Osteoporosis International (2020) 31:1535–1544 https://doi.org/10.1007/s00198-020-05358-4 ORIGINAL ARTICLE Secular trends in the initiation of therapy in secondary fracture prevention in Europe: a multi-national cohort study including data from Denmark, Catalonia, and the United Kingdom M. K. Skjødt 1,2,3 & S. Khalid 4 & M. Ernst 3,5 & K. H. Rubin 3 & D. Martinez-Laguna 6,7,8 & A. Delmestri 4 & M. K. Javaid 4 & C. Cooper 4,9 & C. Libanati 10 & E. Toth 10 & B. Abrahamsen 1,3,4 & D. Prieto-Alhambra 4 Received: 27 November 2019 / Accepted: 18 February 2020 / Published online: 17 March 2020 # The Author(s) 2020 Abstract Summary This paper demonstrates a large post-fracture anti-osteoporosis treatment gap in the period 2005 to 2015. The gap was stable in Denmark at around 88–90%, increased in Catalonia from 80 to 88%, and started to increase in the UK towards the end of our study. Improved post-fracture care is needed. Introduction Patients experiencing a fragility fracture are at high risk of subsequent fractures, particularly within the first 2 years after the fracture. Previous studies have demonstrated that only a small proportion of fracture patients initiate therapy with an anti- osteoporotic medication (AOM), despite the proven fracture risk reduction of such therapies. The aim of this paper is to evaluate the changes in this post-fracture treatment gap across three different countries from 2005 to 2015. Methods This analysis, which is part of a multinational cohort study, included men and women, aged 50 years or older, sustaining a first incident fragility fracture. Using routinely collected patient data from three administrative health databases covering Catalonia, Denmark, and the United Kingdom, we estimated the treatment gap as the proportion of patients not treated with AOM within 1 year of their first incident fracture. Results A total of 648,369 fracture patients were included. Mean age 70.2–78.9 years; 22.2–31.7% were men. In Denmark, the treatment gap was stable at approximately 88–90% throughout the 2005 to 2015 time period. In Catalonia, the treatment gap increased from 80 to 88%. In the UK, an initially decreasing treatment gap—though never smaller than 63%—was replaced by an increasing gap towards the end of our study. The gap was more pronounced in men than in women. Conclusion Despite repeated calls for improved secondary fracture prevention, an unacceptably large treatment gap remains, with time trends indicating that the problem may be getting worse in recent years. Keywords Fracture prevention . Health Services Research M. K. Skjødt and S. Khalid are joint first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00198-020-05358-4) contains supplementary material, which is available to authorized users. * B. Abrahamsen 5 Department of Public Health, Clinical Pharmacology and Pharmacy, b.abrahamsen@physician.dk University of Southern Denmark, Odense, Denmark 6 GREMPAL Research Group, Fundació Institut Universitari per a la 1 Department of Medicine, Hospital of Holbaek, Holbaek, Region recerca a l’Atenció Primària de Salut Jordi Gol i Gurina Zealand, Denmark (IDIAPJGol), CIBERFES, Barcelona, Spain 7 2 Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Department of Medicine, Hospital of Slagelse, Slagelse, Region Vallès), Spain Zealand, Denmark 8 Atenció Primària Barcelona Ciutat, Institut Català de la Salut, 3 Barcelona, Spain OPEN, Open Patient data Explorative Network, Odense University Hospital, Odense, Denmark 9 MRC Lifecourse Epidemiology Unit, University of Southampton, 4 Southampton General Hospital, Southampton, England Nuffield Orthopaedic Centre, Oxford University Hospitals, 10 Oxford, England UCB Pharma, Anderlecht, Belgium 1536 Osteoporos Int (2020) 31:1535–1544 Introduction prevention in Denmark, the UK, and Catalonia from 2005 (2007 for the latter) to 2015. Osteoporosis is defined by microarchitectural changes of the bone and reduced bone mass, causing an increased bone fra- gility and an increased risk of fractures. Low-energy fragility Methods fractures are the clinical consequence of osteoporosis. In 2010, 27.6 million women and men in the European Union This analysis forms part of the Multinational Observational were estimated to have osteoporosis, equivalent to a preva- Database Study on Imminent Osteoporotic Fracture Risk lence of 5.5% of the population. In the same year, a total of 3.5 (the IFRISK study), an observational cohort study evaluating million fragility fractures were sustained. Of these, 600,000 patient characteristics and 1- and 2-year fracture rates in pa- were hip fractures, 500,000 