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    This is an enhanced PDF from The Journal of Bone and Joint Surgery

    1926;8:607-617.J Bone Joint Surg Am.MELVIN S. HENDERSON, THOMAS P. NOBLE and KATHLEEN SANDIFORD CHEMISTRY OF THE BLOODUNUNITED FRACTURES WITH SPECIAL REFERENCE TO THE

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    www.jbjs.org20 Pickering Street, Needham, MA 02492-3157The Journal of Bone and Joint Surgery

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    UNUN ITED FRACTURE S 60 7

    U N UN ITED FRA CTURES W ITH SPEC IA L REFEREN CE TOTH E CH EM ISTRY O F THE BLOOD *

    BY MELV IN S . H ENDER SON , M .D ., THOMAS P . NOBLE , M .D .,Sec tion on O rth o p a ed ic S u rg ery ,

    an dKATHLEEN SAND IFORD , B .A .,

    S ec tio n o n C lin ica l M eta b o lism , M ayo C lin ic, R o ch este r , M in n eso ta

    M any hypo theses have been ev o lved to ex p la in the p rocesse s a t w orkin o ssifica tion . S om e investiga to rs m a in ta in th at the p ro cess is a sim plech em ica l o ne , o the rs exp la in it on the b as is o f th e elec tive a ff in ity o f thece ll, and still o the rs b elieve it is b iochem ica l in o rig in an d due to enzym eac tion . Th eo rie s o f chem ica l ch an ges a re based o n a serie s o f pape rs pub -lished in 18 57 by R ain ey on the prec ip ita tion of ca lc ium carbo na te andca lc ium pho sph ate from co llo ids. R ecen tly these ex pe rim en ts have beenco nfirm ed an d am p lified by W att, w ho , lik e W ells , accep ts the idea o fB arill#{233 }ha t the calc ium of th e b lood ex ists a s a so lub le com plex d oub le sa lt,tr iba sic ca lcium -ca rbon ophosph a te : P 2O 8C a2H 2 : 2 C O2 (CO sH )2C a . Th is ,h e b elieves, exp la in s th e co nstancy of the com position of a ll ty pes o f b oneb y b rin g ing to it th e tw o sa lts in exac tly the p rope r p ro portion s. F romth is stage onw ard W att d iffers from W ells in th a t the fo rm er m a in ta ins th atth is sa lt is taken from th e b lood and depos ited in the b one by th e ac tion ofosteob lasts as fo rm erly su ggested b y K lo tz and by R #{246 }hm ann (a v ita lis ticph ilo sop hy) w h ile W ells b elieves th at it is d ue to a sh if t in the hyd rog en ionco ncen tra tion by a ch ange in the ca rb on d iox id co n ten t (a pu re ly m ech an -i st ic c on ce pt io n) .

    T he ex pe rim en tal w ork of P faun d le r, o f P au li and S am ec and ofF reu denbe rg and G yo rg y re su lted in a num ber o f theo rie s , w ith e lec tivea ff in ity a s the ir base s. P fau nd le r p laced p ieces o f ca rtilage in the ab dom ina lcav itie s o f an im als and fou nd tha t the ir pow er (K alk salz fan ge r) o f tak ingup calc ium w as thu s inc reased , bu t tha t a ll v a rie tie s o f ca rtilage d id no thave the sam e a ffin ity fo r ca lcium . Ep iph yseal car tilage , fo r ex am ple , w asab le to tak e up m uch m ore ca lc ium than costa l o r trachea l ca rtilage . H eco nc lud ed tha t a su bstance w as sec re ted from th e b one -ce ll o r ca rtilage -cell a t a ce r tain stage o f deve lopm en t, w h ich caused th e su rroun d ing tis sueto as sum e a spec ific a ffin ity fo r th e calc ium sa lts o f the b loo d . P au li andS am ec dem ons trated tha t the tis sue flu ids tha t con ta in a grea te r p rop ortiono f p ro tein s a re cap ab le o f tak ing up m ore ca lcium , an d th ey b e liev e th at th eim pregna tion of cartilag e w ith lim e sa lts is d ue to the h igh co n ten t o fp ro te in in th e ca rtilag ino us g ro und -su bstance . F reu denb erg an d G yo rg yin a ser ie s o f ex pe rim en ts pu t ca rtilage , w h ich had been prev iou sly trea ted

    * Read be fore the Am erican O rth opaed ic A ssociation , A tlan ta , G eo rg ia , Ap ril 26to 28 , 1 926 .

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    60 8 M . S . H E NDE R SO N , T . P . N O BL E , K AT H L E E N SAND I F O R D

    w ith a so lutio n o f calc ium chlorid, into a so lution o f phosphate and ob-served bony changes in the cartilage ; how ev er, if they put the cartilagef irs t into a so lution of phosphate and then into a so lution o f calc ium chlo rid,no bony chang e resulted. From this they conc luded that the mechanismo f ossification w as no t pure ly chemical, as the reac tion w as not reversible.

