Evaluation of bone mechanical strenght and fracture risk assessment (Frax®) in patients with hip joint replacement surgery

e v a ­l u a ­t i ­o n o f b o n e m e c h a ­n i ­c a l s t r e n g h t

a n d f r a c ­t u ­r e r i s k a s s e s s m e n t

(

) ­

j o i n t r e p l a ­c e ­m e n t s u r ­g e r y

A.­Rodri­gues,

_{J.­Cae­ta­no-Lopes,}

_A.­Nery

_{,­E.­Vieira-Sousa,}

_{J.­Poli­do-Perei­ra,}

_M.­Vale,

_{P.­Ama­ral,}

J.C.­Romeu,

_{M.­Viana­Quei­roz,}

_{J.­Mon­tei­ro,}

_M.F.­Vaz,

_{J.E.­Fon­se­ca}

_H.­Canhão

Con clu sions: The wor se me cha ni cal pro per ti es ob

-ser ved in the fra gi lity frac tu re pa ti ents were re la ted

to high pro ba bi lity of frac tu re gi ven by FRAX®_.

These ob ser va ti ons, in a very small sam ple, need further con fir ma ti on. Howe ver, they sug gest that

the frac tu re risk as sessment tool, FRAX®_{, may re}

-flect the cur rent me cha ni cal bone be ha vi or of the pa tient.

Keywords: Me cha ni cal Tests; Os te o po ro sis; Hip

Frac tu re; Fra gi lity Frac tu re; FRAX®_.

In tro duc ti on

Os te o po ro sis (OP) is de fi ned as a syste mic ske le tal di se a se, cha rac te ri zed by low bone mass and mi cro ar chi tec tu ral de te rio ra ti on with a re sul ting in -cre a se in bone fra gi lity and, hen ce, sus cep ti bi lity to

frac tu re.1_{Os te o po ro tic frac tu res, na mely hip frac}

-tu res, im po se a ma jor eco no mic bur den on he

alth-care systems.2_{Glo bally, OP af fects around 150 mil}

-li on pe o ple3_{and in Eu ro pe it af fects about 75 mil}

-li on per sons.4_{The Third Na ti o nal He alth and Nu}

-tri ti on Exa mi na ti on Sur vey (NHA NES III) study

per for med in Uni ted Sta tes of Ame ri ca, re ve a led that 20% of post-me no pau sal Cau ca si an wo men, 12% of His pa nic wo men and 8% of Afri can Ame ri

-can wo men, have OP.5_{In Por tu gal, the in ci den ce}

of hip frac tu res cau sed by low or mo de ra te im pact falls in wo men va ri es from 154 to 572 per 100 000 in ha bi tants, whi le in men the in ci den ce is lower

and va ri es from 77 to 232 per 100 000 in ha bi tants.6-8

Cur rently, the stan dard di ag nos tic tool for os teo -po ro sis is Dual X-ray Ab sorpti o metry (DXA) which only me a su res bone mi ne ral den sity (BMD) and does not take into con si de ra ti on the qua lity of bone, in clu ding its mi cro ar chi tec tu ral and struc tu ral de sign. The as sessment of os te o po ro sis by BMD alo

-*Rheu­ma­to­logy­Rese­arch­Unit,­Ins­ti­tu­to­de­Medi­ci­na­Mole­cu­lar, Facul­da­de­de­Medi­ci­na­da­Uni­ver­si­da­de­de­Lis­boa,­Lis­bon **Department­of­Rheu­ma­to­logy­and­Bone­Meta­bo­lic­Dise­a­ses, Hos­pi­tal­de­Santa­Maria,­Lis­bon ***Depar­ta­men­to­de­Enge­nha­ria­de­Mate­ri­ais,­Ins­ti­tu­to­Supe­rior Téc­ni­co,­Ins­ti­tu­to­de­Ciên­cia­e­Enge­nha­ria­de­Mate­ri­ais­e­ Super­fí­ci­es,­Lis­bon ****Department­of­Ortho­pa­e­dics,­Hos­pi­tal­de­Santa­Maria,­Lis­bon

Abs tract

Background: Frac tu re risk as sessment to ols are

use ful to cal cu la te the long term pro ba bi lity of os -te o po ro tic frac tu re. Howe ver, how it re flects bone qua lity is unknown. The aim of this study was to

correlate the FRAX® _{tool with bone mechanical}

properties.

