long-term treatment of vitamin-d resistant rickets

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L on g-T erm T reatm en t o f V itam in -DR esistan t R icke ts

B Y D O N A L D S . P IE R C E , M .D 4 , W IL L IA M M . W A L L A C E , M .D .A N D C H A R L E S H . H E R N D O N , M .D . C L E V E L A N D , O H IO

F ro m the D iv isio n o f O rthop aed ic Su rge ry andth e D epa rtu ien t o f P e d ia trics, U n iver sity H osp ita ls o f C le vela nd ,

an d R ain bow H o sp i ta lfo r C ripp led a nd C o nva les cen t C h ildre n ,Cleveland

E x perience ga ined in the trea tm en t o f tw e lve pa tien ts w ith v itam in -D resis tan tr ick e ts on a long -te rm basis a t the U n ive rsity H osp itals o f C leve land prov id es theb asis fo r th is repo rt. T h is ex pe rience ind ica tes th at th e d isea se is ra re ly w ell co n -tro lled by v itam in D , even in la rge doses , an d w h en co m ple te hea ling does occu ru n d e r v i tamin -D the rap y , tox ic ity a nd co nse qu en t re na l da m ag e a re co ns ta n tth rea ts w h ich m u st be w a tched fo r con tin ua lly . T h is expe rien ce a lso ind ica tes tha to steo tom y or o th er su rg ica l p rocedures sho u ld be perfo rm ed on ly ra re ly prio r top ube rty and th at a r igo rous p ro gram o f b rac ing is m ore ap propria te the rapy u n tilg ro w th is com ple te.

W h ile le ss than 1 00 in sta nce s of v ita m i.n -D re sistan t r ick ets h ave been de -scr ibed ill the lite ratu re , m o st o r tho paed ic and ped ia tric clin ics h av e sm a ll un re -p orte d g rou ps o f c h ild re n un de r tre a tm en t fo r th is c ond itio n w h ich is no w be ingre c ogn iz e d as o ne of th e co m m o nest m etabo lic bo ne d isea se s seen in ch ild ren . T hew ide spectrum of seve rity o f the d isea se d eserves sp ec ia l em p hasis . T h e tw e lvep atien ts stud ied in our clin ic h av e been m a in ta in ed on v itam in -D the rapy . W itha tten tio n to bra cin g , s erious de form it ies have been p reven ted and osteo to m ies haveb een un necessary in eig h t o f o u r tw e lve p a tien ts up to the tim e of w riting . F o urch ild ren , ho w eve r, have requ ired o pe ra tive co rrec tion of de fo rm itie s; and , alth oug hre sp ond ing to very larg e d ose s of v itam in D , fre qu en t in te rru p tion s o f trea tm e n thave b een req u ired b ecause o f v itam in -D in tox ica tion w ith a ttendan t ren a l in ju ry .T hese fou r p atien ts a lm o st con tin uou sly hav e been unab le to p a rtic ipa te in usu alscho o l life and ill tw o of them (W .H . and M .A .R ., T ab le II) th e ex pe c ted s tab iliz a-tio n o f the bo ne d isea se a t pu be rty has failed to occu r.

D e fin ition an d D iagno sisVitaf lUi1-D res is tan t rick ets , a spec ific d iso rd er w ith c lin ica l, roen tg en og raph ic ,

and b iochem ica l ch aracte r is tics sim ila r to those seen in rick ets due to v itam in -Dd efic ien cy , pro gre sse s d esp ite an tira ch i tic p rop hy lax is an d hea ls on ly in re sp onse tola rg e do ses o f v itam in D . T he m e tab o lic ha llm arks o f th e d isea se a re:

1 . H y pop hosp ha tem ia , usu ally a ssoc ia ted in ch ild ren w ith a norm a l se rumca lciu m con cen tra tion and an e lev ated se rum a lka line pho sph ata se and in adu ltsw ith a no rm al se rum calc ium co ncen tra tion an d n orm a l a lka line pho sph ata se ;

2 . P i-ob ab le d e fec tiv e g as tro - iu te stina l ab so rp tion o f ca lciu m and pho spho ru s55 ;3 . D im in ished reabso rp tion of pho spha te from the g lom eru la r filtrate in the

rena l tub u le s w ith n o o th er dem o nstrab le d efects in ren al fu nc tion .* R ead at the A n nua l M ee ting of T he A m e ric an A cad e m y of O rth o p aed ic S u rge on s , C h ic ago ,

Il lin o is, Ja nua ry 2 2 , 196 4 .t S u p p orte d in p ar t by a g ra n t fr o m the L ak e C o un ty S oc ie ty fo r C ripp led C hild ren , Inc . U n ive rs ity of C a liforn ia M e d i c a l C en te r , S a il F ran cis co , C a lifo rn ia . 2 065 A delb ert R oa d, C le ve la nd 6 , O h io .

97 8 THE JOURNAL OF B O N E A N D J O IN T S U R G E R Y


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T R E A T M E N T O F V IT A M IN -D R E S IS T A N T R IC K E T S 97 9T A B L E I

1)IF F E R E N T IA T IO N O F T H E R O E N T G E N 1)IA G N 0S Is O F R IC K E T S

S eru m C on ce ntra tio nsBlood

U rea U n iieP h os - P ho s- C arb on N itro - G b - A m in o

1) ia gnosis C a lcium ph oru s ph ata se l) iox ide g en co se A c ids C o m m e n ttamin -D N- L L H N N N e g. P o s . P os itiv e nu tri-

deficiency tion al h istor yResistan t N -L L H N N N e g. N e g . O ften po sitive

r i c ke ts fa m ily h isto ryF a nc o ni s N -L L H L N -H P os . P u s. O ften po sitive

syndrome fam ily h isto ryR ena l tu bu le N -L L H L N -H P os .? N eg .? N e gat ive

ac idos is fa m ily his toryC h ron ic re nal N -L H N -H L H Ne g. Ntg. R e n a l a noma l ie s

fa i lu re usualH y pop ho sph a- N -L N L N N N e g. N eg . 1 m e plo s-

tasia p i loe th -ano lan) ineP osi t ive

Lowe s N -L L -N H L N -H P os . P us.? G lau com asyndrome

Coe l iac N -L L H N N N eg. N eg . E vid enc e o fric ke ts , stea to rr h eahepat ic o r o f liverric ke ts d isea se

N = n orm al ; L = low ; H = hig h ; ? = equivocal o r v a ria b ly l)r( se rlt .

W in ters and as soc ia tes sho w ed th at in m any in stan ces the d isease is rela tedto an in he rited sex -link ed dom inan t d iso rd e r, in w hich th e m e tab o lic m ech an ism sof ex pres sion rem ain to b e fu lly exp lain ed . U n dou b ted ly , m any instances o f th ed isea se a re spo rad ic an d po ssib ly rep re sen t new m uta tion s o r hom ozygo sity fo r anunreco gn ized au toso m a l recessive fo rm . I t is e ssen tia l tha t the d is ea se b e d iffe r-en tia ted from oth er en titie s in w hich the roen tgen and c lin ica l f ind ings a re sup e r-fic ia lly sim ila r, bu t in w h ich trea tm en t and p rog nos is a re d iffe ren t. T he sa lien td iffe ren tia l fea tu re s a re p re sen ted in T ab le I .Patho log ica l and R oen tg enog raph ic M a n ife sta tio ns

T h e h isto log ica l changes in res is tan t r ick ets re sem ble tho se seen in seve re un -tre ate d d efic ie ncy ricke ts bu t the re a re im portan t d ifferences 1, T he m o st p ro m ine n tde ran gem en t is in en docho ndra l o ssifica tion and is m ost app a ren t a t the ep iph ysea lp la tes an d in the m etap hyses o f lon g bo nes. T h ere is fa ilu re o f m inera liza tion of thecartilage m atr ix a t the zo ne of p rov is iona l ca lcif icatio n . T he ca rtilag e ce lls , a lignedno rm ally in co lu m ns, und ergo d is in teg ratio n w ith co ncurren t ing row th o f cap illa rie s ,bu t ca lc if ica tio n o f th e ca rtilage m a trix does no t o ccu r , le ad ing to a d efic ien t m ine ralla ttice fo r th e depositio n of o steo id . U nca lcif ied islan ds o f ca r tilag e a re freq uen tlyseen deep in th e m etaphys is, fo rm ing no defin ite pa tte rn and no t b e in g ab sorbedo r rem ode led . T he osteo id m a tr ix is incom ple tely m in era lized in m an y a reas. T h etrabeeu lae a re coa rse an d w ide ly sp aced in the m e taphy sis , th rou gho u t the sha ftso f the lon g b ones, an d in th e p elv is and ribs i .18

B io psy m a te ria l rem ov ed from the tib ia o r f ibu la o f five o f ou r pa tien ts a to steo tom y revealed find ings sim ila r to those d esc ribed b y E n gfe ld t and assoc iates 18C harac te ris tica lly , th e co m pac ta is th inne r th an the no rm a l w ith a str ik ing en la rge -m en t o f the H ave rs ian cana ls , va ry in g from pa tien t to pa tien t. T h ere is an irregu larV O L 4 6 -A , N O . 5 . J U L Y 1964


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F IG. 2-A

T R E A T M E N T O F V IT A M IN -I) R E S iS T A N T R IC K E T S 98 1

V O l . . 4 6 -A , NO . 5 , JU L Y 1 964

M A R ., a seve n te en-yea r-o ld g irl, ha d sev ere v itam in -i) res ista n t ric kets a t th e tim e sh e w a sfir st ex am ine d in 1 95 8 . T h is ro en tgen og ram o f the h ips an d pelv is w a s rna (Ie in M a y 19 58 . N oteth in c on ipac ta an d co arse w idely spa ced tra be cu la e 11 1 1 )0 th the l)e lv is an d fem ora . S e vere c oxavara iS l)res(Ilt and the re are L o ose rs z on es at the ju nct ion of th e l)rox im al :111 11 m id dle th ird s ofi )Ot i i f em o ra .

F I G . 2- BR oen tge nog ram s of the tib iae and fihu lae m ade in M ay 19 58 . A n terom edia l bo w ing is sev ere .

L o ose rs zon es are pre sel it a t the jun c tio n o f t ile dista l and m idd le th irds. Th e t rab ecu lae a re(0 ( r an(1 w ide ly s l)a( e(I .


