center JR, tive, controlled fracture prevention study. Osteoporos Int 23:97–
Eisman JA, March L, Seibel MJ (2013) Models of care for the 107
secondary prevention of osteoporotic fractures: a systematic re- 321. Leal J, Gray AM, Hawley S, Prieto-Alhambra D, Delmestri A,
view and meta-analysis. Osteoporos Int 24:393–406 Arden NK, Cooper C, Javaid MK, Judge A (2017) Cost-
307. Marsh D, Currie C, Brown P et al for the British Orthopaedic effectiveness of orthogeriatric and fracture liaison service models
Association (2007) The care of patients with fragility fracture. of care for hip fracture patients: a population-based study. J Bone
British Orthopaedic Association http://wwwbgsorguk/pdf_cms/ Miner Res 32:203–211
pubs/Blue%20Book%20on%20fragility%20fracture%20carepdf 322. de Bruin IJA, Wyers CE, van den Bergh JPW, Geusens PPMM
Accessed 13 Jan 2018 (2017) Fracture liaison services: do they reduce fracture rates?
308. Akesson K, Marsh D, Mitchell PJ, McLellan AR, Stenmark J, Ther Adv Musculoskelet Dis 9:157–164
Pierroz DD, Kyer C, Cooper C (2013) Capture the fracture: a best 323. Lekkerkerker F, Kanis JA, Alsayed N, Bouvenot G, Burlet N,
practice framework and global campaign to break the fragility Cahall D, Chines A, Delmas P, Dreiser RL, Ethgen D, Hughes
fracture cycle. Osteoporos Int 24:2135–2152 N, Kaufman JM, Korte S, Kreutz G, Laslop A, Mitlak B, Rabenda
309. Javaid MK, Kyer C, Mitchell PJ, Chana J, Moss C, Edwards MH, V, Rizzoli R, Santora A, Schimmer R, Tsouderos Y, Viethel P,
McLellan AR, Stenmark J, Pierroz DD, Schneider MC, Kanis JA, Reginster JY (2007) Adherence to treatment of osteoporosis: a
Akesson K, Cooper C (2015) Effective secondary fracture preven- need for study. Osteoporos Int 18:1311–1317
tion: implementation of a global benchmarking of clinical quality 324. Solomon DH, Avorn J, Katz JN, Finkelstein JS, Arnold M,
using the IOF capture the fracture (R) best practice framework Polinski JM, Brookhart MA (2005) Compliance with osteoporosis
tool. Osteoporos Int 26:2573–2578 medications. Arch Intern Med 165:2414–2419
325. Rabenda V, Mertens R, Fabri V, Vanoverloop J, Sumkay F, vertebral fracture risk with raloxifene therapy. J Bone Miner Res
Vannecke C, Deswaef A, Verpooten GA, Reginster JY (2008) 17:1–10
Adherence to bisphosphonates therapy and hip fracture risk in 342. Austin M, Yang YC, Vittinghoff E, Adami S, Boonen S, Bauer
osteoporotic women. Osteoporos Int 19:811–818 DC, Bianchi G, Bolognese MA, Christiansen C, Eastell R, Grauer
326. Hiligsmann M, Gathon HJ, Bruyère O, Ethgen O, Rabenda V, A, Hawkins F, Kendler DL, Oliveri B, McClung MR, Reid IR,
Reginster JY (2010) Cost-effectiveness of osteoporosis screening Siris ES, Zanchetta J, Zerbini CA, Libanati C, Cummings SR
followed by treatment: the impact of medication adherence. Value (2012) Relationship between bone mineral density changes with
Health 13:394–401 denosumab treatment and risk reduction for vertebral and
327. Ross S, Samuels E, Gairy K, Iqbal S, Badamgarav E, Siris E nonvertebral fractures. J Bone Miner Res 27:687–693
(2011) A meta-analysis of osteoporotic fracture risk with medica- 343. Chen P, Miller PD, Delmas PD, Misurski DA, Krege JH (2006)
tion nonadherence. Value Health 14:571–581 Change in lumbar spine BMD and vertebral fracture risk reduction
328. Strom O, Borgstrom F, Kanis JA, Jonsson B (2009) Incorporating in teriparatide-treated postmenopausal women with osteoporosis.
adherence into health economic modelling of osteoporosis. J Bone Miner Res 21:1785–1790
Osteoporos Int 20:23–34 344. Baim S, Wilson CR, Lewiecki EM, Luckey MM, Downs RW Jr,
329. Kanis JA, Cooper C, Hiligsmann M, Rabenda V, Reginster JY, Lentle BC (2005) Precision assessment and radiation safety for
Rizzoli R (2011) Partial adherence: a new perspective on health dual-energy X-ray absorptiometry: position paper of the
economic assessment in osteoporosis. Osteoporos Int 22:2565– International Society for Clinical Densitometry. J Clin Densitom
2573 8: 371–378
330. Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C (2004) 345. Bjarnason NH, Sarkar S, Duong T, Mitlak B, Delmas PD,
The impact of compliance with osteoporosis therapy on fracture Christiansen C (2001) Six and twelve month changes in bone
rates in actual practice. Osteoporos Int 15:1003–1008 turnover are related to reduction in vertebral fracture risk during
331. Rabenda V, Reginster JY (2010) Overcoming problems with ad- 3 years of raloxifene treatment in postmenopausal osteoporosis.
