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Screening for women with increased risk of fragility fractures in a general female population using digital X-ray radiogrammetry (DXR)

Open AccessPublished:November 06, 2020DOI:https://doi.org/10.1016/j.maturitas.2020.10.019

      Highlights

      • Digital X-ray radiogrammetry (DXR) is a simple, accessible method for bone mass evaluation.
      • 14,841 women underwent DXR when attending mammography screening.
      • DXR-derived bone mass correlated with fracture risk.

      Abstract

      Objective

      To evaluate the predictive ability of digital X-ray radiogrammetry (DXR) for fracture in women attending general mammography screening.

      Study design

      In a nested case-control study, women aged between 40 and 75 years, who attended the regional mammography screening program, had their bone mass assessed with DXR and provided information regarding clinical risk factors for osteoporosis. Follow-up was done through cross-referencing with National Patient Registers. Associations between DXR, clinical risk factors and fracture risk were examined. Receiver operating characteristics curves for DXR T-score and different fracture types were plotted, and their respective AUC calculated.

      Main outcome measures

      Fractures (hip, major osteoporotic and any clinical facture). Fracture diagnoses were retrieved from National Patient Registers.

      Results

      14,841 women had their bone mass examined in conjunction with mammography. Of these women, 10,967 returned fully completed questionnaires regarding clinical risk factors. In total 605 fractures (including 355 major osteoporotic fractures and 18 hip fractures) occurred during the follow-up period (median follow-up time was 3.3 years). Women with fractures were older and had lower DXR T-score compared with those without. DXR T-score correlated with fracture risk. HR/SD T-score decrease was 2.15 (CI 1.55–3.00) for hip, 1.47 (CI 1.36–1.59) for major osteoporotic and 1.33 (CI 1.26–1.42) for any clinical fracture. The AUCs for the different fracture types were 0.79 (hip), 0.69 (major osteoporotic) and 0.65 (any clinical).

      Conclusions

      DXR T-score is negatively correlated with risk of fracture in a general female population. This indicates a potential use of DXR in population-based screening for osteoporosis.

      Abbreviations:

      DXR (Digital X-ray radiogrammetry), DXA (Dual-energy X-ray absorptiometry), BMD (Bone mineral density), MOF (major osteoporotic fracture), HR (Hazard ratio), SD (Standard deviation), ROC (Receiver operating characteristic), AUC (Area under curve)

