Research Article Potential Extensions of the US FRAX Algorithm

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1 Journl of Osteoporosis Volume 2012, Article ID , 8 pges doi: /2012/ Reserch Article Potentil Extensions of the US FRAX Algorithm L. Joseph Melton III, 1, 2 Elizbeth J. Atkinson, 3 Sr J. Achenbch, 3 John A. Knis, 4 Terry M. Therneu, 3 Helen Johnsson, 4 Sundeep Khosl, 2 nd Shreysee Amin 1, 5 1 Division of Epidemiology, Deprtment of Helth Sciences Reserch, College of Medicine, Myo Clinic, Rochester, MN 55905, USA 2 Division of Endocrinology, Dibetes, Metbolism nd Nutrition, Deprtment of Internl Medicine, College of Medicine, Myo Clinic, Rochester, MN 55905, USA 3 Division of Biomedicl Sttistics nd Informtics, Deprtment of Helth Sciences Reserch, College of Medicine, Myo Clinic, Rochester, MN 55905, USA 4 WHO Collborting Centre for Metbolic Bone Diseses, University of Sheffield Medicl School, Sheffield S10 2RX, UK 5 Division of Rheumtology, Deprtment of Internl Medicine, College of Medicine, Myo Clinic, Rochester, MN 55905, USA Correspondence should be ddressed to L. Joseph Melton III, melton.j@myo.edu Received 30 April 2012; Accepted 27 June 2012 Acdemic Editor: E. M. Lewiecki Copyright 2012 L. Joseph Melton III et l. This is n open ccess rticle distributed under the Cretive Commons Attribution License, which permits unrestricted use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. To determine if the revised US FRAX cn identify those t high risk for frctures t ny skeletl site, we studied 250 women nd 249 men 40 yers old from n ge-strtified rndom smple of Rochester, MN residents. At bseline, femorl neck (FN) bone density ws ssessed, s were the clinicl risk fctors included in FRAX, long with dditionl frcture risk fctors such s bone turnover mrkers nd fll history. Frcture scertinment through periodic interviews nd comprehensive medicl record review ws performed over 10 yers of followup. In both women nd men, higher FRAX probbility t bseline ws ssocited with greter subsequent likelihood of mjor osteoporotic frcture. However, reltive 10% increse in the FRAX 10-yer frcture probbility ws lso ssocited with 1.4-fold increse (95% confidence intervl (CI) ) in other frctures in women nd 1.7-fold increse (95% CI ) in men. Furthermore, FRAX predicted symptomtic vertebrl frctures nd frctures generlly in both sexes. The ddition of risk fctors not currently included in FRAX did not pper to improve the ccurcy of frcture risk prediction. FRAX my provide conservtive estimte of risk for mjor osteoporotic frctures, but it lso predicts frctures generlly. 1. Introduction Most frctures rise in the intermedite-risk osteopenic popultion rther thn mong those clssified s hving osteoporosis by dul-energy X-ry bsorptiometry (DXA) [1]. To increse the ssessment grdient-of-risk, nd thereby improve both sensitivity nd specificity [2], bone minerl density (BMD) hs been combined with clinicl risk fctors in the World Helth Orgniztion s frcture risk ssessment tool, FRAX [3], which clcultes 10-yer frcture probbility (%). Like most such scoring systems, discordnt results inevitbly rise whereby some ptients t predicted low risk will frcture nd vice vers [4]. This might relte to the existence of importnt risk fctors for frcture not currently represented in FRAX. Indeed, potentil chnges were recently suggested to improve the ccurcy of frcture prediction by FRAX, including incorportion of informtion bout flls, dditionl cuses of secondry osteoporosis, biochemicl mrkers of bone turnover, BMD mesurements t the lumbr spine (LS), nd concurrent osteoporosis tretment [5]. Furthermore, FRAX ws designed to predict the probbility of mjor (i.e., hip, spine, wrist, or humerus) osteoporotic frcture, but other frctures in older individuls re lso relted to low BMD [6], nd FRAX might predict them s well. Finlly, the United Sttes version of FRAX (US FRAX) ws recently revised [7], s the originl version ws thought to overestimte frcture probbility due to the incorportion of symptomtic vertebrl frctures in the lgorithm [8], but the effect of this chnge is not yet cler. The purpose of this study ws to test the recently revised US FRAX for

