Acceleration of Tibial Fracture Healing by Non Invasive Low Intensity Ultrasound

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  • 7/27/2019 Acceleration of Tibial Fracture Healing by Non Invasive Low Intensity Ultrasound

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    Copy r i gh t 1994 by Th e Jou rna l o f B one and J oint Su rge ry . I ncorpora ted

    26 THE JOUR NA L O F BON E AND JO IN T SU RGERY

    A cce lera tion o f T ib ia l F rac tu re -H ea lin gby N on -Invasiv e , L ow -In ten sity Pu lsed U ltra sound*

    BY JAMES D . H ECKM AN . M .D .t, JOHN P . R YA BY t, JO A N M CCABE , R .N .I , JOHN J. F REY . PH .D 1 . A ND R AY F . K ILC OYN E . M .D .# .SA N AN TON IO . TEXAS

    inv est iga tion p erform ed a t Th e U niv ers ity o f Te xas H ea lth S cie nce C en te r a t Sa n Anton io , S an A nto n io

    ABSTRACT : S ix ty -seven c losed o r grad e -I op en frac -tu res o f th e tib ia l sh a ft w ere ex am in ed in a p rosp ec tiv e,random ized , d oub le-b lind eva lua tion of u se o f a n ewu ltra sou nd stim u la tin g d ev ice as an ad junc t to conv en -tiona l tr ea tm en t w ith a cas t . Th ir ty -th ree fra c tu re s w eretrea ted w ith th e ac tive d ev ic e an d th ir ty -fo u r , w ith ap lacebo con tro l d ev ic e . A t th e end of th e trea tm en t,th ere w a s a sta tis tica lly s ig n ifican t d ecrease in th e tim eto c lin ica l h ea lin g (86 5. 8 days in th e a ctive -trea tm en tg roup com pared w ith 114 10 .4 days in th e con tro lg roup ) (p = 0 .01 ) and a lso a s ign ifican t d ecrea se in th et im e to over -a ll (c lin ica l and rad iograph ic ) h ea lin g (9 6 4 .9 days in th e ac tive -tr ea tm en t group com pared w ith154 13 .7 d ay s in the con tro l g roup ) (p = 0 .0001). Thepatien ts com p lian ce w ith th e u se o f th e d ev ice w asexce llen t, a nd th ere w ere n o serio u s com p lica tion s re -la ted to its u se . T h is s tudy con firm s ea rlier an im a l andc lin ica l s tud ies th a t d em onstra ted th e effica cy o f low -in ten sity u ltrasound stim u la tion in the acce lera tion o fth e no rm al frac tu re -repa ir p rocess .

    U ltra soun d h as m any m ed ica l ap p licatio ns, in clu d -in g the rapeu tic , o pe rat ive , and d iagn os tic p ro cedu res .B o th u ltra sou nd the rapy and ope rative u ltra sou nd sub -je ct tissue to pow er leve ls tha t a re capab le o f caus ingcon s ide rab le h ea tin g and b io lo g ic a l e ffec ts . In co nv en -tiona l u ltra so un d the rap y , u ltra son ic in ten s itie s o f on eto th ree w atts pe r squ are cen tim e te r a re used to de -c rea se jo in t s tiffn ess , red uce pa in and m u scle sp asm s,and im p rov e m usc le m ob ility . T he op era tive app lica -

    *O ne or m o re of the au tho rs hav e rece ived or w ill rece iv e ben-e fits fo r p ersona l or p rofess ion al use from a comm ercia l pa rty re-la ted d ire ctly o r in d ire ctly to th e sub jec t o f th is art ic le . In add itio n ,benef its h ave b een o r w ill b e d irec ted to a re sea rch fund o r fou nda -tio n , e duc ationa l inst itu t ion . o r o the r no n-p rof it o rg an iza tion w ithw hich o ne or m o re of the au th ors a re as soc iate d . F unds w e re re-c eived in to ta l o r p art ia l supp ort o f th e re sea rch o r clin ic al stud yp resen ted in th is ar tic le . Th e fund in g sou rce w as E xog en , Inco rpo -rated .

    tD ep artm ent o f O rth op aed ics . Th e U n iversity of T ex as H ea lthSc ien ce C en ter at S an A nton io , 770 3 F loy d Cu rl D rive, San A nto n io ,T ex as 7 82 84 -7 77 4.

    lExogen , In corporate d . 8 10 P assaic A v enu e, W est C a ldw ell ,N ew Jersey 0 7006-6489 .

    3 8 R andolph Ro ad . W h ite P lain s, N ew Y ork 10607 . lHeal th P ro duc ts D eve lopm ent, Inco rpo rated , 1 853 W illiam

    Penn W ay , L ancas te r, Pennsy lvan ia 17601 .#D epar tm ent o f R ad io lo gy , Th e Un ive rsi ty of Co lorado H ealth

    Scienc e C ente r, 4200 E ast N in th A v enu e, D env er, C olo rad o 80262 .

    tion o f u l traso un d em p loy s in ten si ty lev els o f five tom ore than 3 00 w atts pe r squ are cen tim e te r to fragm en tca lcu li an d to ab la te d ise ased tissue s such a s catara cts2 0 .T hese re la tive ly h igh u ltra sou nd in tens itie s a re em -p loy ed to g en era te h ea t w ith in th e tissu e s, th rou ghw hich th e u ltra soun d signa l p asses5 . D iag no s tic ap p lic a -tio ns o f u ltra so und in clu de exam ina tion of v ital o rgans ,eva lua tio n o f fe tu ses , v ascu la r an d pe rip he ral flow stu d -ie s , and oph tha lm ic echo grap hy . T he d iag nos tic ap p lica-tio ns o f u ltrasou nd use m uch low er in ten s itie s , typ ic allyfive to fifty m illiw atts p er squa re cen tim ete r, to av o idexcess ive h ea tin g o f t issu es.

    X av ie r and D ua rte2 rep o rted the acce le ra tion o fth e n o rm al frac tu re-repa ir p rocess in hum ans w ith useo f low -in tens ity (d iag no st ic-rang e ) u ltra sou nd an d alsoin d ic ated th at low -in tens ity u ltra so un d can ind uce h ea l-in g o f un un ited d iaph yseal frac tu re s22 . W ith use o f arab b it fib u la r o s teo tom y m ode l an d a seco nd m ode lth at em plo yed a d ril l-ho le in th e co rtex o f the fem ur o fa rabb it, D u a rte dem on stra ted acce lera tion of th e nor-m al frac tu re -repa ir p ro cess w ith u se o f u ltraso un d .P il la e t a !., w ith u se o f a s ligh tly d ifferen t fibu lar o steo t-om y m ode l, a lso d em on stra ted tha t n on -inv as iv e , low -in ten s ity pu lsed u ltraso und accelera ted fra ctu re -h ealingin the rabb it. K lug et a l . u sed a sc in tig raph ic te chn iqu eto dem onstra te qu ick er m a tu ra tio n o f the callu s an dearlie r h ea lin g in ex pe rim en ta lly ind uced c losed fra c -tu re s in a rab b it m od el a fter u ltra sou nd s tim u lat ion w ithin tensity leve ls tha t w ere an orde r o f m agn itu de h igh erthan th ose used b y D ua rte o r by P illa e t a l. B ecau se w ebe lieve tha t th ese p re lim in ary s tu d ie s c le arly sh ow ed apo si tive e ffe c t o f u ltra sou nd on th e ra te o f o sseou s re-pa ir , w e de s ign ed the p re sen t s tud y to in ve st iga te th eeffe ct o f specifica lly p ro g ramm ed , low -in ten si ty p u lsedu ltra sou nd on th e ra te o f h ea lin g o f co rtic a l frac tu resw h en u sed in p atien ts a s an ad jun ct to co nv en tio na lo rth opaed ic m an ag em en t.

    M ater ia ls and M ethod sThe s tud y w as m u lti- in s titu tio na l, p ro spect ive , ran -

    d om ized , d oub le -b lin d , and p la cebo -co n tro lled . T he rew e re co -in ve s tiga to rs from six te en s ite s in v ario us geo -g rap h ica l are as o f the U n ited S ta te s an d from on e s itein Is ra el.

