Archives of Osteoporosis (2022) 17:87 https://doi.org/10.1007/s11657-022-01117-6 POSITION PAPER Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group P. Chotiyarnwong1,2 · E. V. McCloskey1,3 · N. C. Harvey4 · M. Lorentzon5,6 · D. Prieto‑Alhambra7,8 · B. Abrahamsen9,10 · J. D. Adachi11 · F. Borgström12,13 · O. Bruyere14 · J. J. Carey15,16 · P. Clark17 · C. Cooper4 · E. M. Curtis4 · E. Dennison4 · M. Diaz‑Curiel18 · H. P. Dimai19 · D. Grigorie20,21 · M. Hiligsmann22 · P. Khashayar23 · E. M. Lewiecki24 · P. Lips25 · R. S. Lorenc26 · S. Ortolani27 · A. Papaioannou28,29 · S. Silverman30 · M. Sosa31 · P. Szulc32 · K. A. Ward4 · N. Yoshimura33 · J. A. Kanis3,6 Received: 29 April 2022 / Accepted: 3 May 2022 © The Author(s) 2022 Abstract Summary The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screen- ing for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. Introduction The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. Methods The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation’s Work- ing Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. Results and Conclusion The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare profession- als, and the implementation of systems that facilitate and maintain the screening program. Keywords Fracture risk · Screening · FRAX · Treatment · Cost-effectiveness Introduction population, the members of which do not necessarily per- ceive that they are at risk of, or are already affected by, the In most countries, screening is regarded as a public health disease or its complications. Principles to determine whether measure, the purpose of which is to offer a test to identify the approaches to managing a disease should include a those individuals who are more likely to benefit from fur- screening programme were first proposed over 50 years ago ther investigations and/or treatment to reduce the risk of a [1] (Table 1). disease or its complications. The test is targeted at a defined These principles have remained largely intact since then, with some modification by national and regional screening committees. For example, prior to making a formal assess- P. Chotiyarnwong and E. V. McCloskey are joint first authors ment of a screening program, the UK National Screening * E. V. McCloskey Committee (NSC) examines certain general characteristics, e.v.mccloskey@sheffield.ac.uk unrelated to the specific disease, to guide decision making Extended author information available on the last page of the article (Table 5). These include that the target population to be 13 Vol.:(0123456789) 87 Page 2 of 24 Archives of Osteoporosis (2022) 17:87 Table 1  The original ten principles for a screening programme outlined by Wilson and Jungner [1] 1 The condition sought should be an important health problem 2 There should be an accepted treatment for patients with recognized disease 3 Facilities for diagnosis and treatment should be available 4 There should be a recognizable latent or early symptomatic stage 5 There should be a suitable test or examination 6 The test should be acceptable to the population 7 The natural history of the condition, including development from latent to declared disease, should be adequately understood 8 There should be an agreed policy on whom to treat as patients 9 The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in rela- tion to possible expenditure on medical care as a whole 10 Case-finding should be a continuing process and not a “once and for all” project screened should be sufficiently large to enable safe, clini- self-completion or completion assisted by a family member cally and cost-effective screening, and that the population or caregiver. The questionnaire data would then be utilized to be screened would regard themselves as not necessarily centrally to calculate the 10-year major osteoporotic fracture having symptoms of the disease or to be at risk of the disease probability and the 10-year hip fracture probability. Those (i.e. relatively healthy people). There should exist an effec- with a low risk of hip fracture would receive a letter of reas- tive means of identifying and contacting the whole cohort surance with general lifestyle advice, while the remainder to be offered screening, including proactive approaches (e.g. would have an additional assessment of femoral neck bone written invitation, verbal invitation at other appointments), mineral density (BMD) using local densitometer facilities. with those approached properly informed of the potential The bone density result would then be incorporated in an benefits and risks to make an informed choice. If these char- updated FRAX calculation, with those that have hip fracture acteristics can be satisfied, the subsequent formal assess- probabilities above the intervention threshold being recom- ment of the evidence for screening covers the key issues, mended for treatment. The latter recommendation would identified by Wilson and Jungner, relating to the condition, be communicated to both the individual and their general the test, the treatment and the effectiveness of any proposed practitioner. screening programme. Several further aspects, considered As the effectiveness of any screening programme is not by the UK NSC, are beyond the scope of this report: these only dependent on the screening test but also on the preva- include plans for managing and monitoring the screening lence of the disease of interest, we envisage that the strat- programme, agreed quality assurance standards, adequate egy should initially be considered in older age groups, for levels of staffing and facilities, provision of information example those age 70 years and above as in the SCOOP trial, to potential participants and anticipated public pressure to in those countries with a hip fracture risk comparable to or extend the eligibility criteria for screening. higher than that in the UK [7]. As described below, osteoporosis and, more pertinently, its burden of fractures represents an opportunity for consid- eration of a screening strategy. The purpose of this paper is Methods — survey and responses to propose a screening strategy for fracture risk reduction in postmenopausal women and to examine key issues in rela- The opinion of 29 individual expert members of the Epide- tion to this strategy. miology and Quality of Life (EpiQOL) Working Group on whether screening for high hip fracture risk could fulfil each of the UK NSC criteria (Table 5) for a screening programme The proposed screening strategy was canvassed using a Google Form. The survey was lim- ited to the first 15 criteria as the final four address criteria Given the effectiveness and cost-effectiveness of the inter- that focus on issues around implementation of an accepted vention described later in this document, the strategy is screening strategy. For each criterion, the experts were asked based on the approach undertaken in the Screening for Oste- to say if the proposed strategy fulfilled that criterion (yes, oporosis in Older People (SCOOP) study in the UK [2–6]. in part or no) and could expand on their classification in a In brief, a risk factor questionnaire based on the FRAX® free text field. risk assessment tool would be completed, in paper form Responses were received from 20 experts (69% of those or electronically, by women age 70 years or older through approached), and the overall scores for each criterion are 13 Archives of Osteoporosis (2022) 17:87 Page 3 of 24 87 included in Table 5. Their feedback was incorporated into that estimated for chronic obstructive pulmonary disease each of the sections below. and ischaemic stroke, but lower than that for lung cancer or dementia [12]. In 2019, the cost of osteoporosis, including pharmaco- Results‑Criterion review logical intervention in the EU was estimated at €56.9 billion (1000 million), with two-thirds derived from the treatment The condition of fractures and only 3% representing the costs of pharmaco- logical intervention. Excluding the latter cost, hip fractures represented 54% of the costs. The total cost including values The condition sought should be an important health prob‑ of quality adjusted life years (QALYs) lost was estimated lem Osteoporosis is a systemic skeletal disease, character- at €113 billion, a figure that is expected to rise to €121 bil- ised by low bone mass and microarchitectural deterioration lion in 2025. The cost of osteoporotic fractures accounts for of bone tissue with a subsequent increase in bone fragility approximately 3.5% of healthcare spending (i.e. €55.3 bil- and susceptibility to fracture [8]. The most serious clinical lion in 2019) indicating a very substantial impact of fragil- consequence of osteoporosis is hip fracture, though other ity fractures on the present healthcare budgets of European fractures commonly occur at the spine, forearm and shoul- countries. der, and are often grouped together with hip fractures as The epidemiology of osteoporosis is well characterized major osteoporotic fractures. and described in detail elsewhere [14, 16–19]. The incidence of fragility fractures increases markedly with age, and the Osteoporotic fractures are undoubtedly a common public vast majority of osteoporotic fractures occur in older women. health problem, particularly in ageing societies in terms of Compared with other fractures, a great deal of information patient’s health, quality of life and social care costs [9–12]. is available on the epidemiology of hip fracture as nearly At the age of 50 years, the remaining lifetime probability all such patients are admitted to hospital with data avail- of at least one of the major osteoporotic fractures is 22% in able through surgical and discharge records. In patients with men and 46% in women. In 2000, it was estimated that there fractures at other skeletal sites, only a minority are admitted, were approximately 9 million fractures annually worldwide, though they may attend hospital on an outpatient basis. with over one-third of all osteoporotic fractures occurring in The occurrence of hip fracture, widely regarded as the Europe [13]. The latter accounted for 2 million disability- most serious osteoporotic fracture, reflects decreasing bone adjusted life years (DALYs) annually in Europe, a burden strength with increasing age, with a concomitant increase that exceeded that of hypertensive heart disease or rheu- in falls risk [20]. The risk of falling is somewhat higher in matoid arthritis. The number and burden of osteoporotic elderly women than in elderly men with about one-third of fractures is rising in many countries, partly related to the elderly individuals falling annually [21]. Hip fractures are increased longevity of the populations. The age- and sex- relatively rare at the age of 50 years but become the predom- specific incidence of fracture has also increased in some but inant fracture from the age of 75 years [22]. Patients with hip not all countries [14, 15]. fracture often have significant co-morbidities, and up to 20% In 2019, 4.3 million new fragility fractures were esti- of patients die in the first year following hip fracture, mostly mated to have occurred in the EU, comprising approximately as a result of these underlying medical conditions [23, 24]; 827,000 hip fractures, 663,000 clinical vertebral (spine) nonetheless, it is estimated that approximately 30% of deaths fractures, 637,000 forearm fractures and 2,150,000 fractures are causally related to the fracture event [25]. at other sites (i.e. pelvis, rib, humerus, tibia, fibula, clavicle, In summary, there is ample evidence that osteoporosis scapula, sternum and other femoral fractures) [11]. About and, in particular, osteoporosis-related fractures are a sig- two-thirds of