Osteoporosis International (2020) 31:1–12 https://doi.org/10.1007/s00198-019-05176-3 POSITION PAPER Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures J. A. Kanis 1,2 & N. C. Harvey 3 & E. McCloskey 1,4 & O. Bruyère 5 & N. Veronese 6 & M. Lorentzon 2,7,8 & C. Cooper 3,9 & R. Rizzoli 10 & G. Adib 11 & N. Al-Daghri 12 & C. Campusano 13 & M. Chandran 14 & B. Dawson-Hughes 15 & K. Javaid 9 & F. Jiwa 16 & H. Johansson 1,2 & J. K. Lee 17 & E. Liu 2 & D. Messina 18 & O. Mkinsi 19 & D. Pinto 20,21 & D. Prieto-Alhambra 9,22 & K. Saag 23 & W. Xia 24 & L. Zakraoui 25 & J. -Y. Reginster 12,26 Received: 26 June 2019 / Accepted: 18 September 2019 / Published online: 13 November 2019 # The Author(s) 2019, corrected publication 2020 Abstract Summary Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Methods Clinical perspective and updated literature search. Results The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. Conclusions A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions. Keywords Anabolic agents . Fracture risk assessment . FRAX . Inhibitors of bone resorption . Treatment of osteoporosis Introduction treatment of women at increased risk of fracture. This translation could also enable the incorporation of several recent develop- In 2018, the International Osteoporosis Foundation (IOF) and the ments that significantly impact on strategies for the management European Society for Clinical and Economic Evaluation of of patients. The first is the widespread recognition that the risk of Osteoporosis and Osteoarthritis (ESCEO) updated guidelines a subsequent osteoporotic fracture is particularly acute immedi- for the diagnosis and management of postmenopausal osteopo- ately after an index fracture and wanes progressively with time rosis, subsequently published in full in 2019 [1] and as executive [4–9]. This very high fracture risk and the consequent further summaries [2, 3]. Translation of this guideline into easy to use, utility loss immediately after a subsequent fracture (often termed practical algorithms is needed to facilitate the recognition and “imminent risk” because of the temporal association) suggests that preventive treatment given as soon as possible after fracture would avoid a higher number of new fractures and reduce the attendant morbidity, compared with treatment given later. This Outcomes of an experts’ consensus meeting jointly organised by the European Society for Clinical and Economic Aspects of Osteoporosis, provides the rationale for very early intervention immediately Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the after a sentinel fracture and necessitates treatment with agents International Osteoporosis Foundation (IOF) that have the most rapid effect on fracture reduction. A further recent development is the demonstration of a more rapid and * J. A. Kanis greater fracture risk reduction of anabolic compared with w.j.Pontefract@shef.ac.uk antiresorptive treatments [10–14], with the potential to revo- lutionise treatment strategies, particularly in individuals at Extended author information available on the last page of the article very high fracture risk [15, 16]. 2 Osteoporos Int (2020) 31:1–12 Ten year probability (%) The scope of the present report is to review and update the 40 assessment of osteoporosis, in particular the categorisation of UAT risk to better target therapeutic interventions for the prevention of fragility fracture in postmenopausal women. The guideline is intended for all healthcare professionals involved in the 30 management of osteoporosis. Where available, systematic re- Intervention threshold views, meta-analyses and randomised controlled trials have been used to provide the evidence-base with the available Consider treatment LAT 20 literature updated using PubMed to identify systematic re- views and meta-analyses from January 2017 to December 2018, subsequent to the generation of the recent European 10 Guidelines. The recommendations in this guidance have been endorsed by the Scientific Advisory Board of ESCEO and the No treatment Committee of Scientific Advisors and the Committee of National Societies of the IOF. 0 40 50 60 70 80 Age (years) Fig. 1 Assessment guidelines based on the ten-year probability of a major Risk assessment osteoporotic fracture (%). The dotted line denotes the intervention threshold. Where assessment is made in the absence of BMD, a