    An opportun ity to p art ic ip a te in the s tu dy w as o f-fe red to all ske le ta lly m atu re m en and non-p reg nan t

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    ACCELERAT ION OF TIB IA L FRACTURE -HEAL ING BY NON -IN VA SIV E . LOW -INTEN SITY PULSED U LTRASOUND 27

    VOL . 76 .A , N O . 1 . J AN U AR Y 1994

    w om en seen at ou r in stitu tion s be tw een S ep tem ber 19 86an d D ecem ber 19 90 w ho w ere a t m ost sev en ty -fiv e y ea rso ld and w ho had a c losed or g rad e-I op en tib ia l d iaphy s-eal frac tu re tha t w as p rim arily tran sve rse, sho rt ob liq ue ,o r sho rt sp iral and tha t cou ld be trea ted e ffectiv ely w ithc losed redu ction an d imm obiliza tion in a cast.

    A nte ro pos te r io r and la te ra l rad iog raphs w ere m ad eimm ed ia te ly a fte r th e reduc tio n . W e exc lud ed p a tien tsif e ithe r the an te ro pos ter io r o r the la tera l rad io g rap hsshowed th at the leng th o f the frac tu re line w as m orethan tw ice th e d iam e te r o f the d iaphy seal sh aft (a lon gsp iral o r long ob lique frac tu re ), the d isp lacem en t w asm ore than 50 p er cen t o f th e w id th o f the sh aft, o r thefrac tu re gap w as m ore than 0 .5 cen tim e ter . O the r ex clu -sion c rite ria w ere open frac tu re s , ex cep t g rade I a s de -fined by G u stilo and A nde rson ; frac tu re s o f the tib ia lm etaph ysis ; frac tu res w ith p ers is ten t sho rten in g o f m orethan one cen tim e ter a fte r red uc tion ; frac tu res tha t w ereno t su ff icien tly stab le (recu rren t o r pe rs is ten t ang u la -tion o f 10 deg rees o r m ore in any p lan e ) fo r treatm en tw ith imm obilizatio n in an above -th e-knee cast; f rac tu re sw ith a large b u tte rf ly fragm en t ( la rg er than tw o tim esthe d iam e ter o f th e tib ia l sha ft); p ath o log ica l fractu re s;an d com m inu ted fractu re s (com m inu tion w ith frag -m en ts o f les s than one cen tim e ter in leng th w as accep t-ab le) . P a tien ts w ere a lso exc lud ed if they had s tated tha tthey co u ld no t com ply w ith th e p ro toco l: w e re re ceiv ingste ro ids, an ticoagu lan ts , p rescr ip tion non-stero id al an ti-in f lam m ato ry m ed ica tion , ca lcium -ch an ne l b locke rs , o rd ip hosp hon ate the rapy ; had a h is to ry o f th rom boph le -b itis o r vascu la r in su ff ic ien cy ; o r had a recen t h isto ry o fa lco ho lism o r nu tritio na l de ficiency , o r b o th .

    A fter th ey had agreed to pa rticip ate in the stu dyand gave in fo rm ed con sen t, th e pa tien ts w ere ran dom -ized in to g rou ps o f fou r a t each stu dy site to rece ive anac tive o r a p laceb o-treatm en t dev ice accord ing to a pre -de te rm in ed com pu ter-gene ra ted cod e . T he code w asb rok en on ly afte r th e rad io g rap h ic rev iew s had b eencomp le t ed .

    N ine ty -s ix pa tien ts , w ho had a to ta l o f n ine ty -sevenfrac tu res, w ere en te red in to th e s tudy . F o rty -e igh t o fthe frac tu res w ere ran dom ized to th e ac tive -treatm en tg rou p and fo rty -n ine , to the p laceb o-trea tm en t con tro lg rou p . T h ir teen pa tien ts ( th ir teen frac tu res [1 3 pe rcen t]) w ere los t to fo llow -up , leav ing e igh ty -fou r p a-tien ts (e ig h ty -fiv e frac tu re s [88 p e r cen t]) in w hom th eh ea ling sta tu s o f the frac tu re w as k now n . A n add itio na lseven teen pa tien ts (seven teen frac tu re s [18 pe r cen t])w ere exc luded from the stu dy because o f dev ia tionsfrom the pro toco l.

    O f the th irte en p atien ts (fou r w ho had activ e tre at-m en t and n ine , p lacebo trea tm en t) w ho w ere lost tofo llow -up an d fo r w hom the fina l hea ling sta tu s w as no tknow n , seven had w ithd raw n from the s tud y , five h adb een w ithd raw n by the site inv es tiga to r, and on e h add ied of unre lated cau ses sev en w eeks a fte r the frac tu re.O f th e fiv e pa tien ts w ho w ere w ith d raw n by the s ite

    inv es tiga to r, one had had an open red uc tio n an d in te r-na l fixa tio n o f th e frac tu re an d th e rem ain in g fo u r hadno t com plied w ith the ou tlined tre atm en t p ro toco l .

    O f th e sev en te en p atien ts (e lev en w ho had ac tiv etrea tm en t an d s ix , p la ceb o tre a tm en t) w ho w ere cx -c lud ed becau se o f dev ia tio ns from th e p ro toco l, s ix (tw ow ho h ad ac tiv e tre a tm en t and fou r, p lacebo tre a tm en t)had had an ope ra tive p roced ure w ith in six w eek s a fte rthe in ju ry because o f sev e re an gu la tion of the frac tu reafte r tre a tm en t h ad b egun , seven w ere exc lud ed be -cau se the fractu re d id n o t m ee t the inc lusion crite ria o fthe p ro to co l, an d fou r w e re w ithd raw n by the in ve s tig a-to r because o f fa ilu re to com ply w ith the trea tm en tp ro toco l. T h ese seven te en pa tien ts w ere s till fo llow edan d the ou tcom es o f tre atm en t w e re o b ta in ed .

    T he rem a in ing s ix ty -seven fra ctu re s (th irty -th reetha t w e re trea ted w ith an active u n it an d th irty -fou r,w ith a p la ceb o un it) rep resen t the co re g rou p of frac -tu res in pa tien ts w ho adh ered to th e stud y pro toco l andhad su ff ic ien t fo llow -up da ta. It is th is g ro up from w hichthe c lin ic al and s ta tis tic a l in fe ren ce s w ere d raw n .T he re w e re s ix ty -fo u r c lo sed fra c tu re s (th irty -o nein th e ac tive -tre a tm en t g rou p and th irty -th re e in thep laceb o -tre a tm en t g rou p ) an d th ree g rade -I op en frac -tu re s (tw o in th e ac tiv e-trea tm en t g rou p and on e in th ep laceb o -tre a tm en t g rou p ). T he fra ctu res w e re trea tedcon ven tion ally w ith c lo sed redu ction an d imm ob iliz a -tio n in an above -the -kn ee cas t. T he th ree g rad e-I o penfrac tu res w e re trea ted w ith in itia l d #{2 33 }b ridem en t, and thew ound s w e re a llow ed to h ea l b y secon da ry in ten tio n . Are ta in in g an d a lig nm en t f ix tu re m ade o f m old ed p la sticw as inse rted in to a w ind ow cen te red ov er th e an tero -m edia l su rface o f the cast, a t the s ite o f the tib ia l frac -tu re . T h is fix tu re he ld th e tre a tm en t h ead m odu le inp lace du ring the d aily tw en ty -m inu te trea tm en t p e riod .B etw een tre atm en t pe rio ds , a circu lar, fe lt p lu g w as in -se rted in the fix tu re and a cap w as p la ced ove r it tom ain ta in an even pre ssu re on th e sk in an d to m in im izeth e risk o f edem a a t the s ite o f the w ind ow .