2 2 Journl of Osteoporosis long-term prediction of mjor osteoporotic frctures nd to determine if FRAX cn identify those t risk for frctures t other skeletl sites, including cliniclly recognized but symptomtic vertebrl frctures. We lso exmined whether other risk fctors (e.g., bone turnover mrkers, fll history) dd further predictive ccurcy to FRAX. 2. Mterils nd Methods 2.1. Study Subjects. Following pprovl by Myo Clinic s Institutionl Review Bord, subjects were recruited from gestrtified rndom smples of Rochester, MN women nd men s described previously [9]. There were pproximtely 50 men per decde of ge from yers to ge 80 yers nd over (men ge ± SD, 55 ± 20 yers; ge-rnge, yers). There were lso bout 50 women per decde of ge, including 138 premenopusl women (men, 35 ± 9 yers; rnge, yers) nd 213 postmenopusl women (men, 68 ± 13 yers; rnge, yers) Study Protocol. After providing written informed consent, subjects were interviewed using stndrd protocol to collect informtion required for the FRAX lgorithm (i.e., personl history of moderte trum frcture fter ge 35 yers, rheumtoid rthritis, orl glucocorticoid use, current cigrette smoking, hevy (>2 drinks/dy) lcohol use, nd prentl history of hip frcture). Complete (inptient nd outptient) community medicl records were reviewed to confirm prior frgility frctures nd collect informtion bout conditions predisposing to flls or to secondry (2 ) osteoporosis. Since bseline dt predted widespred vilbility of orl bisphosphonte therpy [10], concurrent osteoporosis tretment included estrogen, selective estrogen receptor modultors or clcitonin, regrdless of the specific indiction for therpy Bone Densitometry. BMD (g/cm 2 ) ws determined for the femorl neck (FN) nd LS using Hologic QDR2000 (Hologic, Wlthm, MA), with coefficients of vrition (CV) of 1.8% nd 0.6%, respectively. FN BMD T-scores were clculted from ntionl reference dt for women [11]. In the bsence of comprble stndrd, we clculted LS BMD T-scores bsed on sex-specific young norml dt from the yer-old Rochester residents [12] Bone Turnover Mrkers. Fsting serum smples were obtined nd, for premenopusl women, were collected during the folliculr phse of the menstrul cycle. Bone formtion ws ssessed by serum osteoclcin (OC) mesured by rdioimmunossy (CIS Biointerntionl, Bedford, MA; interssy CV <6%), wheres bone resorption ws evluted with n ELISA kit (Osteomrk NTx Serum, Ostex Interntionl, Inc., Settle, WA; interssy CV <17%) Frcture Follow-Up. Subjects were followed for ny new frcture (prospective cohort study) by periodic interview nd medicl record review [13]. Since originl X-rys were not vilble for review, the dignosis of vertebrl frcture ws ccepted on the bsis of rdiologist s report of compression or collpse of one or more thorcic or lumbr vertebre. We ctegorized vertebrl deformities ( frctures) tht were only noted incidentlly seprtely from those reported by ttending physicins to be symptomtic (clinicl spine frctures). Ascertinment of cliniclly evident frctures is believed complete [14] FRAX Clcultions. Frcture probbilities were clculted by the World Helth Orgniztion Collborting Centre for Metbolic Bone Diseses, blinded to frcture outcome, using US FRAX models (version 3.1) tht