all incident fractures occurred in women. In nificant and growing health problem for individuals and 2019, the number of deaths causally related to fractures was healthcare providers. Fractures are highly prevalent and are estimated to be 248,487, with about half of these attribut- associated with significant morbidity and mortality. able to hip fractures. The number of fracture-related deaths was comparable or exceeded those from some of the most The epidemiology and natural history of the condition, common causes of death such as lung cancer, diabetes and including development from latent to declared disease, chronic lower respiratory diseases. In 2000, it was estimated should be adequately understood and there should be a that osteoporotic fractures in Europe accounted for more detectable risk factor, disease marker, latent period or early DALYs (2,006,000) than rheumatoid arthritis (1,048,000), symptomatic stage Clinically, bone health is most widely but less than for osteoarthritis (3,088,000) [13]. In 2016, assessed by the non-invasive measurement of BMD by dual- the estimate placed the total DALY loss related to fragility energy x-ray absorptiometry (DXA) as there is a very well- fractures at more than 2.6 million, which was higher than established inverse correlation between BMD and future 13 87 Page 4 of 24 Archives of Osteoporosis (2022) 17:87 fracture risk [26]. As BMD is continuously distributed in All the cost‑effective primary prevention interventions the population, a WHO Scientific Group in 1994 developed should have been implemented as far as practicable To a densitometric definition of osteoporosis using a threshold date, there is no evidence base to demonstrate that cost- of 2.5 standard deviations below the mean BMD in young effective (and indeed effective) primary prevention interven- people of the same sex [27, 28]. Since then, osteoporosis has tions of a non-pharmacological nature reduce the burden of been operationally defined on the basis of BMD assessment, osteoporotic fractures. Where appropriate, lifestyle modifi- with a subsequent refinement to focus on measurements at cations are recommended comprising advice about nutrition the femoral neck [29]. This definition, however, has high (adequate calcium, vitamin D and protein intake), physical specificity but low sensitivity for the prediction of fracture, activity (weight-bearing, muscle strengthening and balance as the majority of osteoporotic fractures occur in individu- training exercise) and risk factor reduction (e.g. smoking als with BMD values above the osteoporosis threshold [27]. cessation, alcohol intake reduction, vision correction, avoid- This is the main reason that BMD measurement alone has ance or reduction in exposure to drugs associated with osteo- not been accepted as a public health screening test in many porosis). In general, a daily dietary calcium intake of around countries to date, though there are notable exceptions includ- 800–1200 mg is recommended, with calcium supplementa- ing the USA [30, 31]. tion where this cannot be achieved [49–54]. National recom- mendations for vitamin D supplementation vary according As a clinical endpoint, osteoporotic fracture has multiple to the target population (whole population or subsets), the factors contributing to the risk of fracture that can enable required dose and the target level of vitamin D as assessed identification of high risk prior to the event occurring. In by serum or plasma 25-hydroxyvitamin D [55–58]. The many ways, this is a different latency to that identified under impact of combined calcium and vitamin D supplementa- established screening programmes in diseases such as breast tion on fracture risk remains uncertain, particularly in the and cervical cancer or diabetic eye disease, where the focus community-dwelling elderly [59–61]. is on early detection of the disease itself. At a simplistic level, it might be assumed that low or decreasing bone mass Thus, whereas patients will continue to receive general is the only latent stage of note for osteoporotic fracture but, advice in the absence of cost-effective primary prevention as described below, this excludes a wealth of information interventions, there remains a need to implement other on other factors that contribute to fracture risk. This aware- proven, cost-effective strategies and interventions. ness has led to the development of risk calculators that take account of several risk indicators as used in the management The test of other diseases such as cardiovascular disease [32–34]. Examples of ‘non-BMD’ factors that contribute to frac- ture risk include ethnicity, age, sex, body mass index (BMI) There should be a simple, safe, precise and validated screen‑ [35], a prior fracture [36], a family history of fracture [37], ing test The increasing recognition and acceptance that long-term use of systemic glucocorticoids [38], a history of treatment for osteoporosis should be targeted on the basis rheumatoid arthritis [39], diabetes [40–42], other causes of of fracture risk requires well-validated assessment tools pro- secondary osteoporosis [43] and lifestyle risk factors such viding ease of use in clinical practice. Over the last 15 years, as physical inactivity [44], falls [45, 46], smoking [47] and three tools have garnered interest, namely the FRAX® tool alcohol consumption[48]. It is important to note that some [62, 63], QFracture [64, 65] and the Garvan tool [66]. Of of these risk factors are partially or wholly independent of these, the FRAX tool has achieved widespread use with BMD, so that their use with BMD can enhance the infor- incorporation into numerous guidelines worldwide, with a mation provided by BMD alone. Conversely, some strong large number of studies evaluating its utility [67]. In contrast BMD-dependent risk factors, for example BMI, can be used to many risk calculators, both in the field of fracture risk for fracture risk assessment in the absence of access to BMD or other disease areas, FRAX is unusual in that the out- tests. This is discussed in more detail in the section on the put from the calculation is calibrated to the epidemiology test. of fracture and mortality for each country/region/ethnicity In summary, the epidemiology and natural history of with an existing FRAX model. In short, this means that if osteoporosis, including the risk factors that contribute to the whole population were to undergo FRAX assessments, the clinical endpoint of fracture, are well documented and then the number of fractures predicted would be the number understood. The recognition of identifiable risk factors and observed. This construct has been used to develop simu- the quantitation of that risk are now possible allowing pre- lated population cohorts in the UK and elsewhere and has ventative interventions to be targeted to those at highest provided a basis for estimating the global burden of high fracture risk. fracture probabilities [18, 68, 69]. Most importantly, in the context of this review, FRAX is the only fracture risk 13 Archives of Osteoporosis (2022) 17:87 Page 5 of 24 87 Fig. 1  An example of the FRAX® fracture risk assess- ment tool webpage for the UK FRAX calculator. The UK cal- culator is linked through to the guidance pages of the National Osteoporosis Guideline Group (View NOGG Guidance button) assessment tool to be studied to date in randomised, con- that FRAX (or QFracture) should be used to estimate trolled studies of population-based screening. 10-year predicted absolute fracture risk prior to deciding on the need for DXA measured BMD [76]. As a completely In brief, the FRAX® tool (https://​www.​sheff ​ield.​ac.​uk/​ non-invasive test, the tool is safe for users. FRAX/​index.​aspx) is a computer-based algorithm devel- The characteristic of major importance, for the pur- oped by researchers at the then WHO Collaborating Centre pose of risk assessment, is the ability of a tool to predict for Metabolic Bone Diseases at the University of Sheffield the occurrence of new fractures, more usefully expressed [43, 70, 71]. The calculation incorporates information gath- as the increase in relative risk per standard deviation (SD) ered from easily obtained clinical risk factors (Fig. 1) to unit increase in risk score, termed the gradient of risk. The estimate the probability of sustaining a fracture in the next gradient of risk for the use of the FRAX clinical risk fac- 10 years. Femoral neck BMD can also be added to the calcu- tors alone, femoral neck BMD alone, and the combination is lation to enhance fracture risk prediction. It has two outputs, shown in Table 2 [77]. It is relevant that the performance of namely the probability of sustaining a hip fracture in the FRAX is enhanced by the use of BMD tests; FRAX without next 10 years, or a major osteoporotic fracture. The outputs BMD has a predictive value for fractures that is comparable are calibrated to age and sex-specific rates of fracture and to the use of BMD alone. Overall, the predictive value com- mortality in a substantial number of countries/territories pares very favourably with other risk engines such as the (currently 85 models covering 77 countries). Gail score for breast cancer [78]. The choice of screening FRAX has been widely used for the assessment of frac- modality to identify high hip fracture risk can be adapted to ture risk since the launch of the FRAX website in 2008. local resources; for example, where BMD measurements are Following regulatory review by the US Food and Drug readily available, it can play a predominant role in screening, Administration, FRAX was incorporated into DXA scan- while screening with FRAX risk factors alone can readily be ners to provide FRAX probabilities at the time of DXA scan- applied in the absence of access to BMD. ning. For those without internet access, hand-held calcula- The performance characteristics of the FRAX clinical tors and an application for Apple smartphones have been risk factors, with and without BMD, have been validated developed. A paper-based FRAX pad in several languages in eleven independent population-based cohorts [77]. Nota- allows patients to document risk variables prior to a visit bly, the gradients of risk and age-adjusted area under the with healthcare professionals. curves (AUC) from receiver-operated characteristic (ROC) It is also worthy of note that the availability and access analysis were comparable in the validation cohorts compared to densitometry in many countries is low [72–75], so that a with the original cohorts. In contrast to separate analyses major advantage of FRAX is the ability to assess fracture of sensitivity and specificity, the AUC provides an index of risk where BMD is unavailable. In the UK, National Institute overall test accuracy if sensitivity and specificity have equal for Health and Care Excellence (NICE) has recommended weights. A test with no predictive (or discriminative) ability 13 87 Page 6 of 24 Archives of Osteoporosis (2022) 17:87 Table 2  Gradients of risk Age (years) Gradient of risk (RR per SD change in with 95% confidence intervals) BMD only Clinical risk factors alone Clinical risk factors + BMD with the use of BMD at the femoral neck, FRAX clinical (a) Hip fracture risk factors or the combination 50 3.68 (2.61–5.19) 2.05 (1.58–2.65) 4.23 (3.12–5.73) for hip and other osteoporotic 60 3.07 (2.42–3.89) 1.95 (1.63–2.33) 3.51 (2.85–4.33) fractures (not confined to major osteoporotic fractures). With 70 2.78 (2.39–3.23) 1.84 (1.65–2.05) 2.91 (2.56–3.31) kind permission from Springer 80 2.28 (2.09–2.50) 1.75 (1.62–1.90) 2.42 (2.18–2.69) Science + Business Media B.V] 90 1.70 (1.50–1.93) 1.66 (1.47–1.87) 2.02 (1.71–2.38) [77] (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) would