    T reatm en t w as s tarted w ith in sev en d ay s afte r th efractu re and consis ted o f o ne tw en ty -m inu te pe rio deach day . T he trea tm en t head m odu le w as p ositio ned inth e w in dow afte r rem ova l o f th e fe lt p lug an d the app li-cat ion o f a sm a ll am oun t o f u ltra so n ic co up ling ge l toth e su rfa ce o f th e h ead . It w as a tta ch ed to a p o rtab lem ain o pe ra ting u n it th at con ta ined the necessa ry c ir-cu itry to d rive the trea tm en t head m odu le and to m on -ito r th e p ro pe r a tta chm en t o f the m odu le in th e cas tfix tu re . A w arn ing s ig na l w as so unded by the m a in op -c ra t ing u n it if the re w as no t p rop er co up lin g to th e sk in .In ad d ition , the m ain o pe ra ting u n it co n ta in ed an in te-g ra l tim er th at m on ito red trea tm en t tim es an d au tom at-ica lly tu rn ed the un it o ff a fte r tw en ty m in u te s. A v isua land au d ib le s ign al a lerted the p atien t tha t the tre a tm en tw as com plete . T h e p a tien ts com plian ce w ith in s tru c-tio ns fo r use o f th e d ev ice w as m easu red by bo th a tim erin side th e m a in op era ting u n it an d a pa tien t-m a in ta ined

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    TABLE IASSESSMENT OF TREATMENT -GROUP COMPARAB IL ITY

    Se x258

    312

    41711

    1517

    312

    267

    924

    36 2.3

    33 4.7(n = 30 )23 2.5

    6 1.0(n=30)4 0.5

    4 0.34 0 .24 0 .3

    250 18 .192-438

    45 4. 9(n = 3)

    0 .37*29

    50 .64*

    33

    0.49*8

    15110

    0.60*3

    1516

    0 .43*295

    0 .77*286

    0 .13*4

    3031 1.8 0 .0 91

    38 4 .9 0 .4 81(n=31)2 3 2.7 0 .9 81

    6 0 .8 0 .7 41

    4 0 .4 0 .8 014 0.3 0 .9 214 0 .2 0 .5 514 0 .3 0 .8 91(n = 33 )

    28419 .2 0 .211142-58649 5.9 0 .621

    A fter red uct ion tAngulat ion (degrees)

    B efore red uct ion t

    Afte r reduct ion tM axim um fractu re gap t ( mm )Length o f frac tu ret ( cm )Days un til star t o f tre atm en tt

    D u rat ion o f fo llow -upt (days)Range

    Days to start o f w eig h t-bear ing t

    28 J . D . H ECKM AN ET AL .

    THE JOURNAL OF BONE AND JO IN T SU RG ERY

    d aily trea tm en t log . Th e ac tive and p laceb o d ev ice s w ereiden tica l in eve ry w ay (they h ad the sam e v isua l, ta c tile ,an d aud ito ry sign a ls) ex cep t fo r th e u ltra sou nd sig na lemit ted .

    T rea tm en t w as con tinued fo r tw en ty w eek s o r un tilth e clin ica l in vestiga to r b elieved tha t the fractu re w ash ea led su ffic ien tly to d is co n tinu e the ac tive o r th e p la-cebo u ltraso un d th erapy .

    T he trea tm en t head m odu le de live red an u ltra -soun d sign al th at w as com posed o f a bu rst w id th o f200 m icroseco nds con ta in ing 1 .5 m egahe rtz sine w aves ,w ith a repe titio n rate o f o ne k iloh ertz an d a sp at ia lave rag e -tem pora l ave rag e in tens ity o f th ir ty m illiw attsp er squ a re cen tim e ter .

    The reg im en fo r trea tm en t o f the frac tu re w as iden -tica l fo r a ll pa tien ts . Im m ob iliza tio n in an abov e-the -k nee cast w as m a in ta ined un til th e in vestiga to r th ough tth at the fractu re w as su ffic ien tly stab le fo r app lica tion ofa sho rt ca st o r a b race. A fter im m ob iliza tion in a cast w asd iscon tin ued , ad d ition al p ro tec tion w ith e ithe r a sp lin to r a b race w as a t th e d isc retio n o f th e in vestiga to r . C as tchan ges w ere perm itted as c lin ica lly in d ica ted . Weigh t -b ea ring w as con tro lled on the b asis o f th e in vestiga to rsc lin ica l ju dgm en t and the to le rance o f the p a tien t. T heo n ly d ifference in the com m on pro toco l o f frac tu re m an -agem en t w as th e in itiatio n of w eig h t-b earing . T he firs tfo r ty - tw o pa tien ts (fo rty -tw o frac tu re s) en ro lled in thes tudy w ere in struc ted no t to bear w eigh t during the f irs te igh t w eeks afte r the fractu re , an d th e rem a in in g fifty -fou r pa tien ts (fif ty -fiv e fractu re s) w ere a llow ed to bearw e igh t a s to le ra ted .

    A ll pa tien ts w e re schedu led to re tu rn fo r fo llow -up rad io g raph s at fou r, s ix , eig h t, ten , tw e lve , fo u r-teen , tw en ty , th ir ty - th ree , and fif ty - tw o w eeks a fte r thefrac tu re. A n te ro pos ter io r an d la tera l rad iog rap hs w erem ad e an d stan da rd ized w hen ev er p ossib le, w ith u se o fth e sam e x-ray m ach ine at each s ite , the sam e exposu rese tting , and a leg -po sition ing dev ice th a t w as fu rn ishedto each site in vestiga to r . C lin ica l fo llow -up eva lua tion sw ere pe rfo rm ed by the site in vestiga to r a t the tim e ofany cast change (u sua lly a t six and ten w eeks) and at th efo llow -u p v isi t w h en rad io g raph ic eva lu atio n in d ic atedth at the frac tu re h ad h ealed su ffic ien tly to a llow re-m oval o f th e cas t.

    The en d-p o in t o f the stu dy w as a hea led frac tu re , a sjud ged bo th on c lin ica l exam ina tion and on rad io -g raph ic exam ina tion (th ree o f fou r co rtices b ridged ). Inadd itio n to the h ea led -fra ctu re end -po in t, in term ed ia tes tag es o f the frac tu re -h ea ling p rocess w ere asse ssed fo rth e d iffe ren ce be tw een the ac tive - trea tm en t and thep lacebo-trea tm en t g rou ps.

    W ith reg ard to th e in te rm ed iate clin ic a l s tage s o fhea ling , tw o p a ram e te rs w ere eva lu ated : th e tim e toc lin ica l h ea ling w as de fin ed as the tim e a t w h ich theind iv idu al site in vestiga to r thou gh t tha t, o n c lin ica l cx -am ina tion , th e frac tu re w as stab le and w as no t pa in fu lto m anua l s tre ss , and the tim e to d isco n tinu atio n of the

    ParameterTreatm

    Activeen t G rou p

    P la ceb o P V alu eN o . o f f rac tu re s 33 34

    Ma l eFema l e

    F ra cture g rad eClosedG rade-I open

    Type o f fra ctu reTransverseShor t obliqueShor t sp ira lC omminu t ed

    L ocatio n of frac tu reP r o x ima lMid d l eDista l

    C omm inuted f ractu reN oY es

    B utterfly fractu reNoY es

    F ibu la r f ractu reNoY es

    Aget (yrs.)Disp l a c emen t (pe r c en t)B efo re re du ctio nt

    *W i t h the F ishe r exa ct te st o r ch i-squa re test .tT he va lue s a re g iv en as th e m ean an d the sta nd ard e rro r of the

    mean .IW ith an aly sis of v arianc e.

    cas t w as do cum en ted as the tim e a t w h ich th e s ite inv es-tiga to r d isco n tin ued use o f th e cas t.

    W ith reg ard to th e in te rm ed iate rad iog rap h ic s ig nso f hea ling , tw o p a ram eters w e re eva lu ated . T he first ,co rtic a l b rid g in g , w as d efin ed a s th e g rad ua l d isapp ea r-an ce o f the in terru p tio n o f the co rtex a t th e frac tu re s iteas a resu lt o f ca llu s fo rm a tio n . T he am oun t o f co rtica lbrid g in g w as qu an tified a s n on e (no chang e a t the co r-t ica l in te rrup tion com pa red w ith th at se en o n a rad io -g raph m ad e in the imm ed ia te p ost-redu ctio n p eriod ),in itia l (w hen a pe rio s te a l re ac tio n at the co rtic a l in te r-ru p tion o f the frac tu re site w as firs t n o ted ), in te rm ed i-

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    ACCELERA TION OF TIB IA L FRACTURE-H EA L ING BY NON -INVA SIV E . LOW -IN TEN SITY PULSED U LTRA SOUND 29

    VOL . 76 -A , N O . I. JA NUARY 1994

    TABLE IIIN TERMED IATE RAD IOGRAPH IC H EALING STAGES

    Days afte r F r ac tu re P V alu etA c tiv e P la ceb o K ru ska l-W all is

    T reatm ent* T re atm en t R an k(N = 33 ) (N = 34)1 ANOVA ANOVA Log -R ank

    3 b ridg ed cor tice sP r inc ipa l in ves tiga to r 8 9 3 .7 14 8 13 .2 0 .00 01 0 .0 001 0 .00 01In dep end en t rad io lo g is t 102 4.8 190 18 .3 0 .00 01 0 .0 001 0 .00( ) l

