Long-Term

Treatment Resistant Rickets

M.D4, WILLIAM

of Vitamin-D

BY

DONALD

S.

PIERCE,

M.

WALLACE,

M.D.,

AND

CHARLES From the

H.

HERNDON,

M.D.,

CLEVELAND, Surgery Hospitals Convalescent and

OHIO

Division

of Orthopaedic University Crippled Cleveland and

the and

Departuient Rainbow

of Pediatrics, Hospitalfor

of Cleveland, Children,

Experience rickets basis trolled

under

gained report. D,

in the basis This even

treatment at the

of twelve University indicates doses, and

patients Hospitals that when This

be

with disease

vitamin-D is rarely healing

resistant provides well does the conoccur that

prior to

on a long-term for by this vitamin

of Cleveland the complete

experience in large

threats
osteotomy

vitamin-D therapy, toxicity which must be watched for

or other surgical procedures

and

consequent
should

renal
experience
performed

damage
also
only

are
indicates
rarely

constant

continually. of bracing
of vitami.n-D

puberty growth scribed

ported

and

that

a rigorous 100

program
instances

is more
resistant

appropriate
rickets

therapy
have

until been deunre-

is complete. While less than

ill

the
as

literature,
of

most

orthopaedic

and

pediatric bone diseases

clinics seen

have

small

groups

children
of the

under
commonest

treatment
metabolic disease been twelve operative
of vitamin

for this
deserves maintained have been patients correction

condition

which

is

now

being
The twelve With have Four

recognized

one

in children.

wide spectrum patients studied

attention to

of severity of the in our clinic have

serious deformities

bracing,

been children,
responding have

unnecessary however,
to very

in eight have
large

of our required
doses

special emphasis. The on vitamin-D therapy. prevented and osteotomies up to the time of writing. of deformities; and,

although

D, frequent
intoxication have been

interruptions
with unable

of treatment

These

been required four patients

ill

because almost
two of them

of vitamin-D continuously
(W.H. and

attendant renal injury. to participate in usual

school life and tion of the bone

M.A.R.,

Table

II) the expected

stabiliza-

disease

at puberty Definition

has

failed and

to occur. Diagnosis disorder with seen clinical, roentgenographic,

VitaflUi1-D

resistant
progresses

rickets,
despite

a specific similar
antirachitic

and large

biochemical

characteristics D. The

to those
prophylaxis

deficiency,

doses of vitamin 1 Hypophosphatemia,

.

metabolic hallmarks usually associated in

in rickets due to vitamin-D and heals only in response to of the disease are: children with a normal serum

calcium concentration and an elevated serum alkaline phosphatase and in adults with a normal serum calcium concentration and normal alkaline phosphatase; 2. Pi-obable defective gastro-iutestinal absorption of calcium and phosphorus55; 3. Diminished reabsorption of phosphate from the glomerular filtrate in the renal
*

tubules
Read
Supported University

with
at the 22,

no other
Meeting
a grant

demonstrable
of The
from

defects
American Academy

in renal
of

function.
Orthopaedic Surgeons, Chicago,

Annual 1964.
in part by of California

Illinois,

January

t
978

Medical

2065

Adelbert

Road,

Cleveland

the Lake County Society for Crippled Center, Sail Francisco, California.
THE JOURNAL OF BONE AND

Children,

Inc.

6, Ohio.
JOINT SURGERY

TREATMENT

OF

VITAMIN-D

RESISTANT

RICKETS

979

TABLE
1)IFFERENTIATION OF THE ROENTGEN

I
1)IAGN0SIs OF RICKETS

Serum

Concentrations Blood
Urea Un

1)iagnosis itamin-D deficiency

Calcium N-L N-L

Phosphorus L L

Phosphatase H H

Carbon l)ioxide N N

Nitrogen N N

Gbcose Neg. Neg. Pos. Pos.?

Neg.

iie Amino Acids Pos. Neg. Pus. Neg.?

Ntg.

Comment

Positive
tional

nutrihistory

Resistant
rickets Fanconis

Often positive family history Often positive family history Negative

family history

N-L

L L H
N

H H N-H
L

L L L
N

N-H N-H H
N

syndrome

Renal
acidosis

tubule
renal

N-L N-L
N-L

Chronic failure Hypophosphatasia

Renal anomalies usual 1rme plospiloethanolan)ine

Positive

Neg.

Neg.