      Keywords

      1. Introduction

      Fractures after low energy trauma (fragility fractures) account for substantial morbidity, increased mortality and health care cost. Osteoporosis affects a large portion of the population, increases with age and is thus projected to rise as the average lifespan gets longer. Since osteoporosis is asymptomatic until the patient presents with a fracture, it mostly goes undetected and untreated. Interventions ranging from pharmaceuticals, physiotherapy and lifestyle adjustments have been developed to reduce the risk of fractures [
      • Compston J.E.
      • McClung M.R.
      • Leslie W.D.
      Osteoporosis.
      ]. However, in order to maximize their potential, they should be initiated early, before fractures occur. This suggests a need for early identification of individuals at risk.
      Several clinical risk factors for osteoporosis and fracture risk have been identified. Various risk assessment tools have been developed and investigated. The Fracture Risk Assessment Tool (FRAX) is the most prevalent and can be used with or without bone mineral density (BMD) measurements [
      • Kanis J.A.
      • Johansson H.
      • Harvey N.C.
      • McCloskey E.V.
      A brief history of FRAX.
      ]. When used in combination with BMD measurements the predictability of FRAX increases.
      Dual-energy X-ray absorptiometry (DXA) is considered the gold standard for diagnosis and follow-up of osteoporosis [
      • Compston J.E.
      • McClung M.R.
      • Leslie W.D.
      Osteoporosis.
      ]. DXA, however, has limitations regarding reproducibility, operator dependence and cost as well as accessibility in terms of geographical reach [
      • Curtis J.R.
      • Laster A.
      • Becker D.J.
      • Carbone L.
      • Gary L.C.
      • Kilgore M.L.
      • Matthews R.S.
      • Morrisey M.A.
      • Saag K.G.
      • Tanner S.B.
      • Delzell E.
      The geographic availability and associated utilization of dual-energy X-ray absorptiometry (DXA) testing among older persons in the United States.
      ]. Thus, more accessible and cheaper methods are needed. Some methods such as quantitative ultrasound have been developed and opportunistic detection through e.g. standard abdominal and thoracic computed tomography have been investigated in an attempt to increase diagnostic availability [
      • Dhainaut A.
      • Hoff M.
      • Syversen U.
      • Haugeberg G.
      Technologies for assessment of bone reflecting bone strength and bone mineral density in elderly women: an update.
      ,
      • Jang S.
      • Graffy P.M.
      • Ziemlewicz T.J.
      • Lee S.J.
      • Summers R.M.
      • Pickhardt P.J.
      Opportunistic osteoporosis screening at routine abdominal and thoracic CT: normative L1 trabecular attenuation values in more than 20 000 adults.
      ]. Digital X-ray radiogrammetry (DXR) uses an automated analysis of plain radiographs depicting metacarpals II-IV to assess bone mass [
      • Rosholm A.
      • Hyldstrup L.
      • Backsgaard L.
      • Grunkin M.
      • Thodberg H.H.
      Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing.
      ]. Earlier publications have described the method in detail and reference populations have been established [
      • Rosholm A.
      • Hyldstrup L.
      • Backsgaard L.
      • Grunkin M.
      • Thodberg H.H.
      Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing.
      ,
      • Hyldstrup L.
      • Nielsen S.P.
      Metacarpal index by digital X-ray radiogrammetry: normative reference values and comparison with dual X-ray absorptiometry.
      ,
      • Black D.M.
      • Palermo L.
      • Sorensen T.
      • Jorgensen J.T.
      • Lewis C.
      • Tylavsky F.
      • Wallace R.
      • Harris E.
      • Cummings S.R.
      A normative reference database study for Pronosco X-posure System.
      ]. Strengths of the method include low cost, high reproducibility, operator independence and short examination time [
      • Reed M.R.
      • Murray J.R.
      • Abdy S.E.
      • Francis R.M.
      • McCaskie A.W.
      The use of digital X-ray radiogrammetry and peripheral dual energy X-ray absorptiometry in patients attending fracture clinic after distal forearm fracture.
      ,
      • Elliot J.R.
      • Fenton A.J.
      • Young T.
      • Mansfield A.
      • Burton C.
      • Wilkinson T.J.
      The precision of digital X-ray radiogrammetry compared with DXA in subjects with normal bone density or osteoporosis.
      ]. DXR derived bone mineral density (DXR-BMD) is associated with DXA-BMD measurements with correlations ranging between 0.5−0.77 with central (hip and spine) DXA [
      • Rosholm A.
      • Hyldstrup L.
      • Backsgaard L.
      • Grunkin M.
      • Thodberg H.H.
      Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing.
      ,
      • Black D.M.
      • Palermo L.
      • Sorensen T.
      • Jorgensen J.T.
      • Lewis C.
      • Tylavsky F.
      • Wallace R.
      • Harris E.
      • Cummings S.R.
      A normative reference database study for Pronosco X-posure System.
      ,
      • Ward K.A.
      • Cotton J.
      • Adams J.E.
      A technical and clinical evaluation of digital X-ray radiogrammetry.
      ,
      • Dhainaut A.
      • Rohde G.E.
      • Syversen U.
      • Johnsen V.
      • Haugeberg G.
      The ability of hand digital X-ray radiogrammetry to identify middle-aged and elderly women with reduced bone density, as assessed by femoral neck dual-energy X-ray absorptiometry.
      ] and between 0.55−0.90 with peripheral (distal forearm) DXA [
      • Rosholm A.
      • Hyldstrup L.
      • Backsgaard L.
      • Grunkin M.
      • Thodberg H.H.
      Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing.
      ,
      • Black D.M.
      • Palermo L.
      • Sorensen T.
      • Jorgensen J.T.
      • Lewis C.
      • Tylavsky F.
      • Wallace R.
      • Harris E.
      • Cummings S.R.
      A normative reference database study for Pronosco X-posure System.
      ,
      • Ward K.A.
      • Cotton J.
      • Adams J.E.
      A technical and clinical evaluation of digital X-ray radiogrammetry.
      ,
      • Dhainaut A.
      • Rohde G.E.
      • Syversen U.
      • Johnsen V.
      • Haugeberg G.
      The ability of hand digital X-ray radiogrammetry to identify middle-aged and elderly women with reduced bone density, as assessed by femoral neck dual-energy X-ray absorptiometry.
      ]. DXR-BMD is also correlated with known risk factors for osteoporosis [
      • Wilczek M.L.
      • Nielsen C.
      • Kalvesten J.
      • Algulin J.
      • Brismar T.B.
      Mammography and osteoporosis screening--clinical risk factors and their association with digital X-ray radiogrammetry bone mineral density.
      ]. Previous studies have shown fracture predictability with DXR-BMD [
      • Bouxsein M.L.
      • Palermo L.
      • Yeung C.
      • Black D.M.
      Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures.
      ,
      • Kälvesten J.
      • Lui L.-Y.
      • Brismar T.
      • Cummings S.
      Digital X-ray radiogrammetry in the study of osteoporotic fractures: comparison to dual energy X-ray absorptiometry and FRAX.
      ]. In a retrospective study including 8257 individuals Wilczek et al. found DXR to be highly predictive of subsequent hip fracture (AUC 0.89 for women and 0.84 in men) [
      • Wilczek M.L.
      • Kalvesten J.
      • Algulin J.
      • Beiki O.
      • Brismar T.B.
      Digital X-ray radiogrammetry of hand or wrist radiographs can predict hip fracture risk--a study in 5,420 women and 2,837 men.
      ].
      Screening for osteoporosis has been examined as a method for early detection and different strategies have been suggested [
      • Merlijn T.
      • Swart K.M.A.
      • van der Horst H.E.
      • Netelenbos J.C.
      • Elders P.J.M.
      Fracture prevention by screening for high fracture risk: a systematic review and meta-analysis.
      ,
      • Shepstone L.
      • Lenaghan E.
      • Cooper C.
      • Clarke S.
      • Fong-Soe-Khioe R.
      • Fordham R.
      • Gittoes N.
      • Harvey I.
      • Harvey N.
      • Heawood A.
      • Holland R.
      • Howe A.
      • Kanis J.
      • Marshall T.
      • O’Neill T.
      • Peters T.
      • Redmond N.
      • Torgerson D.
      • Turner D.
      • McCloskey E.
      • Shepstone L.
      • Lenaghan E.
      • Cooper C.
      • Clarke S.
      • Fong-Soe-Khioe R.
      • Fordham R.
      • Gittoes N.
      • Harvey I.
      • Harvey N.
      • Heawood A.
      • Holland R.
      • Howe A.
      • Kanis J.
      • Marshall T.
      • O’Neill T.
      • Peters T.
      • Redmond N.
      • Torgerson D.
      • Turner D.
      • McCloskey E.
      • Crabtree N.
      • Duffy H.
      • Parle J.
      • Rashid F.
      • Stant K.
      • Taylor K.
      • Thomas C.
      • Knox E.
      • Tenneson C.
      • Williams H.
      • Adams D.
      • Bion V.
      • Blacklock J.
      • Dyer T.
      • Bratherton S.
      • Fidler M.
      • Knight K.
      • McGurk C.
      • Smith K.
      • Young S.
      • Collins K.
      • Cushnaghan J.
      • Arundel C.
      • Bell K.
      • Clark L.
      • Collins S.
      • Gardner S.
      • Mitchell N.
      Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial.
      ]. Current national recommendations vary [
      • Socialstyrelsen The National Board of Health and Welfare
      Nationella Riktlinjer För Rörelseorganens Sjukdomar 2012 National Guidelines for Muskuloskeletal Diseases 2012 - UPPDATERING 2014 (Update 2014).
      ,
      • Compston J.
      • Cooper A.
      • Cooper C.
      • Gittoes N.
      • Gregson C.
      • Harvey N.
      • Hope S.
      • Kanis J.A.
      • McCloskey E.V.
      • Poole K.E.S.
      • Reid D.M.
      • Selby P.
      • Thompson F.
      • Thurston A.
      • Vine N.
      G. The National Osteoporosis Guideline, UK clinical guideline for the prevention and treatment of osteoporosis.
      ,
      • Force U.S.P.S.T.
      Screening for osteoporosis to prevent fractures: US preventive services task force recommendation statement.
      ]. Several population-based screening programs for different diseases exist, but no country has yet implemented population-based screening for osteoporosis. The aim of this study was to assess the predictive performance of DXR with regard to fractures in a population of women called for regular mammography screening.