    C om ple te cor tica l b rid g in g(4 bridged cor t ices)

    P rincipal inv est iga to r I 14 7 .5 1 82 15 .8 0 .00 02 0 .0 001 0 .00 01Ind ep end ent rad io lo g ist 136 9.6 24 3 18 .4 0 .00 01 0 .0 001 0 .0001

    Endo stea l h ealingP r inc ipa l in ve stig ato r 117 8 .5 1 67 13 .9 0 .00 2 0 .0 004 0 .0 004In dep end en t rad io lo g is t 171 13 .6 27 1 19 .6 0 .00 01 0 .0 001 0 .( )00 1

    *T he valu es a re g iven as th e m ean and th e stand ard d ev iatio n o f the m ean , as c alcu lated w ith an aly sis o f v aria nce .t ANOVA = analysis of var ian ce.IN o clin ic al da ta w e re av ailab le for on e f rac tu re th at w as trea ted w ith the p la ceb o devic e.

    a te (an increase in th e d en sity o r size o f the in itia l p en -o steal reac tion ) o r com p lete ( the pen io stea l reactio ncom ple te ly b rid ged the co rtica l in te rrup tion ) . O n eachrad iog raph ic ev a lua tion a t each tim e-p o in t, fou r co rtice s(tw o on the an tero po sten io r rad io g raph and tw o on thela te ra l rad iog raph ) w ere eva lua ted fo r th e am oun t o fco rtical b rid g ing .

    T he o the r p a ram e te r, end ostea l hea ling , w as d efinedas th e g rad ua l d isappea rance on ob lite ratio n of th e frac -tu re line an d its rep lacem en t b y a zone of inc rea sedden sity fo rm ed by en dos tea l ca llu s . The am oun t o f en -d ostea l h ea ling w as quan tif ied as n one (no chang e in th efrac tu re line com pared w ith tha t on the p ost-redu ctio nrad iog raph ), in itial ( the frac tu re lin e had becom e lessd is tin ct), in te rm ed ia te (the re w as m arked conso lid ationo f th e fractu re lin e) , an d com ple te ( the frac tu re lin e h adbeen rep laced by a zone of inc rea sed d en sity fo rm ed byendostea l ca llu s) . A jud gm en t a s to the ex ten t o f en dos -tea l healin g w as m ade on bo th th e an teno posten io r andth e la tera l rad iog raph s a t each fo llow -up v isit.

    To m in im ize th e effe c t o f sub je ctive in terp re ta tio no f th e rad iog raphs by the in d iv id ua l inv estiga to rs , allrad iog raph s w ere asse ssed in in dependen t, b lind ne -v iew s by the p rinc ipa l investiga to r (J . D . H .) and , sepa -ra tely , by th e in depend en t rad io log ist (R . F . K .). T hep rin cip al inv estiga to rs a sse ssm en t o f rad io g rap h ic heal-in g w as u sed fo r p u rp oses o f sta tis tic al ana lysis to com -p a re the efficacy of treatm en t w ith the resu lts o f use o fth e p lacebo dev ice . T he site inv estig ato rs asses sm en t o fc lin ica l hea ling w as used fo r ana lysis o f the c lin ica l co rn -p on en ts o f frac tu re -h ea ling . T im e to respon se w as cal-cu lated as the n um ber o f days a fter th e frac tu re to th ef irs t occu rrence o f th e specif ied ev en t.

    T he ac tive and th e p lacebo -trea tm en t g ro ups w erecom pared w ith rega rd to im po rtan t cha racte ris tics o fth e frac tu re s and p atien ts . A sta tis tic al ana lysis7 w as pe r-fo rm ed w ith use o f the F ishe r ex ac t te st (o r the ch i-squ are te st if the re w ere m ore than tw o ca tegory leve ls)fo r the sex of the p a tien t; the g rad e, typ e, and locatio n

    (p rox im al, m idd le , o r d is ta l) o f th e frac tu re ; the p res-en ce of m ino r com m inu tio n ; the p re sence o f a bu tte rf lyfragm en t; an d the p resence o f a fibu lar frac tu re (T ab leI). S ta tist ica l ana lysis w a s p erform ed by the ana lysis o fva riance fo r the m ean age o f th e p at ien ts in y ea rs , m eanpre -red uc tio n and po st-red uc tion d isp la cem en t, m eanpre -red uc tio n and po st-red uc tion an gu la tion in deg rees ,m ax im um fractu re g ap in m illim ete rs , m ax im um leng tho f th e fra ctu re in cen tim e ters , m ean num be r o f d aysafte r th e fra ctu re b efo re th e s tart o f tre a tm en t, m eannum ber o f days o f fo llow -up , and m ean num ber o f d aysto th e s tar t o f w e igh t-b ea ring (T ab le I).

    Pa tien t com plian ce w as m easu red as th e adh erenceto the sch edu led fo llow -up v isi ts as d ic ta ted by th e p ro -toco l and the frequ en cy of u se o f th e dev ice a s m easu redby th e in terna l dev ice clo ck and a w ritten lo g kep t bythe p a tien t. A dve rse reac tions , pa tien ts com pla in ts , an dcom plic a tion s w e re sp ec ific a lly sou gh t b y each s ite in -vestig ato r a t each v isit and w ere reco rded if fou nd .

    P rev iou s an im a l an d clin ic al s tud ie s5 22 2 c le arlyshow ed a pos itive e ffec t o f u ltra soun d on the rate o fosseou s rep air. T here fo re , an acce lera ted tim e to heal-ing fo r the ac tiv e- trea tm en t g rou p w as hypo thesized a tth e p ro to co l-de s ign p ha se o f th is s tu dy . C onsequen tly ,on e-sided sta tis tic al te sts o f hyp o thesis and one -sided pva lu es w e re calcu la ted to a ssess the sup erio rity o f trea t-m en t w ith th e active dev ice com pared w ith tre atm en tw ith th e p la ceb o , con tro l d ev ice . T he nu ll h yp o th es isth at the t im e to re spon se fo r fra ctu re s tre a ted w ith th eactive dev ice w as the sam e o r w orse th an the tim e toresp onse fo r tho se trea ted w ith the p laceb o d ev ice w aste sted aga ins t the a lte rna te hy po the s is th at the tim e toresp onse w as sup e rio r fo r the fractu re s trea ted w ith th eactive dev ice . S up erio r w as d efin ed a s an acce le ra ted(sho rte r) tim e to th e atta inm en t o f a sp ec ific hea lin gre sp on se , such as a h ea led fra c tu re s ta tu s . T h e re su lt w ass ig n ifican t w hen the p va lue w as 0 .0 5 o r le ss in favo r o fth e act ive -trea tm en t g ro up .

    T h ree s ta tis tic a l app roach e s are p re sen ted fo r a ll

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    30 J . D . H ECKM AN ET A L .

    TH E JOU RNAL O F BONE AN D JO IN T SU RGER Y

    TABLE IIINUM BER AND CUM ULAT IVE NUMBER OF FRAC TUR ES FOR DAYS

    AFTER THE FR ACTU RE TO THE START O F W E IGH T -BEAR IN G

    D ays af ter F racture N o .ActiveCumulat ive No .

    Placebo*Cumulat ive

    0-14 5 5 4 415-28 5 10 4 829-3 5 6 16 7 1536-4 9 3 19 5 2050-63 7 26 5 2564-77 3 29 1 26>77 4 33 7 33

    *N o data were avai lab le on the start o f w e igh t-be aring for o nefra ctu re in the p la ceb o-trea tm ent g rou p .

    ana lyses . A na lysis o f varian ce w as used to ca lcu la te th em ean tim e an d the stan da rd e rro r o f th e m ean , in d ay s,to th e a tta inm en t o f a h ea led frac tu re s ta tu s fo r th eactiv e -trea tm en t and p lacebo -trea tm en t g ro up s . A n aly -sis o f va riance , K ruska l-W allis ana lysis o f va rian ce byran ks32 , an d log -rank life -tab le ana lysis43 t4 w ere used tocom pa re the m ean tim es to hea ling fo r th e tw o gro up s.T he K rusk al-W allis ana lysis w as used becau se it doesno t m ak e the sta tistica l assum ption s o f a G au ss ian d is -tr ib u tio n o r hom ogene ity o f v arian ce s . T h e log -ran klife - tab le ana lysis w as u sed becau se it ana ly zes r igh tcen so red o bse rva tions as censo red o bse rva tions anduses days to th e la st fo llow -up v is it a s the tim e-to -ev en tva lue (o ne frac tu re tha t h ad ac tive treatm en t an d on etha t had th e p lacebo trea tm en t had rig h t censo red esti-m ated va lu es fo r the tim e to a hea led fra ctu re).