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98 2 D. S . P IE R C E , W . M . W A L L A C E , A N I) C . H . H E R N D O NR oen tg en ograph ica lly , in our p atien ts , the appea ran ce o f bo th th e co m pac t

and cau cello us bo ne is s im ila r to th at seen in ricke ts re su ltin g from secon da rypa rath y ro id hy pe rp lasia d ue to g lo m eru lar in su ff iciency or rena l tu bu la r ac ido sis ,o r bo th , bu t d iffe ren t from th a t seen in v itam in -D deficien t ricke ts . T he trab ecu laeapp ea r coa rse an d w id ely spaced ; t he d ensity o f the com p acta is d im in ished . T hesech aracte r is tics are p re sen t in th e yo ung ch ild an d ev en m ore p ro m inen t in the p atien tp ast pu be rty (F ig s. 2 -A and 2-B ) . In the sha fts o f lo ng b on es th e tra be c u la e a ref requen tly long itud ina lly ar ranged show ing little ten dency to a lig nm ent a lo ng lin eso f stress . In a g ro w in g ch ild the ep iph yses a re w idened an d cu p-shaped w ith a h azyap pea rance in the zo ne of p rov ision al calc if ica tion and w id en ing o f th e ep iph ysea lp late T h is is pa rticu lar ly ap pa ren t a t the kn ee. T h ere is frequen tly a b rush lik epa tte rn n o ted in th e m etaph yses rep re sen tin g is lan ds o r co lum n s of unca lc ifiedcart i lage.

T he re is little ang u la r d efo rm ity in th e bon es o f th e u ppe r ex trem ities bu t inthe low er ex trem itie s b ow ing is a p rom in en t featu re . C h aracte r is tica lly , th is co nsis tso f coxa va ra ., an te ro la tera l bow in g of the fem ora, an d bo w in g o f th e tib iae assoc ia tedw ith m ed ia l to rsion . A lth ou gh th e coa rse , w id ely sp aced trabecu lar p atte rn isappa ren t in the ve rteb rae an d p elv is , d efo rm itie s in th ese stru ctu re s d o no t occu ra s a ru le . D ue to the p u ll o f the d iap hrag m , de fo rm a tion of the rib s de ficien t instren g th can prod uce H arr ison s g roo ve . L in ear g row th is re tarded b ecause o f thed iso rgan iza tio n a t the zone of p rov is iona l ca lcif icatio n .Pa th o log ica l P hysio log y

D esp ite ex tensive m e tabo lic investig atio ns by m an y w orke rs 21 32 ,4 1 the reare no d a ta th at unequ ivoca lly d elin ea te the m e tab o lic de fec t in resis tan t ricke ts .U n treated pa tien ts w ith th is d isea se g row a t a reduced ra te an d , o f n ecessity , in -cre ase th e to ta l b od y c on te n t o f bo ne m ine ral . W h ile no m e th od ex is ts to de te rm ineto ta l bod y b one m in era l in v ivo , ev iden ce draw n from roen tgenog raph ic exam ina tionof th e ske le ton , a s w e ll as h is to log ica l an d c he m ica l a n aly ses o f b one sa m ple s tak e nfrom pa tie n ts w ith the d isea se , su gg es t tha t the to ta l bo dy bo ne m ine ra l in c hild re nw ith res is tan t ricke ts is redu ced b elo w th at fo und in norm a l ch ild ren of equ iv alen ta ge an d s ize O n e m u st co nc lu de , the refo re , tha t a c cre tio n o f b one m ine ral w ithgrow th occurs in ch ild ren w ith th is d isease bu t a t a reduced ra te com p ared w ithth e no rm a l. M an y a tte m p ts h av e b ee n m ad e to do cu m en t th e ra te o f a cc re tion b yex te rna l b alan ce tech n iqu es 3,22,25,32,49,55,60#{149} T h e e v id en c e so o b ta ine d is o fte n c on -f lictin g and in te rp reta tion is ham pered b y lack of su itab le co n tro ls . M o st o f the da taa pp ea r to sho w d e cre ase d g as tro -in tes tin al a bso rp tio n o f c a lc ium an d p ho sph orusand dec reased u rin ary exc re tion of ca lciu m w h en co m pared w ith co m p arab lecon tro ls H ow ever, the d iffe ren ces, pa rticu la r ly fo r th e gastro - in te stina l co rn -pon en t., a re rela t ive ly sm a ll and often eq u ivo ca l. C ritic a l con side ratio n o f the p ro b-le rn s in vo lv ed ind ica te th at the techn ique of ex te rna l ba lance is too in sen sitive andtoo fraug h t w ith erro r to de tect accu ra te ly the m inu te bu t im po rtan t ba lancechang es in the face o f the rela tive ly en orm ou s qu an tities in vo lv ed in in tak e, feca lex cre tion , and to ta l b ody m in e ra l. T he neces sary b a lan ce to a llow for slow ske le ta lgr ow th mu st in ra c h itic ch ild ren a s in no rm al ch ild ren , be d isco n tin uous , m ustflu ctu ate , an d b e va rio usly affec ted b y in take , the in tensity o f the g ro w th s tim u lu s,the degree o f im m obiliza tion , an d m any o the r facto rs n #{1 49 }h ese co nsid era tions un-dou b ted ly acco un t fo r the d isp arity in re su lts fo und b y d iffe ren t inv es tiga to rs usingth is techn iq ue and fo r the m ultip licity o f conc lus io ns draw n from them .

F rom o ur ow n exp erience, a s w e ll a s th at o f o th ers , w hen v itam in D is adm in is-te red in q uan titie s su ffic ien t to p rod uce roen tgen and chem ica l sig ns o f hea ling th eabso rp tio n of ca lciu m and pho sph orus fro m the gu t is inc rea sed , the u rin ary ca lc ium

TH E JO U R N A L O F B O N E A N D JO IN T S U R G E R Y


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T R E A T M E N T O F V IT A M IN -D R E S IS T A N T R IC K E T S 98 3lo ss is inc reased , and th e u rin ary p ho spho ru s is eith e r u nchang ed o r in creased . Inm ost in stances the g astro -in te stin al com pon en t o f the b alan ce is a ffec ted to ag rea te r deg ree than the u rina ry losse s and a p ositive ba lan ce ensu es. C on tin ua tionof the v itam in ad m in istra tion is fo llo w ed , a t va rio us in te rv a ls , w ith an inc rea sin glo ss o f ca lc ium and ph osph orus in the u rin e so th at even tu ally the b alance b ecom esnegat ive 4 , 6 3 T his m ay occur w h ile sign s o f h ea ling are still p re sen t. In m ost in stan cesv itam in tox ic ity fo llow s and fo rces d iscon tin ua tion o r reduc tion of do sage .

R ecen t s tud ie s by K le in an d C urtiss # { 1 7 6 }h ow ed increased excre tion of hy droxy -pro line in pa tien ts w ith v itam in -D d efic ien cy , an abn orm a lity w hich is abo lishedw ith ad eq ua te v itam in -D the rap y . T h is obse rva tion w as in terp reted to ind ica tein creased fo rm ation o f sk ele ta l co llagen in th is d isea se . S im ila r stud ie s on p atien tsw ith v itam in -D resis tan t ricke ts have p ro v ided v ariab le re su lts { 176} . In so m e pa tien tsw ith th e d is ea se , pa r ticu lar ly tho se w ith a h igh se ru m ph osph a ta se , hy dro xy pro lineex cre tion is h ig h and d ecrease s co ncom itan tly w ith v itam in -D adm in istra tion o rw ith in trav enou s calc ium in fusio n . H o w eve r , co m ple te re tu rn to norm a l leve ls o furina ry ex cretion w as no t ob served . In o the r p atien ts w ith the re sis tan t fo rm of thed isea se, u rina ry h ydrox ypro lin e ex cre tions w ere w ith in the no rm al range . T hesign ificance of the variab le h ydrox ypro line excre tio n in v itam in-D res is tan t. rick etsis unk now n bu t p rob ab ly rep re sen ts spo n taneou s va ria tion in the in tens ity o f them etab o lic abnorm ality .

In the few stud ie s o f the sk ele ta l dy nam ics in th is d isea se m ade w ith calc iu mi so topes , th e rate s o f bo th bo ne re so rp tion an d bon e acc re tion h av e been tw o to fivetim es tha t n o rm ally expec ted 41#{149}n o th er w ord s the re is an in creased b on e tu rn ove rbu t an ov er-a ll redu ced ra te o f to ta l acc retio n com pared w ith th e no rm al.

D a ta ob tain ed from the stud y of pa tien ts w ith re sis tan t ricke ts h av e beentested ag ain st th ree g en era l hy po th eses.

T h e d isease h as been con side red to rep re sen t a de fec t in bo ne tissu e due tore sis tance to the ac tion of v itam in D . T he w ork of F raser an d asso cia te s dem o n-s tra ted tha t ca r tilag e , in v itro as w ell a s in v ivo , w ill h ea l p rom p tly w hen th e co nceii-tra tion of ph osp ha te in the ba th in g m ed ium is norm a lized o r w hen the se i-ump hosphoru s leve l is inc reased b y in trav en ous in fusion . T hese ob serva tions po in t toa d e fec t in regu la tion pe riphe ral to bon e itse lf.

T he co ncep t o f A lb rig h t th at re sis tan t ricke ts rep re sen ts s econ da iy h ype r-p ara thy ro id ism cau sed by decreased abso rp tion o f ca lciu m has rece ived the m ostex pe rim en ta l sup port i. T he lack of re sp onse to exog en ous ly adm in iste red p ara -thy ro id horm o ne , th e nea r-no rm al in te stina l abso rp tio n of ca lciu m in som e p atien ts ,an d the fin d ing of h isto lo g ica l ev idence of p ara thy ro id hy pe rp lasia have a ll beenc ited in favo r o f th is concep t. S im ila rly , the in fus io n of ca lc ium w ith its inh ib ito ryeffec t u pon para thyro id sec re to ry ac tiv ity h as been show n to reduce rena l phos-ph orus ex cre tio n sh a rp ly 41 in re sis tan t ricke ts an d has been c ited as ev idence infavo r o f secondary hy perpara thyro id ism as the m echan ism lead ing to the h oned isease .