incorported FN BMD T-scores. FRAX model US (Blck) ws used for 1 subject nd US FRAX (Asin) for 5 others; US FRAX (Cucsin) ws used for the remining subjects. The nlysis ws restricted to subjects ge 40 yers (minimum ge ccommodted in FRAX) or over t bseline; those over 90 yers old were set to ge 90 (the mximum ccommodted in FRAX) Sttisticl Anlysis. To ddress clibrtion, we compred the number of first mjor osteoporotic frctures observed with the number predicted by the sum of subject-specific FRAX models. Computtions re bsed on the method of Berry [15], which ccounts for both incomplete followup (censoring) nd the competing risk of deth nd provides tests nd confidence intervls (CI) for the observed/expected rtio tht cn be viewed s stndrdized incidence rtio (SIR). Trends in over- nd underestimtion of frcture risk were evluted by regression extensions of the Berry method using loclly developed softwre [16]. We lso used SIRs to compre the occurrence of specific frctures with tht expected on the bsis of site-specific incidence rtes used in the revised US FRAX [8]. To ddress discrimintion, we computed cumultive 10- yer frcture incidence by qurtile of the FRAX 10-yer frcture probbility estimtes, ccounting for the competing risk of deth. A Cox model pproch [17] llowedusto test whether fctors not currently included in FRAX increse precision of the predictions. A concordnce (C) sttistic for time-to-event dt, similr to re under the receiver opertor chrcteristic curve (AUC) in logistic regression, is given s secondry mesure of the potentil increse. Kpln-Meier methods ssessed survivl in the cohort [18], with expected deth rtes from the 2004 mortlity tbles used in US FRAX [7]. Observed nd expected survivl curves were compred using the log-rnk test [19]. 3. Results Bsed in prt on medicl record documenttion for these subjects tht extended bck 36 yers prior to the initil ssessment, bseline chrcteristics of the subjects re outlined in Tble 1. Within the components of the FRAX lgorithm, women nd men were similr except for prior history of frgility frcture (32% versus 24%; P = 0.039) nd lower FN BMD levels (0.700 g/cm 2 versus g/cm 2 ; P<0.001), s well s more other secondry osteoporosis (P < 0.001),

3 Journl of Osteoporosis 3 Tble 1: Frcture risk fctors t bseline mong 250 women nd 249 men 40 yers of ge rndomly smpled from the Rochester, MN popultion. Women Men FRAX components Prior frgility frcture, % yes 81 (32%) 60 (24%) Rheumtoid rthritis, % yes 4 (2%) 2 (1%) Other secondry osteoporosis, % yes 88 (35%) 17 (7%) Current tobcco smoking, % yes 27 (11%) 32 (13%) Hevy lcohol consumption, % yes 7 (3%) 8 (3%) Prentl hip frcture history, % yes 26 (10%) 29 (12%) Femorl neck BMD (g/cm 2 ), x ± SD ± ± Potentil FRAX extensions Additionl secondry osteoporosis, % yes 85 (34%) 99 (40%) Fll history in pst yer, % yes 111 (45%) 91 (37%) Risk fctors for flls b, % yes 213 (85%) 149 (60%) Concurrent tretment, % yes 48 (19%) 0 (0%) Lumbr spine BMD (g/cm 2 ), x ± SD ± ± Serum NTx (nmbce) c, x ± SD 12.5 ± ± 7.2 Serum osteoclcin (ng/ml), x ± SD 5.80 ± ± 2.78 Any of the following: goiter, thyroidectomy, peptic ulcer disese, gstric resection, intestinl resection, renl filure/uremi, incresed prthyroid function, pncretitis, pernicious nemi, emphysem, chronic bronchitis, or complete bed rest >7 dys in row. b Any of the following: use of cne, stroke, hemipresis, hemiplegi, blnce disorder, trnsient ischemic ttck, ctrcts, other vision problems, hert rrhythmi, posturl/orthosttic hypotension, syncopl ttcks, prkinsonism, polio sequele, multiple sclerosis, or other neurologicl problems. c Serum cross-linked N-telopeptides of type I collgen. mong the women. The ltter discrepncy ws