were clinical vertebral fractures, tients at high risk of osteoporotic fractures. This ongoing study 600,000 were forearm fractures, and 1.8 million fractures were uses routinely collected health data obtained from three categorized as “other” [1]. European administrative health databases. The present work The presence of fragility fractures, irrespective of fracture is a cohort analysis of patients with a first incident osteoporot- location, has been demonstrated to be indicative of a doubling ic fracture in order to examine the changes in the anti- of the risk of a subsequent fracture [2, 3]. Depending on the osteoporosis treatment gap in the three countries from 2005 location of this initial fracture, a relative risk of subsequent to 2015. The osteoporosis treatment gap is defined as the fractures of 1.4 to 19.0 as compared with those without frac- proportion of patients not treated with AOM within 1 year tures has been demonstrated in prior studies [2]. The risk of following their index fracture. subsequent fractures is highest in the first 2 years after a frac- ture, then decreasing over time [4]. Therapy with anti- Population osteoporosis medications (AOM) is effective in preventing subsequent fragility fractures. Accordingly, three Cochrane Eligible patients were men and women, aged 50 years or reviews have confirmed the effectiveness of oral older, with a first incident (= index) fracture at any site except bisphosphonates in secondary prevention of osteoporotic frac- face, skull, and digits, as fractures at these sites are generally tures in general [5–7]. In addition, clinical trials in patients considered non-osteoporotic. If within the 6 months prior to with an osteoporotic fracture have demonstrated the signifi- the incident fracture, a fracture had been coded at the same cant risk reduction of subsequent fractures with other AOM, anatomical site as the incident fracture, the incident fracture including zoledronic acid, denosumab, teriparatide, raloxi- would be considered a repeat admission for the original frac- fene, and strontium ranelate [8–13]. In line with these find- ture rather than a first fracture. Patients had to be registered in ings, national and international guidelines recommend either one of the national health registries at least 1 year prior to their assessment of osteoporosis or initiation of pharmacological index fracture. We pre-specified exclusion of patients with secondary fracture prevention—depending on guideline and Paget’s disease, a history of breast or prostate cancer, or a fracture location—in patients who sustain a fragility fracture, history of bone metastasis. Additionally, CPRD and SIDIAP unless exceptional circumstances exist [14–18]. general practices with a lack of linkage to hospital admissions/ Despite such evidence-based recommendations, a signifi- records were excluded to maximize the quality and complete- cant post-fracture treatment gap is known to prevail across ness of the analytical dataset. healthcare systems and settings [19–28]. Several publications report that in some countries as few as 10–20% of patients Data sources with fragility fractures go on to receive AOM [23–27], with this gap being more pronounced in men as well as in the We extracted patient-level data on the index fracture along elderly [20, 26, 29]. Despite the attention given to the impor- with baseline demographic, clinical, socioeconomic, and med- tance of closing the treatment gap, long-term time trends seem ication information from the following registries: to indicate that the gap has even been increasing in recent years [25, 26]. & Clinical Practice Research Datalink (CPRD) GOLD, Because the treatment gap is strongly affected by changing which comprises data from primary care linked to hospital healthcare resources and medical practices, comparative and and outpatient data (secondary care), including data on longitudinal time series analyses are needed to monitor sec- demography and medication, from over 7 million patients ondary fracture prevention and to understand how structural in the UK. healthcare changes may affect this. However, few analyses are & Sistema d’Informació per al Desenvolupament de la long-term, and most often they present only a national per- Investigació en Atenció Primària (SIDIAP), which repre- spective. The aim of this paper is to evaluate the changes in the sents more than 6 million people in Catalonia (Spain) and anti-osteoporosis treatment gap in secondary fracture is based on primary care records linked to pharmacy Osteoporos Int (2020) 31:1535–1544 1537 dispensations and hospital