T he th ird con cep t o f th e d isease has been tha t o f tu bu la r w asting o f ph os-ph orus as a resu lt o f a g en etica lly o r o the rw ise acqu ired d efect in the tubu la renzym atic m ech an ism s tha t re trieve pho sph oru s from the g lom eru la r f iltrate 4 , 2 5 , 3 2A cco rd ing to th is concep t the io n produ cts necessa ry to p rec ip ita te b one m in era l inthe m a trix a re in ad eq ua te and the d ec reased ca lc ium absorp tio n fro m the g u t is insom e w ay re lated to th e d ec reased d ep ositio n o f bon e m in era l. T he observa tion tha tla rg e o ra l o r in travenou s loads o f pho spha te w itho u t v itam in -D ad m in istra tion ap -p ea r to in c rea se ca lciu m absorp tio n is con sis ten t w ith th is p rop osa l H o w e v e r ,the d irect p ositiv e e ffect o f v itam in D upo n calc ium tran sfe r in th e iso la ted gu tloop h as th row n d oub t u pon the la st item in th is a ttrac tive an d sim p le train o feven ts


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98 4 D. S . P IE RC E, \V . M . W A L L A C E , A N D C . H . H E R N D O NT he observa tion tha t ca lciu m in fusio n lead s to p ro m pt d ec rease in ph osph a tu ria

can no t be tak en as true ev idence fo r the absence of a ren al d efect in tu bu la r pho s-pho ru s reabso rp tio n . If seco nda ry hy pe rp ara thy ro id ism w ere the so le de te rm inan to f pho sph oru s w as ting in re sis tan t ricke ts , it w ou ld be exp ec ted th at calc ium in -fus ion w o uld ab o lish ph osp ha tu ria in th e rach itic sta te . In m o st p a tien ts th is doesn o t o ccu r , the p hosp ha tu ria is o n ly red uced . T he true ab ility o f th e ren al tubu le toreabsor l ) p hospho rus can on ly b e de te rm ined by m ax im u m load ing of th e tubu larm ech an ism w ith a g lom eru la r f iltra te con tain ing su ff ic ien t pho spho ru s to satu ra tethe re so rp tive m ech an ism fu lly fo llow ed b y q uan tita tion of the re so rp tio n of ph os-pho ru s (T m p) und er these co nd itio ns. W h en th is is don e, m o st b u t no t all s tud ieso f p atien ts w ith re sis tan t r ick ets h av e clea rly show n a reduc tion in T m p 58 Ink ind red w ith fam ilial re sis tan t r ick ets , ind iv idua ls a re fo und w ith h ypo pho sph atem iabu t w ith ou t bo ne d is ea se . T he ex p lana tion of th is pa rado x is es sen tial fo r anyun if ied theo ry of the pa thop hys io log y . A s W illiam s an d as soc ia tes 58 p o in ted o u t:11 it seem s probab le tha t the de fec t in ca lc ium abso rp tion cou ld be so de lica te lyba lan ced b y pa rath y ro id o ve rac tiv ity tha t se rum ca lc ium con cen tra tion w ou ld b em ain ta in ed a t a no rm a l leve l th ro ugh ou t life w ith ou t an y sig ns o f hy pe rp ara thy -ro i(lism o the r th an the inc rea sed ph osph ate ex cre tion .

Will iams an d assoc ia tes 58 h av e critica lly and exhaus tive ly rev iew ed the cu r-ren t theo rie s o f th e pa tho phy sio lo gy of re sis tan t r icke ts . T h e u b iqu ity o f the ac tionof v itam in D a t the tis sue leve l and the u n ifo rm ity o f its e ffec t a t th e lev e l o f th em itocho nc irio n su ggest tha t th is d isea se w ill even tu ally be und ersto od a t th e su b-ce llu la r leve l ar id the reby m ultip le tissu e de fec ts w ill be inc luded in its gen es is.Iiitil such kno w ledg e is av a ilab le th erapy can , a t bes t , b e o n ly em p iric an d sub-s ti tu ti veTre al in c i i t

C oord in a ted and h igh ly ind iv idu alized o rth opaed ic and m ed ical trea tm en t isesse iitia l fo r success fu l m an ag em en t. T he age of th e pa tien t in rela tion to h is p o -ten tia l fo r g row th , th e sev erity o f the ske leta l d isea se , th e d eg ree o f im m obiliza tioncaused b y d e fo rm ity o r op era tive in terven tio n , an d the suscep tib ility to hy pe r-v itam in osis D are a ll fac to rs d e term in in g th e degree o f succes s o b ta ined .

V itam in -D th erapy is m ost c lea rly and urgen tly ind ica ted us yo ung er ch ild renw ith frank rach itic chan ges and rap id ly p ro gres sive de fo rm ity . S uch trea tm en t isbegun w ith 50 ,00 0 U S P un its o f v itam in D d aily . V itam in D 2 , ava ilab le in 50 ,00 0-u n it . capsu les o r as a w ate r m iscib le co ncen tra te , co n ta in ing 50 ,0 00 un its pe r cu b iccen tim ete r , is th e p re ferred fo rm of m ed ica tion becau se o f its gene ra l ava ilab ilityand low co st. T he d osage is inc rea sed by 50 ,0 00-un it inc rem en ts a t m on th ly in -te rv a ls un til ev iden ce o f h ealin g i s a pp ar en t. T he ea rlie st ind ica to r o f hea ling is adec rease in the se rum alk alin e ph osp ha tase o r , in som e pa tien ts , an in crease in th eseru m ph osp horus concen tra tion . C hang es in the la tte r pa ram e te r, how eve r , sh ou ldno t be re lied u pon s ince hea ling and v itam in to x ic ity m ay ap pea r w ith no s ign if ican tchang es in the se rum co ncen tra tion of pho spho ru s. R oen tgenog raph ic ev id en ce ofh ea ling is n ex t to ap pea r, u sua lly lagg ing seve ral w eeks beh ind chem ica l chang e.R oen tgenog ram s o f the w rist p re sen t the m o st sens itive m eans o f de tec ting earlychang e. O n such a sch edu le o f v itam in -D ad m in istra tion , ev id en ce of h ealin g w illu sua lly app ea r in th ree to fou r m on th s and a fte r a dosag e lev e l o f 1 50 ,00 0 to 200 ,000u n its is a ttain ed . O n ce ev id en ce o f hea ling is o b ta ined , the leve l o f m ed icatio nsh ou ld be stab iliz ed fo r tw o to th ree m on ths and th en dec reased in one s tep to ap -p rox im a te ly o ne -h a lf the hea ling requ irem en t. M o re p ro lo nged m a in tenance a t h ig hleve ls in ev itab ly re su lts in th e app ea ran ce o f v itam in -D tox icity . It sh ou ld heem phasized tha t th is schedu le o f ev en ts is sub jec t to eio rm ous v a ria tion in tim e

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T R E A T M E N T O F V IT A M IN -D R E S IS T A N T R IC K E T S 98 5an d dosage leve l from pa tien t to pa tien t and in th e sam e pa tien t a t d ifferen t ag es .In a g ene ra l w ay in creas ing ag e w ith its co inc iden t dec rem en t in g row th requ iresreduc tion in d osage .

T h ro ugh ou t the p hase o f ac tive trea tm en t w ith v itam in D , in to x ica tio n is ase r ious and con stan t th rea t. In m an y p atien ts , as w as firs t em p hasized b y P ede rsenand M cC arro ll 47 , th e healin g an d tox ic doses are in the id en tica l range . In ou rea rly expe rien ce w ith v itam in -D trea tm en t o f re sis tan t r ick ets , m uch large r q uan ti-tie s o f the v itam in w ere u sed than recom m en ded he re and the pa tien ts w ere m Ien-tio na lly b ro ug h t to th e p o in t o f tox icity in o rde r to d ete rm ine th e m ax im um to l-c rated do se. H o w ev er , subseq uen t ex pe rience ind icated tha t typ ica l c lin ical sym p-to m s of to x ic ity , su ch as po ly u ria , ano rex ia , and irr itab ility , are m an ife sta tions o facu te rena l in ju ry w ith red uc tion of rena l func tion . F u rth erm o re , th e ap pearanceo f tox icity has o ccu rred in som e pa tien ts w ithou t excessive e lev a tio n of the se rumca lciu m concen tratio n an d w ithou t the app earance o f a p ositive S u lk ow itch tes t(I\I . A . C . an d W . H ., T ab le II) . C lin ica l s tu dy of th ese pa tien ts and m ore recen tkn ow ledge of the ad ve rse e ffec ts o f hy pe rca lcu ria up on k idn ey fun ctio n adequa te lyexp la in th e ap pa ren t pa rado x . It h a s been clea rly dem o nstra ted tha t \ery sh ort(one day) exp osu re o f the k id ney to hy pe rca lcu ria in duces struc tu ral chang es in theconcen tra ting appara tus o f the k idn ey 9 O ur clin ica l s tudy of pa tien ts in w ho m itam in-D in tox ica tion occurred h as ind ica ted tha t hy posth en uria w as w e ll e stab -lished a t the tim e sym ptom s appea red . T he to ta l u rin ary exc re tion of calc iu m intw en ty - fou r h ours w as h ig h b u t b ecause o f the d ilu tion o f the u rine , th e S u lkow itchte st rem ained nega tiv e long after excess iv e ca lcin uria w as estab lished . In m ost o fthe p atien ts stud ied th e ab ility to concen trate the u rine , the azo tem ia , an d thedecreased urea c lea rance re tu rned to norm al in s ix m onths to a year. R epea tedep iso des, h ow ev er , resu lted in cu m ulative and irreve rsib le lo ss o f rena l func t ion .T his occu rred in tw o o f the tw elv e pa tien ts (M . A . C . and W . II., T ab le II) fo llow edill our se ries . In on e o f th ese (M . A . C .) , pe rsis ten t and sev ere hyp e rtensio n fo llow edth ree ep isodes of in tox ica tion . A d eq ua te fo llo w -u p and m eticu lo us a tten tion toc lin ica l d eta ils is essen tia l to the preven tion of these com p lica tions of th erap y .F ailu re o f fo llow -u p due to adve rse soc ial co nd itio ns w as th e m os t frequ en t. fac to rlead ing to the d ev e lo pm en t o f rena l in ju ry in o ur p atien ts .

W e b elieve tha t the s ing le m os t va luab le c rite r ion of th e on set o f to x ic ity isthe se rum calc iu m concen tratio n . W e have com e to rega rd a se ru m ca lciu m co ncen-tra tio n of e lev en m illig ram s per 1 00 m illilite rs a s an ind ica tion fo r in tens ive clin ica leva lua tion in term s o f sy m pto m s and ex am ina tion o f th e u rine and b lood fo r signsof rena l in ju ry . W h en dou b t ex ists v itam in -D ad m in is tra tion sh ou ld b e d iscon-tm ued fo r a one-to - tw o-m o nth p erio d . A s has been in d icated , the S u lko w itch test,in ou r exp erience, is o f little va lue in de term in ing th e p resen ce of tox icity . R ep eatedqu an tita tiv e eva lua tions o f the am oun t o f ca lciu m in the tw en ty -fou r-hou r u rin e inth e sam e ch ild a re u se fu l b u t a re no t usua lly p rac ticab le in the gene ra l m an ag em en to f these ch ild ren . T he tw en ty -fo u r-ho ur exc retio n o f calc ium varie s w id ely in nor-m al in d iv idua ls and d ep en ds on the in tak e o f ca lciu m , bo dy size , age , and m anyunk now n variab le s . T h e d eg ree o f hy pe rca lcin u ria tha t lead s to rena l in j u ry is u n -kn ow n and app ea rs to v ary from pa tien t to pa tien t. F o r th ese rea son s no estab -lished u ppe r lim its fo r th e tw en ty -fou r-hou r exc retio n fo r a g iven p a tien t can beg iven w ith any certainty.