ccounted for by premture (<45 yers) menopuse; excluding tht, the prevlence of the other cuses of secondry osteoporosis, excluding rheumtoid rthritis, ws similr in women nd men (6% versus 7%). With regrd to potentil extensions of FRAX, women were more likely to hve one or more risk fctors for flling (85% versus 60%; P < 0.001), but the difference in reported flls in the previous yer ws not significnt. They lso hd lower LS BMD (0.971 versus g/cm 2 ; P < 0.001) nd lower bone formtion s ssessed by serum OC levels (5.80 ng/ml versus 6.52 ng/ml; P = 0.003), despite comprble bone resorption s ssessed by serum NTx levels (12.5 nmbce versus 12.6 nmbce; P = 0.830). None of the men, compred to 19% of the women (P <0.001), were on n osteoporosis tretment t bseline. Subjects were then followed nd censored t deth or loss to followup (if before 10 yers) or fter 10 yers of followup mong survivors (4455 person-yers). Altogether, 74% were followed for t lest 10 yers, nd deth ccounted for lmost ll of the shorter followup intervls (medin followup of those who died ws 7 yers). Even so, observed survivl t 10 yers ws 77% when 70% ws expected (P <0.001). During this sme 10-yer followup intervl, 218 subjects experienced 380 different frctures, including 165 symptomtic, nonpthologicl vertebrl frctures tht were discovered incidentlly; 4 pthologic frctures (including 2 vertebrl frctures) were excluded from most nlyses. Most frctures were due to no more thn moderte trum (Tble 2). The primry nlysis focused, however, on the mjor osteoporotic frctures (i.e., hip, symptomtic (clinicl) spine, distl forerm, nd proximl humerus). Fortyfour women hd t lest one mjor osteoporotic frcture, including 11 with n incident hip frcture, s did 18 men, including 5 who hd n incident hip frcture. In ddition, 61 women nd 33 men experienced t lest one frcture t nother skeletl site. The medin FRAX probbility for ny mjor osteoporotic frcture ws 7% (rnge, 0 45%), being 10% in women (rnge, 0 45%) nd 5% in men (rnge, 0 30%). The predicted risk ws greter mong women thn men nd incresed in ccordnce with the mjor osteoporotic frctures ctully observed (Tble 3). More frctures were observed thn expected in most qurtiles (overll SIR = 1.6, 95% CI in women nd SIR = 1.4, 95% CI in men). Just 5 frctures were observed in the lowest FRAX qurtile (2 women due to severe trum nd 3 men due to moderte trum), wheres 28 occurred in the highest risk qurtile. Only 16 hip frctures were observed during followup so sttisticl power ws limited, but the risk estimtes for hip frctures in women (SIR = 1.5, 95% CI ) nd men (SIR = 1.7, 95% CI ) resembled those for ll mjor osteoporotic frctures combined. To explore the pprent underestimtion of 10-yer frcture risk, we compred site-specific frcture counts with the numbers expected from the incidence rtes used in revisedusfrax.forcombinedmenndwomenge 50 yers old (the ge group reported for those rtes), there were somewht fewer observed first frctures of the hip (16 versus 24, P = 0.111), greter numbers of distl forerm (19 versus 15, P = 0.285) nd symptomtic vertebrl frctures (20 versus 15, P = 0.166), nd similr numbers of proximl humerus frctures (8 versus 7, P = 0.834) compred to expected. Overll greement between observed nd expected frctures ws better mong the men 50 yers of ge (16