have an AUC of 0.5 (or 50%), while a perfect predic- necessarily remains a more localised remit, given that each tive test would have an AUC of 1.0 (or 100%). For hip frac- health care system will consider local/national factors such ture prediction without BMD, the mean AUC at age 70 years as reimbursement issues, health economic assessment, will- was 0.66 in the validation cohorts compared with 0.67 in ingness to pay for health care in osteoporosis and access to the original cohorts. With the addition of BMD, the mean DXA. The use of health economic analyses to derive inter- AUC was 0.74 and 0.78, respectively [77]. Since that origi- vention thresholds is fraught with problems, the most com- nal validation, a number of independent reviews, including mon of which is that they are time limited due to changes, four systematic reviews, have included detailed descriptions usually reductions, in the costs of treatment. In the presence of the performance of the FRAX tool [76, 79–82]. Bear- of very inexpensive medications, absurd situations can arise ing in mind the flaws that can arise from cross-study and with a recent example from the UK where, following a mul- within-study comparisons of the AUC [83, 84], the reviews tiple technology appraisal (MTA) on bisphosphonate use in have confirmed a significant predictive ability of FRAX for osteoporosis, NICE recommended that treatment with oral future fractures, especially of the hip. For example, in the bisphosphonates may be instituted in those with a 10-year most recent of the systematic reviews, conducted for the probability of major osteoporotic fracture of 1% or more US Preventive Services Task Force, the AUCs for hip frac- [86]. If interpreted as an intervention threshold, virtually ture prediction with FRAX ranged from 0.76, in 12 studies all women aged ≥ 65 and men ≥ 75 years would be recom- comprising just under 200,000 women where FRAX was mended treatment [87]. Shortly thereafter, NICE endorsed calculated without BMD, to 0.79 in 10 studies comprising the assessment and intervention thresholds proposed within approximately 162,000 women when FRAX was calculated the NOGG guidance [50, 88]. with BMD [79]. In a recent independent comparative study A systematic review in 2016 identified assessment guide- in a single population sample, the predictive value for hip lines for osteoporosis that incorporated FRAX, utilising fractures was better for the FRAX tool (AUC: 0.841, 95% CI either age-independent (i.e. fixed) or age-dependent thresh- 0.795–0.887) than for the Garvan fracture risk tool (AUC: olds for further assessment and/or treatment [67]. In most 0.769, 95% CI 0.702–0.836, p = 0.01) [85]. guidelines, treatment for osteoporosis is recommended in In summary, the FRAX tool fulfils the criteria of being individuals with prior fragility fractures, especially fractures a simple, safe, precise and well-validated test. While the at the spine or hip, with the FRAX thresholds reserved spe- AUCs for future hip fracture prediction are perhaps lower cifically for use in those without such fractures. The major- than existing screening tests that detect existing or early dis- ity of guidelines had utilised a fixed intervention threshold, ease, they suggest excellent performance suitable for appli- frequently as a component of more complex guidance (e.g. cation in clinical practice. BMD thresholds). A substantial proportion (about 25%) had The distribution of test values in the target population adopted an age-dependent threshold, with a small minority should be known and a suitable cut-off level defined and proposing a combination of age-dependent and fixed thresh- agreed. olds (so called hybrid thresholds). Screening programmes are usually designed and adopted Age-dependent intervention thresholds, first developed at regional or national levels. The same is true for the by the National Osteoporosis Guideline Group (NOGG), are development and setting of intervention thresholds; this based on the rationale that if a woman with a prior fragility 13 Archives of Osteoporosis (2022) 17:87 Page 7 of 24 87 Table 3  Possible FRAX-based intervention thresholds in examples The test should be acceptable to the population The field of high fracture risk countries if using the same approach as NOGG of research into acceptability of healthcare interventions in the UK (ranked in descending order of hip fracture probability). Values represent FRAX 10-year probabilities of major osteoporotic is, perhaps surprisingly, underdeveloped [95]. DXA-based (MOF) and hip fractures in women at the age of 70 years with a his- measurement of BMD is a noninvasive procedure, and tory of prior fracture and no other risk factors (BMI set to 25 kg/m2) the level of radiation exposure is very low and considered Country Putative MOF prob- Putative hip prob- to be safe for the population [96]. Access to, and use of, ability threshold (%) ability threshold the FRAX online tool suggests that it is viewed to have (%) acceptable clinical utility by health professionals [67, 97, 98], though this has not been formally assessed. In the set- Denmark 28 8.8 ting of primary prevention, a formal assessment has been Sweden 25 8.7 undertaken as part of the SCOOP study [2]. This qualitative Norway 22 7.4 sub-study sought to capture the views of older women and Singapore (Chinese) 19 6.0 GPs about the acceptability of screening, using the FRAX USA (Caucasian) 21 5.0 questionnaire with BMD in those at medium to high risk, to UK 20 4.8 prevent fractures [99]. The women and GPs were found to Canada 19 4.4 view screening positively. Risk assessment using the FRAX Japan 18 3.9 tool, compared to usual care, showed no impact on anxiety (State-Trait Anxiety Inventory) and quality of life (EuroQol 5-Dimension tool and the Short-Form Health Survey 12) fracture is eligible for treatment, then, at any given age, a (P > 0.10 for all outcomes). The authors concluded that an man or woman with the same fracture probability (i.e. at effective and cost-effective screening programme to reduce the ‘fracture threshold’) should also be eligible, even in osteoporotic fractures could be implemented in routine care the absence of fracture [50, 89, 90]. By design, this frac- and would be well received by women and GPs [99]. ture threshold increases with age with a plateau or decline at older ages due to the competing hazard of death. Age- The data to date suggest that assessment of fracture risk dependent thresholds have since been adopted into European by the FRAX tool, with subsequent BMD measurement guidelines [51, 91] and elsewhere [67, 92, 93]. The same where indicated, is acceptable to the populations in which intervention threshold is applied to men, since the effec- it has been used. tiveness and cost-effectiveness of interventions in men are broadly similar to that in women for equivalent risk [94]. There should be an agreed policy on the further diagnostic In the UK, it was noted that the age-dependent probability investigation of individuals with a positive test result and on thresholds introduced inequalities in access to therapy at the choices available to those individuals. The use of risk older ages (≥ 70 years) for women without a prior fracture, calculators to determine who should receive an interven- leading to the development of a hybrid model which reduced tion is somewhat different from many established screening the disparity [69]. For the proposed screening strategy, the programmes. For example, breast tissue calcification might approach would be to adopt the current NOGG thresholds indicate malignancy, but further investigation is required to in the UK. The thresholds at age 70 years for major osteo- confirm or refute the diagnosis of breast cancer. In contrast, porotic fracture and hip fracture in the UK and some other the patient identified at high risk by a risk calculator arrives high-risk countries, if using a similar approach, are shown there because of the known factors entered into the calcula- in Table 3. Other countries that have an average 10-year hip tion. In many osteoporosis guidelines, this risk assessment fracture probability threshold of 5% or more include Austria, may indicate the need for BMD measurement, if not already Denmark, Germany, Greece, Iceland, Iran, Ireland, Israel, undertaken, to provide additional risk information. Italy, Kazakhstan, Kyrgystan, Malta, Moldova, Norway, Singapore, Slovakia, South Korea, Sweden, Switzerland, In clinical settings, this assessment of BMD, usually by Taiwan and Uzbekistan. DXA measurements at the lumbar spine and hip, is used not In summary, there are a number of approaches to defining just for risk prediction, but also for diagnosis, selection of cut-off levels for the FRAX tool as intervention thresholds patients for treatment and monitoring of patients on treat- within a screening program. Of these, the probability thresh- ment. A requirement has been estimated of approximately olds at age 70 in women with a prior fracture seem intuitive, 11 DXA units per million of the general population to permit as all current guidelines would recommend treatment in such implementation of practice guidelines [72], a level which individuals. is only achieved in about 60% of countries in the EU [11, 100]. Strategies that target the use of DXA to those with fracture risks at or near an intervention threshold reduce 13 87 Page 8 of 24 Archives of Osteoporosis (2022) 17:87 the need for DXA while maintaining the identification of and/or improving bone mass can significantly reduce the those at high risk. For example, a comparison of the NOGG incidence of fracture [108] at vertebral (relative risk, RR strategy, comprising risk assessment followed by targeted 0.4–0.6) and non-vertebral sites (RR 0.6–0.8), including DXA, with the previous guidance issued by the Royal Col- reducing the incidence of hip fracture by 30–45% [109–111]. lege of Physicians (RCP) where the presence of a risk factor Classes of drugs demonstrating efficacy in the prevention of simply mandated the use of DXA, NOGG identified a similar fragility fracture include bisphosphonates (e.g. alendronate, proportion of women at high risk (average 34.6% vs. 35.7% ibandronate, risedronate and zoledronate), selective oestro- across all ages), but with lower numbers of scans required at gen receptor modulators [SERM] (e.g. raloxifene, baze- each age [68]. Thus, the NOGG approach required only 3.5 doxifene), parathyroid hormone peptides and derivatives scans at the age of 50 years to identify one case of hip frac- (e.g. teriparatide and abaloparatide), menopausal hormone ture, whereas the previous RCP approach required 13.9. At therapy (MHT) and humanized monoclonal antibodies (e.g. 75 years, the corresponding numbers were 0.9 and 1.5. Com- denosumab and romosozumab). Recent comparative clini- pared to the older strategy, the FRAX-based NOGG strategy cal trials have provided evidence of enhanced anti-fracture used BMD resources more efficiently with lower acquisition efficacy of anabolic compared with antiresorptive therapies costs and lower costs per hip fracture averted [68]. [112–114], prompting considerations of starting treatment Most clinical guidelines agreement the need for addi- with an anabolic agent in patients at very high risk of frac- tional radiological, haematological, biochemical and immu- ture as a more appropriate means of rapidly reducing frac- nological assessments in patients at high risk of fracture or ture risk [115–117]. with recently diagnosed osteoporosis [50, 51, 53]. Broadly, The availability of effective therapies has long given these seek to identify or exclude any undetected underlying rise to considerations