    In ad d itio n , C ox reg re ss ion ana lys is w as used toassess w he th er po ten tia l co variates , such as th e sexand age o f th e pa tien t, th e days to the s tar t o f w e igh t-bea rin g , and the g rade , ty pe , o r lo catio n of th e frac -tu re , had an e ffect o n the hea ling re spon se in the ac tivecom pared w ith the p laceb o-trea tm en t g ro up . If an ef-fec t w as ob se rved becau se o f th e cova riate , th e re su ltsof ac tiv e tre atm en t com pa red w ith tho se o f p laceb otre atm en t w ere s ta tis tic a lly ad jus ted fo r th e cov aria tein o rde r to de term in e w heth er the supe rio rity o f theac tive - trea tm en t g roup com pared w ith th e p lacebo -trea tm en t g rou p w as m a in ta ined in the p re sence of thecova riate e ffec t.

    A ll d a ta ob serv at ion s w e re en tered in to a com pu terfile and then th e com pute r p rin tou t w as p roo fread ca re -fu lly ag a in st the case -reco rd fo rm . A n ind ep enden t, th o r-o ugh com parison of all da ta u sed in the s tatis tic a lana lyses w ith th ose in th e case -reco rd fo rm w as d on eb efo re the s tatis tic a l ana lysis , to en su re th e accu racy ofthe da ta fu r the r. A ll an aly ses w ere p erfo rm ed w ith theS ta tis tica l A na lysis S y stem softw are (SA S Institu te , C a ry ,N orth C aro lina ) on an IBM 3081 m ain fram e com pu ter .

    A ll o f the frac tu res th a t w e re random ized in to eachstud y gro up w ere ana lyzed fo r the tim e to hea ling in anin ten tion -to -trea t log -ran k life- tab le ana lys is . E ach frac -tu re w as consid ered to b e hea led on ly a t th e tim e of a

    sched u led fo llow -up v isit ( fo r ex am ple , at ten , tw e lv e,fou rte en , tw en ty , th irty -th re e , o r fif ty -tw o w eeks) an d noin terim v is it (p lan ned or o th erw ise ) w as used to ass ig na h ea ling tim e . Th e n um ber o f d ay s to the la st com ple tedfo l low -up ex am ina tio n w as u sed fo r the tim e to h ea lin gfo r the frac tu re s tha t had n o t reached a h ea led s ta tu s bythe las t fo llow -up v isit. T h is in ten tion -to -trea t ana ly siseva lua ted w he the r exc lusio n of the w ith d raw n and non -pro to co l-com p lian t pa tien ts b iased the re su l ts o b ta in edin the an a ly sis o f the tim e th a t th e frac tu re s in the co regro up took to hea l.

    Resu l t sW ith reg a rd to the seven teen p atien t an d frac tu re

    pa ram ete rs tha t w ere stud ied (T ab le I), w e cou ld no tde te ct an y app rec iab le d iffe ren ces b etw een the th irty -th ree frac tu res in th e ac tive - trea tm en t co re g rou p an dthe th irty -fo u r fra c tu re s in the p laceb o -tre a tm en t co reg ro up , w ith th e num bers s tu d ied . T h e re fo re , w e b eliev etha t the p la cebo -tre atm en t g ro up w as q u ite s im ila r toth e ac tive -tre a tm en t g ro up .

    T he p atien ts com plian ce w ith th e fo l low -up pro to -co l w as ana lyzed b y calcu la tion o f th e ra tio o f actua lc l in ic a l v isits to the ex pected (schedu led ) num ber o fc lin ical v is its fo r each g ro up . Th e pa tien ts w ho receiv edac tiv e trea tm en t re tu rned fo r the schedu led fo llow -up v isits 8 9 pe r cen t o f the tim e (245 of 276 v is its), andthe p at ien ts w ho w ere trea ted w ith the p la cebo , 90 pe rcen t o f the tim e (256 o f 28 3 v isits) . U sage of the dev icew as com pa rab le b etw een th e ac tiv e-tre a tm en t and thep laceb o-trea tm en t co re g ro ups , a s reco rded by bo th th edev ice tim er and th e pa tien t log , and all o f the pa tien tsin the ac tive -tre a tm en t g ro up u sed th e un it fo r a t lea s tth ir ty -six treatm en t se ss ions.

    T he to tal du ra tion o f fo llow -up , in days, w as com pa-rab le in th e ac tive and the p laceb o-trea tm en t g rou ps; itw as 25 0 18 .1 days (m ean an d stan da rd e rro r o f them ean [an alys is o f va rian ce ]) (rang e, n ine ty -tw o to 438days) fo r th e ac tive - trea tm en t g ro up com pared w ith 2 84 19 .2 d ay s (rang e, 1 42 to 58 6 d ay s) fo r th e p laceb o-t rea tm en t g ro up (p = 0 .2 1 ) (T ab le I). O ne pa tien t in th eac tive -treatm en t g rou p sus tain ed a frac tu re in th e sam ea rea o f the tib ia seven m on th s a fte r the in itia l fra c tu rewas co nside red to be h ea led b o th c lin ica lly and rad io -g rap h ica lly . T h e seco nd fra ctu re occu rred d urin g a so c-cer g am e, from sim u ltan eo us k ick s to th e tib ia b y tw oo th er p laye rs. T h is fra c tu re h ea led fou r m on th s la te r.

    A su bsequ en t, lo ng-te rm fo llow -up w as don e a t therequest o f the Food and D ru g A dm in istratio n to de te r-m in e w heth er a ll hea led fra ctu re s in b o th g ro up s in th es tudy rem a ined h ea led at a m in im um o f tw o y ea rs a f terth e in ju ry . F ifty -f ive pa tien ts (f if ty -six fractu re s) o f thes ix ty -s ix p at ien ts (s ix ty -seven fra ctu re s) w ho had beenen ro lled in the p ro to co l w e re co n ta c ted . A ll fif ty -s ix o fthe fra ctu re s w e re s till hea led . T he du rat ion o f fo llow -upfo r tw en ty -th re e fra ctu re s w as m ore th an fou r y ea rs an dfo r th irty -th re e fra ctu res , it w as tw o to fou r y ears .

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    N =33 N =34 N=33 N=34PR INC IPA L INVESTIGATO R INDEPENDENT RAD IO LOG IST

    ACCELERA TION O F T IB IAL FRACTURE-H EA LING BY NON -INVA SIV E , LOW -IN TENS ITY PU LSED U LTRA SOUND 31

    VOL . 76 -A , NO . 1 . JA NUARY 1994

    TABLE IVSUMM ARY OF TH E C ox REGRESS ION ANALYSES FOR A SSESSM EN T OF TH E S IGN IF IC ANCE OF

    POTENT IA L COVAR IA TES ON ThE T IM E TO A H EA LED FRAC tU RE

    P oten tia l C ov aria teCo re-G ro up Fracture s

    Log -L ikel iho od Chi-Sq ua re P V alue S ig n ifican t Cova ria teSe x 0 .01 0 .92 N oAg e 1.78 0.18 NoD ay s to start o f w eig h t-b ear ing 4 .5 5 0 .03 Ye sA djusted d if ferenc e* 17 .97 0 .00 01 -Fra ctu re g rad e 1 .38 0 .24 NoType of frac tu re 0 .10 0 .76 NoL ocatio n of fractu re 1 .27 0 .26 No*Th e act ive com pared w ith th e p lacebo p va lue , w hen ad jus ted fo r the s tar t o f w e igh t-b ear ing , com pa red favo rab ly w ith the analysis of

    v aria nce an d log- ran k p va lue s of 0 .0 001 .