W hen the lon g-term efficacy of v itam in -D the rapy in re sis tan t ricke ts is re -v iew ed , it is im possib le to sta te w he the r use o f the vitamin has sig n ifican tly con -tr ibu ted to th e fin al resu lt. T he re is n o d oub t th at, d u rin g the ea rly ph ases o f rap idg row th of a ch ild pa rticu la r ly , the ro en tgen and chem ical ev id en ce of th e d is ea secan be suppressed in so m e instances and the rap id p rog re ssio n of de fo rm itie s canVO L. 46 A. N O. 5. J UL Y 1964


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98 6 D. S . P IE R C E , \V . M . W A L L A C E , A N D C H . H E R N D O Npo ssib ly b e preven ted . D uring slow er phases o f g row th it becom es m ore d iff icu lt toassess the va lue o f such trea tm en t. W e d o no t k now w he the r m ild cases o f th ed isease w ould do as w e ll w ith ou t such the rap y . In seve re d is tu rb ances , such as tho sec ited he re , it is p ossib le tha t v itam in the rap y m ay lead to an o ve r-a ll le ss fav orab leresu lt. S ince h ig h tu rno ve r o f b one m ine ra l is cha rac te ris tic o f re sis tan t rick ets and since h ig h do ses o f v itam in D have a p a ra thy ro id -lik e ac tion , it m ay be th atsu ch trea tm en t accen tua te s th e ske le tal in s tab ility an d tha t the appa ren tly favor-ab le ro en tgeno grap h ic and ch em ical ch an ges rep re sen t accele rated rem ova l o f bo nem ine ra l fro m struc tu rally im portan t areas to areas o f g ro w th .

S av ille an d assoc ia te s repor ted tha t the adm in istratio n by m o uth of la rgequan titie s o f in o rgan ic pho spha te to p atien ts w ith re sis tan t r icke ts leads to hea l-ing and rev ersa l tow ard n orm a l o f the m e tabo lic de fec ts . T hese au tho rs a lso n o tedtha t such the rapy ap pea red to reduce the am oun t o f d ihy dro tach yste ro l needed tom a in ta in h ea ling in these pa tien ts , b u t no lo ng-te rm stud y o f the re su lts o f su ch areg im en has been p re sen ted . P ro lon ged ad m in istra tion of ph osp ha te to expe ri-m en ta l an im als leads to ex tensiv e rena l in ju ry and presum ab ly w ou ld ac t s im ila rlyin m an . F or th is rea son , m ost investig ato rs have been re lu ctan t to u tiliz e su chtherapy 58

L affer ty and assoc ia tes stud ied the effec ts o f h ig h ca lc ium in takes in fou r o fthe tw e lve p atien ts rep orted h ere . M e tabo lic stu d ie s in som e o f these p atien ts m di-cated tha t such the rap y ap peared to in crease the in te stin al ab so rp tion of ca lc iu mand to decrease the ra te o f b one re so rp tion as m easu red by iso to p ic techn iq ues.F ina l eva lua tion of th is m eth od of trea tm en t m ust aw a it long -te rm ev a lua tion an dfu rth e r de fin itio n o f the poss ib ility tha t no t all in stances o f res is tan t r icke ts have acom m on m etabo lic d efect.

T he ex ten t o f th e b race su ppo rt tha t w e recom m en d is d ep enden t on theseve rity o f the d isea se . In m ild fo rm s of re sis tan t ricke ts th e ap p licatio n of co r-rec tive b ow -leg b races a t n igh t on ly m ay b e su ffic ien t to p reven t the d ev e lopm en to f d efo rm ity and w e use th is m in im u m sup port un le ss the de fo rm ities are in creas -ing , in w h ich case the b races a re w orn day and n ig h t ex cep t fo r sh o rt p er iods o ffreedom for exe rcis e p urposes. W e have foun d th at ev en in the re la tiv ely seve refo rm s of the d isea se p ro gre ss ive de fo rm ity o f th e tib ia an d fibu la can be a rre stedby th is fo rm o f b rac ing , bu t w e have b een un ab le to arre st com ple tely the an te ro -la tera l bow ing o f the fem ur o r th e coxa va ra by any type of b race y et em plo yed .

I t is recogn ized tha t su rg ica l trea tm en t o f d efo rm itie s sh ou ld b e avo ided be -fo re pu be rty if p ossib le since recu rren ce o f th e d efo rm ity o r deve lo pm en t o f aseco nd ary d e fo rm ity in g ro w ing b one is a stro ng pro bab ility desp ite an adequa tem ed ica l p rog ram and bracin g afte r op era tion . T he re a re in stan ces, h ow eve r, inw hich correc tive osteo to m y m ay be in d icated b efo re pu be rty ev en tho ug h recu r-rence m ay deve lop . W e hav e had tw o pa tien ts (M .A .R . and W .H .) com e u nde ro ur ca re w ho a lready had de fo rm ities o f such sev erity tha t ad eq ua te b rac ing cou ldn o t be ca rried o u t un til s atis fac to ry alig nm en t o f th e low er ex trem ities had b eenach ieved . In o the r pa tien ts w h o d isca rd ed the ir b races, such seve re de fo rm itie s d e-v elo ped th at osteo to m y had to b e pe rfo rm ed p rio r to th e re sum ption of b rac ing .W e be lieve th a t if cox a va ra d ev elo ps to the po in t tha t it p rodu ces an ad ap tiveo b liqu ity in the ro o f o f the ace tabu lu m , co rrec tive sub tro ch an ter ic o steo tom ysh ou ld be pe rfo rm ed w itho u t fu rthe r de lay . A lso , if genu va lgum or g en u va ru mdeve lo ps to the ex ten t th at pa in refe rab le to the co lla te ra l lig am en ts o f the k neejo in t d ev elo ps w e d o no t be lieve tha t osteo to m y shou ld be d elayed . A t the tim e o fp ube rty , the low er ex trem itie s a re care fu lly eva lua ted an d su itab le o steo tom ies a rep erfo rm ed to ach ieve adequa te a lignm en t o f h ips, kn ees, an d ank le s. If a s e r i o u sd eg ree o f b ow ing is a llow ed to pe rsis t, the re is abn orm a l stre ss on th e re la ted jo in t

T H E J O U R N A L O F B O N E A N D J O IN T S U R G E R Y


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A . H . H oen tge nog ran is n lad e in 19 63 . A fter c orre ctive ost eo tom ies w ere pe rfo rm e d iii 1958 ,anterior t.i I)ia l b ow ing recu rre d ill 19 62 . A n atte m p t w a s th en m a de to o bta in cor rect ion by doubleO s t ( O t O H I\ an (l in ser tion o f L o tte s na ils in 1)0 th tib ia e .

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and pa tho lo g ica l fractu re s o f the sha ft o f the b one a t the p o in ts o f m axim um stress(L oo sers zon es) -

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W ith th e feet to gether there w as a s ix- inc h spare be tw een the m edial fem ora l co ndy les . ihelow er e xtre m ities w e r e shor t in pro po rtio ll to the trun k .

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T R E A T M E N T O F V IT A M IN -D R E S IS T A N T R IC K E T S 99 1

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R oe ntg eno gra m s o f the w r ists an d kn ees m ade w hen the bo y w as eig h t ye ars o ld . H e wa s re-ceiv in g a dai ly sup ple m e nt o f 3 .0 gra m s of c alc ium in th e form o f ca lciu m la cta te . T he rad ial an dtil) ia l e p ip hy sea l p la tes a pp ear essen t ia lly n orm al , bu t th ere is p ersiste n t i rreg u la rity of th e d ista lfem o ra l e p iph yse al plate .

cast, m ay cause sev ere o r un co n tro llab le h yperca lcem ia and hy percalc iu i a witha ttendan t depression of the cen tra l n e rvo us system and irreve rs ib le rena l dam age .A ltho ug h the typ e o f os teo tom y em plo yed is dependen t upo n the de fo rm ity to b eco rrec ted , an attem p t is m ade to use techn iques tha t w ill pe rm it th e ea rlie st p os-s ib le po stope rativ e m ob iliza tion . I t is e ssen tia l to reduce the dem ine raliz ing e ffec tso f in activ ity a s m uch as p ossib le w ithou t jeo pa rd izin g h ea ling o f th e osteo to m y .

R ecen tly w e have in on e pa tien t (M .A .R .), w ho se tib iae frac tu red sim u ltane -ous ly a t th e po in t o f m ax im um bow ing , em plo yed a techn ique s im ila r to th at d e-sc r ibed by Sof ie ld an d M illa r in th e m anagem en t o f pa tien ts w ith osteog en esisim pe rfec ta. T h is co nsis ted in m ultip le osteo to m ies o f th e tib ia , the inser tion of anin tram edu lla ry na il, and ea rly w eig h t-bearing a fte r p osto pe ra tive im m o biliza tion inlon g p laste r ca sts (F ig . 3 ) . R esis tiv e exe rcis es to a ll un in vo lv ed ex trem itie s a rein itiated as soon as p oss ib le an d pro tec ted p ar tia l w e igh t-b earing is encourag ed assoo n as p rac ticab le. D e layed un ion , how eve r, is n o t in freq uen t a fte r os teo tom y inre sis tan t ricke ts an d alth oug h the p rogram described is d es irab le , ca re m u st beexe rc ised to ensu re ad eq ua te im m ob iliza tion of th e o steo tom y site . V itam in -Dthe rapy is re ins titu ted as so on afte r op eration as th e p atien t can pa rtic ipa te in anexe rc ise p ro g ram vigo ro us en oug h to co m ba t the dem ine raliz ing e ffec ts o f in ac tiv ity .