    Robison, in 19 23 , presented interesting ev idence which suggests thepresence of an enzyme in the bones and o ssify ing cartilage o f young animals,w hich rapidly hydro lyzes phosphoric e sters w ith the liberation of freephosphate io ns. This w ork has recently been amplified and extended byRobison and Soames. Their conc lusion is that an enzyme (a monopho s-phoric esterase) is present in ossify ing cartilag e , grow ing bone and tee th,but to a le ss ex tent after the animals becom e fully grow n. This enzymeis assumed to act on and hydro lyze the phosphoric e sters (hex osemono-phosphoric ac id and g lyceropho sphoric acid) in the blo od, and liberatephosphate ions in the immediate ne ighborhood o f the site o f o ssification.Consequently , the product o f the concentratio n of the phosphate andcalcium ions becomes g reater than the so lubility product o f calc ium phos-phate, and this is depos ited in a so lid state. A s further ev idence , theseinvestigators demonstrated that calcium pho sphate is deposited in v itro inbone taken from rachitic animals w hen it is immersed in a so lution of suit-able phosphoric e sters.

    How land, in his discus sion of bone-fo rmation in his Harvey Lectureo f 1923 on the pathogenesis o f ricke ts , puts in more concre te form thephysicochem ical theorie s o f W ells on ossif icatio n, and the reader is re ferredto the ir papers fo r a full exposition o f the subjec t. The theory is based onthe fac t that the prec ipitation of salts in so lutio n fo llow s the w e ll-know nlaw of mass ac tion and can be predic ted from the so -called so lubility -product constant w hich is different from , but charac teristic o f, each salt.The so lubility -product law under the mo st simple conditio ns may be statedas fo llow s: in suff iciently dilute so lutions saturated w ith a s lightly so lubleunivalent salt the product o f the concentrations o f the ion spec ies o f thatsalt is constant. Fo r example, the product o f the ionic concentratio ns o fsilver and chlorin div ided by the concentration of the mo lecular s ilverchlorid is a constant w hich cannot be ex ceeded w ithout prec ipitatio n. U n-fortunate ly in the blood w e are no t dealing w ith simple univalent salts inpure w ater but w ith salts o f higher v alence in so lutio n equilibrium in anexceeding ly complex so lvent. Furthermore , variations in the ionic con-centratio ns o f calc ium and pho sphorus in the serum cannot be m easured inc linical w ork and hence a true so lubility constant cannot be de term ined.In spite o f these difficultie s , How land be lieves that info rmation of value tothe c linic ian can be deduced from a rough product obtained by using asapprox imate facto rs the to tal concentration o f calc ium and phosphorus inthe serum . He based the poss ible value of such a product upon experi-Inents carried out in conjunc tion w ith M arrio tt and Kramer. They show edthat a prec ipitate consisting large ly o f tricalc ium phosphate w ith som ecarbonate is formed w hen the hydrog en ion concentration is increased by

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    UNUNITED FRACTURES 60 9

    reduc ing the ca rb on d io x id tens io n in an a rtif icia l serum , if the p rod uc t o fthe concen tratio n of calc ium and phosph ate p resen t ( in m illig ram s fo r each1 00 c .c.) ex ceeds 4 0 . H ow land v isu a lized the m echan ism of bon e fo rm a-tion as fo llow s : Serum con ta in s ca lc ium and in o rgan ic p hosp horus inso lu tio n in m uch h igher co ncen tration than w ate r w ou ld ho ld them , onaccoun t o f the h igh CO 2 tension . T here is som e ev idence to show th atpa rt o f the ca lcium is bo und to p ro tein . If it is a ssum ed tha t th is ca lc ium -p ro te in com pound is po orly io n ized th is w ou ld b e eq u iv alen t to redu c ing theto tal ca lcium concen tratio n . In te rce llu la r flu id o f the tissues con ta insro ugh ly the sam e am oun t o f ca lc ium and phosphoru s, accord ing to ourd e te rm ina tions , as the se rum , bu t the pro te in is m u ch less, apparen tly abou t1 p er cen t., a s con tra sted w ith 7 -9 pe r cen t., in the se rum . T he CO 2 ten sionis rela tive ly h igh o n accoun t o f ce llu la r ac tiv ity . B u t suppo sing tha t theCO 2 tensio n is low becau se th e tissue is inactiv e o r dead , then cond ition sa re fav orab le fo r p rec ip ita tion . C artilag e and the trab ecu lae o f bon e arebo th inac tive tissues and it is in them th a t on e w ou ld ex pec t th e CO 2tensio n low and it is in th em th at p rec ip ita tion takes p lace .