of approaches for fracture preven- disease that might contribute further to fracture risk and its tion; for example, almost 20 years ago, a simulation model management (e.g. identify a reversible or treatable cause investigated the cost-effectiveness of a 5-year treatment to such as primary hyperparathyroidism or coeliac disease), prevent hip fracture in women at average risk [118]. Major and to identify any contraindications to a particular treat- determinants of cost-effectiveness included the age of the ment (e.g. renal impairment in the case of bisphosphonates individual and the cost of treatment. Assuming an efficacy or hypocalcaemia in the use of potent bisphosphonates or of a 35% reduction in relative risk, it was cost-effective to denosumab). treat all women above the age of 81 years with an interven- In summary, there is much agreement across clinical tion cost of $650/year. For cheaper treatments, e.g. $250, it guidelines on the further diagnostic investigation of indi- was cost-effective to give treatments at the age of 70 years, viduals at increased risk of fracture and on the treatment and for the cheapest treatment to treat nearly all postmeno- choices available to such individuals (see next section). pausal women. The authors suggested that controlled pro- spective studies in the apparently healthy population were The treatment worthy of consideration, particularly in the elderly. Since then, several randomised, controlled studies have examined the use of osteoporosis interventions in older populations, There should be an effective treatment or intervention for unselected for osteoporosis. In the Women’s Health Initia- patients identified through early detection, with evidence of tive study, the use of MHT was examined in two studies, early treatment leading to better outcomes than late treat‑ one in women with an intact uterus and one in women with ment Approaches to reduce fracture risk incorporate non- a history of hysterectomy [119, 120]. The effects on fracture pharmacological measures [101, 102] and pharmacological risk were similar between the two studies. In women age treatments. Of the many factors that influence the risk of 50–79 years with an intact uterus, the use of conjugated fracture, age-related reductions in bone mass and increased equine oestrogen and medroxyprogesterone acetate over a likelihood of falling are important contributors [103]. While mean of 5.2 years follow-up reduced the incidence of hip assessment of falls risk and appropriate interventions aimed fracture by 34% (hazard ratio, HR: 0.66; 95% CI: 0.45–0.98], at reducing falls risk have been shown to be effective [104], with a 23% reduction in other osteoporotic fractures (HR: at least in the short term, their impact on the risk of fracture, 0.77; 95% CI: 0.69–0.86) [119]. Importantly, this effect was particularly at the hip, is less certain [105, 106]. For exam- independent of baseline BMD [121] suggesting that treat- ple, in a recent review, multifactorial interventions or single ment efficacy was not dependent on the presence of osteo- exercise-based interventions were found to reduce falls risk, porosis. A similar BMD-independent effect on fracture risk but the impact on fractures was not significant [107]. reduction was observed in a 3-year randomised, placebo- controlled study of the oral bisphosphonate, clodronate, in In contrast, many randomised, placebo-controlled trials women age 75 years and older, again unselected for osteo- have shown that treatments directed at preventing bone loss porosis [122]. This study was underpowered for the outcome 13 Archives of Osteoporosis (2022) 17:87 Page 9 of 24 87 of hip fractures, but treatment was associated with a 23% high specificity, but low sensitivity for future fractures has reduction in osteoporotic fractures. A post hoc analysis dem- underpinned the movement towards the use of absolute frac- onstrated that, while the effect was independent of BMD, ture risk to define intervention thresholds, usually calculated treatment was more effective in women at higher baseline by the FRAX tool. There are differences in approach with fracture risk assessed by the FRAX tool [123]. Thus, at a some guidelines recommending fixed intervention thresh- probability of 15% (25th percentile), the relative risk for olds, while others have proposed age-dependent thresholds fracture was reduced by 8% (RR 0.92, 0.69–1.24), whereas or, in a minority of cases, a hybrid of age-dependent and at probabilities of 24% and 30% (the 75th and 90th percen- fixed thresholds. In the UK, NOGG developed a guideline tiles), the reductions were 27% (RR 0.73, 0.58–0.92) and on the basis of clinical appropriateness, setting the thresh- 38% (HR 0.62, 0.46–0.84) respectively. Several other stud- old at the age-specific probability of fracture equivalent to a ies of a variety of osteoporosis therapies have also shown woman having already sustained a fracture. The latter pro- no interaction between treatment efficacy and underlying cess is supported by, but not dependent on, the demonstra- BMD [124] supporting the use of treatment in those with tion of cost effectiveness; it avoids inappropriate over-treat- high fracture risk even before a BMD in the osteoporosis ment of older individuals and under-treatment of younger range has been reached. individuals. The success of such population-based approaches does not necessarily imply that risk assessments to target thera- Cost-effectiveness is accepted in many countries as a pri- pies are not worthwhile, since it is likely to be even more mary driver of decisions about who should be offered treat- cost-effective to target individuals at higher-than-average ment with particular medications. Such approaches arose risk. Certainly, the more expensive the treatment and the from the perceived need to limit access to expensive treat- cheaper the risk assessment, the stronger the case for select- ments across a range of diseases. Within osteoporosis, for ing high-risk segments of the population. The age at which example, health technology assessments of available treat- intervention might be offered depends critically upon the ments in the UK by the NICE have traditionally stratified the costs of treatment, efficacy and the average risk of hip frac- risk levels at which treatments could be initiated [125–129]. ture, as well as additional skeletal and extraskeletal effects. This stratification was usually based on age, BMD T score The aforementioned cost-effectiveness analysis in 2001 sug- and the presence of one or more individual clinical risk fac- gested that strategies aimed at intervention over the age of tors; the cost-effectiveness thresholds were subsequently 70 years required testing [118]. assumed by the clinical community to be intervention In summary, there is an extensive clinical and economic thresholds. More recently, NICE appraisals have embraced evidence base for effective bone-targeted treatments that can the use of absolute fracture risk, but the continued applica- reduce fracture risk. Unselected population-based studies tion of cost-effectiveness to developing thresholds for now suggest that fracture risk can be also significantly reduced inexpensive drugs led to counterintuitive and potentially with such treatments; targeted intervention of relatively harmful guidance [130]. inexpensive, safe treatments to those within these popula- In summary, many countries have access to evidence- tions that have identifiable increased risk will intuitively based policies and guidelines covering which individuals lead to better outcomes than treatment delayed until after should be offered treatment and the appropriate treatment the subsequent occurrence of fracture. to be offered. There should be agreed evidence‑based policies cover‑ Clinical management of the condition and patient outcomes ing which individuals should be offered treatment and the should be optimised in all healthcare providers prior to par‑ appropriate treatment to be offered Most clinical guidelines ticipation in a screening programme A general approach for the management of osteoporosis adopt a case-finding to reducing the fracture burden in society was outlined by strategy, combining clinical risk factors with measurement the Department of Health in the UK in 2009 (Fig. 2). This of BMD, preferably at the hip, to assess fracture risk and approach recognized the need to start by providing optimal subsequent use of defined intervention thresholds [67]. The care to those with hip fractures, followed by the provision majority recommend treatment for osteoporosis in individu- of services that would identify, investigate and treat those als with prior fragility fractures, especially fractures of the presenting with non-hip fragility fractures (so-called second- spine or hip, without specific need for BMD assessment. For ary prevention). those without prior fractures, intervention thresholds have historically focused on the BMD T score ≤  − 2.5, with treat- A standardized approach to post hip fracture care was first ments reimbursed in many healthcare settings when a BMD- published in a collaboration between the British Orthopae- based diagnosis of osteoporosis is confirmed. As noted pre- dic Association and British Geriatric Society in 2007 [131], viously, the realization that BMD-defined osteoporosis has followed soon after by the establishment of the National 13 87 Page 10 of 24 Archives of Osteoporosis (2022) 17:87 Fig. 2  A systematic approach to fracture prevention adapted from that outlined by the Department of Health in the UK. FLS — fracture liaison services Hip Fracture Database to audit hospital performance. The the effectiveness of FLS in reducing fracture risk, but such database is centrally funded via government but is run inde- trials have shown increased DXA testing, treatment initia- pendently. Importantly, the programme was subsequently tion and early adherence in FLS-like settings [137–139]. supported by the creation in 2010 of a Best Practice Tar- Observational studies have shown reductions in fracture iff (BPT) to financially incentivize improved care. Subse- risk, though somewhat inconsistently, with difficulty in quently, NICE incorporated much of this acute hip fracture interpreting the results due to a number of biases in such management initiative into their own guideline in 2011 study designs [140]. Many of these biases were overcome [132]. The guidelines state that patients should be man- in a recent Swedish study, comparing fracture rates before aged with combined orthopaedic and orthogeriatric care in and after FLS implementation, with non-FLS hospitals as a hip fracture programme with all patients preferably being an added comparator [141]. The risk of recurrent fracture seen preoperatively; due to difficulties in accessing ortho- was 18% lower in the period post FLS implementation com- geriatric services at weekends, the target is that all patients pared with the control period (hazard ratio = 0.82, 95% con- are reviewed within 72 h from admission. Notably, 30-day fidence interval [CI] 0.73–0.92, p = 0.001), with no change mortality fell by 7.6% per year in the 4 years after the intro- in recurrent fracture rate in the non-FLS hospitals [141]. duction of the National Hip Fracture Database compared to The number and standard of FLS worldwide continues to a 1.8% per year decrease in the 4 years preceding its intro- increase under the auspices of the International Osteoporosis duction [133]. Similar systems are being established in other Foundation’s Capture The Fracture ® programme (https://​ European countries [134]. www.​captu​rethe​fract​ure.