In the p repub e rta l ch ild , p ro tec tive b races a re w o rn t1 fte r the osteo t.om ies havehea led and , a s a ru le , up to the ag e o f p ube rty . In a ch ild past p ub erty , b races a reWO1 l l a fte r rem ova l o f th e posto pe ra tive p la ster ca st un til In atu r e healin g a t th eo s te o to m y site is de mo nstra ted .

illu s tra tive C ase R ep ortsT he fo llow ing tw o case rep orts illu stra te the w ide d iffe rences in seve rity cha rac -

ter is tic o f the d isease . P a tien t L .T . rep re sen ts the g roup of pa tien ts w h o have arelatively m ild fo rm of th e d isea se w hich can be co n tro lled by the p lan o f trea tm en tprev ious ly d esc ribed . P a tien t W . H . is rep re sen ta tive o f the g rou p o f sev ere ly in -vo lved ch ild ren w ho se d isease is neve r adequ ate ly con tro lled even b y hug e d oseso f v itam in D an d in w hom the po ssib ility o f v itam in -D tox ic ity is a constan t d an ge r.

C A S E 1 (F igs . 4 -A th ro ugh 4 -E ). L . T ., a b oy, w a s first e xam in ed in A p ril 1958 w h e n he w a sth ree ye ars o ld , b eca use o f b ila teral b ow -leg de form it ies . H e w a s b orn at fu ll-term an d his ea rlyde velopm en t w as e n tire ly no rm al. T he re w as no fa m ily h isto ry of le g deform ities. T i le ch i ld b ega nto w a lk at fou rtee n m o nth s a nd at eigh teen m on ths the m o ther no t ice d increasing bo w ing o f thelo w er ex trem itie s. H e ha d b een giv en co d-l ive r o i l an d vitam in d rop s, as presc ril)ed b y th e fa m ilyph ysicia n , bu t h ad b een g ive n n o o the r m ed ica tion . A t th e tim e of a dm ission to B a bies and C h il-d rens H o sp ita l, ph ysic al e xa m in ation reve ale d a w ell d eve lop ed three-yea r-o ld b oy , som ew ha t


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99 2 D . S. P IE R C E , W M . W A L L A C E , A N D C . H . H E R N I)O Nshor t i n s ta tu re . T he u ppe r e x tr e m i t i e s an d tr u n k w er e e sse ntia lly n orm al; n o ra c h itic ro sa ry w a sd em on str ab le. E xa m in ation of the low er ex trem itie s revealed a seve re bo w -leg de fo rm ity ; wh e nth e p atie n t w as sta n d in g w ith hi s feet tog ethe r, th ere w as a six -inc h spa ce be tw e en th e m e dialfe m o r a l c on d yle s . T h e ran ge of m o tio n in all jo in ts w as n orm al a n d th ere w as n o p a lp a b le e n la rge -m en t o f the m etap hyses . M uscle p o w e r a n d n e u rolo gica l fin d in gs w ere w ith in n or m al l imits.U rina lys is w as w ith in n orm al lim its . B loo d urea n itroge n w a s le ss than 1 0 m illig ra m s pe r 100m illilite rs . T h e to ta l se ru m pro te in w as 7 .45 g ram s pe r 10 0 m ill iliters, w ith a lbu m in 5 .60 a nd g lob u-tin 1 .82 . T he ca lc ium w as 10 .8 m illig ram s per 1 00 m illi lite rs, p hosph oru s 3 .2 m illig ram s pe r 10 0m illiliters , an d a lka line pho spha ta se 13 .8 B o dansk y un its. R o en tgenograph ic ex am in ation at that

tim e r ev e a le d m o de r a te f la rin g o f th e ep iphyses w ith som e w ide n ing o f th e e p ip hv sea l p la tespa rticu la rly on the m e dia l sid e of the d ista l fe m o ral ep iph ysis . T he re w as also a ra the r co arset r ab e c u lar pattern n ote d in a ll o f th e b on e s e xam in e d .

A diag no sis of v i tam in-D re sis tan t ricke ts o f re la tively m ild se ver ity w as m ad e an d th e pat ien tw a s starte d o n 1 00 ,00 0 un its o f vitamin D da i ly . O n th is d osage po lyu ria , noc turia , and mildab d o m in al d isco m fo rt developed . On Ju ly 3 , 1 958 , h is calc iu m w as 1 1 .5 m illig ram s p er 1 00 m illi-l iter s; ph ospho rus , 3 .2 m ill ig ra m s pe r 100 m ill ilite rs; an d alk a lin e phosphatase, 14 .2 B o d a n sk yun its. T he v it .a m in -D d o sa g e w a s dropp ed to 50 ,000 un i ts every seco nd day . O n th is d osa ge th esy m p t o m s of tox icity d isa pp eared a nd d id no t recu r . A t the tim e o f adm is sion the pa tie n t hadb ee n fitte d w ith b ilate ral bow -leg b races w h ic h w er e w or n day an d n igh t, ex ce p t fo r one ho urtw ic e da ily dur ing w h ich tim e the y w ere rem ove d for exe rcis e purpo ses. F o l low ing a p licat iO f l o fthese c orr ec tive b r ace s th e bow -leg de fo rm ity im pro ved with m ost o f th e co rrec tion o c c ur r i ngin th e tib ia . T h e an te rola te ra l bo w ing of th e fe m u r p ers iste d . T his treatm en t w a s con tinu ed o verth e n e xt tw o ye a r s w ith se rum ca lciu m ran g ing fro m 9. 4 to 9. 8 m illig r a m s pe r 10 0 mill i l i ters ;phosphorus, f r om 3. 1 to 4. 5 m illig ram s per 100 m ill iliters; and alkal ine ph osp ha tase , from 9. 5to 20 .6 B oda nsk y un its.

U r i na l y s e s an d blood ur e a n itr o g en d e te rm in a tio n s d u rin g th is per iod ind icate d th at. n oim pa ir m e n t o f r e na l fun c tio n ha d re su l ted fro m the v itam in-D in to x ica tio n . T he p atie n t w aslost to fo l low -up fro m A pril 19 60 to M a rch 1 96 1 , d uring w h ich tim e h e did n ot w ear brace s an ddi d no t tak e vitam in D . R e-e xam in ation in M a rch 19 61 re vea led in c rea se d b o w in g of b oth tib iaea sso cia ted w ith m ed ial to rsion . T he bow -leg b rac es w er e re ap p lie d , to b e w orn day an d n igh te x c ep t fo r tw o da ily exe rcise pe riod s of on e ho ur e ach , a nd 5 0 ,0 00 un its of V itam in D w a s giv ene very o ther day . O n th is reg im e n , th e b ow -leg d efo rm itie s w ere con tr olle d an d by e a r l y 1 96 2 useof th e b rac es w as r ed u ce d to n ig h t w ea r on ly .

S inc e m e tab o lic stu d ie s c on duc ted on oth er pat ien ts at U niversity H o sp ita ls h ad sh ow npos itive ca lc ium an d ph osp horus b a lan ce assoc ia ted w ith reduc tion in b on e r es or pt io n an d gradua ls lo w in g o f ske leta l tu rn over fo llo w ing adm in is tra tion of h igh ca lc ium sup p lem en ts , v itam in Dw a s d iscon tin u ed in M ay 1 9 6 2 an d th ree gram s of ca lc ium in th e fo rm of calc iu m lacta te supp le-m en t w a s g i v e n dai ly . T h e p atien t w as st ill tak in g c a lc iu m w h en h e w as las t exa m ined in O ctob er196 . 1 . R oen tge nog ram s at th at t im e sh ow ed a co arse trab ecu lar pat iern w ith w iden ing of theep iph yse al p la tes a t the d is ta l e nd of the fem ora a nd pro x im al en d of the tib iae , m o re m arked onth e m e d ia l th an o n th e later a l s id e s. T h er e wa s s till m ode rate ly se vere an tero late ral b ow ing ofb o th fem ora, m in im um co xa v a r a , a nd co nsid era ble im p ro v em en t in the b o w in g o f b o th tib iae .M od e rate m ed ia l tib ia l to rsion p ersis ted ; bu t, w ith th e pa tien t stand ing and h is fee t toge the rth e m ed ial fe m or al co ndy les w ere sepa rated by on ly th ree ce n tim eter s . S e ru m c alc iu m w as 9. 0mill ig rams per 100 milliliters; phosphorus, 2. 9 m illig ram s pe r 10 0 m illilite rs ; an d a lka line pho s_pha ta s e , 1 1 B odansky units.

D iscns s i onr IC l h i s p atien t illu strate s th e p ro b lem s enco un te red in trea ting a ch ild w ith re la -

tive ly m ild v itam in -D res is tan t r icke ts . I t sh ou ld be no ted tha t the pa tien ts r ick e tsn ev e r com ple tely healed n or w as the re ev idence o f h ealin g o n h igh calc ium in tak e.I t w as p oss ib le , h ow ev e r, to m a in ta in sa tisfac to ry con tro l an d to p rev en t inc rea s-in g de fo rm ity o f the lo w er ex trem ities by m ean s o f b racin g . I t is p lanned to con-tin ue th is p ro g ram un til a f ter p ube rty an d then , if m ed ia l tib ia l to rsion pe rsis ts , toca rry ou t d ero ta tion osteo to m ies to ach ieve m ore no rm al a lignm en t.

C A S E 2 (F igs . 5- A th rough 5 - D ) . W . H ., a m an tw e nty -on e y ea rs o ld , w as a prem a ture bab y ,w e ig hin g th r ee p o u nd s an d fourteen ou n c es at b irth . H is m otor an d p h ysica l d ev elo p m en t w ereessen tia l ly n orm al a lth o u g h h e d id n o t b e gin to w alk in d ep e n d en t ly u n til h e w as n in e tee n m o n th so ld . In c rea sin g b ow in g of b oth low er ex tre m it ies w as n o ted soo n th ere after . T h e fam ily p h ys ician



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F I G . 5- C F I G . 5- D

T R E A T M E N T O F V IT A M IN -I) R E S IS T A N T R IC K E T S 99 3

V O L . 46-A , N O . 5 , JU L Y 1964

F IG . 5-A F IG . 5-BF ig . 5 -A : \V . H ., a b oy w ith se vere v itam in -I) resista n t r icke ts, a t four y ears of age in 1 94 6 . T h ere

w as m ode rate ly se ver e b o w in g o f 1)0 th fe mo ra.Fig . 5-B : A t tw elv e ye ars of age , th ere w a s se vere cox a va ra , fe m o ral bow ing , an d ge nu yalgum

on the left eve n thou gh th e p atie n t h ad bee n giv e ) h ig h do ses of v itam in I).

F ig . 5 -C : R o entgen og ram of the low er e x trem itie s m ad e on Ja nu ary 16 , 1 947 , w I le tile ioywa s five ye ars o ld . T h ere is w id en ing o f th e e p ip hyseal p la tes, a co arse tra bec u la r p attern , se verean ter olate ral b ow in g of th e fe m o ra, and cox a v ara .