    T his v iew of th e fac to rs th a t con tro l ca lc ifica tion and of th e m echan-ism o f calc ification , exp la ins the n orm al p rocess and the failu re in ricke tsan d te tany o f ch ild ren and the rick e ts o f an im als . It a lso ex p la ins ca lcif ica-tion in d ead or inac tive tissues such as tube rcu lous le sio ns and in the fasc ia lp lanes o f th e m usc le s in m yositis ossif ican s, w h ere the firs t chang e seem sto b e a hy alin e tran sfo rm atio n of the co nnec tive tis sue . W ha t is fu rth erof m uch im portance , it exp la ins the cons tancy of com position of the b onesof a ll an im al spec ies in w hich the calc ium and in o rgan ic p hospho rus con -cen tra tion s o f the se rum so far a s th ey hav e been stud ied d o no t d iffe rg rea tly from th ose o f m an .

    Pu ttin g th is th eo ry to the te st, H ow land found tha t in ricke ts w henth e p ro duc t w as abo ve 40 e ithe r dem onstrab le hea ling w as tak in g p lace o rthe p atien t d id n o t hav e ricke ts; th at w ith p rod uc ts b etw een 30 an d 40rick ets w as u sua lly p re sen t; an d tha t w h en the p rodu ct w as be low 30 rick etsw as inva riab ly p re sen t.

    P e tersen , in 1924 , ap p ly in g th e w ork o f H ow land an d K ram er onricke ts , s tud ied th e ca lcium and pho spho ru s in th e serum in cases o f u n -un ited fractu re and used n orm a lly healin g frac tu re s to con tro l h is re su lts .H e s tud ied n ine n orm a l case s and n ine cases o f non un io n , and used , a sh is index of ab ility to un ite , the sam e va lue of the prod uc t w hich H ow lan dhad found ind ica tive o f th e p re sence or ab sence of rick ets in ch ild ren .P ete rsen s ev id en ce is co nfirm a to ry o f the id ea tha t un ion of a frac tu rew as no t like ly to o ccur if the p rod uc t w as les s than 30 , th at little h ea lingw ou ld occur if it w as b etw een 30 and 35 , and tha t activ e hea ling w ou ld bem o re frequen t if it w e re be tw een 35 an d 40 . H e w as of the o p in io n tha tin case s o f unu n ited fractu re the re is a cons titu tiona l d istu rb an ce cau sing aredu ctio n o f th e concen tra tio n o f ca lc ium and phosp horus be low norm al,and th at the norm a l con cen tra tion can b e resto red by d iet and drug s.L a ter in the sam e y ea r he pub lished the re su lts o f ex pe rim en ts on an im als

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    61 0 M. S . HENDERSON , T. P . N O BL E , K AT H L E E N SAND IF O R D

    and drew the same conc lusio ns as in his s tudy on frac tures in man. Tisdalland Harris , on the other hand, had laid more stre ss on local metabo licfac tors at the site o f fracture . They found that, in the adult, only w henbone is being fo rmed as the result o f a frac ture does the phosphorus contentreach the leve l maintained during the period of no rmal bone -g row th in theyoung .

    Recent studies on the chemistry o f the blood have produced manyestimations of the content o f calc ium and inorganic phosphate. These areexpressed in milligrams of calc ium and phosphorus fo r each 100 c.c . o fserum or plasma ; w hether the serum or plasma is used makes little practicaldifference . The serum calc ium in health is s ingularly constant in allmammals, inc luding man, but show s slight variatio ns w ith age . Theusually accepted figure fo r serum calc ium is 10 mg . for each 100 c .c . plusor m inus 1 mg . w ith a tendency , as show n by Kramer, Tisdall and How -land, for it to run betw een 10 and 11 mg. in children. Rona and Takahashishow ed that part o f the calc ium o f serum w as nondiffus ible and, there fo re ,presumably in combination w ith prote in. From the so lubility constant o fcalc ium carbonate under sim ilar conditions they calculated that the ionizedcalc ium in serum w ould no t be far from 2.2 mg . B rinkman and van D amobtained a s im ilar figure . For c linical s tudie s, how ev er, w e must lim itourse lves to a know ledg e of the to tal calc ium present in the serum .

    The ino rg anic phosphate (expres sed as phospho rus ) in the serum orplasma is no t as constant as the calc ium and varie s re lative ly more be tw eenthe child and the adult. Tisdall and Harris fo und, in children from thefourth month to the eighteenth year, an averag e of 5 .4 mg. o f phosphorusin 100 c .c . o f serum, and in adults from tw enty to forty -fo ur years, 3 .8 mg.A nderson g ives an average o f 4 .8 mg . for children up to tw elv e y ears and3 .3 fo r adults . In our serie s o f examinatio n w e found an av erage of 4 .2 mg.fo r children and 3 .4 mg . fo r adults . The estimation of inorg anic phosphateis somewhat tricky partly because the amount obtained, after the bloodhas been allow ed to s tand to o long in contac t w ith the c lo t, is usually con-siderably increased, probably by hydro ly sis or organic phospho rus com-pounds diffusing out from the corpusc le s . It is , there fore , necessary tostandardize the time betw een the taking o f the blood and the estimatio ns.M aitland and Robison found that after the blood had been laked w ithdis tilled w ater, the amount o f inorganic phosphate in w hole blo od increasedrapidly , as much as 10 per cent. in fiv e m inutes and 50 per cent. in tw o hoursat room temperature . A t 3 7#{ 17 6}. the increase w as considerably greater.In the presence of 1 per cent. o f trichlo racetic ac id no increase occurred atall in tw o hours at 37# { 17 6}. In unlaked blood at room temperature , theseinv estigators found only a slig ht increase in six hours, but experimentsreported by Kay and Robison show that w hen unlaked blood is kept forfive hours at 370 C. the amount o f inorganic phosphate in the plasma isincreased about 20 per cent. In a contro l serie s w e have found, likeHow land and Kramer, that the increase during the first six hours w as slighteven w hen the serum was allow ed to s tand in contac t w ith the c lo t; if ,