BMD The IOF and ESCEO recommend that risk of fracture should be test is recommended for individuals where the probability assessment lies in the orange region i.e. between the lower assessment threshold (LAT) expressed as an absolute risk, i.e. probability of fracture over a and the upper assessment threshold (UAT). The intervention threshold ten-year interval [1]. The absolute risk of fracture depends upon and BMD assessment thresholds used are those derived from [1] and age and life expectancy as well as the current fracture risk. The reproduced in the Appendix, Table 5, with kind permission from period of 10 years was chosen to cover the likely length of Springer Science and Business Media treatment and the time over which benefits may continue or risks arise if treatment is stopped [17]. Algorithms that integrate forearm or humerus). Women with probabilities below the the weight of clinical risk factors for fracture risk, with or with- lower assessment threshold can be considered at low risk. out information on BMD, were developed in 2007 by the then Women with probabilities above the upper assessment thresh- WHO Collaborating Centre for Metabolic Bone Diseases at old can be considered for treatment. Women with probabilities Sheffield. The resulting FRAX tool (www.shef.ac.uk/FRAX) between the upper and lower assessment threshold should be computes the 10-year probability of hip fracture or a major referred for BMD measurements and their fracture probability osteoporotic fracture, the latter comprising a clinical spine, reassessed [1]. The age-dependent intervention threshold is set hip, forearm or humerus fracture. The tool has been externally at a risk equivalent to that associated with a prior fracture in a validated in independent cohorts [18] and calibrated to the ep- woman of the same age with average BMI and, therefore, rises idemiology of fracture and death in 67 countries covering more with age [21]. The same thresholds are used in men since the than 80% of the world population at risk [19]. cost-effectiveness of interventions is broadly similar in men and women [22, 23]. Intervention and assessment thresholds Fig. 2 Infographic outlining of the characterisation of fracture risk by„ FRAX has been incorporated into more than 100 guidelines FRAX major osteoporotic fracture probability in postmenopausal worldwide but the approach to intervention thresholds has women. Initial risk assessment uses FRAX with clinical risk factors alone. FRAX probability in the red zone indicates very high risk and varied widely [19, 20]. For the purposes of this report, the that an initial course of anabolic treatment followed by antiresorptive guidance of the IOF and ESCEO [1] is used as an example therapy may be appropriate. FRAX probability in the green zone and shown in Fig. 1. suggests low risk, with advice to be given on lifestyle, calcium and In the European guidance, it is recommended that postmen- vitamin D nutrition and menopausal hormone treatment considered. FRAX probability in the intermediate (orange) zone should be followed opausal women with a prior fragility fracture should be treated by BMD assessment and recalculation of FRAX probability including without further assessment, although BMD measurement and femoral neck BMD. After recalculation, risk may be in the red zone incorporation into the FRAX calculation is sometimes appro- (very high risk), orange zone (high risk, which suggests initial priate, particularly in younger postmenopausal women. In antiresorptive therapy) or green zone (low risk, either in the original green zone or in the original orange zone but below the intervention women without a previous fragility fracture, the management threshold). Note that patients with a prior fragility fracture are at least strategy should be based on assessment of the ten-year prob- designated at high risk and possibly at very high risk dependent on the ability of a major osteoporotic fracture (clinical spine, hip, FRAX probability Osteoporos Int (2020) 31:1–12 3 Ten year probability (%) 40 UAT Intervention threshold 30 Intervention threshold LAT 20 Very high risk 10 Low risk 0 40 50 60 70 80 Age (years) Inial assessment FRAX: Clinical risk factors Measure BMD Recalculate FRAX Low risk High risk Very high risk Some agencies have been reluctant to reimburse treatments fracture is less than 10%. In the UK, for example, the