F ig . 5 -D : R o en tge nog ram s of the fem ora , p elv is, an d lum bar sp ine m ad e w h en th e b oy w asth irtee n \c ea rs o ld . T he c oxa va ra had be en c orrecte d by sub tro cha n te ric o ste o to m ie s an d feln ora lI )o \% ing had bee n im prove d by supraco nd ylar osteo to m ies. N ote the c oarse w ide ly spac ed t.ra bec u la ein the pelv is, s acrum , an d ribs .

esta b lishe d a d iagn osis of rick ets in 1 94 4 w he n the pa tien t w as tw o y ears o ld an d ga ve him ole ump er co m orp h u m su p p le m en t, o n e fu l l d ro pp er tw ice a day . B eca use o f failu re to respo nd to th isme d ic at ion , the p atie n t w as re fer red to B ab ies and C hild re ns H osp ita l fo r ev alu atio n an d treat-m en t. O n adm is sio n to the h osp ita l a t th e a ge of fo ur, in 1 946 , the p atie n t had typ ica l ra ch i ticdefo rm itie s inc lud ing pigeo n breas t, H a rrisons g roo ve, th ick en ing of th e w r ists , an d la tera l b ow ingo f the fem ora a nd tib iae . R oe ntg eno gra m s m ad e a t th is tim e sh ow ed co arse trab ecu lae a nd w iden edep ip hy sea l p la tes cha rac teristic o f r ick ets . S erum ca lciu m w as 9. 0 m illig ram s pe r 1 00 m il li li te rs ;phosphorus, 2.5 m illig ra m s p er 10 0 m ill ilite rs; an d a lka line ph osp ha tase , 23 B oda nsk y u nits . N om alabsorp tio n w a s d e mon str ate d by m ea ns o f g lu co se a nd v ita m in -I) to leranc e tests . T he pat ien tw as p la ced on 5 0 ,0 00 un it- s o f v itam in D a d ay w ith a sub seq ue n t ris e in se rum p ho sph oru s to 3 .6m illig ra m s p er 10 0 m ill iliters. A fter four m on ths o f treatm e nt, roe n tg eno gra ns sho w ed eviden ce ofhea ling a t th e ep iph yseal p la tes. F rom 194 6 to 1 951 , the p atie n t rem ained on larg e do ses of v i tam in


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99 4 D. S . P IE R C E , W . M . W A L L A C E , A N D C . W H E R N D O ND ex ce pt for te m p ora ry w ith dra w a l be cau se o f in to x ic atio n in 19 47 . B ra ces w e re no t u se d du rin gth is period an d , a lthoug h roen tgenog ram s of the ep ip hyseal p la tes show ed n o ev idence of ac tiv eric kets, increas ing bo w in g dev elo pe d . In 195 1 , w h en he wa s n in e yea rs o ld , b i la tera l su p rac on dylaros teo to m y w as perfo rm ed and v itam in D w as increased to 500 ,000 un its a day . T he o steo tom iessh o w ed ro en tgen og rap h ic e v id enc e o f he alin g in e igh t to ten w e eks . F o ur a nd a half m o nth s afte rth e 50 0 ,0 00 un its o f v it am in D w a s s tar ted , serum ca lciu m w as 10 .0 m ill ig ram s per 1 00 mill i l i ters ;ph osp horus, 3 .3 9 m il lig ram s pe r 10 0 m illilite rs ; and a lka lin e phospha tase , 6 .4 B odan sky un its . T h epat ien t no w had m ild n au sea a n d ab d o m in al d isco m fort an d th e v ita m in D w as d is co ntin ue d.B ec ause of lo or fo llo w -up , the pat ien t w as n ot seen ag ain for a pprox im a tely six m o nth s, a t w h ichtim e the seru m ca lciu m w a s 9 .2 3 m illig ra m s pe r 1 00 m illilite rs; p ho sp ho ru s, 3 .1 6 m ill ig ra m s pe r10 0 m illili ters ; a nd the alkal ine ph ospha tase , 13 .9 B od ansky units. R oe ntg eno gram s m a de a t thatt im e rev ealed a ctiv e ric kets. V itam in D w a s re ins titu te d a t 50 ,00 0 u nits a d ay . T his d id no t c on tro lth e ric k e ts a n d th e d efo rm itie s in th e low er e x tre m ities rap id ly recu rre d , co ns isting o f b i la te ralm e dia l tib ia l to rs ion , b i la te ral c oxa va ra , an d g enu va lgu m o n th e le ft. H e w as rea dm itte d to theho sp ita l in A pril 19 54 at tw elve ye ars o f ag e. A t th is t im e bila te ral su b tro ch an teric fe m o ral oste-o to m ies w ere pe rfo rm e d to cor rec t the co xa va ra a nd a le ft supraco ndy lar os teo tom y w as a gainp e r f o r m ed to c orre ct re cur ren t g enu va lgu m . T h e vitam in D w as in cre ase d to 100 ,00 0 un its da ilyafter ope ration an d in crea sed p rog res sive ly to 50 0 ,0 00 un its a d ay . E v en on 500 ,00 0 units o f v i ta-mm D the c alc ium rem ain ed at 9 .2 8 m ill ig ram s pe r 1 00 m illilite rs , the ph osp horus a t 3 .6 m illig ram spe r 10 0 m illilite rs , an d the a lk alin e ph osp ha tase a t 25 .4 B od ansky u nits. A fte r tw o m o nths bec auseof fe ar of toxicity , th e do sage w as reduced to 10 0 ,0 00 u nits a day , w ith little c h an ge in b lo od v alu es .T h e o ste oto m ies h ea led w ith o u t d if ficu lty a n d , on th is occ as ion , a k n o ck -k n e e b rac e w as ap p lie dto p re ven t re cu r re n t d efor m ity at th e le f t kn ee . O v e r the nex t seve ra l m on ths an a ttem p t wa sm ade to ad ju st th e dosage o f v itam in D to a leve l tha t w ou ld resu lt in healing o f the ricke ts bu tw ou ld b e lo w en o u gh to p r eve n t to xici ty . T h e d osa ge w as g rad ual ly inc rea sed ag ain to 5 00 ,000u nits d aily . A t th is lev el ro en tgen ogram s dem on stra te d im pro vem en t o f bo ne stru ctu re at theep iphy seal p late s , bu t a fte r b ein g on th is do sag e fo r a p eriod o f approx im a tely tw o m on ths the rew as a gain ev ide nce of to x ic ity w ith calc ium at 1 3 .0 7 m illig ram s per 10 0 mill i l i ters, p hosph oru s at5 .88 m illig ram s per 10 0 m il lili ters , and a lkal ine p hosph atase a t 6 .87 B o dan sk y units. A cc ord ing ly ,th e v itam in D wa s re d u ced to 350 ,000 un its d aily in N o vem be r 19 54 an d th en gradu ally do w n to250 ,00 0 u nits dai ly by M arch 195 5 . H o w ev er, eve n on th is re duc ed d osa ge, the pa tie n t sho w e dd ef in ite ev id e n ce of tox ic ity w ith nausea , vom iting , and n oc tu ria. S e r u m ca lciu m w as 14 .68 mill i -g ra m s pe r 10 0 mill i l i ters; p h osp h or u s , 3 .80 m illig ram s p er 100 m ill iliters; an d alkal ine ph osp hatase ,7.77 B odanskv un its. T h e defo rm ity of his low e r e x trem itie s h ad bee n sat isfa cto rily co n tro lle d b ym e ans of b rac e pro tec tio n . T h ere w as ro en tgen ograph ic e v id enc e of ac tive ric kets a lth oug hsym p to m s o f tox ic ity w ere presen t A n a ttem pt w as m ade to m ain ta in the dosage jus t be low leve lsof tox ici ty , b u t su ch a d ose w a s n ot su ffic ien t. to c on tro l the ricke ts , an d even w ith b race p ro tec tionth e d e for mity of th e left k n e e re cu r re d . A t th is t i m e th e d eform it,v w as p rim ar ily d ue to bow in g o fth e tib ia a sso cia ted w ith m ed ial to rsion . B ecau se o f the rath er rap id in c rea se in de fo rm ity and theva lgu s stra in th at w a s prese n t a t the kn ee, the p atie n t w as read m itted to the h osp ita l in Ju ly1 955 , at th e a ge o f th irteen , a n d d er ota tion oste oto m y o f th e left t ib ia wa s p erfo rm ed . P ostope ra-t ively h e re ceiv ed vitam in D ran g in g from 1 00,0 00 to 300 ,000 un its da ily . T he osteo tom y hea ledw itho ut d iffic u lty an d roe n tg eno gra m s sh ow ed e vid enc e of hea ling of the ricke ts, b u t the re w asn o im p ro vem e n t in blood ch em is try . O n February 1 6 , 1 956 , the v itam in 1 ) w as d isc on tinu ed a ndth e pa tien t w as giv en I .0 g ram of p ho sph ate th ree tim es dai ly b u t w ith no e ffect on h is b loo dchemistry . A fte r a pe riod of s ix we e k s , th e ca lciu m r em ain ed a t 10 .4 m ill ig ra m s p er 10 0 milliliters,pho sph orus a t 2 .9 m illig ram s per 10 0 m illilite rs , and a lka lin e pho sph atase at 1 6 .5 B odansky un its.A t tha t tim e 500 ,000 un its o f vitam in D w a s a dd ed to the the rape u tic reg im e n w ith no ap p r e c iab leef fec t o n h is b loo d ch em istry afte r a per iod of tw o m on ths . In ord er to ave rt th e d eve lop m e nt o fv ita m in -I) in to x ica tio n , the v ita m in D w as re duc ed to 50 ,00 0 units dai ly and the pho sp horusinc reased p rogressive ly u p to 7 gram s a d ay . A lte r a period of fou r m onths th ere w a s sti ll no ev iden tc han ge in b lood ch em istry , th e calcium re m ain in g in the ran ge of 1 0 .4 m illig ra m s p er 100 milliliters,t he p ho sp ho ru s in th e rang e of 2 .7 m il lig ram s p er 1 00 m illiliters , and th e a lka line ph osph a tase inthe ra ng e o f 24 . 1 B o dan sk y un its . T he p hospho rus w as th en disco n tinue d s ince i t ha d pro duc edn o b en efic ia l e ffec ts a n d th e v ita m in D w as in creased to 100 ,00 0 u nits a day . T he de form ity inthe le ft tib ia g rad ua lly recu rred and m odera te m ed ia l bow ing and ro ta tio n of the righ t tib iadeveloped . T h e r e wa s m od erate ly severe pers isten t an te ro la te ra l bo w ing of bo th fem ora b u t theco xa v ara rem ained w ell co rrec ted . In A u g u s t 1957 th e pa tien t wa s aga in readm itted to U nive rsityHosp ita ls at th e ag e of fif tee n a nd a seco nd dero tat ion osteo tom y w as pe rfo rm ed on the left tib ia .H e w a s trea ted po sto perativ ely w ith 1 00 ,000 u n its o f v itam in D , bu t as soon as th e o ste oto mysh o w e d evid en ce of heal ing h e w as placed in a b ra ce an d th e vitam in D w as d isco n tin u e d . Th epat ien t rece ive d n o vitam in D afte r tha t tim e . T h e ep iphysea l p la tes closed afte r p uberty w hen