Me thods: Six pa ti ents sub mit ted to hip re pla ce

-ment sur gery, ei ther due to os te o po ro tic frac tu res or to os te o arthri tis, were eva lua ted. Bone sam ples were col lec ted and the me cha ni cal pro per ti es as ses sed by com pres si on tests. Pa ti ents’ data re gar ding the pre sen ce of cli ni cal risk fac tors for frac tu -re we-re -re gis te -red. La bo ra to ri al as sessment of bone me ta bo lic pa ra me ters and a dual Xray ab sorpti o -metry (DXA) were done.

Re sults: Analysis of the load-dis pla ce ment cur ves

showed that pa ti ents with fra gi lity frac tu res (n=4) had low va lu es of elas tic mo du lus, yi eld load and energy ab sor bed un til yi eld po int. Os te o arthri tis pa ti ents tend to have a bet ter bi o me cha ni cal per for man ce. Fe mo ral neck DXA scan was also per for -med in 3 pa ti ents. Fra gi lity frac tu re pa ti ents had a lower bone mi ne ral den sity than the pa ti ents with

os te o arthri tis. FRAX®_{al go rithm was ap pli ed and a}

po si ti ve re la ti on was found betwe en FRAX®_{re sults}

and bi o me cha ni cal pa ra me ters. Blo od bone me ta -bo lic markers were wi thin the nor mal ran ge for all the sub jects.

ne un de res ti ma tes the risk of ha ving an os te o po ro -tic frac tu re. For exam ple, the an nu al in ci den ce of hip frac tu re in cre a ses ap pro xi ma tely 30 fold be-tween 50-90 ye ars but this is out of pro por ti on to what would be ex pec ted by com pu ting the frac tu re risk as so cia ted with the loss of bone that would occur du ring this 40 ye ars time fra me (only a 4 fold in

-cre a se in frac tu re risk).2_{Al though bone mass is an}

im por tant com po nent of the frac tu re risk, other abnor ma li ti es in bone struc tu re con tri bu te to fra gility.

The strength of bone is de ter mi ned by its com -po si ti on and struc tu re. It must be stiff, fle xi ble and

light.9_{Bone is a com po si te struc tu re com po sed}

mainly by type I col la gen and cal ci um hydroxya pa

-ti te crystals.10_{The in cre a se in tis sue mi ne ral den sity}

po ten ti a tes bone stiffness but sa cri fi ces fle xi bi lity. On the other hand, newly for med col la gen gi ves fle xi bi lity to the bone but de cre a ses stiffness. The com po si ti on and de gree of col la gen cross-linking

also in flu en ce the me cha ni cal per for man ce.11,12

Howe ver, the oc cur ren ce of frac tu re de pends on many as pects like the pro pen sity to falls, energy of im pact, bone size and not only on bone bi o me cha

-ni cal pro pri e ti es and mi cro ar chi tec tu re.13-16_{A com}

-pu ter-ba sed al go rithm, FRAX®_{, has re cently been}

developed by the University of Sheffield in order to as sess the ten year pro ba bi lity of frac tu re, taking into ac count cli ni cal and epi de mio lo gi cal risk fa c -tors, as well as DXA re sults. The cli ni cal risk fac tors in clu de low body mass in dex, pri or lowener gy frac -tu re, pa ren tal his tory of hip frac -tu re, long term use of oral glu co cor ti coids, rheu ma toid arthri tis and other se con dary cau ses of os te o po ro sis, cur rent ci -ga ret te smoking and al co hol in take. The ten year

frac tu re pro ba bi lity cal cu la ted by FRAX®_{de pends}

on the frac tu re rate of each country. At the mo ment, in ter ven ti o nal thres holds are being de ve lo ped ba -sed on cost-ef fec ti ve ness analysis of each country in or der to al low the di rect ap pli ca ti on of this me

-tho do logy to cli ni cal prac ti ce.2,17_{Howe ver, a di rect}

link bet ween the frac tu re risk as sessment at 10

ye ars ob tai ned by the FRAX®_{tool and the bone bio}

me cha ni cal pro per ti es at the mo ment of the evalua ti on would fur ther con tri bu te to re fi ne the cor rect thres hold for tre at ment de ci si on ba sed not only on epi de mio lo gi cal cost-ef fec ti ve ness analy-sis but also on physio pa tho lo gi cal and cli ni cal

data.18

The re fo re, the aim of this ex plo ra tory study was to cor re la te the in di vi dual ten year pro ba bi lity of frac tu re, ba sed on cli ni cal frac tu re risk fac tors and DXA re sults, with bone me cha ni cal pro per ti es.