4 4 Journl of Osteoporosis Tble 2: Frcture outcomes over 10 yers mong Rochester, MN women nd men 40 yers of ge t bseline, by precipitting trum. Frcture site Women Men Moderte n (%) Severe n (%) Moderte n (%) Severe n (%) Skull/fce 1 (0.5%) 0 (0%) 0 (0%) 0 (0%) Cervicl spine 1 (0.5%) 1 (3%) 0 (0%) 0 (0%) Other vertebre symptomtic 20 (11%) 2 (7%) 11 (8%) 0 (0%) Other vertebre symptomtic 68 (37%) 1 (3%) 96 (67%) 0 (0%) Ribs 29 (16%) 4 (14%) 14 (10%) 4 (21%) Sternum/clvicle/scpul 2 (1%) 4 (14%) 2 (1%) 1 (5%) Proximl humerus 5 (3%) 2 (7%) 1 (1%) 2 (11%) Otherrm 4(2%) 0(0%) 2(1%) 0(0%) Distl forerm 16 (9%) 2 (7%) 1 (1%) 2 (11%) Hnd/fingers 8 (4%) 4 (14%) 2 (1%) 2 (11%) Pelvis 6 (3%) 0 (0%) 3 (2%) 2 (11%) Proximl femur 12 (6%) 0 (0%) 5 (3%) 0 (0%) Other leg 9 (5%) 3 (10%) 5 (3%) 3 (16%) Feet/toes 4 (2%) 6 (21%) 1 (1%) 3 (16%) Totl Mjor osteoporotic frctures. Tble 3: First mjor osteoporotic frctures observed mong Rochester, MN women nd men compred to numbers predicted by revised US FRAX (FN BMD), by ge t bseline nd qurtile of full 10-yer frcture probbility (%). Qurtile b 40 yers old t bseline 60 yers old t bseline Observed Predicted SIR (95% CI) Observed Predicted SIR (95% CI) Women Q1 (0 to <4.7) ( ) 0 c N.A. Q2 (4.7 to <10.4) ( ) ( ) Q3 (10.4 to <17.9) ( ) ( ) Q4 (17.9 to 44.9) ( ) ( ) Subtotl ( ) ( ) Men Q1 (0 to <3.6) ( ) (0.1 31) Q2 (3.6 to <5.2) ( ) ( ) Q3 (5.2 to <8.1) ( ) ( ) Q4 (8.1 to 29.8) ( ) ( ) Subtotl ( ) ( ) Totl ( ) ( ) Stndrdized incidence rtio (SIR) nd 95% confidence intervl (CI). b Qurtiles (Q) defined using ll ges. c No subjects in this group. versus 14, P = 0.642) thn the women (41 versus 32, P = 0.099), but none of these differences ws sttisticlly significnt. However, FRAX predicted frctures t other sites bout s well s it did mjor osteoporotic frcture risk (Tble 4). Thus, reltive 10% increse in FRAX 10-yer frcture probbility ws ssocited with 1.9-fold increse in mjor osteoporotic frctures, nd 1.4-fold increse in ll other frctures, in the women. Among the men, 10% increse in the FRAX probbility ws ssocited with 2.1-fold increse in mjor osteoporotic frctures nd with 1.7-fold increse in other frctures. FRAX predicted symptomtic vertebrl frctures s well s symptomtic ones, s it did frctures generlly. After forcing the full FRAX probbility for ech subject into model, the potentil contribution of dditionl risk fctors ws evluted (Tble 5). Although sttisticl power ws limited, there ws no dditionl contribution from history of flling; the presence of risk fctors for flling ws ssocited with n incresed risk tht ws not sttisticlly significnt, but dding them did not improve the C-sttistic over tht for FRAX lone (C-sttistic, 0.75 in women nd 0.65 in men). Results were not chnged by counting the number of flls or fll risk fctors (dt not shown). Likewise, the presence of dditionl cuses of secondry osteoporosis or the use of estrogen hd little effect on the results. There ws lso no significnt contribution to frcture prediction,

5 Journl of Osteoporosis 5 Tble 4: First nonpthologic frcture of ech type observed nd hzrd rtio (HR) per 10% increse in the full 10-yer US FRAX (FN BMD) probbility mong Rochester, MN women nd men 40 yers of ge,by type of frcture outcome. Frcture type Women Men Observed HR (95% CI) Observed HR (95% CI) Any mjor osteoporotic frcture ( ) ( ) Symptomtic vertebrl frcture b ( ) ( ) Any symptomtic vertebrl frcture c ( ) ( ) Any other frcture c ( ) ( ) Other xil frcture ( ) ( ) Other ppendiculr frcture d ( ) ( ) Any nonpthologic frcture ( ) ( ) Defined ccording to FRAX s proximl femur, clinicl spine, distl forerm, or proximl humerus frctures. b Included in mjor osteoporotic frctures. c Not included in mjor osteoporotic frctures. d Excluding 2 pthologic ppendiculr frctures. Tble 5: Effect of dditionl risk fctors to predict first mjor osteoporotic frcture (Fx) over 10 yers mong Rochester, MN women nd men 40 yers of ge, fter djusting for the full US FRAX (FN BMD) probbility. Model Women(44Fxs) Men(18Fxs) HR (95% CI) C b HR (95% CI) C b Fll history in pst yer (y/n) 0.8 ( ) ( ) 0.65 Fll risk fctors (y/n) 1.5 ( ) ( ) 0.64 Additionl cuses of secondry osteoporosis (y/n) 0.5 ( ) ( ) 0.64 Concurrent estrogen use (y/n) 1.2 ( ) 0.74 N.A. Lumbr spine BMD (g/cm 2 )(persd ) 1.2 ( ) ( ) 0.66 Femorl neck-lumbr spine T-score difference (per unit ) 1.0 ( ) ( ) 0.62 Serum NTx c (nmbce) (per SD ) 1.1 ( ) ( ) 0.67 Serumosteoclcin (OC, ng/ml) (persd ) 1.3 ( ) ( ) 0.65 NTx/OCrtio (persd ) 1.4 ( ) ( ) 0.66 Hzrd rtio (HR) nd 95% confidence intervl (CI). Concordnce (C) sttistic. Serum cross-linked N-telopeptides of type I collgen. once the FRAX probbility ws known, from the ddition of LS BMD T-scores, the discrepncy between FN nd LS T- scores or mesures of bone resorption (NTx) or formtion (OC). However, the rtio of resorption to formtion (NTx OC) did predict frctures independently of FRAX in both women (HR = 1.4, 95% CI ) nd men (HR = 1.2, 95% CI ), lthough the C-sttistic ws little chnged by this ddition. Generlly, ll of the models predicted frctures better mong women thn men. 4. Discussion In popultion-bsed cohort consisting of both sexes nd ll relevnt ges, we found, s expected, tht frctures incresed with the predicted frcture probbility nd were more common mong women thn men. Few frctures were observed in the lowest qurtile of FRAX probbilities, nd ll were ttributed to severe trum mong the women. By contrst, 36% of the women nd 10% of the men in the highest risk qurtile hd experienced mjor osteoporotic frcture t 10 yers. A similr result ws seen for older women in the Study of Osteoporotic Frctures [20]. A more novel result is our finding tht FRAX predicted frctures t other skeletl sites bout s well s it did mjor osteoporotic frctures. This might be expected from the fct tht bone density predicts frcture risk generlly in older individuls [6] nd, indeed, predicts frctures ttributed to high-energy trumtic events s well s it does those resulting from flls [21, 22]. This is cliniclly relevnt since the overll societl burden of frctures is not limited to the trditionl osteoporotic frctures. Although FRAX itself hd been extensively vlidted [23], the initil version of US FRAX ws revised becuse it seemed to overestimte frcture risk [8], prticulrly with respect to vertebrl frctures. By contrst, the revised version underestimted frcture risk in this cohort, where we hd unusully complete frcture scertinment bsed on review of ll community rdiogrphs on the subjects. A priori, we hd specified tht greement within 25% between observed nd expected frctures would constitute close fit with FRAX, but this conservtive criterion ws not met for either sex. While no single community is representtive of country-specific FRAX model [5], investigtors in other settings hve likewise found tht FRAX my somewht

6 6 Journl of Osteoporosis underestimte [24 29] or, insted, overestimte [30, 31] mjor osteoporotic frcture risk, though some reported comprisons my be misleding [32]. Such differences my not be cliniclly significnt since ptients re usully ctegorized into brod risk groups [33], nd FRAX better predicts frcture risk thn BMD per se in ny cse [23]. The difference between observed nd predicted frctures ws prtly due to more complete scertinment of symptomtic vertebrl frctures in our setting, lthough better thn expected survivl my lso hve plyed role. The min difference between originl (version 2.0) nd revised (version 3.1) US FRAX ws reduction in the vertebrl frcture incidence rtes used in the model [8]. Comprbly gend sex-djusted, the revised vertebrl frcture incidence rtes were only 27% s gret s those used originlly, nd the corresponding overll incidence of mjor osteoporotic frcture ws reduced by bout one-third [7], which is consistent with the discrepncy found