      2. Methods

      Between March 2010 and July 2012 women attending the general mammography screening program at a mammography-screening center (Unilabs AB, Tumba, Stockholm County, Sweden) were asked to participate in the study. Inclusion in the study was performed Monday and Wednesday every week. There were no exclusion criteria. Participation in the study was high (75.5%). Reasons for non-participation were inability to understand the study information (40%) and unwillingness to participate (60%). After informed consent had been given, patients filled out a form regarding clinical risk factors for low BMD and fracture risk (Appendix 1) and had a DXR examination of the non-dominant hand.
      Some women attended screening several times during the two-year inclusion period and thus had multiple DXR examinations. Only the first DXR examination was used for analysis. Fractures occurring prior to and after inclusion in the study were identified in the Swedish National Patient Register provided by the Swedish National Board of Health and Welfare. Data from the registers were retrieved in 2015 and included entries between 1990 and 2014. The 31th of December 2014 was used as censor date. Individuals who suffered fractures or died during the follow up were censored.
      For cross referencing, the Swedish personal identity number was used. Fractures were identified through ICD-10 codes (Appendix 2) and categorized into three groups (hip, major osteoporotic and any clinical fracture). Major osteoporotic fractures (MOF) included hip, spine, humerus and forearm fractures. All fractures except those in the skull, fingers and toes were classified as any clinical fracture. Individuals with hip fractures prior to DXR were excluded from hip fracture analyses to minimize the risk of false classification of hip fractures occurring before DXR as having occurred after DXR. Since a forearm fracture should not exclude an individual with a subsequent hip or spine fracture from analysis, women with MOF registered before DXR were not automatically excluded. However, women with MOF fractures diagnosed less than 6 months before DXR were excluded if the fracture type was the same as the subsequent MOF, e.g. forearm fracture <6 months before DXR and forearm fracture after DXR led to exclusion.
      To minimize the risk of erroneous registrations of hip fractures following DXR, only those coded for both diagnosis and adequate intervention (either upper femur fracture surgery or hip replacement, i.e. ICD-10 surgical codes NFJ and NFB) were included. In order not to exclude patients with a hip fracture who were too critically ill for surgery, patients who died within three days after a registered fracture were also included. The Swedish National Cause of Death Register provided date of death.
      16,424 DXR examinations of 14,841 women were made in conjunction with mammography during the study period. Out of the 14,841 women, 10,967 returned fully completed questionnaires regarding clinical risk factors. Thirty-seven women were excluded from hip fracture analyses due to hip fractures prior to DXR examination. Seven hundred forty-two individuals had a non-hip major osteoporotic fracture prior to DXR but were not excluded. The study population selection process is illustrated in Fig. 1.
      Fig. 1
      Fig. 1Flowchart illustration of the study population selection.
      This study had obtained approval from the local ethical board in Stockholm (2009/1820-31/2).