​org/). In the next tier of the pyramid in Fig. 2, it was recognized There is some overlap between the next two tiers of the that patients presenting with a fragility fracture, related or strategy shown in Fig. 2, namely individuals at highest risk unrelated to a fall, should be assessed for osteoporosis and of fragility fracture and older people, as age itself is a promi- receive effective management to improve their bone health nent risk factor for fracture. The individuals encompassed and reduce future fracture risk. The preferred solution is the by these tiers are largely those where the burden of osteo- establishment of Fracture Liaison Services, which are usu- porosis assessment and management falls on primary care ally hospital-based and provide a co-ordinator to identify health professionals, and it is this constituency to which the patients aged 50 and over with a first fracture [135, 136]. proposed screening approach would be largely directed. The identification is followed by risk assessments and initia- There is good evidence that, in this setting, treatment rates tion of evidence-based interventions for bone health and falls are very low. For example, in a recent study, treatment rates prevention. Ideally, the service would also monitor adher- in women ≥ 70 years, deemed to be at high risk of fracture, ence and any recurrent events, but this is frequently passed were examined in primary care in 8 European countries back to primary care services. Treatment includes prescrib- [142]. The women were enrolled when visiting their gen- ing bone strengthening medicines, as well as referral to falls eral practitioner, regardless of the reason for attendance, risk assessment and prevention services where appropriate. and data captured on fracture risk and osteoporosis treat- To date, no randomised control trials have demonstrated ments. Increased risk of fracture was characterized as one or 13 Archives of Osteoporosis (2022) 17:87 Page 11 of 24 87 Table 4  Comparison of screening strategies across the SCOOP, ROSE and SOS studies in women Age range SCOOP ROSE SOS 70–85 years 65–80 years 65–90 years Number recruited (with base- Control 6250 Control 17,157 (9326) Control 5457 line FRAX if different) Screening 6233 Screening 17,072 (9279) Screening 5575 1st screening step Assessment FRAX 10-year hip probability without FRAX 10-year MOF prob- FRAX 10-year MOF probability with BMD ability without BMD BMD (plus VFA) Definition of positive test Probability ≥ age-dependent assessment Probability ≥ 15% or more See treatment criteria below threshold nd 2 screening step Assessment DXA measurement of BMD DXA measurement of BMD N/A Treatment criteria Probability (with BMD) ≥ age-dependent BMD T-score ≤  − 2.5 Probability ≥ age-dependent thresh- intervention threshold olds + BMD T score ≤  − 2, or a prevalent vertebral fracture, or met criteria within Dutch guidelines Performance per prevented fracture NNS/NNT (Ost frac- 133/19 319/34 178/32 ture) NNS/NNT (Hip 115/17 281/30 552/98 fracture) more of the following, a history of fracture, FRAX 10-year solely at providing information to allow the person being probability of fracture above country-specific thresholds, or screened to make an “informed choice”, there must be evi- a T score ≤  − 2.5 at the spine or hip. In the 3798 enrolled dence from high quality trials that the test accurately meas- patients, median FRAX probability (calculated without ures risk. The information that is provided about the test and BMD) was 7.2% for hip fracture and 16.6% for major osteo- its outcome must be of value and readily understood by the porotic fracture. Overall, 2077 women (55%) met one or individual being screened. more of the criteria for increased risk of fracture (median As stated earlier, the proposed screening programme is 10-year probabilities of hip and major osteoporotic fracture based on the randomised, controlled SCOOP study which 11.2% and 22.8% respectively). An osteoporosis diagnosis is described in more detail below [3]. Two additional ran- was recorded in 804 patients (21%); most (80%) of these domised studies, namely the Risk-stratified Osteoporosis were at increased fracture risk. The treatment gap (the pro- Strategy Evaluation study (ROSE) from Denmark [145] and portion at high risk but untreated) was 75%, varying from the SALT Osteoporosis Study (SOS) from the Netherlands 53% in Ireland to 91% in Germany [142]. The treatment gap [146], have used FRAX-based approaches for population was somewhat lower in women with an osteoporosis diagno- screening and are also discussed below. sis compared to those without (31% vs. 94% respectively). These data are very similar to osteoporosis treatment gaps The SCOOP study assessed in other recent studies [11, 143], and reflect the need for integrated approaches to fracture prevention [144]. The Screening for Osteoporosis in Older People (SCOOP) As described above, strides are being made in the clini- study was a multicentre, primary care-based screening pro- cal management of fracture risk, but the impact on patient gramme [3]. Approximately 52,000 women age 70–85 years and healthcare outcomes remains sub-optimal. The proposed were identified in 100 primary care practices in England; screening program, if well implemented, would actually when those with exclusion criteria which included ongoing address the current deficiencies in care of a high-risk sub- treatment for osteoporosis and certain concurrent conditions group within the population, i.e. it should be regarded as (e.g. known dementia, terminal illness or recent bereave- a means to optimize healthcare in a greater proportion of ment), letters of invitation were sent to 38,600 women. Of those at risk. the latter, 25,571 women did not respond (n = 11,068) or declined the invitation (n = 13,870), leaving 13,029 eligible The screening programme participants. A total of 12,483 (95.8% of eligible, 32.3% of those invited) women were finally included in the ran- There should be evidence from high quality randomised con- domised controlled trial which had a planned follow-up of trolled trials that the screening programme is effective in 5 years. reducing mortality or morbidity. Where screening is aimed 13 87 Page 12 of 24 Archives of Osteoporosis (2022) 17:87 Fig. 3  Expected and observed incidences of hip fracture in the control and screening arms of the SCOOP study. The number of hip fractures within each group is shown in white text within the bars. The percent- ages in blue represent the crude incidences of hip fracture The steps in the screening protocol are outlined in recommendation for treatment [4]. Another approach to Table 4. It should be noted that the FRAX risk assessment determine the contribution of intervention in such a small was on the basis of 10-year hip fracture probability. It was proportion of the screening arm to the overall hip fracture undertaken at study enrolment in the screening arm and, in reduction is shown in Fig. 3. Here, a comparison of observed the control arm, calculated using the baseline questionnaire versus expected number of hip fractures was undertaken; the at the end of the study. In the latter, fracture risk assess- expected number of hip fractures was calculated from base- ment and management were left to normal clinical practice line FRAX probabilities using an adaptation of the FRAX under the care of the GP. In the screening arm, hip fracture tool with a 5-year time horizon to reflect the duration of the probabilities were calculated from the self-completed risk SCOOP study. questionnaires; if the 10-year probability was above an age- The adapted FRAX tool predicted that a total of 212 dependent assessment threshold, the participant was invited women (3.39%) in the control arm would sustain one or for a DXA scan to measure femoral neck BMD. Those with more hip fractures during the SCOOP study; the actual num- probabilities below the threshold were informed that they ber with incident hip fractures was 218 (3.49%), an observed were at low risk of hip fracture. In those attending for a to expected ratio (O/E ratio) of 1.03 (95%CI 0.90–1.18). DXA scan, the femoral neck BMD was then used in the In the screening arm, in contrast to an expected number of recalculation of their 10-year hip fracture probability. If the 212 women with incident hip fractures, only 164 women latter value lay at or above an age-dependent intervention (2.63%) sustained such fractures, with an O/E ratio of 0.77 threshold, the participant and their GP were informed of (95%CI 0.66–0.90). In the 898 women allocated to the high a high risk of hip fracture and treatment, largely with oral risk group in the screening arm and recommended for treat- bisphosphonates, was recommended. ment, a total of 70 hip fractures were expected, but only 39 In the screening arm, only 898 women (14.4% of the were observed (O/E ratio 0.56, 0.40–0.77). Thus, of the 48 group) were identified as at high risk of hip fracture and fewer hip fractures than expected, 31 (64.6%) were in this recommended for treatment. Overall, the screening strategy small subgroup (14.4% of the screening group). did not reduce the incidence of all osteoporosis related frac- The numbers needed to screen (NNS) to prevent one ture, (hazard ratio [HR] 0.94, 95% CI 0.85–1.03, p = 0.178), osteoporotic or hip fracture in SCOOP were 133 and 115 but the number of hip fractures in the screening arm was respectively; for the same outcomes, the numbers needed to significantly lower than that in the control arm (164 vs. 218 treat (NNT) were 19 and 17 respectively (Table 4). respectively, HR 0.72, 0.59–0.89, p = 0.002) [3]. The lack of DXA scanning in the control arm restricted any subsequent The ROSE study comparisons between the two study arms to FRAX prob- abilities calculated without BMD. A subsequent analysis The ROSE study in southern Denmark was a randomised showed a significant interaction between baseline FRAX controlled trial in 34,229 women aged 65–80 years, to hip fracture probability and the effectiveness of screening investigate the effectiveness of a two-step population-based to reduce the incidence of hip fractures, i.e. the reduction osteoporosis screening programme using FRAX® to select was only seen at high baseline risks associated with the 13 Archives of Osteoporosis (2022) 17:87 Page 13 of 24 87 women for DXA scans [145]. The steps in the screening 1 clinical risk factor for fracture [146]. The latter included protocol are outlined in Table 4. previous fracture after age 50 years, parental hip fracture, Randomisation to screening (n = 17,072) or control BMI < 19 kg/m2, rheumatoid arthritis, early menopause (n = 17,157) groups took place before the letters of invita- (< 45 years of age), malabsorption syndrome, chronic liver tion were sent out. Those invited were asked to return a self- disease, type I diabetes mellitus or immobility (severe walk- completed questionnaire, including the FRAX risk factors. ing difficulties and/or use of walking aid). Exclusion criteria A total of 27,157 women (79.3% of the cohort) returned the included a predicted short life expectancy, current or recent questionnaires, but FRAX probabilities were only calculable osteoporosis treatment, high body weight (> 135 kg) or glu- in 20,905 women (61% of cohort). Following the exclusion cocorticoid use ≥ 7.5 mg prednisone equivalent/day. of women already on osteoporosis treatment, 18,605 women From a total pool of almost 54,000 women in primary (54.4%) were included in the next stage of the study where care, 25,314 completed a baseline questionnaire and 11,032 the FRAX 10-year major osteoporotic fracture probability fulfilling the inclusion/exclusion criteria were entered into was used to determine the need for a DXA scan to measure