    Analys is o f variance show ed tha t the m ean tim e toth e en d-po in t o f the stu dy (a h ea led frac tu re) , a sjudged bo th c lin ica lly b y the site inv estiga to r and ra-d io graph ica lly (th ree of four b ridg ed cortices) by thep rinc ip a l inves tiga to r , w as 96 4 .9 days fo r the ac tive -trea tm en t g roup com pared w ith 15 4 13 .7 d ays fo r th ep lacebo- trea tm en t g ro up (p < 0 .000 1 [an aly sis o f v an -an ce , K ruska l-W allis ran k an alys is o f variance , and lo g-rank life - tab le ana lys is]) (F ig . 1 ) . A t 12 0 d ays afte rth e frac tu re , 88 p er cen t o f the frac tu re s in th e ac tive -trea tm en t g roup w ere h ea led com pared w ith 4 4 pe rcen t in the p laceb o-treatm en t g rou p ; a t 150 d ay s, 94per cen t o f the frac tu res in th e activ e- trea tm en t g ro upwere h ea led com pared w ith 62 pe r cen t in the p laceb o-treatm en t g roup (F ig . 2 ) .

    T he m ean tim e to c lin ica l h ea lin g , a s a sse ssed b yth e site in vestiga to r , w as 8 6 5 .8 days fo r the ac tive -treatm en t g ro up com pared w ith 11 4 10 .4 days fo r th ep laceb o-trea tm en t g ro up (p = 0 .01 , 0 .03 , an d 0 .01 [ana l-ys is o f va riance , K rusk al-W allace ana ly sis , and lo g -ranklife - tab le ana lys is , re sp ec tive ly ]). T he m ean tim e to d is-con tinua tion of th e cast w as 94 5. 5 days fo r the ac tive -treatm en t g roup com pared w ith 1 20 9 .1 day s fo r the

    p lacebo-trea tm en t g rou p (p = 0 .00 8 , 0 .0 05 , and 0 .01 ).T he tim e to clin ica l h ea ling w as no t reco rded fo r on ep atien t in the p laceb o-treatm en t g roup .

    T he in te rm ed iate stages o f rad io g rap h ic healin gw ere d ete rm ined by th e p rinc ipa l in vestiga to r fo r a lls ix ty -sev en pa tien ts . A na lysis o f v arian ce of the tim e tocom ple te hea ling fo r the firs t, secon d , th ird , an d fourthco rtices dem onstrated an inc reased rate o f b rid g ing inth e activ e -trea tm en t g ro up com pared w ith th a t in th ep lacebo-trea tm en t g rou p . Th ere w as a sign ifican t in -crease (acco rd ing to ana lys is o f v arian ce , rank an a ly siso f variance , and log-ran k life -tab le ana lysis ) in the dif-feren ces be tw een the g roup s w ith rega rd to the num bero f days a fte r th e frac tu re tha t b r idg in g had occurred ;th ese d iffe ren ces w ere th irty , fif ty -n ine , and six ty -e igh tdays fo r the second , th ird , and fourth co rtices , respec-tive ly (F ig . 3) .

    The rad io graph ic assessm en ts o f the p rin c ip al inves-tig a to r an d the indepen den t rad io log ist fo r the tim e toco rtica l b rid g ing fo r th ree and fou r co rtices and th e tim eto com ple te en dos tea l h ea ling prod uced com parab lesta tistical resu lts, w ith th e rad io log is ts a ssessm en ts re -flec ting m o re conserv a tive eva lua tions (T ab le II). T he

    F IG . I

    = S .E .M .

    . ACT IVEL I P LACEBO

    G raph show in g the days to he alin g of the fractu re (clin ic ally and rad iog rap h ic ally ) a s a sse ssed b y th e pr incipal inve stig ato r an d th eind ep end ent rad io log ist. S . E . M . = s tan dard erro r o f th e m ean .

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    Lu-JLUI

    LU

    I--I

    U

    % q q ,c DAYS TO HEAL ING OF THE FRACTURE

    F IG . 2G rap h show ing th e cum ula tive p erc en tage of c lin ica lly an d rad io grap h ic ally h ealed f rac tu re s in th e co re group a s a fun ction o f tim e. T he

    su per io r ity o f the act ive -tre atm en t g rou p is seen , w ith 56 per c en t of th e fra ctu res h ea led com pa red w ith 18 p er cen t of the f rac tu re s in thep lacebo- trea tm ent g rou p , at n ine ty day s afte r the f rac tu re . O ne fractu re in th e p la ceb o-trea tm ent g rou p h ealed at 4 65 day s a fte r the frac tu re ,and n o cl in ic al d ata w ere ava ila b le fo r on e f ractu re in th is g rou p . T he p v alu e is fo r ana lys is o f v arianc e, rank an aly sis of va ria nce , an d log- ran klife -ta b le ana lysis. SEM = sta nd ard e rror of the m ean .

    32 J . D . H ECKM AN ET A L .

    THE JOURNAL OF BONE AND JO IN T SURGERY

    princ ipa l inv es tiga to r de te rm ined the tim e n eed ed fo rb ridg in g of th ree co rtice s to be 89 3 .7 d ay s fo r theac tive - trea tm en t g ro up com pared w ith 1 48 13 .2 daysfo r th e p la cebo -tre atm en t g ro up (p = 0 .0001 [an a ly sis o fva riance , K ruska l-W allace an aly sis , an d log -rank life -tab le ana lysis]) , and the ind ep enden t rad io lo g ists a sse ss-m en t w as 1 02 4 .8 days fo r th e ac tive -trea tm en t g ro upcom pared w ith 190 18 .3 d ays fo r the p lacebo-trea tm en tgro up (p = 0 .0001 [ana lysis o f variance , K ruska l-W allaceana ly sis , and log -rank life -tab le ana ly sis]) .

    The tim e to com ple te co rtic a l b rid g in g (a ll fou r con -tic e s) , a s as ses sed by the p rinc ipa l in vestiga to r , w as 11 4 7 .5 days fo r the ac tive -treatm en t g ro up com pared w ith18 2 15 .8 d ay s fo r th e p lacebo -treatm en t g roup (p =0 .00 02 , 0 .0 001 , and 0 .0 00 1 [ana lysis o f v a riance , K ru ska l-W alla ce ana lys is , an d lo g -rank life-tab le an a ly s is ]) , andth e in depend en t rad io log is ts a sse ssm en ts w ere 13 6 9 .6 day s fo r the ac tive - trea tm en t g ro up com pared w ith2 43 18 .4 d ay s fo r th e p lacebo-trea tm en t g roup (p =0 .0 001 [an aly sis o f va riance , K ru ska l-W allace ana lysis ,and lo g -rank life -tab le ana lysis ]) .

    T h e tim e to com ple te end ostea l h ea ling , a s a sse ssedby the p rinc ipa l inv es tig a to r, w as 117 8 .5 days fo r theac tive -trea tm en t g rou p com pared w ith 16 7 13 .9 daysfo r the p lacebo-trea tm en t g rou p (p = 0 .00 2, 0 .0 00 4, an d0 .0004 [ana lysis o f v ariance, K ru ska l-W allace ana lysis ,and lo g -rank life- tab le ana lys is]) , and th e ind ep en den trad io log ists a sse ssm en t w as 171 13 .6 d ay s fo r th eact ive -trea tm en t g ro up com pa red w ith 2 71 19 .6 d ay sfo r the p lacebo-trea tm en t g ro up (p = 0 .0001 , 0 .0001 , an d0 .0001).

    A sm ok ing h isto ry w as o b ta ined from th ir ty -sev encore -g rou p p atien ts (th irty -e igh t frac tu res) . Am ong th efou rte en fra ctu res in th irte en pa tien ts w ho had neve r

    AC TIV E (N=33)MEAN SE M96 4 .9PLACEBO (N - 3 4 )MEAN SE M154 13 .7P V a I u= O . 00 0 1

    T PLACEBO -.- ACT IVE

    sm ok ed , n in e w ere trea ted w ith th e ac tive dev ice an dh ealed in a m ean of 87 3 .9 days , com pared w ith 1 32 11 .2 d ay s fo r the five tha t w ere treated w ith the p lacebod ev ice (p = 0 .00 2). Am ong the frac tu re s in the rem a in in gp a tien ts , w ho w ere ex -sm oke rs o r w ho w ere sm ok in gdurin g the trea tm en t pe riod , e leven tha t w ere trea tedw ith th e active dev ice healed in a m ean o f 11 5 11 .2days , com pared w ith a m ean o f 1 58 28 .6 d ay s fo rth irte en fra c tu re s th at w e re trea ted w ith the p lacebod ev ice (p = 0 .09 ) .