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    UNUNITED FRACTURES 61 1

    how ever, under the latter conditions, tw enty -four hours elapsed, theamount obtained w as from 60 to 100 per cent. greater.

    A lterations in the calc ium and phosphorus content o f the blood can beproduced in several w ay s. B inger show ed that the intravenous injec tionof orthophosphates o f sodium into dogs at the right reaction and in amountsof 15 0 mg. fo r each kilogram o f body w eight, caused the serum calc ium todrop from 10 to 6 mg. fo r each 100 c .c . and w as accompanied by a conditiono f te tany . The te tanic state caused by the phosphate is , according toB inger, no t dependent on the drop in calc ium alone but also varie s w ith thedeg ree of alkalinity o f the so lution used. On the other hand Salveson,Hastings , and McIntosh, in a recent extensive study o f the subject, foundthat large doses o f pho sphate , adminis tered over a period of one o r tw odays, produced marked te tany independently of the hydrogen ion con-centratio n o f the so lution used ; t hey conc luded that the c linical symptomsof tetany , produced by the o ral adminis tration of phosphate , are due to adecrease in blo od calc ium .

    The results o f feeding calc ium in ex cess to animals are somew hatv ariable . Some inv estig ato rs f ind an increase in the plasma calc ium , buta decrease in the plasma phosphorus. In like manner, exces s phospho rusin the die t raise s the concentratio n of phosphorus in the plasma. M cCol-lum , S immons, Shipley and Park found that w hen a die t high in calc iumand low in prote in is fed to rats , absorption of calcium is improved andthat o f phospho rus impaired. How land and Kramer, also s tudy ing ratson this diet, observed that the concentratio n of calc ium in the serum israised and that o f ino rganic phosphorus low ered. S alvesen, Hastings , andMcIntosh considered that calc ium chlorid g iv en orally is the most e ffectiv esalt. The administration of calc ium salts to man, by mouth or hypo-derm ically , m ay correc t defic iency in calc ium but canno t materially raisethe calc ium content abov e no rmal. There is never a defic iency o f limesalts in a normal die t. If hypo calcem ia ex ists , the cause mus t e itheroperate in the gastro -intestinal trac t to prev ent abso rption, or depend onexcess ive elim ination in the urine o r feces , o n som e condition in the tissuesw hich facilitate s absorptio n of calc ium from the blo od stream , o r on thede fic iency o f some ho rmone (parathyro id) in the blo od stream w ho sepresence is e ssential for a normal content o f blo od calc ium . Orr has shownthat the absorption of bo th calcium and pho sphorus from the inte stineis hampered by diet w hich increases the alkalinity o f the sto o ls . Calc iumsalts appear to ex ist in the blo od in a saturated so lution and this is depend-ent on the hydrog en ion concentratio n and the carbon dio x id tensio n ofthe blo od. It has been show n that cod-liv er o il and ultra-v io le t rays as sistin maintaining the proper concentratio n and utilization of both calc iumand pho sphorus. Co llip has demonstrated that by the use o f the parathy-ro id extract prepared by him the blood calc ium can be more than doubledby repeated subcutaneous injec tions at sho rt intervals; this is the onlysubstance that w ill materially increase the blood calc ium above normal.

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    61 2 M . S . H E NDE R O N , T . P . N O BL E , K A T H L E E N SAND IF O R D