Ma te ri al and me thods

Study po pu la ti on

Pa ti ents sub mit ted to hip re pla ce ment sur gery, ei ther due to os te o po ro tic frac tu res or to os te o arthri -tis, were eva lua ted. La bo ra to ri al pa ra me ters of bone me ta bo lism, such as bone alka li ne phos pha ta se (ALP), bone spe ci fic alka li ne phospha ta se (BSALP), pro col la gen type 1 N-ter mi nal pro pepti de (P1NP), col la gen type 1 beta C-ter mi nal te lo pep ti de (bCTX), se rum cal ci um and phospho rus and pa ra -thor mo ne le vels, were as ses sed. Fe mo ral neck BMD was me a su red by DXA scan using a Lu nar Pro digy den si to me ter (GE He althca re, Uni ted King dom) and t sco re re sults were cal cu la ted using NHA NES re fe -ren ce va lu es for wo men aged 20-29 ye ars.

Risk fac tors for frac tu re were ob tai ned from a cli -ni cal pro to col – age, sex, low body mass in dex

(BMI≤19 kg/m2_{), pri or fra gi lity frac tu re, pa ren tal}

his tory of hip frac tu re, long term use of oral glu co -cor ti coids (eg. for 3 months or more), rheu ma toid arthri tis and other se con dary cau ses of os te o po ro -sis, cur rent smoking and al co hol in take (3 or more units/day). The pro ba bi lity of frac tu re at ten ye ars

was pre dic ted using the FRAX®_{tool avai la ble on li}

-ne (http://www.shef.ac.uk/FRAX/), ca li bra ted to the epi de mio logy of frac tu re and life ex pec tancy of Spain, sin ce in Por tu gal this data was not avai la ble. The al go rithm pro vi des two out puts, the ten year pro ba bi lity of ha ving a ma jor os te o po ro tic frac tu -re (cli ni cal spi ne, hip, fo -re arm or hu me rus) and the ten year pro ba bi lity of a hip frac tu re alo ne.

Me cha ni cal tests

At the time of sur gery, pro xi mal fe mo ral sam ples were col lec ted and sto red at -80ºC. Sam ples were de fros ted at room tem pe ra tu re be fo re tes ting.

Com pres si on tests on fe mo ral epiphysis were per for med in a uni ver sal tes ting ma chi ne (Ins tron 5566™, Ins tron Cor po ra ti on, Can ton, USA) using a load cell of 10kN (Fi gu re 1A). The bi o me cha ni cal strength va ri a bles were dis played from the load-dis pla ce ment cur ves (Fi gu re 1B) ob tai ned with the

Blu e hill 2 Softwa re (Ins tron, Copyright 1997-2007)

and analyzed using Mat Lab 7.1 softwa re (R14 SP3, The Mathworks, Inc, Copyright 1984-2006). The softwa re has the abi lity to build stressstrain re -pre sen ta ti ons from load-dis pla ce ment po ints once ini ti al di men si ons are pro vi ded for each spe ci men. In this test, a cross head spe ed of 0.1mm/s was used and elas ti city mo du lus, yi eld load and ener-gy un til yi eld po int were ob tai ned.

Re sults

Study po pu la ti on and cli ni cal risk fac tors for frac tu re

Six patients submitted to hip re -pla cement surgery were evalua ted for clinical risks factors for frac-ture. Five pa ti ents were wo men and one was a man. The arthro plasty was per for med in four pa -tients due to low energy trau ma and in the other two be cau se of os -te o arthri tis (Ta ble I). All pa ti ents with a fra gi lity frac tu re had between one to three cli ni cal risk fac tors. Pa ti ent num ber one was un der syste mic cor ti cos te roid the -rapy for se ve ral ye ars due to asth-ma. Pa ti ent num ber two had ter mi nal chro nic re nal fai lu re sin ce 2006. Pa ti ent num ber 3 had se -ve ral spi ne os te o po ro tic frac tu res and pa ti ent 4 had si mul ta ne ously type 1 dia be tes mel li tus and to -bac co ha bits. This last pa ti ent was un der bisphospho na te tre at ment for se ve ral ye ars. The pa ti ents sub -mit ted to hip re pla ce ment sur gery due to os te o arthri tis did not re fer any cli ni cal risk fac tor for frac tu re. Fe mo ral neck DXA scan was per for med in 3 pa ti ents. Pa ti ents with fra gi lity frac tu re had a lower bone mi ne ral den sity than tho se