    A s m en tion ed prev iou sly , the on ly d iffe rence w ithreg a rd to th e m an ag em en t o f the pa tien ts w as th e tim eto the sta rt o f w e ig h t-b ea rin g . T he jus ti fica tio n fo r th ecom bina tion o f a ll co re -g ro up frac tu re s in the e ff icacyana lysis w as the essen tia lly iden tical pa tte rn of frac tu reand m ean tim e a fte r the frac tu re to the sta r t o f w e igh t-b ea ring in th e ac tiv e-tre a tm en t and p la cebo -trea tm en tgrou ps (T ab le s I and III) an d on th e sta tis tic a l ana lysisby Cox regression of th e effec t o f th e sta rt o f w e igh t-bea rin g o n th e e fficacy re su lts o f the ac tive treatm en tcom pared w ith the p laceb o treatm en t. The C ox reg re s-sion ana lys is e stab lish ed th at w h en the ac tive -trea tm en tan d the p la cebo -trea tm en t g rou ps w e re s ta tist ica lly ad -ju s ted to a comm on start o f w e ig h t-b ea rin g e ffec t, th eac tiv e-tre a tm en t g ro up m a in ta in ed a sign ifican t su pe -n io rity fo r th e tim e to a hea led frac tu re (p = 0 .0001)(T ab le IV ). Th is resu lt is iden tica l to th e p v alu e o f0 .0001 in the ana lys is o f va rian ce , K ruska l-W allis rankana lys is o f varian ce, an d log-ran k life -tab le ana lys is (F ig .1 ) and confirm s th at th e day th at w e igh t-b ea ring star tedd id no t s ig n ifican t ly a ffe ct the effic a cy re su lts o f tim e toa hea led frac tu re.

    In ad d ition , th e C ox reg ress ion an aly s is es tab lishedtha t o th er c lin ic al ly re lev an t cov an ia tes , su ch as th e sex

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    COR TE XBR IDGED

    4T H -

    3R D

    2N D

    1S T -

    89 3.7

    86 3.9

    p VALUE0.00020 . 00010 . 0001

    0 . 00010 . 00010 . 0001

    __x -11 4 . -. - 18 27 .5 .---.- 158

    - .x . - 14 8- 13.2

    13 .1

    3 .9

    0.020.050 . 01

    - A CT IV E (NXPLACEBO (N -34(

    0.10.50.2

    70 80 90 100 110 120 130 140 150 160 170 180 190DAYS AFTER THE FRACTURE

    F IG . 3

    A( ( ELERAT ION O F T IB IAL FRACTURE-H EA LING BY NON -INVAS IV E . LOW -IN TENS ITY PU LSED U LTRA SOUND 33

    VO L . 76 -A , NO . I. JANUARY 1994

    Graph showing th e ra te o f p ro gres sio n of h ealing by the am ount o f co rtex brid ged . Th e v alu es a re g iven as the m ean and th e s tan dard er rorof the m ean . P va lue s are g iven for ana lys is o f v aria nc e, ra nk ana lys is o f v aria nc e, and log -ran k life-tab le ana lyses.

    an d age o f the pa tien t an d th e g rade , ty pe , and loca tio nof the frac tu re , a lso had no s ign if ican t e ffec t on th eefficacy re su lts o f tim e to a h ea led frac tu re (T ab le IV ).

    Log-rank life- tab le ana lysis w as used in an in ten tion -to -treat ana lys is fo r a ll f rac tu re s rand om ized in to th estud y . T he tim e to a hea led frac tu re w as s ign ifican t fo rth e ac tive -treatm en t g roup a t the 0 .005 p ro bab ility leve l,wh ich com pares favo rab ly w ith th e an a lysis o f va riance ,K nu ska l-W allis , and log -rank p v alu es fo r tim e to a h ea ledfrac tu re in th e co re g rou p . T h is re su lt co n firm s th e va lid -ity o f the u se o f the co re g ro up o f p ro toco l-com plian tpa tien ts fo r clin ica l an d sta tistical in fe rences .

    Th ere w ere tw o adverse reac tio ns and one com pli-cation in th e six ty -s ix pa tien ts in the core g roup . O nepa tien t (w ho had ac tiv e treatm en t) repo rted m usc le -cram ping a t one w eek . T he cram ping reso lved , w ithou ttrea tm en t, b y th e seco nd w eek . O ne pa tien t (w ho hadp laceb o trea tm en t) had sw e lling in th e cas t a t the six -week fo llow -u p v is it. T h is p rob lem h ad reso lved b ythe n ex t v isit. N o o the r ad ve rse reac tion s w ere rep orted .O ne pa tien t w ho used a p la ceb o d ev ice h ad a pu l-m onary em bolus a t th e four-w eek fo llow -up v is it. T hepa tien t w as m an aged success fu lly w ith a ntic oa gu la ntthe rapy and rem ained in the s tu dy .

    DiscussionThe in trigu ing clin ica l find ing s of X av ie r and D u-

    an te2 , sup ported b y p lacebo-co n tro lled an im al stud iesby D uarte and by P illa et a l., d em on stra ted th at u ltra -so und acce le ra te s the no rm al frac tu re -rep air p ro cess ind iaphy sea l b one . T h ese find ing s led u s to design a p ro -spec tiv e, rand om ized , doub le -b lind , p lacebo-con tro lleds tudy to assess bo th the sa fety an d the e ffec tiven ess o fthe use of low -in tens ity u ltrasoun d to accele ra te h ea l-

    in g o f fresh fra ctu res in hum ans . T he rand om iza tio nprocess created tw o ve ry sim ilar g rou ps o f pa tien ts an dth e re fo re p erm itted an unb ia sed asse ssm en t o f th e e f-fe ct o f the ac tive -tre a tm en t dev ice . W hen the se tw ogro ups w e re com pa red , th e tim e to a h ealed fra ctu rew as fo und to be sig n if ican tly acce le ra ted w hen theac tive - trea tm en t dev ice w as app lied fo r o ne tw en ty -m inu te pe riod each d ay fo r as m any as tw en ty w eek sin the imm ed iate po st-frac tu re pe rio d in pa tien ts w hohad a c losed o r g rad e-I o pen tib ia l d iaphy seal frac tu re .

    The trea tm en t reg im en w as to lera ted w ell b y thepa tien ts , an d no seriou s com plica tion s a ttr ibu tab le tothe trea tm en t w e re id en tified . N o p atien t had n o tic e -ab le edem a a t the s ite o f the w in dow or sk in irr ita tionas a consequence of u se of the dev ice. Th e pa tien tsfo und th e p ortab le un it ea sy to use and w ere ab le toach ieve adequ a te coup ling co n tac t be tw een the sk inan d th e treatm en t head su rface . N o specif ic m ech an icalor techn ica l p rob lem s w ere encoun te red du ring thestudy .

    The spec ific m ech an ism by w h ich low -in tensitypu lsed u ltra sou nd accele rate s th e n orm al d iaph ysea lfractu re -repa ir p rocess is unk now n . T he presen t s tudydo es n o t add re ss th is question . O th er au th o rs h av e re-po rted o n b io lo g ic a l e ffe cts cau sed by s ta tic m echan i-cal fo rces and by the p re ssu re w aves o f u ltraso un dsm echan ic a l p ertu rba tio n2 7 . T he se p ressu re w aves m aym edia te b io log ica l ac tiv ity d irectly b y m echan ica l de -fo rm ation o f th e cell m em b ran e o r ind irec tly by ane lectr ical effec t caused by cell de fo rm atio n .

    K nis tiansen reported on th e accele ra tion of the tim eto a h ea led frac tu re and on o the r rad io g raph ic pa ram e -tens o f h ea ling o f m etap hysea l b on e in a sim ila r do ub le -b lind , rand om ized , p laceb o -con tro l led s tud y w ith use

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    34 J . D . H ECKM AN ET AL .