here. The rtionle for revising US FRAX ws to focus on the symptomtic vertebrl frctures thought to be more cliniclly relevnt [8], lthough even symptomtic vertebrl frctures my led to dverse outcomes [34]. How this ltter group should be hndled remins to be resolved. In preliminry nlysis, we lso evluted severl dditionl risk fctors tht hve been suggested for use in n expnded FRAX model [5]. Thus, bone loding from fll domintes skeletl frgility due to bone loss [35], but self-reported history of flling in the previous yer did not enhnce prediction of mjor osteoporotic frcture over FRAX lone, nor did risk fctors for flling, nd prcticl pproches for including fll risk in FRAX re lcking [36]. Likewise, risk fctors for secondry osteoporosis beyond those lredy included in FRAX were not ssocited with significnt increse in frcture risk, but mny exert their effects through reduced bone density [37], which ws lredy tken into ccount. By contrst, some comorbid conditions predicted short-term frcture risk in lrge clinicl study, but the C-sttistic ws not better thn tht for FRAX lone [38], s lso seen here. Discordnt LS nd FN BMD results in some ptients prompted considertion of dding LS BMD to FRAX [39], but LS T-scores did not dd significntly to frcture prediction in this study, nor did the difference between LS nd FN T-scores [40]. The rtio of resorption to formtion mrkers did predict overll risk independently of FRAX, but the ccurcy of frcture prediction ws not much enhnced, nd mny prcticl issues remin to be resolved [41]. Finlly, FRAX pertins to untreted ptients, but reltively few women nd none of the men were on osteoporosis tretment t bseline. This study hs severl strengths. In prticulr, it is prospective study of rndomly smpled community women nd men with long followup nd superior scertinment of subsequent frctures. Risk fctors were recorded before ny knowledge of resultnt frctures, nd frctures were documented in detiled medicl records tht spnned ech subject s entire period of residency in the community. The min limittion is the reltively smll smple size, with correspondingly low numbers of frctures, especilly hip frctures, nd reduced sttisticl power, especilly for ssessing dditionl risk fctors tht might be included in FRAX in the future. In ddition, these subjects were reltively helthy, with better thn expected survivl, lthough men 10-yer FRAX probbilities were in keeping with those seen in other popultion-bsed cohorts of similr ge [25, 29]. To obtin sufficient durtion of followup for frcture outcomes, we studied women enrolled in nd men in ; concurrent osteoporosis tretment t bseline ws therefore mostly estrogen, s lendronte ws not introduced into widespred clinicl prctice until 1995 [10]. Finlly, our results re not generlizble to nonwhites becuse the study cohort nd the underlying Rochester popultion re lrgely white [13]. Moreover, the locl popultion is lrgely of northern Europen extrction, lthough ge-djusted seculr trends nd hip frcture incidence rtes in this community re comprble to those for United Sttes whites generlly [42] nd, indeed, consistent with the expected hip frcture incidence rte used in the revised US FRAX [7, 8]. 