Lowes

N-L N-L

L-N L

H H

L N

N-H
N

Pos. Neg.

Pus.? Neg.

Glaucoma Evidence
steatorrhea

syndrome
Coeliac
rickets,

of
liver

hepatic
rickets

or of
disease

normal

; L

low ; H

high

; ?

equivocal

or

variably

l)r(serlt.

Winters and associates showed that in many instances the disease is related to an inherited sex-linked dominant disorder, in which the metabolic mechanisms of expression remain to be fully explained. Undoubtedly, many instances of the disease are sporadic and possibly represent new mutations or homozygosity for an unrecognized autosomal recessive form. It is essential that the disease be differentiated from other ficially similar, but differential features
Pathological

entities in which the roentgen and in which treatment and prognosis are presented in Table I. Manifestations in resistant there
of long

clinical findings are different.

are superThe salient

and histological
deficiency

Roentgenographic changes
rickets

The
treated

rickets important and

There

resemble differences is most

is failure

those
1,

seen

in

severe

un-

but

are

The

most
at the

prominent
epiphyseal
of the

derangement
plates and

is in endochondral
in the metaphyses

ossification
bones.

apparent

of mineralization

cartilage normally

matrix at the zone in columns, undergo

of provisional disintegration

calcification. The with concurrent

cartilage ingrowth

cells, aligned of capillaries,

but calcification of the cartilage matrix does not occur, leading to a deficient mineral lattice for the deposition of osteoid. Uncalcified islands of cartilage are frequently seen deep in the metaphysis, forming no definite pattern and not being absorbed or remodeled. The osteoid matrix is incompletely trabeeulae are coarse and widely spaced in the of the long bones, and in the pelvis and ribs i.18 Biopsy
osteotomy

mineralized metaphysis, or fibula

by

in many throughout of our

and

areas. The the shafts patients

associates

material
revealed

removed
findings

from
similar

the
to those

tibia

of five
Engfeldt

at
18

described

Characteristically, the ment of the Haversian

VOL 46-A, NO. 5. JULY

compacta canals,

is thinner than the varying from patient

normal with a striking enlargeto patient. There is an irregular

1964

980

1). 5.

PIERCE,

\V.

M. WALLA(E,

.N1)

C.

H.

HERYDON

Fw.
Biopsy

1-A

sistant eralized

fatty

the proximal end rickets. Ihere is marked irregularity interstitial lamellae. The marrow marrow (C. M., Table II) ( 15-micron
Sl)((ilfleIl (If

of

tibia of a fifty-year-old man with vitamin-I) rein the architecture of the ost.eons with l)oorly mill511:1(1s contain tracts of fibrosis and areas of normal celloidin section; hematoxvlin and (05111, X lot)).

tile

FI;. Biopsy
Note casional 5l)((1ll(11 irregularity of of till. tibia froni a fifteen-year-old

1-B the
eInl)ty

of active and (051!!,

osteons, \Vi(lelliflg of tracts of dead i)0!Ie characterized by osteorlasis were observed in neighboring X l(X)i.

the

girl Haversian fields

with

lacunae. ( lO-luicron

severe Vitan)i!1-i) resistant canals, active osteogenesis, It should also h)e nOte(1
1)araflin section

rickets. an(I octhat areas

; lunlatox\lin

architectural pattern active ost.eoclasis. The of uncalcified osteoid. fibrosis (Figs. vas 110 attempt 1-A and
to

ill

which

there

ai-e

regions

of

active

osteogenesis

and

areas
areas

of
of

matrix is often The marrow,

poorly calcified and in many instances, biopsy findings

THE

there shows

are

occasional
tracts available,

extensive
not

1-B).

correlate

As sequential histological

material was with adequacy

JOU I(NAI. OF BONE

there

of treatment.
AN!) JOINT

SURGERY

TREATMENT

OF

VITAMIN-I)

RESiSTANT

RICKETS

981

FIG.

2-A

MAR., a seventeen-year-old girl, had severe vitamin-i) resistant rickets at the time she was first examined in 1958. This roentgenogram of the hips and pelvis was rna(Ie in May 1958. Note thin conipacta and coarse widely spaced trabeculae 111 1)0th the l)elvis and femora. Severe coxa vara iS l)res(Ilt and there are Loosers zones at the junction of the l)roximal :11111 middle thirds of i)Ot ii femora.

FIG.