inpatient data. Data from Data was censored at the first occurrence after the index SIDIAP is available from 1st January 2006, a date consid- date of either an additional osteoporotic fracture, death or ered of standard and established use of electronic medical migration, or 1 year after the date of the index fracture. All records in Catalonia. analyses were stratified according to fracture location and year & Danish Health Registries (DHR), including the National of fracture. In an additional analysis, we further stratified the Prescriptions Database (which contains data on all filled data according to gender. In the presentation of the data, we prescriptions since 1995), the National Patient Registry pooled the data into 4 distinct time periods for smoothening (which contains diagnosis codes and treatments for all (2005–07, 2008–10, 2011–13, and 2014–15, respectively). patients since 1977 for hospitals and since 1995 for out- patient clinics), and the National Cause of Death register (which includes date and cause(s) of death). These regis- Results ters cover the entire Danish population until death or emigration. A total of 1,282,991 patients were eligible for the study. After the pre-specified exclusion of patients less than 50 years old at the time of the index fracture (n = 602,167), those with an Study period index date after 31st December 2015 (n = 7862), those with a history of Paget’s disease (n = 358), breast or prostate cancer Baseline was defined as the date of the index fracture. The (n = 23,668), and/or bone metastasis (n = 691),1 a total of baseline period (i.e. the lookback or “window” period) to 648,369 fracture patients were included in this study. Of these, identify baseline demographic, clinical, and socioeconomic 83,514 were recorded in CPRD (UK), 55,304 in SIDIAP characteristics was defined as the 12 months leading up to (Catalonia), and 509,551 in DHR (Denmark). Table 1 shows the index fracture. The exception was medical history (cancer, the baseline characteristics of each of these sub-cohorts. At cardiovascular disease, diabetes, arthritis, liver disease, de- baseline, the groups differed significantly on several charac- mentia, neurological conditions, asthma or chronic obstructive teristics. Notably, the participants from the UK were older pulmonary disease, chronic kidney disease, endocrine disease, (mean age 78.9 years), one in five was male, and more had a and malabsorption), for which no limitations in the length of history of cancer (8.9%) or chronic kidney disease (11.9%). In the lookback period was applied. comparison, the Danish cohort were younger (mean age Follow-up data included treatment with AOM within 1 year 70.8 years), one in three was male, and they had the lowest of the index fracture, defined as any use of bisphosphonates, Charlson Comorbidity Index (CCI) score (86.4% had a CCI of teriparatide, denosumab, strontium ranelate, or raloxifene. For 0). The Catalan cohort were relatively comparable with the SIDIAP and DHR, treatment was characterized by pharmacy Danish, yet had the highest CCI score (> 26% had a CCI of dispensation of AOM, while for the CPRD, it was character- 2 or more), also exceeding that of the UK population. ized by AOM prescription. These differences were due to the Interestingly, the number of participants on steroids in the past content of the data sources. Data was collected for patients year was comparable between the three countries, irrespective with an index fracture between 2005 (2007 for SIDIAP) and of the differences in age and CCI score. Prevalent use of anti- 2015. osteoporosis medication at baseline was highest in Catalonia The study protocol was approved by the ISAC ethics com- (10.3%) followed by the UK (9.2%), while the use in mittee for use of CPRD data, by the SIDIAP Scientific and Denmark was substantially lower (4.8%). Ethics Committee, and for the use of the Danish Health Registries by the Danish Medicines Agency, the Danish Treatment gap: general trend Data Protection Agency, and Statistics Denmark. Figure 1 shows the treatment gap across all fracture loca- Statistical analysis tions for the UK, Catalonia, and Denmark from 2005 to 2015 (Catalonia from 2007). The treatment gap was largest The three databases were curated using a bespoke (protocol- in Denmark, and remained stable over the study period at based) common data model and code lists. A single script 88–90%. In comparison, the treatment gap was lowest in (written in R version 3.3.2) was used for the analysis, which the UK at the starting point in 2005–07 and demonstrated a was run independently