    We have carried out quantitative estimations* o f the calc ium andphosphorus in the blood of a cons iderable number of patients w ith un-united frac ture. Fo r many reasons it is no t alw ays possible in a busysurg ical serv ice to fo llow up the case and compile suffic ient readings suitablefo r publication. In additio n to this incomple te data w e hav e tw enty casesof typical ununited fracture in w hich one blood examination w as madebefo re operatio n and at least tw o determ inatio ns after operatio n (Table 1 ).The accompany ing table s g ive the percentag es o f calc ium and phosphorusand the products o f the figures. A s contro ls w e hav e listed a serie s o fe ighteen cases o f chronic eczema (Table 2 ) , in each of w hich at least tw osim ilar te sts w ere made ; the av erages w ere for calcium 10 .3 mg., pho spho rus3 .1 mg., and the product 31 .9 . The average preoperative readings forthe tw enty cases o f ununited fracture w ere : calc ium 10 .2 mg., pho sphorus3 .3 mg ., product 33 .7 . The postoperative de term inatio ns made w ithinthirty days w ere: calc ium 9.8 mg ., phospho rus 3 .6 , product 3 5 .3 ; the obser-vations betw een thirty and s ix ty days w ere : calc ium 10 .0 mg ., pho sphorus3 .4 , product 34 .0 and those o ver six ty day s w ere : calc ium 10 .2 mg ., phos-pho rus 3 .1 and product 31 .6 . It w ill be no ted that the averag e o f the earlypo stoperativ e calc ium determ inatio ns w as slig htly low er and of thephosphorus slightly higher than the preoperative , and that the increasein phospho rus resulted in a s lightly higher product. The indiv idual v aria-tions , how ever, are w ithin the experimental erro r of the method and are nog reater than those found in our contro l serie s .

    In one case o f frac ture o f the tibia, w ith a persistently high readingfo r phosphorus , union w as very rapid. W hen the readings for phosphorusw ere persistently low , union progres sed slow ly , and it w as ev ident thatm etabo lism of bone w as slugg ish. O f the tw enty cases presented, unionoccurred in fifteen after operatio n, in tw o it did not, and three are s tillunder observ atio n, in one of w hich union w ill probably o ccur w ithoutfurther diff iculty . In the tw o cases o f nonunion, in w hich union failed,both the phosphorus and calc ium w ere either equal to or on the high s ideo f the averag e be fo re operation. In one case there w as a slight decreasebe low normal in the phosphorus, resulting in a slig htly low ered product.In the other there w as a decrease in the calc ium w ith an e levation of thephosphorus, re sulting in a slightly decreased product immediately afteroperation. S ix months later, how ever, the product had returned to abovethe o rig inal lev e l but there w as a subsequent drop tow ard the end of theyear.

    * The calc ium w as determ ined by the Kramer and Tisdall method and the ino rganicphosphate by the B ell and D oisy method. In c linical laboratories errors in the calculatio n of serum calc ium frequently arise from contam ination of the syringe or tube w itht h e ca lciu m o f t h e w a t er u sed in b oilin g or c lea n in g ; t h er efo r e , t h e b lo od w a s co llect edin a sy ring e w hich had been bo iled in double distilled w ater and w as placed in tubes w hichhad been prev iously w ashed w ith hot c leaning so lutio n, rinsed w ith dis tilled and re-dis tilled w ater, and then dried in ho t air. The serum w as obtained at once by centri-fug ing and the calc ium prec ipitated directly as calc ium oxalate . The serum pro te in w asimmediate ly prec ipitated by trichloracetic ac id and the filtrate thus obtained w as usedfo r the determ ination of the inorganic phosphate. D aily blanks fo r calcium w ere madeand the proper correction determ ined; phosphorus blanks w ere run at frequent intervalsand fo und ne gjig ible .

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    61 4 M . S . H E NDE R SO N , T . P . NO BL E , K AT H L E E N SAND I F O R D

    A lthough our data lend no suppo rt to the c linical value o f blo odcalc ium and phosphorus de term inatio ns in the routine treatm ent o f de -lay ed union, as seen in a general orthopaedic c linic , y e t w e w ish to po intout that they do not thereby invalidate the underly ing theory that bone -formation is at least in part dependent on a phy sico chemical m echanism .One facto r to rem ember in this connec tion is that our cases are all in adultsand that normally the amount o f phosphorus in the serum is le ss than inchildren and also varies under different conditio ns to a le sser deg ree ; there-fore, o ne can hardly antic ipate that the c linical so lubility -product w illhav e the sam e significant values as found in children suffering from ricke ts .W ith this decrease in max imal v ariability in adults the possible significantvariations may w e ll decrease to within the lim its o f the experimental errorso f the determ ination themselv es , to say nothing o f the errors in the so lubility

    T ABL E 2C ALC IUM AND INO R G ANIC P H O SP H AT E O F THE BLOOD IN

    E IG H T E E N C A SE S O F C H R O N IC EC Z E M A

    Inorganic . I n o r ga n icC a s e A ge Calcium phphate PrOduct Case A ge Calcium pho sphate Product

    1 . 1 7 1 0 .4 2 .9 3 0 .2 10 . 56 10 .8 2 .3 2 4 .811 .1 3 .0 33 .3 9. 7 2 .5 24 .3

    2 . 24 10 .8 3 .0 32 .4 11 . 59 10 .6 3 .4 36 .011 .0 2 .9 31 .9 10 .9 3 .6 39 .2

    3 . 25 1 0 .8 3 .7 40 .0 12 . 59 10 .7 2 .9 3 1 .01 0 .0 3 .7 37 .0 10 .2 3 .1 3 1 .6