2-B
tile

Roentgenograms of the Loosers zones are preselit (0(r( an(1 widely sl)a(e(I.
VOl.. 46-A, NO.

tibiae and fihulae at the junction

made
of

in May 1958. Anteromedial distal and middle thirds.

The

bowing is severe. trabeculae are

5, JULY

1964

982

D.

S. PIERCE,

W.

M. WALLACE,

ANI)

C. H.

HERNDON

and

Roentgenographically, caucellous bone but hyperplasia different

in our patients, the appearance of both the compact is similar to that seen in rickets resulting from secondary from due to glomerular insufficiency or renal that seen in vitamin-D deficient rickets. tubular The acidosis, trabeculae

parathyroid or both,

appear coarse characteristics past puberty

frequently

and widely are present (Figs. 2-A

spaced ; the density of the compacta is diminished. These in the young child and even more prominent in the patient and 2-B) In the shafts of long bones the trabeculae are
.

longitudinally

arranged

showing

little

tendency

to

alignment

along

lines

of stress. appearance plate pattern cartilage. There

In a growing child the epiphyses are widened and cup-shaped with a hazy in the zone of provisional calcification and widening of the epiphyseal This noted is particularly apparent at the in the metaphyses representing angular deformity in the knee. There is frequently islands or columns of the upper of a brushlike uncalcified but in

is little

bones

extremities

the lower extremities bowing is a prominent feature. Characteristically, this consists of coxa vara., anterolateral bowing of the femora, and bowing of the tibiae associated with medial torsion. Although the coarse, widely spaced trabecular pattern is apparent in the vertebrae and pelvis, deformities in these structures of the is retarded do not occur as a rule. Due to the strength can produce disorganization at the
Pathological Physiology

pull of the diaphragm, deformation Harrisons groove. Linear growth zone of provisional calcification.

ribs deficient in because of the

Despite

extensive

metabolic

investigations

by

many

workers

21 32 ,41

there

are no data that unequivocally Untreated patients with this

delineate the metabolic disease grow at a reduced

defect in resistant rickets. rate and, of necessity, in-

crease
total

the total
body bone

body
mineral

content
in vivo,

of bone
evidence

mineral.
drawn

While
from

no method
roentgenographic

exists

to determine
examination

of the skeleton, as well as histological from patients with the disease, suggest
with growth resistant rickets

and chemical analyses of bone samples taken that the total body bone mineral in children
that found in normal children of equivalent

is reduced

below this

age and the

size
occurs

One

must attempts

conclude,
with

therefore,
disease but

that
at

accretion
a reduced

of bone
rate

mineral
compared

with
with

in children

normal.

Many

external flicting

balance techniques and interpretation

made to document 3,22,25,32,49,55,60#{149} The evidence

is hampered by lack of suitable

have

been

the rate so obtained

controls.

of accretion is often
Most of the

by condata

appear

to show
.

decreased
the

gastro-intestinal
excretion of differences,

absorption

of calcium

and

phosphorus

and decreased urinary controls However,

ponent., are relatively

calcium when compared with comparable particularly for the gastro-intestinal cornof the insensitive proband

lerns

involved

indicate

small that

and often equivocal. Critical consideration the technique of external balance is too accurately the minute enormous quantities The necessary balance
as in normal

too fraught with error to detect changes in the face of the relatively excretion, and total body mineral.
growth must, in

but important balance involved in intake, fecal to allow for slow skeletal
be discontinuous, must

rachitic

children
affected and disparity
multiplicity

children,

fluctuate, the degree doubtedly

this technique

and be variously of immobilization, account

and

by intake, the intensity of the growth stimulus, many other factors n#{149} These considerations unin results as that found of others, by different
drawn from

for the
for the

investigators
them.

using

of conclusions

From

our

own

experience,

as well

when

vitamin

D is adminis-

tered in quantities sufficient to produce roentgen and chemical absorption of calcium and phosphorus from the gut is increased,
THE

signs of healing the the urinary calcium

BONE AND JOINT SURGERY

JOURNAL

OF

TREATMENT

OF

VITAMIN-D

RESISTANT

RICKETS

983 or increased. is affected Continuation increasing becomes instances

of hydroxy-

loss

is increased,

and the than

the the

urinary urinary

phosphorus component losses and

is either of the a positive

unchanged balance ensues. the balance

In to a

most greater of the

loss

instances degree vitamin

4,63

gastro-intestinal

of calcium

administration and phosphorus This may occur

is followed, in the urine while signs

at various intervals, so that eventually are still present. or reduction

increased

with an balance In most of dosage.

negative vitamin

of healing

toxicity follows Recent studies by proline in patients with with adequate vitamin-D
increased formation

and forces Klein and vitamin-D therapy.

discontinuation Curtiss #{176} showed deficiency, an This observation in this

excretion

abnormality which was interpreted Similar results phosphatase, studies

#{176}.

is abolished to indicate on patients

of skeletal

collagen

disease. variable serum

with with

vitamin-D the disease,

resistant rickets have provided particularly those with a high and decreases concomitantly calcium infusion. However,
was not observed.