5. Conclusions In this study popultion, the revised US FRAX provided conservtive estimte of frcture probbility, but much of the discrepncy between the mjor osteoporotic frctures predicted nd those ctully observed could be ccounted for by unusully complete scertinment of symptomtic vertebrl frctures in this popultion. Agreement is likely better in routine clinicl pplictions of FRAX. We hd limited power to determine the role of other risk fctors in potentilly improving risk ssessment by FRAX, but we did find tht bone turnover mrkers my provide dditionl predictive informtion nd be worthy of further study. While it cnnot be expected tht ny estimte of risk will correctly identify which specific individuls will or will not experience future frcture [4], n incresed probbility of frcture s determined by FRAX ws ssocited with incresed risk for mjorosteoporoticfrctureswellsforfrcturesgenerlly, including symptomtic vertebrl frctures. Although not specificlly creted for ssessing the risk of other types of frctures, FRAX my be eqully useful in their prediction due to risk fctors tht these frctures shre with the more typicl osteoporotic frctures currently modelled in FRAX. Conflict of Interests The uthors hve no relevnt conflict of interests. Acknowledgments The uthors would like to thnk Leon Bellrichrd, R.N., Mrci Erickson, R.N., Wendy Gy, R.N., Julie Gingrs, R.N., Jon LPlnte, R.N., Brbr Nolte, R.N., nd Cynthi Nosek, R.N. for ssistnce with dt collection nd Mry Roberts for help in prepring the pper. This work ws supported by reserch Grnts AR (Ntionl Institute of Arthritis, Musculoskeletl nd Skin Diseses) nd UL1 TR (Center for Trnsltionl Scientific Activities) nd mde possible by the Rochester Epidemiology Project

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8 8 Journl of Osteoporosis [33] NOF Guide Committee, Clinicin s Guide to Prevention nd Tretment of Osteoporosis, Ntionl Osteoporosis Foundtion, Wshington, DC, USA, 2010, defult/files/pdfs/nof ClinicinGuide2009 v7.pdf. [34] C. Pongchiykul, N. D. Nguyen, G. Jones, J. R. Center, J. A. Eismn, nd T. V. Nguyen, Asymptomtic vertebrl deformity s mjor risk fctor for subsequent frctures nd mortlity: long-termprospectivestudy, Journl of Bone nd Minerl Reserch, vol. 20, no. 8, pp , [35] T. L. N. Järvinen, H. Sievänen, K. M. Khn, A. Heinonen, nd P. Knnus, Shifting the focus in frcture prevention from osteoporosis to flls, The British Medicl Journl, vol. 336, no. 7636, pp , [36] T. Msud, N. Binkley, S. Boonen, nd M. T. Hnnn, Officil positions for FRAX clinicl regrding flls nd frilty: cn flls nd frilty be used in FRAX. From Joint Officil Positions Development Conference of the Interntionl Society for Clinicl Densitometry nd Interntionl Osteoporosis Foundtion on FRAX, Journl of Clinicl Densitometry, vol. 14, no. 3, pp , [37] M. Espllrgues, L. Smpietro-Colom, M. D. Estrd et l., Identifying bone-mss-relted risk fctors for frcture to guide bone densitometry mesurements: systemtic review of the literture, Osteoporosis Interntionl, vol. 12, no. 10, pp , [38] E. M. Dennison, J. E. Compston, J. Flhive et l., Effect of co-morbidities on frcture risk: findings from the Globl Longitudinl Study of Osteoporosis in Women (GLOW), Bone, vol. 50, no. 6, pp , [39] E. M. Lewiecki, J. E. Compston, P. D. Miller et l., Officil Positions for FRAX Bone Minerl Density nd FRAX simplifiction from Joint Officil Positions Development Conference of the Interntionl Society for Clinicl Densitometry nd Interntionl Osteoporosis Foundtion on FRAX, Journl of Clinicl Densitometry, vol. 14, no. 3, pp , [40] W.D.Leslie,L.M.Lix,H.Johnsson,A.Oden,E.McCloskey, nd J. A. Knis, Spine-hip discordnce nd frcture risk ssessment: physicin-friendly FRAX enhncement, Osteoporosis Interntionl, vol. 22, no. 3, pp , [41] S. Vsikrn, R. Estell, O. Bruyère et l., Mrkers of bone turnover for the prediction of frcture risk nd monitoring of osteoporosis tretment: need for interntionl reference stndrds, Osteoporosis Interntionl, vol. 22, no. 2, pp , [42] L. J. Melton III, A. E. Kerns, E. J. Atkinson et l., Seculr trends in hip frcture incidence nd recurrence, Osteoporosis Interntionl, vol. 20, no. 5, pp , 2009.

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