on each database. For each database, decreasing trend during the two subsequent time periods. we summarized the baseline characteristics (both demograph- In 2011–13, 37% of all patients aged 50 years or older and ic and clinical) descriptively. Continuous variables were sum- presenting with a first fracture were treated with anti- marized using mean and standard deviation, while categorical osteoporosis medication within 1 year (i.e. a treatment variables were summarized by the number and/or proportion 1 of participants. Please note that groups are not mutually exclusive 1538 Osteoporos Int (2020) 31:1535–1544 Table 1 Baseline characteristics CPRD SIDIAP DHR N 83,514 55,304 509,551 Age, years (mean (SD)) 78.9 (11.2) 70.2 (13.7) 70.8 (12.4) Sex, male (%) 22.2 31.7 30.9 BMI; kg/m2 (mean (SD)) 25.0 (5.5) 28.9 (5.2) N/A Medical history (%) Cancer 8.9 5.9 7.0 COPD 5.8 5.9 5.3 IHD 2.8 N/A 4.2 CKD 11.9 7.3 1.2 Charlson comorbidity index (%) 0 59.2 48.5 86.4 1 18.1 24.9 7.9 2 10.8 13.3 3.6 3 6.4 6.8 1.1 ≥4 5.5 6.5 1.1 Steroid use in previous year* (%) 7.8 8.2 8.3 PPI use in previous year (%) 23.0 48.9 14.5 Anti-osteoporosis medication in previous year† (%) 9.2 10.3 4.8 BMI body mass index, CKD chronic kidney disease, COPD chronic obstructive pulmonary disease, IHD ischaemic heart disease, N/A not available, PPI proton pump inhibitor * Steroid use is defined as filled prescriptions of a glucocorticoid at a total dose equivalent to ≥ 450 mg prednisolone during the baseline period † Anti-osteoporosis medication includes bisphosphonates, teriparatide, denosumab, raloxifene, and strontium ranelate and for SIDIAP also bazedoxifene gap of 63%). In the last time period (2014–15), the treat- the 2008–10 time period and until the end of this study, at ment gap in the UK increased again but still remained which point it was around 88%. Overall, within each coun- lower than that seen in 2005–07. In Catalonia, the treat- try, the trends for individual fracture sites were similar to ment gap was at 80% in 2007 and has been increasing since those seen for all fractures. Details regarding the treatment Fig. 1 The treatment gap for all fractures across the United Kingdom, Catalonia and Denmark. The treatment gap is given as the proportion of patients not treated with AOM within 1 year following their index fracture Osteoporos Int (2020) 31:1535–1544 1539 gaps can be found in Figs. 1, 2, 3, 4, and 5 and supplemen- Treatment gap: gender discrepancies tary Tables 1, 2, 3. Figure 5 demonstrates the treatment gap across the three da- The United Kingdom tabases stratified according to gender for all, hip, and spine fractures, respectively. Across the UK, Catalonia, and Figure 2 shows the treatment gap in the UK from 2005–07 to Denmark, a similar trend of a larger treatment gap in men than 2014–15, stratified according to fracture location. As de- in women was observed, irrespective of fracture location. The scribed above, the treatment gap diminished from 2005–07 trend for non hip, non spine fractures and wrist fractures was to 2011–13 then started to increase again. As is seen in similar (data on file). We did not observe any consistent Fig. 2, this was a general tendency across fracture locations. changes in the gender difference over the years. Secondary prevention among hip fracture patients was better than average throughout the study period. Discussion Catalonia This analysis shows the presence of very significant treatment As demonstrated in Fig. 3, the treatment gap in Catalonia gaps in the secondary fracture prevention across three increased from the 2008–10 time period and throughout the European countries but with some differences between the study across all fracture locations. Like in the UK, the second- countries. In the UK, the treatment gap was 63–73% during ary prevention among hip fracture patients was marginally the study period; in Catalonia, it was 80–88%; and in better than average. Interestingly, secondary prevention Denmark, it was stable at 88–90%. Although the UK exhibit- among patients with spine fractures was remarkably better, ed a narrowing treatment gap in the first years of our analysis, yet the treatment gap still increased over time. as well as an overall reduction in the treatment gap from 2005 to 2015, a trend towards an increase is noted towards the end Denmark of the study period. In Denmark, the gap was large and stable during the analysis, and in Catalonia, the treatment gap The treatment gap in Denmark was stable throughout the showed an increasing overall trend since the 2008–10 time study period, as is seen in Fig. 4. This was