inter- on the basis of fracture probability, particularly at younger vention threshold for women aged 50–54 years is 8.18%. At ages where the 10-year probability of a major osteoporotic the same age, however, the remaining lifetime probability of a 4 Osteoporos Int (2020) 31:1–12 Fig. 3 Treatment pathways according to the categorisation of fracture risk. For treatment modalities (inhibitors of bone resorption, anabolic agents, etc.), see Appendix, Table 6 Low risk High risk Very high risk Opmize calcium and Opmize calcium and Opmize calcium and vitamin D status vitamin D status vitamin D status Risk appropriate Risk appropriate Risk appropriate exercise and falls exercise and falls exercise prevenon prevenon Consider anabolic Consider oral Reassurance, lifestyle agent followed by bisphosphonate or advice. Consider MHT inhibitor of bone other inhibitor of and SERMs resorpon*. Consider bone resorpon* LOEP MHT, menopausal hormone therapy; SERM, selecve estrogen receptor modulator; LOEP, local osteo-enhancement procedure * See Appendix, table A2 Fig 4 Proportion (%) of % Low risk High risk Very high risk postmenopausal women by age in a simulated normal population of 100 50633 women from the UK [51] 14 14 16 16 16 17 17 17 16 characterised at low, high and very high risk. The high-risk 80 13 16 category includes women with a 17 19 20 22 25 prior fracture not characterised at 28 31 very high risk. Numbers in the 60 high and very high risk categories refer to the percentage so characterised at each age interval 40 20 0 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ 50+ Age (years) Osteoporos Int (2020) 31:1–12 5 major fracture is high (57%). Moreover, there are cost- Table 2 10-year probability of major osteoporotic fracture (MOF) for Icelandic women at different ages, categorised by (A) a clinical vertebral effective scenarios for treatment available at these levels of fracture within the previous 2 years and (B) a prior fracture of risk [1]. undetermined recency. The right-hand column provides the ratio by In addition to the 10-year probability of a major osteopo- which to adjust FRAX probabilities by virtue of a recent clinical rotic fracture, the European guidance also provides interven- vertebral fracture. From [59], with kind permission from Springer Science and Business Media tion thresholds that are based on the 10-year probability of hip fracture. Either or both thresholds can be used; indeed, the 10-year probability of MOF Ratio screening for prevention of fractures in older women (SCOOP) trial showed that a screening strategy decreased Age (A) Recent (B) Prior fracture vertebral fracture in adult life the incidence of hip fracture (but not other fractures), based on treatment targeted by hip fracture probability [24]. 50 29.0 11.7 2.47 To enhance fracture risk assessment, relatively simple ar- 60 36.1 19.4 1.86 ithmetic adjustments have been developed, which can be ap- 70 41.9 27.6 1.52 plied to conventional FRAX estimates of probabilities of hip 80 42.5 34.2 1.24 fracture and a major fracture to adjust the probability assess- 90 34.7 33.3 1.04 ment with knowledge of High, moderate and low exposure to glucocorticoids [25] Concurrent data on lumbar spine BMD [26, 27] these thresholds are given in the Appendix (Table 5) based Trabecular bone score of the lumbar spine [28–30] on the weighted average of 5 European countries (Germany, Hip axis length [31] France, Italy, Spain and the UK) but will vary by country. Falls history [32] Immigration status [33] Type 2 diabetes [34, 35] Impact on treatment Chronic kidney disease [36] Recency of fracture [9, 37] The rationale for the more refined characterisation of risk is to direct appropriate interventions. Thus, initial treatment recom- mendations for women at high risk might most usually start Categorisation of risk with an inhibitor of bone resorption. For example, the UK National Institute for Clinical Excellence (NICE) and the The assessment strategy above permits the classification of IOF/ESCEO guidelines recommend oral bisphosphonates [1, risk. In addition to the categories of low and high risk es- 38, 39] but a very large range of pharmacological interven- poused in the current IOF-ESCEO guideline, very high risk tions are recommended worldwide (Appendix, Tables 6 and can be identified as outlined in Fig. 2. Very high risk is defined 7). In contrast, women at very