the study. Of the 5575 women randomised to the screen- BMD (termed the per protocol analysis 1 population). If the ing arm, the screening procedures were only conducted in FRAX MOF probability was 15% or greater, the women 4228 (75.8%). The procedures included DXA, vertebral were recommended a DXA scan; this comprised 7056 (76%) fracture assessment (VFA), FRAX assessment, falls history out of 9279 women in the screening arm of the study, but and blood tests to exclude secondary osteoporosis. Follow- DXA scans were only obtained in 5009 women (54% of the ing this, treatment was recommended in 1417 women (25% high-risk subgroup). Following the DXA scan, osteoporo- of all women randomised to screening or 33.5% of those sis treatment was indicated based on criteria defined within undergoing the screening procedures). Treatment criteria Danish guidelines; in brief, treatment was recommended via predominantly comprised a FRAX 10-year MOF probability, the GP or specialist clinic if the BMD T score at the spine calculated with BMD, greater than age-dependent thresh- or total hip was ≤  − 2.5, if a vertebral fracture was detected olds (these ranged from > 15% in women aged 60–65 years, on lateral spine imaging during the DXA assessment, or if to > 32% in women aged 85–91 years). This criterion did the BMD T score was <  − 1.0 and the woman was receiving not mandate treatment if the T score was >  − 2.0; 170 ongoing supraphysiologic doses of glucocorticoids [147]. women were excluded from treatment on this basis [148]. In the screening arm, treatment was recommended in 1236 Some women also received treatment if they fulfilled the women and was started in 986 women. Thus, in the screen- criteria published within Dutch guidelines but did not reach ing arm, treatment was recommended in 7.2% of all the the FRAX-based thresholds; an additional 36 women were women randomised and invited to take part, or 13.3% if the treated on this basis [148]. denominator is the number of women completing a FRAX Over a planned study follow up of 3 years, 626 women in assessment (per protocol analysis 1). the screening group had a fracture compared to 632 in the Overall, in 10, there was no difference in incident frac- usual care group (HR 0.97, 95%CI 0.87–1.08). The point tures (MOF, hip fracture, and all fractures) between the estimate of the hazard ratio for other fracture outcomes, screening and control arms during a follow-up of approxi- including osteoporotic fractures, major osteoporotic frac- mately 5 years. In contrast, in the per-protocol analysis 1, tures and hip fractures was somewhat lower (0.91), but did while no difference was observed in all incident fractures not reach statistical significance. For example, 133 women or MOF, a borderline significant reduction in hip fracture sustained hip fractures in the screening arm compared to 143 risk was observed in the screened group (169 vs 202 hip women in the usual care arm (HR 0.91, 95% CI 0.71–1.15). fractures, HR 0.82, 95%CI 0.67–1.01, p = 0.059). The effect In an exploratory analysis among participants with a recent was even more marked in the smaller subgroup who attended fracture (< 2 years before baseline), fewer women sustained for DXA scans (HR 0.74, 95%CI 0.58–0.95, p = 0.018), but hip fractures in the screening arm but the number of events the latter needs to be interpreted with caution due to the was small (10 versus 25, HR 0.38; 95% CI 0.18–0.79). The relatively large dropout rate (46%) in those recommended authors noted that the outcome of the trial may have been for DXA scans [145]. impacted by nonparticipation and medication nonadherence The NNS to prevent one osteoporotic or hip fracture in in the screening group. ROSE were 319 and 281 respectively; for the same out- The NNS to prevent one osteoporotic or hip fracture in comes, the NNT were 34 and 30 respectively (Table 4). SOS were 178 and 552 respectively; for the same outcomes, the NNT were 32 and 98 respectively (Table 4). The SOS study SOS in the Netherlands was also a pragmatic randomised controlled trial in women aged 65–90 years with at least 13 87 Page 14 of 24 Archives of Osteoporosis (2022) 17:87 A. Outcome - Hip fracture B. Outcome – Major osteoporo c fracture Fig. 4  Forest plots of screening for prevention of hip (A, adapted the SCOOP and SOS studies. In B, the meta-analysis from [149] has from [149]) and major osteoporotic (B) fractures versus usual care. been updated to include the major osteoporotic fracture outcome from Note: From the ROSE study, the data from the first per protocol the SCOOP study. A Outcome — hip fracture, B Outcome — major analysis were used, as these were most comparable to the data from osteoporotic fracture Meta‑analysis of FRAX‑based screening RCTs reduction observed in the outcome of hip fracture, leading the authors to conclude that implementation of screening in As part of a systematic review of randomised studies of older women should be considered a serious option. screening for high fracture risk, the investigators of the In summary, three randomised controlled studies and a SOS study subsequently undertook a meta-analysis of the subsequent meta-analysis have established efficacy for the three studies described in detail above [149]. This analy- use of FRAX screening to reduce the risk of hip fracture, as sis comprised a total of 42,009 participants, reflecting all well as other fracture outcomes. the women participating in the SCOOP and SOS studies, plus all the women providing a FRAX-based assessment at There should be evidence that the complete screening entry to the ROSE study. The latter group was deemed to programme (test, diagnostic procedures, treatment/ be comparable to the participants in the other two studies. intervention) is clinically, socially and ethically acceptable The proportions receiving treatment recommendations in to health professionals and the public. the studies were 13% in ROSE, 14% in SCOOP and 25% in SOS, with subsequently 11%, 15%, and 18% respectively None of the steps or assessments in the proposed screen- commencing therapy. Despite these relatively low treatment ing programme is novel. The FRAX questionnaire has been rates, the meta-analysis showed a statistically significant used in routine clinical practice since its launch in 2008. decrease of 5% in the incidence of osteoporotic fractures The website alone, which is not the only means of accessing (HR 0.95, 95% confidence interval (CI) 0.89–1.00) when the FRAX calculation, has had approximately 34 million comparing screening to usual care. Most notably, there was calculations over the last 10 years (site accessed on 16th a 20% decrease in hip fractures (HR 0.80; 95%CI 0.71–0.91) July 2021). In a recent review, there was widespread usage (Fig. 4A). There was also a 9% decrease in major osteoporo- of the online tool globally [98], with its daily place in the tic fractures (HR = 0.91; 0.84–0.98), but this analysis didn’t management of patients at risk of fracture reflected in the include the outcome of major osteoporotic fractures in 9 (HR marked downturn in usage associated with the onset of the 0.88, 0.79–0.98, p = 0.018) [150]. Addition of the SCOOP global pandemic [151]. result to the meta-analysis resulted in a similar overall reduc- Bone mineral density measurement by DXA has been tion in major osteoporotic fractures (Fig. 4B). There was no part of routine clinical care of osteoporosis since the 1980s difference in all-cause mortality (HR 1.04; 0.95–1.14). It and is a widely accepted technique for both patients and is worth noting that both ROSE and SOS used the FRAX doctors. The radiation dose is low (equivalent to 2–3 days MOF output to target assessment; if the FRAX Hip output of background radiation) [152], the scanning time is rapid had been used as in 9, it is possible that the reduction in hip (a few minutes) and the scan does not require the patient to fractures would have been somewhat greater. be enclosed or in a tunnel. In the pooled cohort, the NNS and NNT for hip fractures A randomized controlled trial of screening using BMD were 272 and 28 respectively. The meta-analysis clearly found no evidence of an adverse effect on either quality of life showed population screening to be effective, with the biggest or anxiety [153], while qualitative studies have reported some 13 Archives of Osteoporosis (2022) 17:87 Page 15 of 24 87 anxiety (i.e. a low BMD conveying a feeling of weakness) but The opportunity cost of the screening programme others have reported more positive views of BMD measure- (including testing, diagnosis and treatment, ment [154, 155]. A specific assessment of the acceptability administration, training and quality assurance) should of the proposed screening approach used in the SCOOP study be economically balanced in relation to expenditure has been published [99]. The results showed that women and on medical care as a whole (value for money). Assessment GPs viewed screening positively, recognizing its potential to against these criteria should have regard to evidence improve fracture prevention and future health. from cost benefit and/or cost effectiveness analyses In summary, none of the components of the screening and have regard to the effective use of available resource. programme are new or untested, with many years of experi- ence suggesting that the programme is clinically, socially Several cost-effectiveness analyses of population screening and ethically acceptable to health professionals and the strategies in osteoporosis have been published over the last public. 20 years, but relatively few have been tested in randomized controlled trials [153, 161]. Of the three recent randomised controlled studies using FRAX, only the SCOOP study has The benefit gained by individuals from the screening published cost-effectiveness analyses to date. The first of programme should outweigh any harms, for example these used a within-trial design limited to the time frame of from overdiagnosis, overtreatment, false positives, false the trial (5 years), with questionnaires (EQ-5D-3L) admin- reassurance, uncertain findings and complications. istered to document self-reported quality of life (QoL) at 6-month intervals during the first year and then at annual As noted, qualitative data indicate that the proposed screen- intervals used to derive QALYs[6]. The screening arm had ing programme is not associated with any increase in anxi- a non-significant average incremental QALY gain of 0.0237 ety. The numbers needed to treat to prevent one hip fracture, (95% CI –0.0034 to 0.0508) for the 5-year follow-up, with derived from the meta-analysis, compare very favourably an incremental cost per QALY gained of £2772 compared with those for the use of statins to prevent non-fatal myo- with the control arm. Cost-effectiveness acceptability curves cardial infarctions or strokes in patients with (https://​www.​ indicated a 93% probability of the intervention being cost- thennt.​com/​nnt/​stati​ns-​for-​heart-​disea​se-​preve​ntion-​with-​ effective at values of a QALY greater than £20,000. The known-​heart-​disea​se/) or without (https://​www.​thennt.