      2.1 Statistics

      Numbers and percentage (%) or mean and standard deviation (SD) of sample characteristics for each outcome (hip fracture, major osteoporotic fracture, and any clinical fracture) were presented. Median person-years of follow-up and incident rates for each outcome were calculated. Self-reported risk factors were analyzed independently. Alcohol consumption was categorized as zero, low (≤2 units and/or ≤2 times per week) and high consumption (≥3 units or ≥3 times per week).
      Cox proportional hazard models were used to assess the association of DXR and fractures (hip fracture, major osteoporotic fracture, and any clinical fracture), where the hazard ratios (HR) and 95% CI were calculated. We presented crude HR (model 1) and adjusted HR (model 2, 3, and 4) separately for each outcome. Model 2 was adjusted for age. Model 3 was adjusted for age, height, and weight. Model 4 was adjusted for the risk factors asked for in the questionnaire (Appendix II). Individuals with any missing data in their questionnaires were excluded in model 4. Proportional hazard assumptions were tested through Schoenfeld residuals tests.
      The outcomes are time-dependent therefore; we used cumulative sensitivity/dynamic specificity time-dependent receiver operating characteristic curves (ROCs) and area under curves (AUCs) to evaluate the predictive ability of DXR for each outcome [
      • Blanche P.
      • Dartigues J.-F.
      • Jacqmin-Gadda H.
      Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks.
      ]. The age-adjusted model (model 2) was used to plot ROC curves for DXR. Statistical analysis was performed using R 3.6.1 software (http://www.r-project.org). The R packages survival and time ROC were used.