Fi gu re 1. Ex pe ri men tal se tup and

load-dis pla ce ment cur ves ob tai ned af ter fe mo ral head com pres si on. Ima­ges­of­the

tes­ting­ma­chi­ne­and­a­hu­man­fe­mo­ral head­stan­ding­on­the­in­fe­rior­pla­te­of­a com­pres­si­on­test­se­tup­(A).­Patient­1 and­5­load-displacement­compression curve­(B).­Cur­ves­were­ob­tai­ned­in­ or­der­to­de­ter­mi­ne­the­yi­eld­po­int­= (yi­eld­dis­pla­ce­ment,­yi­eld­load),­or­af­ter­ cal­cu­la­ti­ons,­the­elas­tic­mo­du­lus­(slo­pe of­the­cur­ve­betwe­en­the­ori­gin­and the­yi­eld­po­int)­and­the­energy­un­til­ yi­eld­po­int­(area­un­der­the­grap­hic from­the­ori­gin­un­til­the­yi­eld­po­int, cal­cu­la­ted­using­tra­pez

age dif fe ren ce was of 4 ye ars. The analysis of the load-dis pla ce ment cur ves (Fi gu re 1B), from the fe mo ral he ads of pa ti ents 1 and 5, showed that the fra gi lity frac tu re sam ple (Ta ble II) had lower, elas-ticity mo du lus (re flec ting re du ced stiffness), yi eld load (me a ning that a lo wer load was ne e ded to cause the first mi cro frac tu res and to start a plas tic and de fi ni ti ve de for ma ti on of bone) and energy un til yi eld po int (that is, the ener gy that bone can sup port be fo re frac tu re) than the os te o arthri tic one.

Re gar ding the other fe mo ral he ads, with ex cep -ti on of the elas -tic mo du lus, the load and the ener-gy ab sor bed un til the yi eld po int were hig her in the os te o arthri tic fe mo ral he ads than in the fra gi -lity frac tu re ones.

Pa ti ent num ber 4, who had a fra gi lity frac tu re and was un der bisphospho na te the rapy, was an ex cep ti on, re ve a ling a bet ter bi o me cha ni cal per -with os te o arthri tis (Ta ble I).

Bi o che mi cal markers of bone tur no ver were wi -thin the nor mal ran ge in all pa ti ents.

Frac tu re risk as sessment pre dicts me cha ni cal bone be ha vi or

Analysis of the loaddis pla ce ment cur ves of pa -tients sub mit ted to hip re pla ce ment sur gery was done. In this kind of cur ves the size of the fe mo ral he ads has an im pact in the bi o me cha ni cal be ha -vi our. Os te o arthri tic sam ples tend to have a lar ger di a me ter than fe mo ral he ads col lec ted from fra gi -lity frac tu res, in the same way that men tend to have lar ger fe mo ral epiphysis than wo men. So, in or der to make a more ac cu ra te com pa ri son, it was used the lar gest fra gi lity frac tu re wo man s fe mo ral head (pa ti ent 1) and the smal lest os te o arthri tic (pa ti ent 5), whe re the dif fe ren ce in di a me ter is 1.27cm. The se pa ti ents were both wo men and the

Table I. Epidemiological and clinical characteristics of the patients and their clinical risk of fracture assessment