T H E J O U R N A L O F B O N E A N D JO IN T S U R G E R Y


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T R E A T M E N T O F V IT A M IN -I) R E S IS T A N T R IC K E T S 99 5h e w as ab o u t fif tee n ye ar s o ld an d the re w as n o in cr ea se in d e form ity th er ea ft.e :. \V h en h e w aslast see n , the pa tien t had a sh or t statu re , the tru nk be ing essen tially no rm al w hereas tile low erex trem itie s w ere short; th e upp er ex trem itie s w ere es sen tia lly n orm a l. T h ere w as res id u a l a n ter o-la te ral b ow ing of th e fe m o ra, a m ild rec urre n t gen u v alg um on the left, and m od ern tely sev erem ed ial tib ia l to rs ion o n the rig h t. B oth kn ees sh ow ed m od era te ligam en tou s lax ity w ith inc rea sedm obility , bu t th e o ver -all a lignm en t of the ex trem itie s w as acc ep tab le . A de ro ta tio n os teo tom yo f the righ t tib ia w as ind ica ted bu t the p a tien t re fu sed fu rthe r su rgery .D iscus s i on

T h is case dem o nstra tes the d iff icu lties en co un te red in the n rnnagem en t o f ap atien t w ith sev ere v itam in -D resis tan t r ick ets . A t tim es du rin g th e cou rse o f trea t-m en t th ere w as no roen tgenog raph ic ev idence o f hea ling of the rach itic le sio n at theep ip hysea l p la tes on doses o f v itam in D w hich proved to be to x ic . A t o the r pe rio dsh ealin g of the rach itic les ion sho w n ro en tgeno grap h ically w as accom p lished on con-side rab ly sm a ller do sages o f v itam in D . A t no tim e w as the re con sis ten t co rrec tio nin the b lo od -chem istry p atte rn . I t w as im possib le to m ain ta in the pa tien t on a con-s tan t v itam in -D d osage , a s the to x ic lev e l va ried from tim e to tim e, and , also , th ed osage req u ired to con tro l th e rach itic lesio n varied from tim e to tim e . T h is casedemons t ra tes th e re lativ e fu tility o f pe rfo rm in g correc tive o steo tom ies p rio r toc losu re of th e ep iph ysea l p la tes w hen th e rach itic lesion is no t w ell co n tro lled . R e-cu rren t de fo rm ity is to be an tic ipa ted und er su ch c ircum stances w ith th e n ecessityo f rep eatin g th e os teo tom ies. W e be lieve tha t it is p re ferab le to con tro l th e de -fo rm itie s b y m ean s o f b race co rrec tion th rou gh th e ag e o f pub erty , at w h ich tim ed e fin itiv e o steo tom ies can b e p erfo rm ed w ith g rea te r as su ran ce o f p e rm anen t im -provement .

T ab le II p resen ts a sum m ary o f ce rtain o f the p ertinen t c lin ica l d ata OH th etw elv e p atien ts fo llo sed . T he he igh t-age co lum n is calcu la ted acco rd ing to W il-k in s n T h e num era to r rep re sen ts th e age a t w h ich th e ave rag e n orm a l ind iv idu alw ould atta in th e sam e h eig h t as th e pa tien t and the d en om in a to r sho w s the actu alch ro no lo g ica l age o f the pa tien t a t the tim e the m easu rem en t w as m ade . Inspectio nof the tab le ind ica te s th e w ide sp ec trum of in tensity o f the d isea se . T h e d egree o fd ev iatio n o f the se rum concen tratio ns from th e norm a l range , the degree o f flu ctu -a tio ii o f th ese va lues w ith trea tm en t, the seve rity o f th e de fo rm itie s , the num ber o fep isodes of v itam in-D in to x ica tion , and , in m any in stances, the frequency of op -e rativ e co rrectio n of de fo rm ity , a ll co rrela te w ith th e seve rity o f th e g row th d is-t.u rb an ce as in d ica ted by the h e igh t-age in dex . P ain in th ese p a tien ts is re lated tothe seve rity o f the de fo rm ity and to the sev erity o f the u nde rly ing m e tab o lic p ro b -lem and is sh ow n in the tab le a s a m an ife sta tion of th e seve rity o f the to ta l p rocessin the in d iv id ua l p a tien t. It is caused eith er by fa tigue fractu re o r b y s tre tch ing o fthe lig am en ts caused by angu latio n d efo rm itie s in th e low er ex trem itie s . T h e nu m -be r o f o steo tom ies tha t w ere requ ired in each p atien t is reco rd ed a lso to ind ica teth e seve rity o f the p ro cess.

Conclusions1 . T h e c lin ica l cou rse and re sp onse to m ed ica l an d o rth opaed ic trea tm en t o f

a g roup of pa tien ts w ith v itam in -D res is tan t r icke ts is desc rib ed . T h e w ide va ria tionin c lin ica l sev e rity o f th e d isea se is em p hasized . S o m e pa tien ts w ith m ild d iseasem ay b e m anaged success fu lly w ith com b ined o rtho paed ic an d m ed ica l treatm en tw h ile in o the rs th e d isea se p ro gre sses desp ite m eticu lo us atten tio n to the de ta ils o ft reatmen t .

2 . T he h aza rds o f th erapy w ith large d oses o f v itam in D are em ph as ized .P atien ts in w hom h ea ling o f the p ro cess is accom p an ied b y o r qu ick ly fo llow ed byev idence of v itam in in to x icatio n sh ou ld no t be sub jec ted to rep ea ted s im ila rep iso des. S u ch ev en ts lead to cum ula tive and irrev ersib le ren a l in ju ry .


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99 6 D. S. P IE R C E , W . M . W A L L A C E , A N D C . H . H E R N D O N3. A rigoro us p rogram of brac ing is o f defin ite va lue in check ing the pro gress ion

of de fo rm ity , e sp ec ia lly in th e tib ia , p rio r to p ub erty , th ereby m in im iz ing th e m ag-n itu de of the co rrec tive su rge ry to be p erfo rm ed .

N O T E : R eq u ests for r ep r in ts shou ld b e ad dre ssed to D r . C . H . H erndo n , 2 06 5 A de lbe rt R oad ,C le veland 6 , O hio .

R ef e r en ces1. A E G E R T E R , E . E ., a nd K I R K P A T R I C K , J . A ., JR. : O rtho ped ic l)iseases : Phy sio logy , Pa tho log y ,

R ad io logy . E d . 2 . P h i lad elp h ia , \V . B . S au nde rs C o., 1 963 .2. A L B R IG H T , F U L L E R , aIld R E IF E N S T E IN , E . C ., JR. : Para thyro id G lan ds a nd IsIetab o lic B one

D ise ase . B altim o re, T h e W ill iam s an d W ilk ins C o ., 194 8 .:3 . A L B R IG H T , F U L L E R , an d S U L K O W I T C H , H . \V . : T he P a rt Played by th e S ec ond ary H yp erp ara -thyro id ism in th e 1) iso rde red C alc ium an d P ho sph oru s M e tab o lism in R ic kets. In Pr oc e e d in gso f tile A m erican S oc ie ty fo r C lin ica l Inves tig ation . J. C lin . Inves t., 17 : 52 5 , 19 38 .

4. A L B R IG H T , F U L L E R ; B U T L E R , A . M .; and B L O O M B E R G , E S T H E R : R ick ets R e sis tan t to V itam inD T h era py . A m . J. D is. C hild ., 54 : 529 -547 , 1937 .

5. A L B R IG H T , F U L L E R ; S U L K O W IT C H , H . W .; an d B L O O M B E R G , E S T H E R : A C om par ison o f theE ffec ts of V itam in D , D ihy dro tac hys tero l (A .T .1 0), an d P ara thy ro id E x tra ct on the D is-o rde red M e tai)o lism of R ick ets . J . o l in . Inv est. , 1 8 : 1 65-169 , 19 39 .

6 . A ND ER SO N, J .: A M eth od for E s tim atin g T m for P h osp h ate in M an . J . P h ysio l., 13 0 : 26 8-2 77 , 195 5 .

7. A Y E R , J . L . ; S C HIES S , \V . A .; an d P I T T S , It. F .: In d ep e n d en c e of P h o sp h ate R ea b sorp tio n a n d(i lom eru lar F i ltra tion in th e l)o g . A m . J . P h ys io l. , 151 : 16 8-1 73 , 19 47 .

8. B A K W IN , H A R R Y ; B O D A N S K Y , O S C A R ; an d S C H O R R , R IC H A R D : R efr actor R ic ke ts . A m . J . D is .C 1ii ld ., 59 : 56 0-5 70 , 19 40 .

9. B E N J A M I N , H . R ., an d H E S S , A . F . : T h e F o rm s o f th e C alciu m a nd In org an ic P hosph oru s inH u m a n an d A nim al Sera . I. N orm al, R ach itic, H yperca lcem ic , and O ther C ond itio ns. J. B io l.C h e m . , 1 00 : 2 7-55 , 1 933 .

10 . B E Y E R , K . H .; W R I G H T , L . D .; R u sso , H . F .; S K E G G S , H . R .; an d 1 A T C H , E . A .: T he R e nalC lea ran ce of E ssen t ia l A m in o A cids: T ry p to pha ne , L eu cin e, Iso leu cin e an d V aline. A m . J .P h ysio l., 1 46 : 330 -33 5 , 19 46 .

11 . B O Y D , J . I)., an d S T E A R N S , G E N E V IE V E : C o n com ita n ce o f C h ron ic A c ido sis w ith L ate R ick ets .A m. J. D i s . C hild ., 64 : 594-6 07 , 194 2 .

12 . C l I R I S T E N S E N , J . F .: T h ree F a m ilia l C ase s of A typ ica l L a te R ick e ts. A cta P a ed iat., 2 8 : 24 7-2 70 , 1 94 0 .

1 :3 . 1 ) A E S C H N E R , C . % V . , JR .: V ita m in 1 ) R es ista n t R ick ets . D ia gno sis an d M an ag em e n t. T ex asState J. M e d . , 53 : 32 4-3 29 , 19 57 .