      3. Results

      The observation time was 48,937 person years for the hip fracture group. The corresponding number for the major osteoporotic and any fracture groups was 48,478 and 48,011 person years respectively.
      In total 605 clinical fractures occurred during the observation time. Of these 344 were major osteoporotic fractures, of which 18 were hip fractures. The average age was 53 years (Table 1). Individuals with fractures were older, 56 years, and had lower DXR T-scores (Table 2).
      Table 1Characteristics of the participants in the STOP cohort.
      HipMOFClinical
      No fractureFractureNo fractureFractureNo fractureFracture
      AllnPercentnPercentAllnPercentnPercentAllnPercentnPercent
      Parental hip fracture012,71512,70199.89140.1112,74212,45797.762852.2412,74212,24096.065023.94
      11708170799.9410.061716166897.20482.801716162794.81895.186
      Smoking010,12910,12199.9280.0810,150994197.942092.0610,150977296.283783.724
      14556454899.8280.184572444097.111322.894572434895.12244.899
      Alcoholconsumption03747373899.7690.243752365297.331002.673752359895.91544.104
      Low17458745399.9350.077479732797.971522.037479719696.222833.784
      High23393339299.9710.033403331897.50852.503403324495.331594.672
      Rheumatic disease013,70313,68999.90140.1013,73713,42997.763082.2413,73713,19296.035453.967
      177677599.8710.1377975396.66263.3477973894.74415.263
      Diabetes (insulin treated)014,30314,28999.90140.1014,33914,01597.743242.2614,33913,76495.995754.01
      128228099.2920.7128226593.97176.0328226092.2227.801
      Stand without arms078778599.7520.2579676696.23303.7779675194.35455.653
      113,90113,88799.90140.1013,92913,61997.773102.2313,92913,37396.015563.992
      Fallen during last month013,12113,10899.90130.1013,15212,86597.822872.1813,15212,64296.125103.878
      11592158999.8130.191598154396.56553.441598150594.18935.82
      Right-handedness01237123599.8420.161238121498.06241.941238119396.37453.635
      113,42313,40999.90140.1013,45913,14397.653162.3513,45912,90795.95524.101
      Fracture due to low-energy trauma012,48612,47599.91110.0912,49112,22297.852692.1512,49112,02296.254693.755
      12199219499.7750.232231216096.82713.182231209994.081325.917
      Height loss >3 cm013,04513,03199.89140.1113,07212,78197.772912.2313,07212,54795.985254.016
      11064106399.9110.091073103696.55373.451073101894.87555.126
      Menopaus <45 years011,64611,63699.91100.0911,67111,41797.822542.1811,67111,21796.114543.89
      11860185499.6860.321870180896.68623.321870176694.441045.561
      Cortisone treatment013,49113,47799.90140.1013,52313,21797.743062.2613,52312,97895.975454.03
      11125112399.8220.181129109596.99343.011129107495.13554.872
      Hyperparathyroidism014,12614,11199.89150.1114,16013,83097.673302.3314,16013,58095.95804.096
      1261261100.0000.0026225898.4741.5326225396.5693.435
      Anorexia014,56314,54799.89160.1114,59914,25997.673402.3314,59914,00395.925964.082
      14242100.0000.004242100.0000.00424210000
      Malabsorption014,39114,37599.89160.1114,42514,08897.663372.3414,42513,83695.925894.083
      17474100.0000.00747398.6511.35747297.322.703
      Angina or myocardial infarction014,22514,21099.89150.1114,25913,93497.723252.2814,25913,68795.995724.012
      137237199.7310.2737436096.26143.7437435093.58246.417
      Other disease related to osteoporosis013,50313,49199.91120.0913,53313,22797.743062.2613,53312,98695.965474.042
      140540499.7510.2541240397.8292.1841239796.36153.641
      Hemiplegia014,48914,47399.89160.1114,52514,19297.713332.2914,52513,94095.975854.028
      17575100.0000.00757093.3356.67756789.33810.667
      Reduced mobility014,13614,12299.90140.1014,16213,84497.753182.2514,16213,596965663.997
      135635499.4420.5636735195.64164.3636734493.73236.267
      All14,80414,78699.88180.1214,84114,49797.683442.3214,84114,23695.926054.077
      0 = no; 1 = yes.
      Table 2Age and DXR T-score per fracture type.
      nAge at examSDT-scoreSD
      Hip
      No fracture14,78653.19.6−0.581.28
      Fracture1860.17.9−1.911.59
      MOF
      No fracture14,49753.09.6−0.571.28
      Fracture34457.71.3−1.211.36
      Clinical
      No fracture14,23653.09.6−0.571.27
      Fracture60556.49.1−1.031.38