Femoral neck DXA

scan FRAX®

Clinical Major Hip

Age BMI BMD risk osteoporotic fracture

Diagnosis (years) Gender (Kg/m2₎ T score (g/cm2_{) factors (n) fracture (%) (%)}

Patient­1 FF 77 F 24.4 – – 2 28.0 15.0 Patient­2 FF 67 F 24.6 -3.8 0.525 2 21.0 12.0 Patient­3 FF 86 F 20.4 – – 1 26.0 15.0 Patient­4 FF 69 F 24.0 -2.0 0.738 3 11.0 4.7 Patient­5 OA 73 F 24.8 -1.6 0.673 0 5.4 1.4 Patient­6 OA 85 M 25.9 – – 0 6.6 3.6 FF­–­Fragility­fracture OA­–­Osteoarthritis FF­–­Fragility­fracture OA­–­Osteoarthritis

Table II. Values calculated from mechanical compression load-displacement curves of human femoral epiphysis

Elastic Yield Energy until Energy until

Diameter modulus load Densification yield point densification

Diagnosis (mm) (N/mm) (N) load (N) (N/mm) point (N/mm)

Patient­1 FF 41.87 240.7 4.602 4.237 39.465 80.603 Patient­2 FF 38.49 132.8 2.003 2.484 11.688 27.468 Patient­3 FF 41.18 319.8 2.842 4.927 13.804 59.818 Patient­4 FF 41.29 407.6 6.608 7.101 44.441 96.741 Patient­5 OA 43.13 287.5 5.826 4.571 58.939 104.210 Patient­6 OA 48.60 449.2 3.828 2.170 17.482 48.987

for man ce than the others with fra gi lity frac tu re.

The FRAX®_{al go rithm was ap pli ed and the pro}

ba bi lity of hip frac tu re and the ten year pro ba bi lity of ha ving a ma jor os te o po ro tic frac tu re was de ter mi ned in each pa ti ent (Ta ble I) and then com -pa red with bi o me cha ni cal -pa ra me ters (Fi gu re 2).

In fra gi lity frac tu re pa ti ents FRAX®_{out put was}

always abo ve 20% (2128%) with ex cep ti on of pa tient 4 that had pro ba bi lity of ha ving a ma jor os -teo po ro tic frac tu re of 11%. The se pa ti ents had worst me cha ni cal be ha vi our. Mo re o ver, in this group pa ti ent 4 was the one that have the bet ter me cha ni cal per for man ce along to the lower FRAX out put, rein for cing the mul ti fac to rial me cha nism of frac tu re. In Pa ti ents 5 and 6 (os te o arthri tis) the risk of ma jor os te o po ro tic frac tu re was of 6,6% and 5,4% res pec ti vely and they had good me cha ni cal per for man ce.

A po si ti ve re la ti on was found betwe en the re

-sults from FRAX®_{and the bi o me cha ni cal pa ra me}

-ters re sul ted from the com pres si on tests. Pa ti ents with hig her frac tu re risk were found to have poor bi o me cha ni cal per for man ce.

Dis cus si on

The fracture risk as sessment tool – FRAX®_{– was de}

ve lo ped at the Sheffield University, ba sed in cli ni -cal risk fac tors for frac tu res iden ti fi ed in pre vio us metaanalysis. It uses data from nine co horts, in -clu ding tho se from North Ame ri ca, Eu ro pe, Asia and Aus tra lia and it has been va li da ted in ele ven in de pen dent po pu la ti ons with si mi lar ge o grap hic

dis tri bu ti on.18_{The FRAX}®_{tool cal cu la tes the ten}

year abso lu te risk for frac tu re and re pre sents a step forward when com pa red to the re la ti ve risk pro vi ded by DXA me a su re ments; it can have ma jor im pli ca ti ons in the fu tu re, with im pact in phar ma co -e co no mic and cli ni cal tr-e at m-ent d-e ci si ons. Bon-e

051000020004000P . 2P . 3P . 1P . 5P . 6P . 43000500060007000252015

10

30

FRAX - major osteoporotic fracture(%)

Yeld load (N)Fragility fractureOsteoarthritis050100200P . 2P . 3P . 1P . 5P . 6P . 4300400500252015

10

30

FRAX - major osteoporotic fracture(%)