high risk might be more suit- as a fracture probability that lies above the upper assessment ably treated with an anabolic treatment followed thereafter by threshold after a FRAX assessment, with or without the inclu- an inhibitor of bone resorption [40] (Fig. 3). sion of BMD, i.e. where BMD testing is unavailable, the same Non-pharmacological management should be considered probability threshold can be used. The numerical data for for all patients but may be adapted according to the category Table 1 Examples of risk assessment in women from the UK (BMI set hip fracture, exposure to glucocorticoids, exposure to higher than average to 25 kg/m2). Risk factors include prior fracture (of uncertain recency), doses of glucocorticoids and bone mineral density (BMD) T-score at the prior clinical vertebral fracture within the past two years, family history of femoral neck Age (years) Prior fracture Recent spine fracture Family history GC GC high dose BMD (T-score) 10-year probability (%) Category of risk 70 Yes - 20 Low1 70 Yes - 17 Low 70 Yes Yes - 30 Very high 70 Yes - 30 Very high 60 Yes − 1.5 10 Low 60 Yes − 2.0 13 High 60 Yes Yes − 2.0 15 Very high 1 Qualifies for treatment by virtue of a prior fracture 6 Osteoporos Int (2020) 31:1–12 Table 3 Unadjusted probabilities of a major fracture in women with Prior fracture in adult life Recent clinical vertebral fracture a prior fragility fracture by age using the UK FRAX model Age Probability (%) Category of risk Probability (%) Category of risk together with the categories of risk and adjusted FRAX 50 7.3 High 18.0 Very high probabilities for women with a 60 12.2 High 22.7 Very high recent clinical vertebral fracture. 70 20.3 High 30.9 Very high BMI set at 24 kg/m2 80 27.6 Very high 34.2 Very high 90 33.9 Very high 35.3 Very high of fracture risk [41, 42]. For all patients, education on osteo- Examples of very high risk porosis (e.g. knowledge of osteoporosis, medications, diet and exercise) and advice for daily weight-bearing physical activity A prior fragility fracture provides informative examples of the are appropriate [43–45]. Where indicated, the addition of fall categorisation of risk and recommendations for treatment which prevention measures, including supervised exercise and/or re- are illustrated for a woman age 70 years in Table 1. A prior habilitation, has been shown to be useful in reducing falls [46, fragility fracture of undetermined recency is associated with a 47] but the effects on fracture risk remain uncertain [47]. 10-year probability of a major osteoporotic fracture of 16%. Programmes should continue over a duration of at least Whereas this probability is designated as low, treatment with an 50 hours, be progressive in nature and include strength and inhibitor of bone resorption is indicated by the IOF-ESCEO balance training components [48–50]. guidance and many other guidelines by virtue of the prior fracture The implications of the categorisation of risk on the use of [19]. A family history of hip fracture in the absence of any other anabolic regimens in this way are shown in Fig. 4 as applied to risk factors provides a similar fracture probability is characterised the age-specific NOGG guidance [21]. As would be expected, at low risk and lifestyle advice recommended. The combination the proportion of women characterised at low risk decreased of a prior fragility fracture of uncertain recency and a family with age and, conversely, those at high risk increased with age. history of hip fracture is associated with a much higher risk than The proportion of women characterised at very high risk in- either risk factor alone or falls into the category of very high risk creased with age though the quantum of effect was modest. where an anabolic regimen might be recommended. Overall, in women aged 50 years or more, 64.8% were A further example of the interaction of risk factors on the categorised at low risk, 19.7% at high risk and 15.6% at very categorisation of risk is provided in the context of exposure to high risk. Numerical data by age are given in the Appendix glucocorticoids (see Table 1). Awoman aged 60 years exposed to (Table 6). average doses of glucocorticoids and a femoral neck T-score of − Table 4 The effect on hip fracture (number/1000 patient years) of an that of the antiresorptive at 40%. The time course of a subsequent hip anabolic agent (AA) given for