      Table 3 shows the HR/SD T-score decrease using four models with increasing variables. DXR T-score alone showed a highly statistically significant (p < 0.01) association with all fracture types. With DXR T-score only, the hazard ratio per standard deviation (HR/SD) decrease in T-score was 2.15 (CI 1.55–3.00) for hip, 1.47 (CI 1.36–1.59) for major osteoporotic and 1.33 (CI 1.26–1.42) for any clinical fracture. When adding age to the model, the HR/SD T-score decrease was somewhat smaller and when adding clinical risk factors, T-score was no longer statistically significant (p < 0.05) for hip fractures, but remained so for major osteoporotic and any clinical fracture.
      Table 3HR/SD T-score for hip, major osteoporotic and clinical fractures in four models with different variables. ***Significant at the 1 percent level, **Significant at the 5 percent level, *Significant at the 10 percent level.
      HipMOFClinical
      123412341234
      T-score2.15*** (1.55, 3.00)1.93*** (1.28, 2.91)1.63** (1.03, 2.56)1.36 (0.79, 2.35)1.47*** (1.36, 1.59)1.27*** (1.15, 1.40)1.30*** (1.18, 1.45)1.29*** (1.14, 1.46)1.33*** (1.26, 1.42)1.20*** (1.11, 1.29)1.23*** (1.14, 1.33)1.23*** (1.13, 1.35)
      Age1.03 (0.97, 1.10)1.06 (0.98, 1.14)1.13** (1.02, 1.25)1.04*** (1.02, 1.05)1.03*** (1.02, 1.05)1.03*** (1.02, 1.05)1.03*** (1.02, 1.04)1.02*** (1.01, 1.03)1.02*** (1.01, 1.03)
      Height0.95* (0.91, 1.00)1.04 (0.93, 1.17)1.02** (1.00, 1.04)1.03*** (1.01, 1.06)1.02*** (1.01, 1.04)1.03*** (1.01, 1.05)
      Weight0.99 (0.95, 1.03)0.94** (0.88, 1.00)1.00 (1.00, 1.01)1.00 (0.99, 1.01)1.00 (1.00, 1.01)1.00 (0.99, 1.01)
      Parental hip fracture1.12 (0.14, 9.15)0.93 (0.63, 1.36)1.19 (0.92, 1.55)
      Smoking3.78* (0.90, 15.82)1.43*** (1.10, 1.86)1.17 (0.96, 1.43)
      Alcohol consumption (low)0.46 (0.12, 1.85)0.70** (0.52, 0.95)0.86 (0.68, 1.08)
      Alcohol consumption (high)0.00 (0.00, Inf.00)0.77 (0.54, 1.09)0.96 (0.73, 1.25)
      Rheumatic disease1.74 (0.21, 14.18)1.10 (0.65, 1.87)1.07 (0.72, 1.61)
      Diabetes (insulin treated)11.59** (1.43, 94.19)1.66 (0.77, 3.59)1.41 (0.76, 2.61)
      Stand without arms0.09*** (0.02, 0.46)0.78 (0.45, 1.34)0.79 (0.52, 1.20)
      Fallen during last month1.36 (0.17, 11.06)1.44** (1.01, 2.06)1.27* (0.96, 1.67)
      Right-handedness0.28 (0.06, 1.38)1.00 (0.63, 1.61)1.21 (0.83, 1.76)
      Fracture due to low-energy trauma0.00 (0.00, Inf.00)1.01 (0.72, 1.42)1.23* (0.97, 1.57)
      Height loss >3 cm0.00 (0.00, Inf.00)1.05 (0.67, 1.66)0.92 (0.64, 1.32)
      Menopaus <45 years0.81 (0.16, 4.05)0.97 (0.68, 1.39)1.00 (0.77, 1.31)
      Cortisone treatment1.53 (0.19, 12.42)1.07 (0.66, 1.72)1.14 (0.80, 1.61)
      Hyperparathyroidism0.00 (0.00, Inf.00)0.19* (0.03, 1.35)0.57 (0.24, 1.38)
      Anorexia0.00 (0.00, Inf.00)0.0000 (0.00, Inf.00)0.0000 (0.00, Inf.00)
      Malabsorption0.00 (0.00, Inf.00)0.0000 (0.00, Inf.00)0.52 (0.07, 3.72)
      Angina or myocardial infarction0.00 (0.00, Inf.00)0.81 (0.35, 1.84)1.11 (0.63, 1.96)
      Other disease related to osteoporosis0.00 (0.00, Inf.00)0.56 (0.21, 1.54)0.67 (0.34, 1.31)
      Hemiplegia0.0000 (0.00, Inf.00)1.27 (0.17, 9.67)2.44 (0.74, 8.04)
      Reduced mobility0.00 (0.00, Inf.00)0.91 (0.38, 2.21)0.86 (0.43, 1.71)
      N14,80414,80414,37110,94014,84114,84114,40510,96714,84114,84114,40510,967
      Confidence intervals are indicated within the parentheses.
      The AUC for hip, major osteoporotic and clinical fractures were 0.79, 0.69 and 0.65 respectively (Fig. 2, Fig. 3, Fig. 4).
      Fig. 2
      Fig. 2Age-adjusted ROC curve for DXR T-score and hip fracture. AUC 0.79.
      Fig. 3
      Fig. 3Age-adjusted ROC curve for DXR T-score and MOF. AUC 0.69.
      Fig. 4
      Fig. 4Age-adjusted ROC curve for DXR T-score and clinical fracture. AUC 0.65.
      Due to young age of the cohort, a supplementary analysis restricted to women >55 years was done. It included 6309 women with DXR, of whom 4704 women had returned fully completed questionnaires. Among this older subset there were 15 hip fractures, 220 major osteoporotic fractures and 345 clinical fractures. The corresponding AUCs were 0.69 (hip), 0.58 (major osteoporotic) and 0.57 (clinical), respectively (Fig. 5, Fig. 6, Fig. 7).
      Fig. 5
      Fig. 5Age-adjusted ROC curve for DXR T-score and hip fracture among women >55 years. AUC 0.69.
      Fig. 6
      Fig. 6Age-adjusted ROC curve DXR T-score and MOF among women >55 years. AUC 0.58.
      Fig. 7
      Fig. 7Age-adjusted ROC curve and DXR T-score and clinical fracture among women >55 years. AUC 0.57.