​com/​ authors concluded that the analysis demonstrated that a sys- nnt/s​ tatin​ s-f​ or-h​ eart-d​ iseas​ e-p​ reven​ tion-w ​ ithou​ t-p​ rior-h​ eart-​ tematic, community-based screening programme of fracture disea​se-2/) known heart disease. The screening test identi- risk in older women in the UK represents a highly cost- fies a risk or, more accurately in the case of FRAX, a prob- effective intervention. The most recent analysis used a more ability, rather than a specific disease or a pre-disease state; established health economic Markov model study design, the use of false positives and false negatives in this setting whereby disutilities of fractures, derived from other qual- is complex. The positive and negative predictive values are ity of life studies, were applied to the women sustaining probably of most importance to clinicians and patients alike, incident fractures [162]. In addition, the cost-effectiveness combined with information on the safety and efficacy of the analysis modelled a linear offset of effect of the screening treatments. There is therefore a need to ensure that the indi- programme and calculated the cost-effectiveness over a vidual patient’s understanding of risk is addressed, that their longer time horizon (remaining lifetime). The model was understanding of the importance of the adverse outcome (i.e. populated with costs related to drugs, administration and fracture, particularly hip fracture) is good, and the benefits screening intervention derived from the SCOOP study with and risks of the treatment or intervention are clear. All the fracture risk in the control and screening arms correspond- treatments used in 8 are licensed and many are long-estab- ing to the observed risk observed in the study. The analysis lished with very well characterised data on efficacy and side reported that screening of 1000 patients would save 9 hip effects. Public and individual awareness of rare side effects fractures and 20 non-hip fractures over the remaining life- of osteoporosis treatments, namely atypical femoral frac- time (mean 14 years) and save costs (£286) in comparison tures (AFF) and osteonecrosis of the jaw (ONJ), can impact with usual management. The analysis strongly suggests that on treatment uptake despite occurring at very low rates in there are no opportunity costs to a screening programme the treated osteoporosis population (approximately 1 in based on the SCOOP study, and its implementation could 1000–100,000 for AFFs and 1 in 10,000–100,000 for ONJ) actually be cost saving. and usually only after several years of exposure [156–159]. Thus, the opportunity costs of the screening programme The risks of these outcomes are far outweighed by the num- are low or even cost-saving. They are comparable to or better ber of fractures at the hip and other sites prevented by treat- than many public health measures [163] or other established ment [156, 160]. screening programmes [164, 165] 13 87 Page 16 of 24 Archives of Osteoporosis (2022) 17:87 All other options for managing the condition should have and on fracture risk in women identified as being at risk of been considered (such as improving treatment or providing fracture through screening. It is widely recognised that the other services), to ensure that no more cost effective effect of anti-osteoporosis treatments differs across skeletal intervention could be introduced or current interventions sites. For example, analyses consistently show the largest increased within the resources available. reductions in vertebral fractures (50–70%), intermediate reductions in hip fractures (40–50%) and somewhat lower Current approaches to fracture prevention are addressed in reductions in non-vertebral, non-hip fractures (20–25%). the section on clinical management of the condition above. Both the UK NSC and the EU HTA reports acknowledged In the Department of Health guidance in the UK, a focus that there was evidence of potential benefit for hip fractures is given to interventions that will reduce falls risk and/or [168–170], though neither conducted a meta-analysis that fracture risk [166]. Falls reduction strategies are also rec- combined the similar populations in both the SCOOP and ommended in many international guidelines as a means of ROSE studies (i.e. confined to those who returned a base- reducing falls-related injuries, of which fracture is one of the line risk questionnaire). It is also important to bear in mind most serious consequences, especially hip fracture. While that unlike randomised controlled trials of treatments ver- assessment of falls risk and appropriate interventions aimed sus placebo, the recent studies of screening have examined at reducing falls risk has been shown to be effective, at least strategies rather than treatment; importantly, the proportion in the short term, their impact on the risk of hip fracture targeted for treatment in these studies was small (e.g. 14% is less certain [104, 107]. Furthermore, the reduction in in SCOOP) meaning that the majority of participants in both hip fractures in the SCOOP study was not mediated by any arms of the studies did not receive any therapeutic interven- impact of the screening programme on falls risk [167]. tion. A 25% reduction in non-vertebral, non-hip fractures In summary, while falls prevention measures should con- during treatment would be manifest by only a 3.5% reduc- tinue to be included in individual patient management, the tion in the whole cohort where treatment was just targeted role for bone-targeted treatments should be prioritised. to 14% of the population. It should also be noted that the proposed screening program, predicated on FRAX 10-year probability of hip fracture, targets interventions to individu- Conclusion als with a higher risk of a fracture that is more reversible by osteoporosis treatments. A previous post hoc analysis within In this paper, we have sought to assess the potential for a the SCOOP study showed that the reductions in hip fractures screening programme to identify women at increased risk at baseline high FRAX hip probability are of a similar mag- of hip fracture. We have approached this by proposing a nitude to that observed in randomised controlled studies of programme based on that used successfully in the SCOOP antiresorptive treatments, an observation that is supported study and then addressing 15 of the 19 criteria established by the analysis presented in this report of the 55% reduc- by the UK National Steering Committee for the assessment tion in hip fractures in the small high-risk cohort. We would of such a programme (Table 5). Notably, evidence address- conclude that there is good evidence that women identified ing these criteria were reviewed for osteoporosis screening by screening are responsive to appropriate management with by the UK NSC in 2019 (evidence cut-off September 2018), anti-osteoporosis agents, particularly with regard to preven- following an external review, and concluded screening could tion of hip fractures as reflected in the recent meta-analysis. not currently be recommended [168, 169]. A similar con- Finally, uncertainties have been raised about how much clusion was reached in an assessment under an EU Health added benefit would be gained by population screening Technology Assessment report also published in 2019 [170]. over usual care, and the cost-effectiveness of a population These conclusions were largely based on areas of continu- screening programme. While none of the screening stud- ing uncertainty which may be seen as relevant to screening ies were designed to directly capture impacts on morbidity in the UK and beyond. For example, uncertainty remained and mortality, hip fractures are well documented to result about the accuracy of screening tests in women who would in significant morbidity, hospitalisation, surgery and pro- be included in a population screening programme. We would longed rehabilitation with a significant number of patients argue that there is compelling evidence from systematic not returning to their pre-fracture level of mobility and reviews and individual studies that the accuracy for future independence. The proposed strategy combines a low-cost hip fractures, as reflected by the AUCs, is appropriate for a assessment with targeted intervention using low-cost generic clinical tool for the prediction of future events as opposed to treatments, predominantly oral bisphosphonates; the sub- the detection of existing or early disease as in other screen- sequent 28% reduction in the incidence of hip fractures is ing programmes [171]. a highly impactful strategy compared to usual care. Even Uncertainty has also been expressed about the effect of more importantly, the standard cost-effectiveness analysis treatment and changes in lifestyle on some types of fracture, demonstrates that the strategy dominates usual care, i.e. it 13 Archives of Osteoporosis (2022) 17:87 Page 17 of 24 87 is actually cost saving. Future health economic modelling various criteria from a wide variety of geographic and should enable assessment of different screening strategies healthcare system settings. The report is meant to serve as for hip fracture risk, including the wider utilisation of BMD a basis for engagement and discussion with policy makers as part of the strategy. and payers around the potential for screening in osteoporosis The major limitation of this report, perhaps, is that it is with a particular focus on high hip fracture risk. not based on a systematic review to address the available lit- From the evidence reviewed in this report, we would erature on the areas addressed by each specific criterion, and contend that the case for screening to identify women at the selected randomised controlled trials excluded other non- increased risk of hip fracture is now made and that future FRAX approaches. For example, we did not include a study research should focus on strategies for optimal implemen- that addressed screening for prevalent vertebral fractures as tation of this approach across different healthcare systems the latter was of relatively short duration (1 year) and had and settings. We would certainly conclude that any tran- medication uptake as the main endpoint [172]. However, sition towards screening that leads to improved identifica- the expert panel comprises a wide, in-depth knowledge and tion of hip fracture risk in older women in primary care expertise in the fields of risk assessment, guidelines, treat- (e.g. enhanced case-finding) will undoubtedly have positive ment and health economics of osteoporosis. The approach impacts on the clinical, personal and economic burden of used attempted to measure the level of consensus on the this most serious of osteoporotic fractures. Appendix Table 5  Current UK criteria used by the UK NSC for assessment of ses represent the number of responses saying yes, in part or no for a screening programme. For each criterion, a decision has been made each criterion (a total of 20 experts responded to the survey). The as to whether screening for hip fracture risk using the proposed pro- final four criteria were considered beyond the scope of this paper gramme would satisfy the criterion needs. The numbers in parenthe- Criterion Met (✓) or not met (χ) (Yes, in part, no) The condition • The condition should be an important health problem ✓ (17,3,0) • The epidemiology and natural history of the condition, including development from ✓ latent to declared disease, should be adequately understood and there should be a detect- (18,2,0) able risk factor, disease marker, latent period or early symptomatic stage • All the cost-effective primary prevention interventions should have been implemented as ✓ far as practicable (12,7,1) The test • There should be a simple, safe, precise and validated screening test ✓ (16,3,1) • The distribution of test values in the target population should be known and a suitable ✓ cut-off level defined and agreed (17,2,1) • The test should be acceptable to the population ✓ (19,1,0) • There should be an agreed policy on the further diagnostic investigation of individuals ✓ with a positive test result and on the choices available to those individuals (17,3,0) The treatment • There should be an effective treatment or intervention for