remarkably similar period. Across the three countries, the treatment gap was con- across fracture locations, with only minor deviations across sistently larger in men than in women. the time periods. As in Catalonia, the treatment gap among The results of our analysis are in line with other studies on hip fracture patients was smaller than average yet even smaller secondary fracture prevention, which have demonstrated sig- for spine fracture patients. The treatment gap among patients nificant treatment gaps across healthcare systems and settings with spine fractures demonstrated an increasing trend towards [19–26, 28, 30]. While many such studies are based in North the end of this study. America [19–22, 25, 26, 28], our study along with several Fig. 2 The treatment gap in the United Kingdom stratified according to fracture location (all, hip, spine, non hip non spine, and wrist fractures, respectively) and time period 1540 Osteoporos Int (2020) 31:1535–1544 Fig. 3 The treatment gap in Catalonia stratified according to fracture location (all, hip, spine, non hip non spine, and wrist fractures, respectively) and time period others demonstrate that the treatment gap seems to be a uni- th at a g en era l tr en d to w ar ds a d ec lin ing us e o f versal problem [23, 24, 30], also pertaining to European bisphosphonates, which has coincided with reports of rare or healthcare systems with a high level of access. Previous lon- very rare adverse events as demonstrated by Jha et al. (2015), gitudinal studies have demonstrated an increasing treatment may contribute to the increasing treatment gap and hence gap over time [25, 26], and while our study provides more wash out some of the effect of initiatives to improve secondary recent data with significant differences between the UK, fracture prevention [31, 32]. This trend was observed despite Catalonia, and Denmark, the overall impression is that the the fact that the absolute risk of such deleterious adverse gap is stable or increasing in recent years. Hence, despite events, notably atypical femur fractures, and osteonecrosis repeated calls for improved secondary fracture prevention on of the jaw, is very low [32, 33]. Further, the International an international scale and improved availability of AOM— Osteoporosis Foundations Capture the Fracture programme including the emergence of new osteoporosis drugs with was launched in 2012, coinciding with the smallest treatment new characteristics that could widen patient acceptance of gap in the UK in our analysis (during the 2011–13 time peri- AOM as well as the availability of generic AOM—we have od), yet it is unlikely that our data reflects the full impact of a yet to see signs that this is improving. It deserves mentioning programme that has been expanding significantly since then. Fig. 4 The treatment gap in Denmark stratified according to fracture location (all, hip, spine, non hip non spine, and wrist fractures, respectively) and time period Osteoporos Int (2020) 31:1535–1544 1541 Fig. 5 The treatment gap in the United Kingdom (a), Catalonia (b), and Denmark (c), stratified according to time period, gender, and fracture location (all, hip, and spine, respectively) Our analysis demonstrated significant differences in sec- yet all the countries in this study sustain a government- ondary fracture prevention between the geographic areas cov- funded national healthcare system (although in Catalonia, ered, with the UK achieving a substantially smaller treatment co-payment policies was implemented in 2011, yet this does gap than Catalonia and, in particular, Denmark. As this study not seem to further fuel the increasing treatment gap), and, is based on administrative health databases, these differences further, the Danish population did not appear to be significant- may be reflective of underlying differences in data generation. ly more impaired than the Catalan or UK populations, yet still Hence, in Denmark and Catalonia, patients are counted as on- demonstrated the poorest secondary fracture prevention. treatment if they fill their prescriptions for AOM at the phar- Another reason for the differences between the countries macy, while in the UK, the patients are counted as on- may be differences in national osteoporosis guidelines. treatment if they are prescribed an AOM. Patients with prima- While guidelines today seem to agree on the relevance of ry non-adherence would thus be counted in the CPRD as on AOM therapy in patients with fragility fractures, as most re- treatment, while they would count as untreated in Denmark cently evidenced by the ASBMR