the first 18 months followed by an fracture is non-linear as given in [58]. The two right-hand columns show antiresorptive (AR) for a total of 10 years. The clinical scenario is a the effects of an antiresorptive followed by an anabolic agent for the last postmenopausal woman from the UK with a recent major osteoporotic 18 months of a 10-year treatment fracture. The efficacy (RRR) of the anabolic agent is modelled at 70% and Untreated AA/AR Fractures savedb AR/AN Fractures savedb RRR 70/40%a RRR 40/70% Age N/1000 N/1000 N/1000 N/1000 N/1000 50 8.1 2.4 5.7 4.7 3.4 55 12.8 3.8 9.0 7.5 5.3 60 20.4 6.1 14.3 11.9 8.5 65 31.3 9.4 21.9 18.3 13.0 70 48.3 14.5 33.8 28.3 20.0 75 73.6 22.1 51.5 43.1 30.5 80 104.7 31.4 73.3 61.2 43.5 85 160.4 48.1 112.3 93.8 66. 6 90 180.9 54.3 126.6 105.8 75.1 a It is assumed that the effect of the anabolic agent is maintained with the subsequent antiresorptive agent b First fractures Osteoporos Int (2020) 31:1–12 7 1.5 would be characterised as being at low risk in the absence of importance of the sequence. The assumptions used and data other clinical risk factors. A lower T-score of − 2.0 would place for other ages are given in Table 4. her in the category of high risk. However, for high doses (> 7.5 mg daily), probabilities should be upward-revised by about Conclusion 15% [25, 52] which would place the patient at very high risk. There is now a substantial body of evidence that the risk of The risk categorisation of individuals deemed to merit treat- a subsequent osteoporotic fracture is particularly acute imme- ment into high and very high risk and aids the targeting of diately after the index fracture and wanes progressively with anabolic therapy followed by antiresorptive medications. time [4–8, 53–57]. Thus, the incidence of a second fracture in those who will sustain a further fracture is particularly high in Acknowledgements We are grateful to the Scientific Advisory Board of the first 2 years after the index event [58]. In the case of hip ESCEO and the Committee of Scientific Advisors and the Committee of National Societies of the IOF for their review and endorsement of the fracture, 61% of subsequent fractures over a 10-year time recommendations in this guidance. horizon will occur within the first 2 years. For forearm, spine and humerus fractures the recurrence within two years is 54, Compliance with ethical standards 42 and 53%, respectively. A recent population-based study demonstrated that the phenomenon of immediate risk was also Conflicts of interest NM Al-Daghri G Adib, C Campusano, M age dependent [9]. For a woman at age 70 years, a prior clin- Chandran, F Jiwa, H Johansson, JK Lee, E Liu, D Pinto, N Veronese, ical vertebral fracture within the past 2 years is associated with W Xia, L Zakraoui have no conflicts of interest to declare. O Bruyère received research grants from Biophytis, IBSA, MEDA, a 1.52-fold higher fracture probability than for a woman of the Servier and SMB and consulting or lecture fees from Amgen, Biophytis, same age with a prior fragility fracture of uncertain recency IBSA, MEDA, Servier, SMB, TRB Chemedica and UCB. [59] (Table 2). Thus, a recent clinical vertebral fracture uplifts C Cooper reports personal fees from Alliance for Better Bone Health, the fracture probability from 16 to 24% and would place the Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. woman in the category of very high risk (see Table 1). B. Dawson-Hughes has received grant support from Pfizer and DSM Risk stratification with NOGG guidelines* BMI set at and consulting fees from TTY Biopharma Co, Ltd, Intrinsic Therapeutics 25 kg/m2 and Agnovos. The ratios given in Table 2 can be used to adjust fracture NC Harvey has received consultancy/lecture fees/honoraria/grant funding from Alliance for Better Bone Health, Amgen, MSD, Eli Lilly, Radius probabilities derived from FRAX for recency of clinical ver- Health, Servier, Shire, UCB, Consilient Healthcare and Internis Pharma. tebral fracture. Table 3 gives the current probabilities of a MK Javaid has received honoraria, unrestricted research grants, travel major fracture in women with a prior fragility fracture of un- and/or subsistence expenses from Amgen, Lilly UK, Internis, Consilient certain recency using the UK FRAX model together with the Health, Zebra Medical Vision, Kyowa Kirin Hakin and UCB. JA Kanis reports grants from Amgen, Eli