patients identified through early ✓ detection, with evidence of early treatment leading to better outcomes than late treatment (16,3,1) • There should be agreed evidence-based policies covering which individuals should be ✓ offered treatment and the appropriate treatment to be offered (19,1,0) • Clinical management of the condition and patient outcomes should be optimised in all ✓ healthcare providers prior to participation in a screening programme (18,1,1) The screening programme • There should be evidence from high-quality randomised controlled trials that the screen- ✓ ing programme is effective in reducing mortality or morbidity. Where screening is aimed (16,3,1) solely at providing information to allow the person being screened to make an informed choice (e.g. Down’s syndrome, cystic fibrosis carrier screening), there must be evidence from high-quality trials that the test accurately measures risk. The information that is provided about the test and its outcome must be of value and readily understood by the individual being screened 13 87 Page 18 of 24 Archives of Osteoporosis (2022) 17:87 Criterion Met (✓) or not met (χ) (Yes, in part, no) • There should be evidence that the complete screening programme (test, diagnostic pro- ✓ cedures, treatment/intervention) is clinically, socially and ethically acceptable to health (19,1,0) professionals and the public • The benefit from the screening programme should outweigh the physical and psychologi- ✓ cal harm (caused by the test, diagnostic procedures and treatment) (19,1,0) • The opportunity cost of the screening programme (including testing, diagnosis and treat- ✓ ment, administration, training and quality assurance) should be economically balanced (16,4,0) in relation to expenditure on medical care as a whole (i.e. value for money). Assessment against these criteria should have regard to evidence from cost benefit and/or cost-effec- tiveness analyses and have regard to the effective use of available resource • All other options for managing the condition should have been considered (e.g. improv- ✓ ing treatment, providing other services), to ensure that no more cost-effective intervention (14,4,2) could be introduced or current interventions increased within the resources available • There should be a plan for managing and monitoring the screening programme and an Beyond scope agreed set of quality assurance standards • Adequate staffing and facilities for testing, diagnosis, treatment and programme manage- Beyond scope ment should be available prior to the commencement of the screening programme • Evidence-based information, explaining the consequences of testing, investigation and treatment, Beyond scope should be made available to potential participants to assist them in making an informed choice • Public pressure for widening the eligibility criteria for reducing the screening interval, Beyond scope and for increasing the sensitivity of the testing process, should be anticipated. Decisions about these parameters should be scientifically justifiable to the public Acknowledgements This position paper was prepared by the Interna- grants and personal fees from Kyowa Kirin, personal fees for Gedeon tional Osteoporosis Foundation Epidemiology/Quality of Life Working Richter outside the submitted work. BA also serves on the NovoNord- Group and has been endorsed by the International Osteoporosis Foun- isk Foundation Grants Committee on Endocrinology and Metabolism. dation. We are grateful for administrative support from Dr Dominique M.L. reports lecture fees from Amgen, Astellas, Lilly, Meda, Rena- Pierroz. pharma and UCB Pharma and consulting fees from Amgen, Radius Health, UCB Pharma, Renapharma and Consilient Health, outside the Funding Work informing this project was supported by the UK Medi- submitted work. D.P-A. reports institutional receipt of speaker fees cal Research Foundation (MRF-145–0011-DG-HARV-C0913). N.C.H., from AMGEN and UCB Biopharma; consultancy fees from UCB Bi- E.M.C., E.M.D. and C.C. are supported by the UK Medical Research opharma; research grants from UCB, Amgen, and Les Laboratoires Council (MC_PC_21003; MC_PC_21001). Servier, all outside of the submitted work. J. A. reports grants and personal fees from Amgen outside the submitted work, grants from Radius and has been an advisor to Gilead and is part of their speaker’s Declarations bureau, outside the submitted work. F.B. is employed and is a share- holder in Quantify Research, a health economic research consultancy, Ethics approval and consent to participate This narrative article con- outside of the submitted work. O.B. reports grant support from IBSA, tains no original data and thus issues of ethics, informed consent and MSD, Nutraveris, Novartis, Pfizer, Rottapharm, Servier and Ther- patient confidentiality do not apply. amex; consulting or lecture fees from Bayer, Genevrier, IBSA, Rot- tapharm, Servier, SMB and TRB Chemedica; all outside the submitted work. All other authors have no relevant conflicts of interest in relation Conflict of interest E.V.M reports consultant/advisor fees, speaker to the submitted work. honoraria and or, research funding from AgNovos, Amgen, Consilient Healthcare, Fresenius Kabi, Gedeon Richter, Internis, Lilly, Novartis, ObsEva, Synexus and UCB, all outside the submitted work. E.M.C. Open Access This article is licensed under a Creative Commons Attri- reports lecture fees and travel support from Eli Lilly, Pfizer and UCB, bution 4.0 International License, which permits use, sharing, adapta- outside the submitted work. N.C.H. reports personal fees, consultancy, tion, distribution and reproduction in any medium or format, as long lecture fees and honoraria from Alliance for Better Bone Health, AM- as you give appropriate credit to the original author(s) and the source, GEN, MSD, Eli Lilly, UCB, Kyowa Kirin, Servier, Shire, Consilient provide a link to the Creative Commons licence, and indicate if changes Healthcare and Internis Pharma, outside the submitted work. J.A.K. were made. The images or other third party material in this article are reports a grant from UCB, outside the submitted work. He is the ar- included in the article's Creative Commons licence, unless indicated chitect of FRAX® but has no financial interest. C.C. reports personal otherwise in a credit line to the material. If material is not included in fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, the article's Creative Commons licence and your intended use is not Pfizer, Roche, Servier and Takeda, outside the submitted work. B.A. permitted by statutory regulation or exceeds the permitted use, you will reports grants and personal fees from UCB, personal fees from Amgen, need to obtain permission directly from the copyright holder. To view a grants from Novartis, grants and personal fees from Pharma-cosmos, copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. 13 Archives of Osteoporosis (2022) 17:87 Page 19 of 24 87 References European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 8:136 18. Oden A, McCloskey EV, Kanis JA, Harvey NC, Johansson H 1. Wilson JMG, Jungner G (1968) Principles and practice of screen- (2015) Burden of high fracture probability worldwide: secular ing for disease. 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Khosla S, Burr D, Cauley J et al (2007) Bisphosphonate-associ- Publisher's note Springer Nature remains neutral with regard to ated osteonecrosis of the jaw: report of a task force of the Ameri- jurisdictional claims in published maps and institutional affiliations. can Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491 13 87 Page 24 of 24 Archives of Osteoporosis (2022) 17:87 Authors and Affiliations P. Chotiyarnwong1,2 · E. V. McCloskey1,3 · N. C. Harvey4 · M. Lorentzon5,6 · D. Prieto‑Alhambra7,8 · B. Abrahamsen9,10 · J. D. Adachi11 · F. Borgström12,13 · O. Bruyere14 · J. J. Carey15,16 · P. Clark17 · C. Cooper4 · E. M. Curtis4 · E. Dennison4 · M. Diaz‑Curiel18 · H. P. Dimai19 · D. Grigorie20,21 · M. Hiligsmann22 · P. Khashayar23 · E. M. Lewiecki24 · P. Lips25 · R. S. Lorenc26 · S. Ortolani27 · A. Papaioannou28,29 · S. Silverman30 · M. Sosa31 · P. Szulc32 · K. A. Ward4 · N. Yoshimura33 · J. A. Kanis3,6 1 17 Department of Oncology & Metabolism, Mellanby Centre Clinical Epidemiology Unit of Hospital Infantil de México for Musculoskeletal Research, MRC Versus Arthritis Federico Gómez‑Faculty of Medicine, Universidad Nacional Centre for Integrated Research in Musculoskeletal Ageing, Autónoma de México, UNAM, Mexico City, Mexico University of Sheffield, Sheffield, UK 18 Hospital Universitario Fundación Jiménez Díaz, Madrid, 2 Department of Orthopaedic Surgery, Faculty of Medicine, Spain Siriraj Hospital, Mahidol University, Bangkok, Thailand 19 Department of Internal Medicine, Division of Endocrinology 3 Centre for Metabolic Bone Diseases, Northern General and Diabetology, Medical University of Graz, Graz, Austria Hospital, University of Sheffield, Herries Road, 20 Carol Davila University of Medicine, Bucharest, Romania Sheffield S5 7AU, UK 21 4 Department of Endocrinology & Bone Metabolism, National MRC Lifecourse Epidemiology Centre, University Institute of Endocrinology, Bucharest, Romania of Southampton, Southampton, UK 22 5 Department of Health Services Research, CAPHRI Care University of Gothenburg, Gothenburg, Sweden and Public Health Research Institute, Maastricht University, 6 Australian Catholic University, Melbourne, Australia Maastricht, the Netherlands 7 23 Oxford NIHR Biomedical Research Centre, University Center for Microsystems Technology, Imec and Ghent of Oxford, Windmill Road, Oxford OX3 7LD, UK University, 9050 Ghent, Belgium 8 24 GREMPAL (Grup de Recerca en Malalties Prevalents New Mexico Clinical Research & Osteoporosis Center, de L’Aparell Locomotor) Research Group, CIBERFes Albuquerque, NM, USA and Idiap Jordi Gol Primary Care Research Institute, 25 Department of Internal Medicine, Endocrine Section & Universitat Autònoma de Barcelona and Instituto de Salud Amsterdam Public Health Research Institute, Amsterdam Carlos III, Gran Via de Les Corts Catalanes, 591 Atico, UMC, Vrije Universiteit Amsterdam, Amsterdam, 08007 Barcelona, Spain the Netherlands 9 Department of Clinical Research, Odense Patient Data 26 Multidisciplinary Osteoporosis Forum, SOMED, Warsaw, Exploratory Network, University of Southern Denmark, Poland Odense, Denmark 27 10 IRCCS Istituto Auxologico, UO Endocrinologia E Malattie Department of Medicine, Holbæk Hospital, Holbæk, del Metabolismo, Milano, Italy Denmark 28 11 Department of Medicine, McMaster University, Hamilton, Department of Medicine, Michael G DeGroote School ON, Canada of Medicine, St Joseph’s Healthcare-McMaster University, 29 Hamilton, ON, Canada GERAS Centre for Aging Research, Hamilton, ON, Canada 12 30 Quantify Research, Stockholm, Sweden Cedars-Sinai Medical Center, Los Angeles, CA, USA 13 31 Department of Learning, Informatics, Management Bone Metabolic Unit, University of Las Palmas de and Ethics (LIME), Karolinska Institutet, Stockholm, Sweden Gran Canaria, Hospital University Insular, Las Palmas, 14 Gran Canaria, Spain WHO Collaborating Center for Public Health Aspects 32 of Musculo‑Skeletal Health and Ageing, Division of Public INSERM UMR 1033, University of Lyon, Hôpital Edouard Health, Epidemiology and Health Economics, University Herriot, Lyon, France of Liège, Liège, Belgium 33 Department of Preventive Medicine for Locomotive 15 School of Medicine, National University of Ireland Galway, Organ Disorders, 22Nd Century Medical and Research Galway, Ireland Center, University of Tokyo, Hongo 7‑3‑1, Bunkyo‑ku, 16 Tokyo 113‑8655, Japan Department of Rheumatology, Galway University Hospitals, Galway, Ireland 13