clinical recommendations and Catalonia. This may cause an overestimation of the true (Conley et al., 2020) focusing on hip and vertebral fractures adherence to osteoporosis guidelines in the UK. For compar- in patients aged 65 years or older [14, 15, 18, 33], UK guide- ison, a primary non-adherence rate of 20% has been calculated lines have historically been less reliant on DXA-scans for the in SIDIAP, which beyond pharmacy dispensation data also diagnosis of osteoporosis and thus for AOM treatment initia- holds prescription data like in the UK. Also, while the DHR tion than Danish or Spanish guidelines. This may have facil- is based on hospital data, CPRD and SIDIAP are based on itated a smaller treatment gap in the UK in the early years of primary care records linked to secondary care. This may ex- this analysis yet does not explain why the treatment gap per- plain some of the baseline differences, as primary care records sists in Denmark and Catalonia in recent years and increases generally tend to be more granular with regards to medical towards the end of this study in the UK. We are not aware of history as compared with secondary care records. Further, evidence of diminishing use of DXA-scans in these countries, we predefined exclusion of patients with a lack of linkage to as has been demonstrated in the USA (coinciding with re- secondary care records, which has been suggested to account duced reimbursement) [34]. for 40% of CPRD practices and 70% of SIDIAP practices. Finally, differences in the healthcare system may affect the This exclusion carries the risk of skewing the study population size of the treatment gap, in particular the implementation of and may add to the differences in the treatment gap observed care models for secondary prevention of fragility fractures. In between the UK, Catalonia, and Denmark. a literature review, Ganda et al. (2013) demonstrated that frac- However, despite such potentially influencing factors, we ture liaison services (FLS) are associated with significant im- believe that the national differences are, at least in part, indic- provements in BMD testing and treatment initiation in patients ative of more profound differences in secondary fracture pre- who have sustained a fragility fracture [35]. They found that vention. These could reflect differences in access to care, increasing intensity of the FLS intervention was associated 1542 Osteoporos Int (2020) 31:1535–1544 with greater effectiveness of the FLS and that the FLS is cost- Our study has a number of strengths including the large effective in daily clinical practice [35]. The UK began number of patients and fractures evaluated, the robustness of implementing FLS services systematically a decade ago. the methodology, and the use of validated databases. More recently, an FLS database for England and Wales was In conclusion, this study provides long-term, comparative established under the auspices of the Royal College of data regarding the treatment gap after an incident osteoporotic Physicians, and this has captured data in real time since fracture among patients from the UK, Catalonia, and January 2016. It has been reported that in 2017, 43% of all Denmark. We have demonstrated that despite repeated calls fragility fractures were submitted to an FLS service [36]. Of for improved pharmacological secondary prevention, an un- these, 70% were assessed within 90 days of their fracture, and acceptably large treatment gap still exist, more pronounced in 43% were recommended AOM treatment initiation [36]. men than in women. Differences in the treatment gap are Catalonia now has a relatively high number of accredited evident across the countries evaluated in our analysis, possibly FLS services according to the IOF “Capture the Fracture” arguing in favour of the effectiveness of structural healthcare Map of Best Practice (www.capturethefracture.org) yet is still interventions. Regardless, our study highlights that additional less comprehensively covered than the UK. Despite these re- efforts to reduce the treatment gap are highly and urgently ports being more recent than the study period covered in this needed. paper, they point towards a higher level of attention towards secondary fracture prevention in Catalonia and, particularly, Funding information UCB funded this study. All analyses were conduct- ed independently by the academic researchers involved. MKJ is support- the UK. By contrast, fracture liaison services had not been ed by the National Institute for Health Research (NIHR) Oxford systematically implemented in Denmark within the study pe- Biomedical Research Centre (BRC). riod, and only three Danish hospitals now run an IOF “Capture the Fracture” accredited programme. This failure to Compliance with ethical standards provide follow-up services for fracture patients may contrib- ute to the differences in the treatment gap observed between The study protocol was approved by the ISAC ethics committee for use of the three countries in this analysis. CPRD data, by the SIDIAP Scientific and Ethics Committee, and for the use of the Danish Health Registries by the Danish Medicines Agency, the An important aspect that needs to be kept in mind is that a Danish Data Protection Agency and Statistics Denmark. 