    TH E JOU RNA L OF BON E AND JO INT SURGERY

    of the sam e u ltra so un d tre a tm en t on C o lles fra ctu re s. W e be lieve th at ad d itio na l c lin ic a l co rro bo rat ion o f th eK no ch and K iug repo rted an in cre a sed rate o f healing acce le ra t ion o f h ea lin g o f fre sh fra ctu re s w ith u se o fo f fra ctu res at va riou s loca tion s in h um an s w ith use o f sp ecific a lly p rog ram m ed , p u lsed , low -in ten si ty u ltra-u ltra sou nd trea tm en t w ith sign al in tens it ies th at w e re so und tre a tm en t m ay lead to its u se fu l app lic a tion in theon e o rde r o f m agn itu de m o re th an th e s ig na l in ten sit ies trea tm en t o f frac tu res .u sed in the p re sen t stud y .

    B eyond the p rel im ina ry clin ic al s tud ie s o f X av ie r No i T he auth ors than k the fo llow ing site inve stig ators : W . C . B rady . D . C aho rn . K .1 Chi l l ag . R . M . C hris tian . J . C ron ke y. J. R . D e An d ra d e. J . W . Dunlap . J r. . D . N . Ervin. J.and D uarte--- , K n ls tlansen , an d the p re sen t stud y , w e G am we ll. R . G arla nd . M . lu sim . T . K r ist ian sen . P . E . L ev in , T . M cE lligo t , M . C . M e ie r . D . G .

    a re n o t aw a re o f any o th er stud ies tha t do cum en t the T hca sal Ihank Kerne ffec tiv eness o f low -in tens ity p u lsed u ltra sou nd in th e Char le s . R oger T a lish . a nd A r th u r L ifsh ey for the ir en g ine er in g a ssistan ce and the la te S aw nie. , . . Gas ton . M .D .: A rthu r Pilla. Ph .D . : J am es R yab s. Ph .D .: an d R ob ert S if fe rt . M .D . for th eiracce lera tlo n o f th e fra c tu re -hea ling p ro ce ss in h um ans . in vU ua ble c ou nse l du r ing th e p rep ara tion o f th is stud y .

    Reference s1 . B in de rm a n, I.; Z or , U .; K aye , A . M .; S h im sh on i, Z .; H a rel l, A .; an d S om jen , D .: Th e tran sdu ction of m echan ica l fo rc e in to b io me cha nic al

    ev en ts in bon e cel ls m ay in volve a ctiv ation o f p hospho lip ase A 2. C alc if T issu e In tern a t., 42: 26 1-2 66 , 1 98 8 .2. Chapm an , I. V .; M acN ally , N . A .; an d f lick er , S .: U ltrasound- ind uced ch ang es in ra tes o f in flu x and eff lux of po tas sium io ns in rat

    thym ocytes in v i tro . U ltra sou nd M ed . an d B io l ., 6 : 47 -58 , 1980 .3. Conov er , W . 3.: P ra ctic a l N on param etr ic S ta tist ics. Ed. 2 . N ew Y ork . W iley , 1 980 .4. Cox , D . R .: R eg res sion models and life -tab les . J . Ro y. S ta tis t. S oc . , S er ies B , 34 : 187 -22 0 , 1 972 .5. Duan e, L . R .: T he stim ula tion of bon e grow th by u ltraso und . Arch . O rth op . an d T raum a Su rg . , 101 : 1 53-159 , 198 3 .6. Dyson , M : Th erapeu tic applica tion s of u ltra sou nd . In B io log ica l E ffec ts o f U ltrasoun d , pp . 12 1-1 33 . E dite d by W . L . N yho rg and M . C .

    Zisk in . N ew Y ork , C hu rch ill L iv in gstone , 1 98 5 .7 . F leiss, J. L. : S ta tis tica l M eth ods for R a tes an d P rop ort ion s. Ed. 2 . New Yo rk , W iley , 1 98 1 .8. Gu stilo , R . B ., a nd Anderson , J . T .: P rev en t ion of in fec tio n in th e treatm en t of o ne thou san d and tw enty -five open fra ctu res of lon g

    bon es. R etrosp ect ive an d pro spe ctive analyse s. J . B one an d Jo in t S urg ., 58-A : 4 53-458 , Jun e 1 976 .9. M ug, W .; F ranke , W . G .; an d Knoch , H . G .: Sc in t igraph ic contro l of bone -fra ctu re hea lin g und er u l tra son ic st im ula tion : an an im al

    experim en ta l s tu dy . Europ ean J. N u cl. M ed ., 11 : 494 -497 , 1986 .10 . Knoch , G . H ., a nd K lu g , W .: S t im u la t ion o fF racture H ea ling w ith U ltrasou nd , tra nsla ted by T . C . Te lge r. B erlin , S pr ing er, 1 99 1 .1 1 . K ris tiansen , T . K .: T he effec t o f low pow er spec ifica lly p ro gramm ed ultraso und on the h ealing tim e o f fresh frac tu res us in g a Colles

    mode l . J . O rth op . T raum a, 4 : 2 2 7- 22 8, 1990 .12 . Lehm ann , E . L .: Nonpa ram etric s: S ta tist ica l M e tho ds Based on Ran ks. Sa n Franc isco , H old en-D ay . 1 975 .13 . M ante l, N .: Ev alua tio n o f su rv iv al da ta an d tw o new ran k ord er s ta tistic s ar isin g in its c ons ide rat ion . Cance r C h em o the r. R ep ., 50 :

    1 63 -1 70 , 1 96 6.14 . M ante l, N .: R ank ing pro ced ure s for arb itra rily restr ic te d o bse rva tion . Biometrics, 23 : 65-78 , 1 967 .15 . N yborg , W . L .: M echan ism s . In B io log ica l E ffec ts o f U ltraso un d , pp . 2 3-3 3 . Ed ite d by W . L . N ybo rg an d M . C . Z isk in . N ew Yo rk .

    Church i l l L iv ing sto ne, 1 985 .16 . Pil la , A . A .; M on t, M . A .; N a sse r, P . R .; K han , S . A .; F igue iredo , M .; K aufm an , J . J .; a nd S iffert , R . S .: N on -in vas ive low -in ten sity p u lsed

    u ltraso und ac celera tes bo ne hea lin g in the rab b it . J . O r tho p . T raum a, 4 : 246 -253 , 1990 .17 . Ryaby , J . T .; M ath ew , J .; P illa , A . A .; and D uarte-A lves , P .: L ow -in ten sity pu lsed u ltrasound m odula tes adenylate cyc lase a ctiv ity and

    tran sfo rm ing g row th factor be ta syn the sis . In E lectrom ag net ics in M ed ic in e an d B io log y , pp . 95-100 . Ed ited b y C . T . B r igh ton an d S . R .Pollack . S an F ran cisco , San F ran cisco P re ss, 1 99 1 .

    18 . Schef fe , H .: T he A na lysis o f Va rian ce . N ew Y ork , W iley , 19 59 .19 . St. John Brow n , B .: H ow safe is d iagn os tic u ltraso nog rap hy ? Canad ian M ed . A ssn . J ., 131: 30 7-3 11 , 198 4 .20 . W ells, P . N . T .: S urg ica l ap p licat ion s of u lt raso un d . In B io log ica l E ffe c ts o f U ltrasoun d , pp . 15 7-1 67 . E dited by W . L . N ybo rg an d M . C .

    Z isk in . N ew Y ork , Church il l L iv ings ton e, 198 5 .21 . Xavier , C . A . M ., an d D uarte, L . R .: E stim u lac#{2 27 } u ltr a-son ica de cab osseo : ap p l i ca c# {2 26 } c l i n ic a . R ev. B ras i/e ira O rto p ., 18 : 7 3-8 0 , 1 98 3 .2 2 . X av ier , C . A . M , and Duarte , L . R .: T rea tm ent of non un ion s by ultraso un d stim u lation : f irst c lin ica l app lic atio ns . R ead at th e M ee ting of

    the Latin -Am erican O rth op ed ic A ssociatio n , a t the A nnua l M eeting o f Th e Am er ican A cad em y o f O rth op aed ic S urg eon s, San Fran-cisco , C a lifo rn ia , Jan . 25 , 19 87 .

    23 . Z isk in , M . C .: A pp lic ations o f u ltr asound in m edic ine - com pa rison w ith o th er m od alit ies . In U ltrasoun d: M ed ica l A pp l ica tion s,B io log ica l E f fec ts, a nd H azard Po ten tia l, pp . 49-59 . Edited by M . H . R epach oli, M . G ran dolfo , a nd A . R ind i . N ew Y ork , P lenumP res s, 1 98 7 .