    10 .5 3 .1 3 2 .64 . 2 9 9 .9 3 .1 30 .7

    10 .9 3 .2 34 .9 13 . 62 10 .7 3 .0 3 2 .110 .4 3 .0 3 1 .2

    5 . 41 10 .0 2 .5 2 5 .010 .3 2 .7 27 .8 14 . 63 9 .7 3 .5 3 4 .0

    10 .1 3 .7 3 7 .46 . 47 10 .6 2 .8 2 9 .7

    10 .0 3 .3 3 3 .0 1 5 . 63 1 0 .1 3 .0 3 0 .310 .8 3 .4 3 6 .7 10 .4 2 .8 2 9 .1

    7 . 50 10 .1 3 .4 3 4 .3 1 6 . 66 10 .0 3 .6 3 6 .010 .6 3 .6 38 .2 10 .0 3 .6 3 6 .0

    1 0 .3 3 .1 3 1 .98 . 52 10 .6 2 .8 29 .7 10 .3 3 .7 3 8 .1

    10 .8 3 .0 32 .49. 7 3 .1 3 0 .1 17 . 72 10 .4 2 .7 28 .110 .0 3 .7 37 .0

    9 . 55 9 .8 2 .8 27 .4 1 0 .5 3 .0 31 .59 .7 3 .2 31 .0

    10 .6 3 .2 33 .9 18 . 78 1 0 .0 3 .0 30 .0___ _____ ___ ____ ___ ___ __ 9. 6 2 .3 22 .1A verage calcium = 10 .3 A verag e ino rganic phosphate = 3 .1 Average product = 31 .9

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    UNUN ITED FRACTURES 61 5

    constant obtained by using the to tal concentratio n of these substances.A s How land po inted out, it w as finally possible to harmonize the v iew sin regard to the e tio logy o f ricke ts o f those who believed the disease due toa de fic iency of some particular v itam in in the diet and o f tho se who thoughtthat it w as due so le ly to env ironmental facto rs such as sunlig ht, and sofo rth. It seems unlike ly that bone-fo rmation is so lely a question o f physicalchem istry . W e are to o imbued w ith the philosophy o f Haldane to denyan important ro le to the bone-form ing ce lls themse lves; w hether or not thece lls w ork by the production o f a spec ific enzym e is immaterial althoughits positive demonstratio n may be anticipated. How ev er, as o rthopaedicsurgeons , w e must treat in a prac tical m anner the ununited frac tures thatcom e to o u r a t t en t ion . While w e may not be able in a g iv en case todemonstrate the v alue of calc ium and cod-liver o il, nev erthe le ss , as theycertainly can do no harm , w e must use them on theore tic grounds in con-junc tion w ith an o therw ise w ell-balanced nourishing die t ; the use o f sun-shine as w e ll as artific ial light mus t also no t be neg lec ted especially incases that prov e obstinate to operativ e treatment. A s surgeons w e cannotfail to be impressed w ith the importance o f a proper approx imatio n of thefragments by surg ical procedures w hen necessary and by methods w hichcause as little local injury as poss ible .

    S U MM A R Y

    The failure o f a frac ture to unite is difficult to explain. That it m ayin certain instances be due to cons titutional causes is hardly to be doubted.Inv estig atio n to de term ine this fac to r is to be commended and constitu-tional m ethods of treatment should be used as a routine in addition tosurg ical m ethods. S tudy of the calc ium and phosphorus content o f theblood, if carried out from the investigative standpo int, may prove o f v aluein the future although in routine w ork it rare ly leads to information o fc linical v alue . Successful treatment o f the averag e run of ununited frac -tures is in the great majority o f cases a surg ical problem and depends muchmore frequently on correc t surg ical technic than on methods direc tedtow ard overcom ing the as y et unknow n constitutio nal or chemical fac torsconcerned in o ssification.

    B I B L I O G R A P H Y1. ANDER S ON , G R A C E H.: The Calc ium and Phospho;us Content o f the B lood in

    N ormal and Rachitic Children. B rit. J. Child. D is ., X X I, 33-4 8; 107-119 , 19 24 .2. B AR I L L A .: D c laction de lacide carbonique sous pression su r l ea p ho sp ha te s

    m#{ 233} talliques , combinaison (carbonophosphates) ou disso lution, applications div erses.J . de pharm . et de chim ., X IX , 14-71; 196; 24 5; 295 , 1 904 .

    3. BARILL A .: R O le des constituants de la dissoc iation de la carbonophosphate tri-calcique dans la g# { 233 } nesedu tissue osseux et de s div ers es c onc re tio ns a base dephosphate et de carbonate de calc ium . J. de pharm . et de chim . L, 342-346 , 1910 .

    4. B E L L , R . D ., AN D Do I sy , E. A .: Rapid Co lo rimetric Methods for the D eterm inatio nof Pho sphorus in U rine and B lood. J . B io l. Chem ., X LIV , 55-6 7 , 192 0 .

    5. B I NG ER , C .: Tox icity of Phosphates in Relatio n to B lood Calc ium and Tetany .J. Pharmaco l. and Exper. Therap., X , 105 -120 , 19 17-19 18 .