Elasticity Modulus (N/mm) 0 5 1000 0 2000 4000 P . 2 P . 3 P . 1 P . 5 _{P . 6} P . 4 3000 5000 6000 7000 25 20 15 10 30 FR A X m aj o r o st e o p o ro ti c fr ac tu re (% ) Yeld load (N) Fragility fracture Osteoarthritis 0 5 0 100 200 P . 2 P . 3 P . 1 P . 5 P . 6 P . 4 300 400 500 25 20 15 10 30 FR A X m aj o r o st e o p o ro ti c fr ac tu re (% ) Elasticity Modulus (N/mm) Figure 2. Relation­between­the­ten­years­probability­of­having­a­major­ osteoporotic­fracture­given­by­FRAX®­and­the­biomechanical­parameters­elastic modulus­and­yield­load

pro per ti es, na mely me cha ni cal ones, de pend on bone struc tu re, which ul ti ma tely are in flu en ced, through com plex and not fully un der sto od me cha -nisms, by cli ni cal risk fac tors and bone mi ne ral den sity, which are the va ri a bles re qui red for the

cal cu la ti on of frac tu re risk pro ba bi lity by FRAX®_.

Howe ver, it is unknown how frac tu re risk com pu ta ti on by FRAX re flects bone qua lity and me cha ni -cal pro per ti es at the time of as sessment, which is of ma jor im por tan ce sin ce the OP the ra peu tic in

-ter fe res with bone qua lity.19-21_{This work, per for}

-med as an ex plo ra tory pro of of con cept ap pro ach, re la tes the ten year pro ba bi lity of frac tu re gi ven by

FRAX®_{with the de te rio ra ti on of the qua lity of bone}

analysed by me cha ni cal tests. Des pi te pro mi sing, this study has ma jor li mi ta ti ons such as the sam -ple size and the fact that the who le fe mo ral head was used for the com pres si on tests, which me ans that cor ti cal, tra be cu lar and wa ter bone com po -nents were tes ted si mul ta ne ously which might

have dif fi cult data in ter pre ta ti on.22_{Howe ver, in}

vivo, load is ap pli ed on who le fe mo ral head and in

de ed the se fac tors in fluen ce the me cha ni cal res -pon se in real life con di ti ons. The pro blem is that fe mo ral he ads are nei ther ho mo ge ne ous, nor per fect sphe res with the same di men si ons, which in -du ces bias in the com pres si on re sults and li mits their re pro du ci bi lity. The re fo re, the lack of re pro -du ci bi lity does not al low us to have an ac cu ra te com pa ri son betwe en the two study groups. Howe -ver, com pa ring pa tients 1 and 5, who have the most alike age and ana to mic fe a tu res, sug gests that the bi o me cha ni cal be ha vi our is wor se for the pa ti ents that had a fra gi lity frac tu re than for tho se with os -te o arthri tis.

This ex plo ra tory study al lows us to sus tain the

hypo the sis that FRAX®_{can have a cor re la ti on with}

me cha ni cal pro per ti es and it is our view that this con cept should be tes ted in a lar ger sam ple with me cha ni cal tests per for med in cylin ders of tra be -cu lar bone ex trac ted from the fe mo ral epiphysis, which ena bles to cal cu la te stress and strain and will al low to com pa re the me cha ni cal re sults from dif fe rent sam ple di men si ons, thus, con duc ting to a hig her re pro du ci bi lity.

Con clu si on

The wor se me cha ni cal pro per ti es ob ser ved in the pa ti ents that sus tai ned a fra gi lity frac tu re were re la ted with the hig her pro ba bi lity of frac tu re

calcu la ted by FRAX®_{. The se ob ser va ti ons, in a}

very small sam ple, need fur ther con fir ma ti on. Howe ver, they sug gest that the frac tu re risk as

-sessment tool FRAX®_{may re flect bone me cha ni cal}

be ha vi our.

Acknowledgements

Work supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2006 and by the PTDC/SAU-BEB/65992/2006 grant from Fundação para a Ciência e Tecnologia.

Cor res pon den ce to Hele na Canhão

Rheu ma to logy Rese arch Unit,

Ins ti tu to de Medi ci na Mole cu lar, Edi fí cio Egas Moniz, Facul da de de Medi ci na da Uni ver si da de de Lis boa Av. Pro fes sor Egas Moniz

1649-028 Lis bon, Por tu gal Tel: +351-213999545, Fax: +351-217999504

E-mail: hele na ca nhao@net ca bo.pt Re fe ren ces

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VIII Jornadas do Aparelho Locomotor.

Novos Desafios em Reumatologia

Braga, Portugal

30 a 31 de Outubro de 2009