      4. Discussion

      To our knowledge, this is the first large-scale study to have evaluated DXR’s potential use in population-based screening. DXR T-score was statistically associated with an increased risk of hip, major osteoporotic as well as any clinical fracture. The association between DXR T-score and fracture was weaker than in previously published studies [
      • Bouxsein M.L.
      • Palermo L.
      • Yeung C.
      • Black D.M.
      Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures.
      ,
      • Kälvesten J.
      • Lui L.-Y.
      • Brismar T.
      • Cummings S.
      Digital X-ray radiogrammetry in the study of osteoporotic fractures: comparison to dual energy X-ray absorptiometry and FRAX.
      ,
      • Wilczek M.L.
      • Kalvesten J.
      • Algulin J.
      • Beiki O.
      • Brismar T.B.
      Digital X-ray radiogrammetry of hand or wrist radiographs can predict hip fracture risk--a study in 5,420 women and 2,837 men.
      ,
      • Bach-Mortensen P.
      • Hyldstrup L.
      • Appleyard M.
      • Hindso K.
      • Gebuhr P.
      • Sonne-Holm S.
      Digital x-ray radiogrammetry identifies women at risk of osteoporotic fracture: results from a prospective study.
      ]. However, this is probably due to the unselected study population’s relatively young age and the short follow up time, which led to few incident fractures in our study. Most other fracture prediction studies have included older cohorts with higher fracture risk and/or performed longer follow-up [
      • Shepstone L.
      • Lenaghan E.
      • Cooper C.
      • Clarke S.
      • Fong-Soe-Khioe R.
      • Fordham R.
      • Gittoes N.
      • Harvey I.
      • Harvey N.
      • Heawood A.
      • Holland R.
      • Howe A.
      • Kanis J.
      • Marshall T.
      • O’Neill T.
      • Peters T.
      • Redmond N.
      • Torgerson D.
      • Turner D.
      • McCloskey E.
      • Shepstone L.
      • Lenaghan E.
      • Cooper C.
      • Clarke S.
      • Fong-Soe-Khioe R.
      • Fordham R.
      • Gittoes N.
      • Harvey I.
      • Harvey N.
      • Heawood A.
      • Holland R.
      • Howe A.
      • Kanis J.
      • Marshall T.
      • O’Neill T.
      • Peters T.
      • Redmond N.
      • Torgerson D.
      • Turner D.
      • McCloskey E.
      • Crabtree N.
      • Duffy H.
      • Parle J.
      • Rashid F.
      • Stant K.
      • Taylor K.
      • Thomas C.
      • Knox E.
      • Tenneson C.
      • Williams H.
      • Adams D.
      • Bion V.
      • Blacklock J.
      • Dyer T.
      • Bratherton S.
      • Fidler M.
      • Knight K.
      • McGurk C.
      • Smith K.
      • Young S.
      • Collins K.
      • Cushnaghan J.
      • Arundel C.
      • Bell K.
      • Clark L.
      • Collins S.
      • Gardner S.
      • Mitchell N.
      Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial.
      ,
      • Cappelle S.I.
      • Ramon I.
      • Dekelver C.
      • Rozenberg S.
      • Baleanu F.
      • Karmali R.
      • Rubinstein M.
      • Tondeur M.
      • Moreau M.
      • Paesmans M.
      • Bergmann P.
      • Body J.J.
      Distribution of clinical risk factors for fracture in a Brussels cohort of postmenopausal women: the FRISBEE study and comparison with other major cohort studies.
      ]. As Swedish mammography screening addresses all women aged between 40 and 74 years and has an attendance rate of approximately 80% it provides an excellent opportunity to reach out to women compared with other types of screening. As osteoporotic fractures mostly affect older individuals, the inclusion of all women undergoing mammography screening regardless of age probably limited the frequency of osteoporosis-related fractures within our relatively short follow-up time.
      The AUC for DXR T-score only and hip, major osteoporotic and any clinical fracture were 0.79, 0.69 and 0.65 respectively (Fig. 2, Fig. 3, Fig. 4). When narrowing the analyses to those older than 55 years, the association between DXR T-score and fractures weakened. This effect is mainly mathematical. Younger individuals have a higher BMD and very low risk of fracture. Risk assessment including those will result in a very high specificity, biasing ROC. However, the young age, short follow-up time and few incident fractures may result in a lower sensitivity of the model as random fractures due to more severe or unfortunate falls not primarily influenced by bone fragility will be relatively more frequent in such a cohort. Using national registries only, we were unfortunately unable to distinguish fractures related to low-energy trauma from those due to high-energy trauma. The impact of fractures not related to bone fragility would probably lead to a general underestimation of the method’s predictive capacity. Previous DXR studies based on older cohorts with higher risk of fracture have reported better fracture prediction [
      • Bouxsein M.L.
      • Palermo L.
      • Yeung C.
      • Black D.M.
      Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures.
      ,
      • Kälvesten J.
      • Lui L.-Y.
      • Brismar T.
      • Cummings S.
      Digital X-ray radiogrammetry in the study of osteoporotic fractures: comparison to dual energy X-ray absorptiometry and FRAX.
      ,
      • Wilczek M.L.
      • Kalvesten J.
      • Algulin J.
      • Beiki O.
      • Brismar T.B.
      Digital X-ray radiogrammetry of hand or wrist radiographs can predict hip fracture risk--a study in 5,420 women and 2,837 men.
      ,
      • Bach-Mortensen P.
      • Hyldstrup L.
      • Appleyard M.
      • Hindso K.
      • Gebuhr P.
      • Sonne-Holm S.
      Digital x-ray radiogrammetry identifies women at risk of osteoporotic fracture: results from a prospective study.
      ].
      Strengths of this study include high participation rate (75.5%), the large size of the cohort and no loss to follow up due to Swedish high-quality national patient registers. The main study limitation is the short follow-up time given the cohort’s low risk of fracture, especially hip fracture.
      A previous study of a subset (based on low DXR Z-score) of the current cohort identified a high prevalence of individuals with previously unknown conditions that can potentially cause secondary osteoporosis [
      • Wilczek M.L.
      • Kalvesten J.
      • Bergstrom I.
      • Pernow Y.
      • Saaf M.
      • Freyschuss B.
      • Brismar T.B.
      Can secondary osteoporosis be identified when screening for osteoporosis with digital X-ray radiogrammetry? Initial results from the Stockholm Osteoporosis Project (STOP).
      ]. Treatment of these women may reduce their fracture risk. Screening at a higher age would make more sense from a clinical perspective as it would target individuals more likely to be candidates for pharmaceutical interventions aimed at increasing BMD [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • Reginster J.Y.
      C. On behalf of the scientific advisory board of the european society for, O. Economic aspects of, A. The committees of scientific, F. National societies of the international osteoporosis, european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ]. On the other hand, the relative influence of DXA-BMD on fracture risk seems to decrease with age as other risk factors become more prevalent and have larger impact [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • Reginster J.Y.
      C. On behalf of the scientific advisory board of the european society for, O. Economic aspects of, A. The committees of scientific, F. National societies of the international osteoporosis, european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ].
      Another factor to consider when interpreting the results of this study is the low diagnostic precision of vertebral and rib fractures diagnoses using clinically based diagnoses without radiological confirmation. This problem has been described in previous studies [
      • Schousboe J.T.
      Epidemiology of vertebral fractures.
      ,
      • Murphy C.E.
      • Raja A.S.
      • Baumann B.M.
      • Medak A.J.
      • Langdorf M.I.
      • Nishijima D.K.
      • Hendey G.W.
      • Mower W.R.
      • Rodriguez R.M.
      Rib fracture diagnosis in the panscan era.
      ]. Thus, the number of identified vertebral and rib fractures in our cohort might be under- and overestimated respectively. Underdiagnosis of vertebral fracture may have reduced the predictive ability of DXR with regard to major osteoporotic fractures in this study.
      Though results regarding the effect of non-pharmacological management of osteoporosis and fracture risk have been contested [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • Reginster J.Y.
      C. On behalf of the scientific advisory board of the european society for, O. Economic aspects of, A. The committees of scientific, F. National societies of the international osteoporosis, european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ], several modifiable lifestyle-related factors such as smoking, high alcohol consumption or physical inactivity have been shown to be associated with fracture risk. It is unknown for what age group DXR has its best predictability, although previous studies in groups with greater fracture risk and higher age indicate better results than our study [
      • Bouxsein M.L.
      • Palermo L.
      • Yeung C.
      • Black D.M.
      Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures.
      ,
      • Wilczek M.L.
      • Kalvesten J.
      • Algulin J.
      • Beiki O.
      • Brismar T.B.
      Digital X-ray radiogrammetry of hand or wrist radiographs can predict hip fracture risk--a study in 5,420 women and 2,837 men.
      ,
      • Bach-Mortensen P.
      • Hyldstrup L.
      • Appleyard M.
      • Hindso K.
      • Gebuhr P.
      • Sonne-Holm S.
      Digital x-ray radiogrammetry identifies women at risk of osteoporotic fracture: results from a prospective study.
      ].
      In conclusion this large prospective study in a general female population found correlation between decreased DXR T-score and risk of fracture, indicating a potential use of DXR in population-based screening for osteoporosis. However, longer follow-up is needed to validate the results and their persistence over time.