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    61 6 M . S . HENDERSON , T. P. N OBLE, KATHLEEN SAND IFORD

    6. BR INKM AN , R . AND VAN DAM , E . : Proc . Kon. A kad. v . W etensch., Amsterdam ,X X I I , 762 , 1920 .

    7. C O L L I P , J . B . : The Ex traction of a Parathyro id Hormone w hich w ill Prevent orContro l Parathyro id Tetany and w hich Regulates the Leve l o f B lo od Calc ium .J . B io l. Chem., LX III, 395 -438 , 192 5 .

    8. F R EUDENB ER G , E . AN D GY#{ 246 }RGY , P . : D er V erkalkungsvorgang be i der Entw icklungdes Knochens. Ergebn. d. inn. Med. u. K inderh., X X IV , 17-2 8 , 1 923 .

    9. H AL V ER SO N , J . 0 ., M O H L E R , H . K . AN D B ER G E IM , O L A F : The Calc ium Content ofthe B lo od S erum in C ertain Patho log ical Conditions . J. B io l. C hem ., X X X II,1 7 1 - 17 9 , 1 9 1 7 .

    10 . HENDER S ON , M . S . : Pseudarthros is o f the Tibia in Children. J. B one & JointSurg ., V II, 340-354 , A pr. 19 25 .

    11 . H ENDE R SO N , M . S . : U nunited fractures . J . Am . M ed . A ssn . , L XXXV I , 8 1-8 6 ,1926.

    12 . H E ss, A . F. AND G UTM AN , P . : The Cure of Infantile R ickets by Sunlight as D emon-strated by a Chemical A lteration of the B lo od. Proc . S oc . Exper. B io l. & Med.,X IX , 31-34 , 19 21-1922 .

    13 . H O FM E I ST E R , F R ANZ : fJber A blagerung und Resorption von Kalksalzen in c lanGew ehen. Handb. d. B iochem ., III, 4 29-45 3 , 1910 .14 . H O W L AND , J O H N : The Etio logy and Pathogenesis o f R ickets. Harvey Lectures.

    Philade lphia, Lippinco tt, X V III, 189-2 16 , 1 922-1 923 .15 . H OW LAND , J O H N AN D K R AM ER , BE NJ AM IN : Calcium and Phosphorus in the Serum

    in Re lation to R ickets. Am . J. D is. Child., XX I I , 105-11 9 , 19 21 .Facto rs w hich D eterm ine the Concentration o f C alc ium and of Inorganic Pho sphorusin the B lo od S erum o f Rats . Johns Hopkins Ho sp. B ull., XXX III, 31 3-3 17 , 1 92 2 .Facto rs Concerned in the Calcif ication o f B one. Proc . Am . Pediat. So c., XXX IV ,204-208 , 1922 .

    1 6 . H O W L AND , J O H N AND M AR R IO T T , W . M cK . : O b se r va t io n s u p on th e C a lc iu m C on t en tof the B lood in Infantile Tetany and upon the Effec t o f T r ea tm en t b y C a lc iu m .Quart. J. M ed., X I , 289 -31 9 , 19 18 .

    1 7 . KAY , H . D . AN D R O B ISO N , R O BE R T : P a r t III. The A ction of B one Enzyme on theOrganic Phosphorus Compounds in B lo od. B iochem . Jour., X V III, 755-764 , 1 924 .

    18 . K L O T Z , O SK AR : S tu d ie s u p on C a lca r eou s D eg en e r a t ion . I. The Pro cess o fPatholog ical Calcification. J. Exper. Med., V II, 63 3-6 75 , 1905 .19 . K R AM ER , B EN J AM IN AND T ISDAL L , F. F.: A S imple Technique fo r the D eterm inatio n

    of C alc ium and Magnes ium in Small A mounts of S erum . J. B io l. Chem ., X LV II,475-4 81 , 1 921 .

    20 . K R AM ER , B E NJ AM IN , T I SDAL L , F. F., AN D H OW L A N D , J O H N : T he C linic al S ig nif ic anc eof Calcium Concentratio n in the Serum of Children and Poss ible Errors in itsD eterm inatio n. Am. J. Dis . Child., X XII, 560-564 , 1921 .

    21 . M CC 0L L UM , E. V ., SIM M O ND S, N INA , SH IP L E Y , P . G . AND P AR K , E. A .: S tudies onExperimental Ricke ts . X V I. A D elic ate B io log ic al Te st for C alc ium -depositingSubstances. J. B io l. Chem ., LI, 41-49 , 1922 .

    22 . M AR T LAND , M AR J O R IE AND R 0B I s0N , R O BE R T : N o t e on th e E st im a t io n o f P h os -phorus in blood. B iochem . Jour., X V III, 76 5-768 , 1 924 .