herence to osteoporosis medication. Expert Rev Pharmacoecon Osteoporos Int 12:922–930
Outcomes Res 10:677–689 346. Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C,
332. Hiligsmann M, Bours SP, Boonen A (2015) A review of patient McClung MR, Reid IR, Resch H, Siris E, Uebelhart D, Wang
preferences for osteoporosis drug treatment. Curr Rheumatol Rep A, Weryha G, Cummings SR (2011) Effects of denosumab on
17(9):61. https://doi.org/10.1007/s11926-015-0533-0 bone turnover markers in postmenopausal osteoporosis. J Bone
333. Iglay K, Cao X, Mavros P, Joshi K, Yu S, Tunceli K (2015) Miner Res 26:530–537
Systematic literature review and meta-analysis of medication ad- 347. Diez-Perez A, Adachi JD, Agnusdei D, Bilezikian JP, Compston
herence with once-weekly versus once-daily therapy. Clin Ther JE, Cummings SR, Eastell R, Eriksen EF, Gonzalez-Macias J,
37:1813–1821 Liberman UA, Wahl DA, Seeman E, Kanis JA, Cooper C for the
334. Diez-Perez A, Naylor KE, Abrahamsen B, Agnusdei D, Brandi IOF CSA Inadequate Responders Working Group (2012)
ML, Cooper C, Dennison E, Eriksen EF, Gold DT, Guañabens N, Treatment failure in osteoporosis. Osteoporos Int 23:2769–2774
Hadji P, Hiligsmann M, Horne R, Josse R, Kanis JA, Obermayer- 348. Marseille E, Larson B, Kazi DS, Kahn JG Rosen S (2015)
Pietsch B, Prieto-Alhambra D, Reginster JY, Rizzoli R, Silverman Thresholds for the cost-effectiveness of interventions: alternative
S, Zillikens MC, Eastell R (2017) International Osteoporosis approaches. Bull WHO 93:118–124
Foundation and European Calcified Tissue Society Working 349. Gyrd-Hansen D (2006) Looking for willingness to pay (wtp)
Group. Recommendations for the screening of adherence to oral threshold for a qaly—does it make sense? A critical view. The
bisphosphonates. Osteoporos Int 28:767–774 International Society For Pharmacoeconomics And Outcomes
335. Carr AJ, Thompson PW, Cooper C (2006) Factors associated with Research (ISPOR). https://www.ispor.org/news/articles/July07/
adherence and persistence to bisphosphonate therapy in osteopo- WTP-CW.asp Accessed 18 February 2018
rosis: a cross-sectional survey. Osteoporos Int 17:1638–1644 350. Kanis JA, Jonsson B (2002) Economic evaluation of interventions
336. Rabenda V, Bruyère O, Reginster JY (2011) Relationship between for osteoporosis. Osteoporos Int 13:765–767
bone mineral density changes and risk of fractures among patients 351. National Institute for Health and Care Excellence (2011) NICE
receiving calcium with or without vitamin D supplementation: a technology appraisal guidance 161 (amended). Alendronate, eti-
meta-regression. Osteoporos Int 22:893–901 dronate, risedronate, raloxifene, strontium ranelate and teriparatide
337. Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson for the secondary prevention of osteoporotic fragility fractures in
DE, Ross PD (2002) Changes in bone density and turnover ex- postmenopausal women (amended). In: NICE London
plain the reductions in incidence of nonvertebral fractures that 352. Nimdet K, Chaiyakunapruk N, Vichansavakul K, Ngorsuraches S
occur during treatment with antiresorptive agents. J Clin (2015) A systematic review of studies eliciting willingness-to-pay
Endocrinol Metab 87:1586–1592 per quality-adjusted life year: does it justify CE threshold? PLoS
338. Delmas PD, Li Z, Cooper C (2004) Relationship between changes One 10(4):e0122760. https://doi.org/10.1371/journal.pone.
in bone mineral density and fracture risk reduction with 0122760
antiresorptive drugs: some issues with meta-analyses. J Bone 353. Hiligsmann M, Evers SM, Sedrine WB, Kanis JA, Ramaekers B,
Miner Res 19:330–337 Reginster JY, Silverman S, Wyers CE, Boonen A (2015) A sys-
339. Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, tematic review of cost-effectiveness analyses of drugs for post-
LaCroix AZ, Black DM (2002) Improvement in spine bone den- menopausal osteoporosis. Pharmacoeconomics 33:205–224
sity and reduction in risk of vertebral fractures during treatment 354. National Institute for Health and Care Excellence (2011b) NICE
with antiresorptive drugs. Am J Med 112:281–289 technology appraisal guidance 160 (amended). Alendronate, eti-
340. Watts NB, Geusens P, Barton IP, Felsenberg D (2005) dronate, risedronate, raloxifene and strontium ranelate for the pri-
Relationship between changes in BMD and nonvertebral fracture mary prevention of osteoporotic fragility fractures in postmeno-
incidence associated with risedronate: reduction in risk of pausal women (amended). NICE London