100% treatment rate would not necessarily be indicative of For this type of study, formal consent is not required. good clinical practice. Contraindications to the medications certainly exist and the benefit from treatment depends on life Conflicts of interest MKS has institutional research contract with UCB and expectancy and the risk of side effects. In addition, patient educational grant from UCB. SK has nothing to disclose. ME has institutional research contract with UCB. KHR has nothing to disclose. DML received preferences may also limit the number of patients that can be personal fees from Amgen, Eli Lilly, Novartis, Ferrer, and Rubió. AD reports initiated on pharmacological therapy. To this end, the Royal grants from UCB during the conduct of the study. MKJ received honoraria, College of Physicians introduced an FLS key performance unrestricted research grants, and travel and/or subsistence expenses from indicator where 50% of patients should be initiated on phar- Amgen and UCB. CC received personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, macological therapy [36]. This could be too low a target and Roche, Servier, Takeda, and UCB. CL and ET are employees of UCB benchmarking from secondary prevention in myocardial in- Pharma. BA has institutional research contracts with Novartis and UCB with farction; Leslie et al. (2012) argued that a pharmacological funds paid to the institution and received speaker fees from Amgen and intervention target of 80% of patients with hip or spine frac- personal consultancy fees from UCB and Kyowa-Kirin UK. DPA received institutional research grants from UCB and Amgen, grant from Les tures may in fact be more reasonable [37]. Irrespectively, the Laboratoires Servier, educational grants from Johnson & Johnson, and speak- treatment gaps across the countries evaluated in this analysis er and consultancy fees paid to his department by Amgen and UCB. Janssen, are too large and require prompt addressing. on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse A limitation relevant to CPRD and SIDIAP is that we only Management Partners have supported training programmes organized by DPA’s department and open for external participants. capture those patients registered in the database and linked to hospital records. Both databases have been validated as rep- Open Access This article is licensed under a Creative Commons resentative of the national/regional population, yet, as signif- Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and icant proportions of the patients in CPRD and SIDIAP were reproduction in any medium or format, as long as you give appropriate excluded due to a lack of linkage to hospital records, there is a credit to the original author(s) and the source, provide a link to the risk that our results may not be representative of the general Creative Commons licence, and indicate if changes were made. The population. images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a Another limitation is that use of zoledronic acid and credit line to the material. If material is not included in the article's denosumab are not regularly reflected in CPRD for this time Creative Commons licence and your intended use is not permitted by period, while in Denmark hospital-administered zoledronic statutory regulation or exceeds the permitted use, you will need to acid is not reflected in the National Prescription Registry. obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. This may cause an underestimation of the treatment rate. Osteoporos Int (2020) 31:1535–1544 1543 References osteoporosis. Climacteric 18:805–812. https://doi.org/10.3109/ 13697137.2015.1045484 1. Hernlund E, Svedbom A, Ivergård M et al (2013) Osteoporosis in 14. Nielsen MF, Harsløf T, Kvist T, et al (2016) National the European Union: medical management, epidemiology and eco- Behandlingsvejledning: Osteoporose. 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