Lilly and Radius Health and adjusted probabilities for women with a clinical vertebral frac- consulting fees from Theramex. JAK is the architect of FRAX® but has ture within the past two years. no financial interest. M Lorentzon has received lecture fees from Amgen, Lilly, Meda, Renapharma and UCB Pharma and consulting fees from Amgen, Radius Health, UCB Pharma, Renapharma and Consilient Health, all Impact of sequential treatment on fracture outside the presented work. EV McCloskey has received consultancy/lecture fees/grant funding/ In patients at very high risk of fracture, starting treatment with honoraria from ActiveSignal, AgNovos, Amgen, AstraZeneca, Consilient an anabolic agent seems most appropriate to promptly reduce Healthcare, Fresenius Kabi, Gilead, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Radius Health, Redx Oncology, the fracture risk [60–62]. Given that treatments with anabolic Roche, SanofiAventis, Servier, Synexus, Tethys, UCB, Viiv, Warner agents are limited to 12–24 months and that efficacy will wane Chilcott, I3 Innovus and Unilever. once treatment is stopped, the real potential of the anabolic OD Messina has received honoraria from Amgen, Lilly, Novartis and treatments is that their greater effect on BMD and fracture can Pfizer O Minski received honorary fees for lectures, from Abbvie, Roche, be maintained with the inhibitors of bone turnover once ana- Pfizer, Pierre Fabre, Janssen, Novartis and MSD. bolic treatment is stopped [11, 63, 64]. Take for example a D Prieto-Alhambra’s research group has received research grants from hypothetical anabolic agent that reduced the risk of hip frac- Amgen, Servier and UCB; speaker fees from Amgen and UCB; educational ture by 70% (relative risk reduction, RRR = 70%). In this case, grants from Johnson & Johnson and consultancy fees from Amgen and UCB. J-Y Reginster has received advisory board or consulting fees from the anabolic agent, followed by an antiresorptive to maintain IBSA-Genévrier, Pierre Fabre, Radius Health, TEVA and Mylan; lecture the effect for a total of 10 years, might be expected to save fees from Agnovos, IBSA-Genévrier, Mylan, CNIEL, Dairy Research 33.8 hip fractures/1000 patient years in women age 70 years Council (DRC) and Theramex and institutional grant support from with a recent fragility fracture. In contrast, an antiresorptive IBSA-Genévrier, Mylan, CNIEL and Radius Health. R Rizzoli has received consulting fees or advisory board fees from (RRR = 40%) followed by an anabolic regimen for the last Radius Health, Labatec, Danone, Nestlé, CNIEL and Sandoz. 18 months of a 10-year treatment would save only 20.0 hip K Saag reports grant support from Amgen and Radius and consulting fractures/1000 patient years. The difference illustrates the fees from Amgen, Radius and Roche. 8 Osteoporos Int (2020) 31:1–12 Appendix Table 5 Intervention thresholds as set by FRAX-based 10-year osteoporotic fracture equivalent to women without clinical risk factors probability (%) of a major osteoporotic fracture equivalent to women (a body mass index of 24 kg/m2 and without BMD). The upper with a previous fracture (no other clinical risk factors, a body mass assessment threshold is set at 1.2 times the intervention threshold. The index of 24 kg/m2 and without BMD). The lower assessment thresholds UK FRAX model is used. From [1], with kind permission from Springer set by FRAX is based on the 10-year probability (%) of a major Science and Business Media. Ten-year fracture probability (%) Age range (years) Intervention threshold* Lower assessment threshold Upper assessment threshold** Lifetime risk at intervention threshold* 50–54 7.8 4.0 9.4 57 55–59 11 5.3 13.2 54 60–64 14 7.3 16.8 50 65–69 19 9.8 22.8 47 70–74 22 12 26.4 43 75–79 26 16 31.2 39 80–84 31 20 37.2 36 85–89 33 18 39.6 34 *Threshold for high risk **Threshold for very high risk Table 6 Pharmaceutical interventions used in the Inhibitors of bone resorption Stimulators of bone formation management of postmenopausal osteoporosis. The list is not Vitamin D derivatives comprehensive but includes Alfacalcidol Abaloparatide agents approved in Europe, the Calcidiol Teriparatide (including biosimilars) USA and member countries represented by the authors Calcitriol Romosozumab Bisphosphonates Alendronate (including effervescent formulation) Clodronate Uncertain action Neridronate Strontium ranelate Risedronate (including gastric resistant formulation) Ibandronate Zoledronate MHT and SERMs Oestrogen only MHT Opposed MHT (with progestogen) Tibolone Bazedoxifene Raloxifene Other Vitamin K Calcitonin Denosumab MHT, menopause hormonal treatment; SERMs, selective oestrogen receptor modulator Osteoporos Int (2020) 31:1–12 9 Table 7 Number of postmenopausal women by age in a simulation cohort of 50,633 women from the UK [51] and the proportion (%) characterised at low, high and very high risk. The high risk category includes women with a prior fracture not characterised at very high risk Age (years) 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85+ Total Number 8799 8384 8552 6671 5792 4784 3807 3844 50,633 Low risk (%) 73.0 70.1 67.1 65.1 61.4 58.0 54.8 52.0 64.8 High risk (%) 13.4 15.9 17.0 19.1 22.2 24.7 28.2 31.1 19.7 Very high risk (%) 13.7 14.0 16.0 16.0 16.3 17.3 17.1 16.9 15.6 Open Access This article is licensed under a Creative Commons 9. Johansson H, Siggeirsdóttir K, Harvey NC, Odén A, Gudnason V, Attribution-NonCommercial 4.0 International License, which permits McCloskey E, Sigurdsson G, Kanis JA (2017) Imminent risk of any non-commercial use, sharing, adaptation, distribution and fracture after fracture. Osteoporos Int 28:775–780 reproduction in any medium or format, as long as you give appropriate 10. 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Zakraoui 25 & J. -Y. Reginster 12,26 1 8 Centre for Metabolic Bone Diseases, University of Sheffield Medical Region Västra Götaland, Geriatric Medicine Clinic, Sahlgrenska School, Beech Hill Road, S10 2RX Sheffield, UK University Hospital, Gothenburg, Sweden 2 9 Mary McKillop Health Institute, Australian Catholic University, NIHR Musculoskeletal Biomedical Research Unit, University of Melbourne, Australia Oxford, Oxford, UK 3 10 MRC Lifecourse Epidemiology Unit, University of Southampton, Service of Bone Diseases, Geneva University Hospitals and Faculty Southampton, UK of Medicine, Geneva, Switzerland 4 11 MRC and Arthritis Research UK Centre for Integrated Research in Syrian National Osteoporosis Society, Damascus, Syria Musculoskeletal Ageing Mellanby, Sheffield, UK 12 Chair for Biomarkers of Chronic Diseases, Biochemistry Dept., 5 World Health Organization Collaborating Center for the Public College of Science, King Saud University, Riyadh, Kingdom of Health Aspects of Musculoskeletal Health and Aging, Department of Saudi Arabia Public Health, Epidemiology and Health Economics, University of 13 Clinica Universidad de los Andes and Faculty of Medicine, Liège, Liège, Belgium Universidad de los Andes, Santiago, Chile 6 National Research Council, Neuroscience Institute, Aging Branch, 14 Osteoporosis and Bone Metabolism Unit, Department of Via Giustiniani, 2, 35128 Padova, Italy Endocrinology, Singapore General Hospital, ACADEMIA, 20, 7 Geriatric Medicine, Department of Internal Medicine and Clinical College Road, Singapore 169856, Singapore Nutrition, Institute of Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 12 Osteoporos Int (2020) 31:1–12 15 22 Jean Mayer USDA Human Nutrition Research Center on Aging at GREMPAL Research Group, CIBERFes and Idiap Jordi Gol, Tufts University, Boston, MA, USA Instituto de Salud Carlos III and Universitat Autonoma de 16 Barcelona, Barcelona, Spain Chair of the Committee of Patients Societies at the International 23 Osteoporosis Foundation, Osteoporosis Canada, Toronto, Canada University of Alabama at Birmingham, Birmingham, AL, USA 17 24 Beacon International Specialist Centre, Petaling Jaya, Malaysia Department of Endocrinology, Key Laboratory of Endocrinology, 18 Ministry of Health, Peking Union Medical College Hospital, IRO Medical Research Center, Buenos Aires and Rheumatology Chinese Academy of Medical Sciences & Peking Union Medical section, Cosme Argerich, Buenos Aires, Argentina College, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, 19 Department of Rheumatology, Ibn Rochd University Hospital, Beijing 100730, China Casablanca, Morocco 25 Service de Rhumatologie, University Tunis Manar and Hôpital 20 Department of Physical Therapy, Marquette University, Mongi-Slim, la Marsa, Tunisia Milwaukee, WI, USA 26 Department of Public Health, Epidemiology and Health Economics, 21 Department of Medical Social Sciences, Feinberg School of University of Liège, Liège, Belgium Medicine, Northwestern University, Chicago, IL, USA