14 . I ) E N T , C . E .: R ic kets a nd O s teo m alacia fro m R en al T ubu le l)efects. J. B o ne an d Jo in t S u r g.,3 4-B : 2 66-274 , M ay 1952 .

15 . 1)E N T , C . E ., an d H A R R I S , H . : H e red itary F orm s of R icke ts and O steom aiacia . J. B o ne an dJ oilI t S u rg., 38-B : 204 -22 6 , F eb . 195 6 .

16 . E D I T o R I A L : A c tion o f P arath vro id H o rm one . N e w E ng land J . M ed., 26 9 : 92 4-9 25 , 196 3 .17 . E H R I N G , F. ; H E I T E , H . .1 . ; K A L K O F F , K . W . ; a nd R A U S C H , L. : Z u r B ed eutu ng der N ie ren fun k-

tio nsp rufung tile h oc hdo sie rt.e r V itam in 1)-T h erap ie . H autart .z , 6 : 59 -64 , 19 55 .18 . E N G F E L D T , B E N G T ; Z E T T ER S T R #{ 246} M , It. ; an d W I N B E R G , J. : P rim a ry V itam i 1-I) R es is tan tR icke ts. II I. B ioph ys ical S tud ies of S ke leta l T issu e. J. B on e a nd Jo in t S u rg . , 38 -A : 13 23 -

1 33 4 , I )ec . 19 56 .19 . E P S T E I N , F . H .: C a lciu m an d th e K idn e,v . J. C h ron . I) is., 1 1 : 25 5-2 77 , 1 960 .20 . F A N C O N I , C l.: T ub ula r Insu ffic ien cy a nd R ena l l)w arfism . A rc h . l) is. C hild ., 29 : 1-6 , 1 954 .2 1 . F A N oN I, G u lD o: i)istu r b an c es in C alc iu m and P ho spho rus M etabo lism . W ith S pec ia l E m pha-

sis on I)isturban ce s o f th e R ena l E xcre tion of Ph osp ha tes . M etabo lism , 4 : 95 -10 6 , 1 95 5 .22 . F I E L o , M . H ., a nd R E IS S , E R IC : V ita m in 1)-R esis tan t R ick ets : T he E ffect o f C alciu m In fusionon P hospha te R eabsorp tion . J. C lin . Inve st., 39 : 1 807 -18 12 , 196 0 .23 . F IR SC IIE IN , H . B .; M A R T I N , C . R . ; M U L R Y A N , B . J . ; S T R A T E S , B . ; an d N E I M A N , W . F .:

M e cha nism of A c tion of P ara thvro id H orm one I on Io n G rad ien ts . J. A m . C hem . S oc., 8 0 :16 19 -16 23 , 1 958 .

24 . F I S H M A N , W . H .: M ethon ine -In duc ed Amino-Ac idur ia ill \it.a min I ) R e sis tan t R ick ets.M e tab o lism , 4 : 10 7-1 09 , 19 55 .

25 . F R A S E R , I).; G E I G E R , D . W .; M U N N , J . I).; S E A T E R , P . E .; J A H N , It.; a n(i L IU , E .: C alc ific atio nS tu d ies in C lin ica l V ita m in I) I )e fic ie lc v and in H ypop hospha tem ic \/itam in 1)-R efrac toryR ic kets: T h e Ind uc tion of C alc ium 1)e pos itio n in R ac hit .ic C art ilag e w itho u t t il e A dm in is tr a-tiO ll of V ita m in I). In T ra nsac tions of th e S oc iet. \ fo r P ed iatr ic R esearch . A m . J. I)is. C hild .,96 : 460 -46 1 , 19 58 .

2 6 . G Im 1 , A . M .: V ita m in-R esista n t R ic kets . A rch . i)is . C hild ., 14 : 50 -63 , 193 9 .27 . H A iu m .T o N , B E N G T , and D E W A R , M . M .: E ffec t o f C itra te an d T a rt.ra t.e o n E xper imen ta lR ic kets. A m . J. i) is . C hild ., 54 : 5 48 -55 6 , 19 37 .

28 . H A R R I S O N , H . C .; H A R R I S O N , H . E .; an d P A R K , E . A .: V itam in I ) an d C itra te M e tab o lism .E ffect o f V itam in 1 ) in R ats F ed D iets A d equ ate in B oth C alc ium and P hospho rus . A m . J.P hy sio l., 1 92 : 432 -43 6 , 195 8 .

29 HARRISO\ H } M ec h an ism s of tion o f % lttnliIl I) [P r d .n tiaI & ddress ] Pedittric1 4 : 285-2 95 , 195 4 .30 . HARRISON H . E .: T he In ter re la tio n of C itra te and C alc ium M e tab olism . [E dito ria i.1 A m . J.

M e d . , 20 : 1 -3 , 19 56 .31 . H A R R I S O N , H . E .: V ita m in D a nd P hosph ate T ra nsp ort . P ed iatrics , 28 : 53 1-5 44 , 1 961 .32 . H A R R I S O N , H . E ., an d H A R R I S O N , H. C .: T he R ena l E xc re tio n of In o rga n ic P h osp h ate in

R elatio n to the A ction of V itam in I) an d P ara th yro id H or m on e . J . C lin . In ve st., 20 : 47 -55 ,1 9 4 1 .


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T R E A T M E N T O F V IT A M IN -D R E S IS T A N T R IC K E T S 99 73 3 . H A RR IS O N , H . E ., an d H A R R IS O N , H . C .: Vitamin D a nd C itra te M e tab o lism : S tud ies on

I tac h itic In fan ts. a le J . B io l. an d M e d ., 24 : 2 73-28 3 , 19 52 .3 4 . H E S S , A . F . ; W E I N S T O C K , M . ; R I V K I N , H . ; an d G R O S S , J. : O b se rva tion s S u gg estin g a L o c a l

F ac tor in P athog ene sis and H e aling o f R ick ets . P roc . S o c. E xpe r. B io l . an d M e d., 2 7 : 140 -14 2 , 1 929 .

3 5 . H O L T , L . E. ; G Y # { 2 4 6 } R G Y , P. ; P R A T r , E . L .; S N Y D E R M A N , S . E .; and W A L L A C E , \V . M .: Pro teinan d A m in o A cid R eq u irem en ts in E a rly L ife . N e w Y ork , N ew Y ork U niv ers ity P ress , 19 60 .

3 6 . JO N E S , J. H ., an d R A P O P O R T , M IL T O N : F u rth er O b ser va tion s o n th e R ela tion of C a lciu m a n dPhosphorus In ta k e to th e H y p er calc ein ia an d H yp e rp h o sp h a tem ia In d u c ed by IrradiatedE rgos te ro l. J. B io l. C h em ., 93 : 15 3-166 , 19 31 .37 . J O N X I S , J. H . P ., a nd H U IS M AN , T . H . J.: A m ino-A cidu ria in R ach itic C hild ren . L a nc et, 2:428-4 31 , 1953 .38 . K A JD I, LA S L O : C om pa riso n of th e E ffect o f V ita m in D a nd C itra te Ofl M in era l M etabo lismin L a te R icke ts. In T ransac tions o f the A m erican Ped ia tric S oc ie ty . A m . J. i)is . C h ild ., 68 :352 -35 3 , 19 44 .

39 . I t A L K O F F , K . \V ., and R A U S C E , L. : W eite re U nte rsuc hun gen fib er di e N eb enw irkun g vo nV itam in 1)2 . A rc h . D er m a to l . u . Syphil . , 19 1 : 352 -36 0 , 19 50 .

40 . K L E IN , L E R o Y , an d C U R T I S S , P . H ., JR. : T h e E ffe ct o f V itam in I) o n U r in a ry H y d r oxy p r olin ein V it.a m in -D D e ficienc y R ick ets a nd R es ista n t R ick ets . In P roc ee ding s of T he A m e rica nA c ade m y of O r tho pae d ic S urgeo ns . J. B o ne an d Jo in t S urg ., 45-A : 15 42 , O c t. 1 963 .

41 . L A F F E R T Y , F . % V.; HERNDON , C . H .; an d P E A R SO N, 0 . H .: Pa thog en es is o f V itam in 1)-R es is tan tR ic kets and th e R e spo nse to a H igh C alcium In tak e . J. C li n. E nd oc ri no l., 23 : 903-9 17 , 1963 .42 . L A T H E M , \V 1L L O U G H B Y B A K E R , K A T H E R IN E ; an d B R A D L E Y , S . E .: U rinary A m ino A cid E x -cretio n ill R ena l D isease, w ith O b se rvat ion s o n th e F a nco ni S y nd rom e. A m . J. M ed ., 18 :249-258 , 1 9 5 5 .

4 3 . L IT M A N , N . N .; U L S T R O M , R . A .; and W E S T I N , \V . % V .: V itam in D R esis tan t R icke ts. Califo rn iaM ed ., 86 : 248-253 , 1 9 5 7 .

4 4 . L U D E R , J O S E P H , an d S H E L D O N , \V IL F R ID A F am ilia l T u b u lar A bsorp tion D efec t o f G l u c o sean d A m in o-A cids . A rch . D is. C h ild ., 30 : 160 -16 4 , 1 955 .4 5 . M C C E JN E , I) . J .; M A S O N , H . H .; an d C L A R K E , H . T .: In trac tab le H ypo phospha tem ic R ick ets

v ith R ena l G lyco su ria a nd A cidos is ( the F an con i S yn dro m e ). R ep ort o f a C ase in WhichIncreased U rin ary O rga n ic A cids W ere I)e tec ted and Ide n tified , w ith a R e vie w of the L itera -to re . A m . J . 1 )is . C h ild ., 65 : 8 1-1 46 , 1 94 3 .

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Surg . , 33-A : 20 3-220 , Ja n . 19 51 .48 . R o B E R T s o N , B . R .; H A R R I S , R C .; and M C C U N E , D . J.: R e frac to ry R ick ets: M ech anism ofTherapeu tic A ctio n of C ale ife ro l. In T ran sa ctio ns of the S o cie ty for P e d ia tric R esearch . A m .J. D is . C hild ., 64 : 948 -94 9 , 1 94 2 .49 . R O B I N S O N , H . W ., a n d N E L S O N , \ . E . : P hosphoru s C learan ce in C hild ren w ith V itam in1 )-R es ista n t R ic kets. In T ransac tions of the S oc ie ty fo r P ed ia tric Re se ar c h . Am . J. l)is . C hild .,69 : 323 -331 , 1945 .

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V O L . 46 -A , N O 5, JULY 1964

long-term treatment of vitamin-d resistant rickets

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