nonvertebral fracture is not related to change in BMD. J Bone 355. Kanis JA, McCloskey E, Jonsson B, Cooper C, Strom B,
Miner Res 20:2097–2104 Borgstrom F (2010) An evaluation of the NICE guidance for the
341. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD prevention of osteoporotic fragility fractures in postmenopausal
(2002) Relationships between bone mineral density and incident women. Arch Osteoporos 5:19–48
356. Hiligsmann M, Kanis JA, Compston J, Cooper C, Flamion B, additional results from a double-blind, placebo-controlled
Bergmann P, Body JJ, Boonen S, Bruyère O, Devogelaer JP, randomised study. Osteoporos Int 20:811–817
Goemaere S, Kaufman JM, Rozenberg S, Reginster JY (2013) 366. Harvey NC, Kanis JA, Odén A, Burge RT, Mitlak BH, Johansson
Health technology assessment in osteoporosis. Calcif Tissue Int H, McCloskey EV (2015) FRAX and the effect of teriparatide on
93:1–14 vertebral and non-vertebral fracture. Osteoporos Int 26:2347–
357. Kanis JA, Hiligsmann M (2014) The application of health tech- 2353
nology assessment in osteoporosis. Best Pract Res Clin 367. Harvey NC, Kanis JA, Odén A, Nakamura T, Shiraki M,
Endocrinol Metab 28:895–910 Sugimoto T, Kuroda T, Johansson H, McCloskey EV (2015b)
358. Brandão CM, Machado GP, Acurcio F (2012) Pharmacoeconomic Efficacy of weekly teriparatide does not vary by baseline fracture
analysis of strategies to treat postmenopausal osteoporosis: a sys- probability calculated using FRAX. Osteoporos Int 26:2347–
tematic review. Rev Bras Reumatol 52:924–937 2354
359. Strom O, Borgstrom F, Sen SS, Boonen S, Haentjens P, Johnell O, 368. McCloskey EV, Johansson H, Odén A, Austin M, Siris E, Wang
Kanis JA (2007) Cost-effectiveness of alendronate in the treatment A, Lewiecki EM, Lorenc R, Libanati C, Kanis JA (2012)
of postmenopausal women in 9 European countries–an economic Denosumab reduces the risk of all osteoporotic fractures in post-
evaluation based on the fracture intervention trial. Osteoporos Int menopausal women, particularly in those with moderate to high
18:1047–1061 fracture risk as assessed with FRAX®. J Bone Miner Res 27:
360. Borgstrom F, Johnell O, Kanis JA, Jonsson B, Rehnberg C (2006) 1480–1486
At what hip fracture risk is it cost-effective to treat? International 369. Donaldson MG, Palermo L, Ensrud KE, Hochberg MC,
intervention thresholds for the treatment of osteoporosis. Schousboe JT, Cummings SR (2012) Effect of alendronate for
Osteoporos Int 17:1459–1471 reducing fracture by FRAX score and femoral neck bone mineral
361. Lippuner K, Johansson H, Borgstrom F, Kanis JA, Rizzoli R density: the Fracture Intervention Trial. J Bone Miner Res 27:
(2012) Cost-effective intervention thresholds against osteoporotic 1804–1810
fractures based on FRAX(R) in Switzerland. Osteoporos Int 23: 370. Kim K, Svedbom A, Luo X, Sutradhar S, Kanis JA (2014)
2579–2589 Comparative cost-effectiveness of bazedoxifene and raloxifene
362. Makras P, Athanasakis K, Boubouchairopoulou N, Rizou S, in the treatment of postmenopausal osteoporosis in Europe using
Anastasilakis AD, Kyriopoulos J, Lyritis GP (2015) Cost- the FRAX algorithm. Osteoporos Int 25:325–337
effective osteoporosis treatment thresholds in Greece. 371. Hiligsmann M, Ben Sedrine W, Reginster JY (2013) Cost-
Osteoporos Int 26:1949–1957 effectiveness of bazedoxifene compared with raloxifene in the
363. Marques A, Lourenço O, Ortsäter G, Borgström F, Kanis JA, da treatment of postmenopausal osteoporotic women. J Bone Miner
Silva JAP (2016) Cost-effectiveness of osteoporosis treatment in- Res 28(4):807–815
tervention thresholds for the treatment of osteoporosis based on 372. Kendler DL, Marin F, Zerbini CAF, Russo LA, Greenspan SL,
FRAX in Portugal. Calcif Tissue Intl 99: 131–141 Zikan V, Bagur A, Malouf-Sierra J, Lakatos P, Fahrleitner-
364. Harvey NC, McCloskey E, Kanis JA, Compston J, Cooper C Pammer A, Lespessailles E, Minisola S, Body JJ, Geusens P,
(2017) Bisphosphonates in osteoporosis: NICE and easy? Lancet Möricke R, López-Romero P (2017) Effects of teriparatide and
390(10109):2243–2244. https://doi.org/10.1016/S0140-6736(17) risedronate on new fractures in post-menopausal women with se-
32850-7 vere osteoporosis (VERO): a multicentre, double-blind, double-
365. McCloskey EV, Johansson H, Odén A, Vasireddy S, Kayan K, dummy, randomised controlled trial. Lancet pii: S0140-
Pande K, Jalava T, Kanis JA (2009) Ten-year fracture probability 6736(17)32137–32132. https://doi.org/10.1016/S0140-6736(17)
identifies women who will benefit from clodronate therapy– 32137-2