      Contributors

      ML Wilczek contributed to planning the study, analyzing results, and manuscript writing.
      L Battha contributed to statistical analysis and manuscript writing.
      BM Brumpton contributed to statistical analysis and manuscript writing.
      B Freyschuss contributed to planning the study, analyzing results, and manuscript writing.
      TB Brismar contributed to planning the study, analyzing results, and manuscript writing.
      All authors approved the final version of the manuscript.

      Conflict of interest

      The authors declare that they have no conflict of interest.

      Funding

      Financial support was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet.

      Ethical approval

      This study obtained approval from the local ethical board in Stockholm (2009/1820−31/2).

      Research data (data sharing and collaboration)

      There are no linked research data sets for this paper. It is not possible to anonymize the data.

      Provenance and peer review

      This article was not commissioned and was externally peer reviewed.

      Acknowledgements

      We wish to thank Ewa Köhler and Anita Hällgren for recruiting study participants. We are also grateful to Johan Kälvesten and Jakob Algulin for valuable input when planning the study.

      Appendix A. questionnaire regarding clinical risk factors

      Tabled 1
      How tall are you?(cm)
      How much do you weigh? (if you do not know your precise weight, please provide how much you think you weigh)(kg)
      YesNo
      Can you stand up from a seated position without using your arms?
      Have you fallen during the last month?
      Do you smoke or have you smoked >10 years?
      Are you right-handed?
      Have you during the last 20 years suffered from a fracture due to low-energy trauma, i.e. fall in the same plane (e.g. tripping, sliding)
      Have your mother or father suffered from a hip fracture?
      Compared to when you were the tallest, have you lost more than 3 cm in height?
      Did you reach menopause before you turned 45 years?
      Have you been treated with cortisone for more than 3 months? (not counting inhalation steroids).
      Do you have any of the following diseases?
      Rheumatic disease (diagnosed by a physician)?
      Insulin treated diabetes?
      Hyperparathyroidism?
      Anorexia?
      Malabsorption?
      Angina or myocardial infarction?
      Other disease that could cause osteoporosis?
      Hemiplegia?
      Significantly reduced mobility? (<100 m without support of cane or similar aid)
      How many days per week do you drink beer, wine or liquor?0 1 2 3 4 5 6 7
      How many glasses do you normally drink per occasion?1 2 3 4 5 6 7

      Appendix B. ICD codes used for fracture identification

      Hip fractures ICD-10 codes: S72.0, S72.1 and S72.2
      Major osteoporotic fractures ICD-10 codes (hip, spine, humerus, forearm): S72.0, S72.1, S72.2, S12, S22.0 S22.1, S32.0, S32.1, S32.2, S32.7, S32.8, S42.2, S42.3, S42.4 and S52.
      Clinical fractures: All ICD-10 S-codes except for S codes for skull, fingers and toes (S02, S62.5, S62.6, S62.7, S92.4, S92.5, S92.7)

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