    23 . O R R , W. J ., H O L T , L . E ., J R., W ILK IN S , L . AN D B OON E , F. H.: The Calc ium andPho sphorus M etabo lism in Rickets w ith Spec ial Reference to U ltrav io le t RayTherapy. Am. J. D is. Child., X XV I, 3 62 -37 2 , 19 23 .24 . P A R K , E. A ., Guy , R U T H A . AN D P OW E R S , G . F.: A Proof of the Regulatory Influenceof Cod Liver Oil on Calc ium and Pho sphorus Metabo lism . Am. J . D is. Child. ,X XV I , 103 -111 , 192 3 .

    25 . PAUL ! , \ V. AND SAM EC , M .: U eber L#{ 246} slichke itsbee influssung von Electro ly ten durchEiweissk rper. B io chem . Ztschr., X V II, 235-256 , 1909 .

    2 6 . P E T ER S EN , H. A .: A Clinical S tudy of U nunited Frac tures w ith Spec ial Reference

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    UNUN ITED FRACTURE S 61 7

    to the In org an ic Bone-form in g E lem en ts in the B lood S erum . J . B on e & Join tSu rg ., V T, 88 5-901 , Oct . 1924.

    27 . PFAU ND LER , M EINH ARD : tbe r d ie E lem en te d e r G ew ebsv e rka lku ng und ih reB eziehung zur R ach itis fra ge . Jahrb . f . K i n de rh e il k ., LX , 123 -177 , 190 4 .

    28 . RA IN EY , G E 0R ;E : Q uo ted b y W att.29 . RA IN EY , G EO RGE : O n th e Form ation of the Sk ele tons of A nim als, an d O th er H ard

    S tructure s form ed in C onnec tion w ith L iv in g T issu es. B rit. and Fo reign M ed.C hir. R ev ., X X , 45 1-476 , 185 7 .

    30 . ROB IS0N , RO BER T : The Poss ib le S ign ificance of H exosep hosphoric E ste rs inO ssifica tio n . B iochem . Jo ur. X V II, 286-293 , 19 23 .

    31. R oB isoN , RO BERT AN D SO AM ES , K ATHAR INE M . : P ar t I I. T he P hosphoricEs tera se o f O ssify in g C ar tila ge. B io chem . Jo ur. , XV III , 7 40-754 , 1924 .

    32 . R # { 2 4 6 }HMANN : Q uoted b y F reudenberg and G yorgy .33 . RONA , P . A ND T AK AH AS HI, D .: B e itrag zu r F rage nach dam V erh alten des C alc ium s

    im Serum . B iochem . Z tschr., X L IX , 370-380 , 1913 .34 . SALVESEN , H . A ., HASTINGS , A . B . AND M CIN TO SH , J . F .: B lo od Ch anges and

    C lin ica l S ym p tom s Fo llow in g O ral A dm in istra tion o f Phospha te s . J . B io l.Chem . , LX , 31 1 -326 , 19 24 .

    35 . SCHwARZ , R ., EDEN , R . A ND H ERR MA NN , E .: Uber d ie chemischen Vo rg a ng e , be ide r F rak tu rhe ilun g und de ren B ee in fiu ssu ng . B iochem . Z tsch r ., CXL IX , 100-108,1924 .

    36 . TISDALL , F . F .: A N ote on th e K ram er-T isda ll M eth od fo r th e D ete rm ina tion ofC alcium in Sm all Am oun ts o f S e rum . J. B io l. C hem . LV I, 439-4 41 , 192 3 .

    37 . TISDALL , F . F . A ND H AR RIS , R . I .: Calc ium and Pho sph orus M etabo lism in Pa tien tsw ith F rac tu res. J . A m . M ed . A ssn ., LX X IX , 884 -887 , 192 2 . A N ote on th ePhospha te C on ten t o f th e S erum of Cases of Bo ne T uber cu lo sis T rea ted byHelio therapy . C an . M ed . A ssn . J., X II I, 1 77-17 8 , 192 3 .

    3 8 . WAT F , J . C .: T h e Behav io r o f Calc ium Phosp ha te and C alc ium C arbona te (bonesal ts) P re cip i ta ted in V ario us M edia w ith A pplic ations to B one Form a tion .B io l. B ull., X L IV , 2 80-317 , 19 23 .Th e D epo sition of C alcium Phosph ate and Calcium C arb on ate in B on e and inA rea s o f C a lc if ica tio n . A rch . S urg ., X , 98 3-9 90 , 19 25 .

    39 . WELL S , H . G .: C alc ific a tion a nd O ss if ica tion . H arv ey L ec tu re s. Ph iladelph ia,Lipp inco t t , V I, 102-146, 1 910 -1911 ; A lso: A rch . m t. M ed ., V II , 72 1 -753 , 191 1 .C hem ica l P a tho logy . 5 ed . Ph ilade lph ia , W . B . Saunders C o ., 7 90 pp. , 1925 .

    40 . WILLS , LU CY : B lo od C a lcium and Inorgan ic Phosp ha te s in C h ild ren w ith M arkedLack of Muscle T one . B rit. M ed . J ., I, 3 02-30 4 , 192 5 .


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