2018 European Guidance Diagnosis and Management Osteoporosis

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Osteoporosis International (2019) 30:3–44

European guidance for the diagnosis and management of osteoporosis

Summary of main recommendations

* J.A. Kanis Diagnosis of osteoporosis

Lifestyle and dietary measures Systems of care

Table 2 Estimated number of

Fracture probability (%)

Biochemical assessment of fracture risk

Fig. 3 Ten-year probability (%) Ten-year probability (%)

high, moderate, and low exposure to glucocorticoids Assessment of risk

Table 5 Average adjustment of

10 year probability (%)

High Intermediate Low 10

Age range Intervention Lower assessment Upper assessment

Ten year probability (%)

demand the consideration of three assessment scenarios that

Table 7 Gradients of risk (the

threshold used by the National Osteoporosis Foundation of Other assessment models

Fig. 10 The impact of a fixed Identified for treatment (%)

p = 0.002). The effect on hip fracture increased significant- General management

Fig. 11 The risk of hip fracture Hip fracture risk (%)

With kind permission from 20

Table 8 Anti-fracture efficacy of

NA no evidence available, + effective drug

Placebo Drug RR 95% CI

a. Vertebral fracture (high risk population)

FN femoral neck, TH total hip, LS lumbar spine, NA not available

RRR vs. placebo (%)

Vitamin D derivatives Vertebroplasty and kyphoplasty

Fig. 13 Schema of a Fracture

Falls risk Exercise Bone-speciﬁc

Recommended management plan to GP

T-score = − 2.5 SD No BMD 10

Intervention No prior Prior Prior

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