In some patients hydroxyproline or of

excretion is high with intravenous

urinary excretion

with vitamin-D complete return patients with were within

excretion

administration to normal levels resistant normal form range.

disease,
significance is unknown metabolic isotopes,

urinary
of the

hydroxyproline
variable

In other excretions spontaneous

the the

of the The
rickets

hydroxyproline

in vitamin-D

resistant.

but

probably

represents

variation

in the

intensity

of the

abnormality.

In the few studies of the skeletal dynamics the rates of both bone resorption and

in this disease made with calcium bone accretion have been two to five

times that normally expected 41#{149} In other words there is an increased bone turnover but an over-all reduced rate of total accretion compared with the normal. Data obtained from the study of patients with resistant rickets have been tested against three general The disease has been hypotheses. considered to represent a defect in bone associates when or when
observations

tissue the the

due demonconceiisei-um
point

to

resistance to the action of vitamin D. The work of Fraser and strated that cartilage, in vitro as well as in vivo, will heal promptly tration
phosphorus

of

phosphate
level

in
is increased

the

bathing
by

medium

is normalized
infusion. These

intravenous

to

a defect in regulation peripheral The concept of Albright parathyroidism caused

i.

to bone itself. that resistant absorption

rickets

represents has

secondaiy received the

hypermost parapatients, all been

inhibitory renal phos-

by

decreased

of calcium

experimental support thyroid hormone, the and

cited effect

The lack of response to exogenously administered near-normal intestinal absorption of calcium in some evidence
Similarly, activity

the

finding
of

of histological
this concept. secretory
41

of parathyroid
the infusion has been

hyperplasia
of calcium shown to with reduce

have
its

in favor upon of

parathyroid

phorus
favor disease.

excretion
secondary

sharply

in

resistant

rickets
as the

and

has

been

cited
leading

as evidence
to the hone

in

hyperparathyroidism

mechanism

The phorus enzymatic According the matrix some large pear way oral as

third

concept

of the that

disease or

has

been

that from

of tubular defect glomerular the

wasting in the filtrate

of phostubular
!4,25,32

a result mechanisms

of a genetically retrieve

otherwise necessary calcium of bone without with

acquired

phosphorus

to this concept are inadequate related or intravenous calcium effect doubt positive thrown

the ion products and the decreased deposition of phosphate loads absorption of vitamin upon the

to precipitate absorption mineral. vitamin-D this proposal The

bone mineral in from the gut is in observation administration

However,

to the decreased

that ap-

to increase

is consistent D upon last item

the direct loop has events

.

calcium transfer in this attractive

in the isolated gut and simple train of

984 The cannot phorus observation be taken reabsorption.

D.

S. PIERCE,

\V.

M.

WALLACE,

AND

C. H. HERNDON

that as true

calcium evidence

infusion for the

leads absence

to prompt of a renal

decrease defect the were

in phosphaturia in tubular sole phosdeterminant

If secondary

hyperparathyroidism

of phosphorus wasting in resistant rickets, it would be expected that calcium infusion would abolish phosphaturia in the rachitic state. In most patients this does not occur, the phosphaturia is only reduced. The true ability of the renal tubule to reabsorl) phosphorus can only be determined by maximum loading of the tubular mechanism with a glomerular filtrate containing sufficient phosphorus to saturate the resorptive phorus (Tmp) of patients kindred with but without unified
11

mechanism under these with resistant familial resistant bone disease. of the probable

fully followed conditions. rickets have

by quantitation of the When this is done, most clearly shown a reduction

resorption but not in

all Tmp

of phosstudies
58

In any

rickets, individuals The explanation of

are found with hypophosphatemia this paradox is essential for

58

theory it seems

pathophysiology. that the defect

As Williams and associates in calcium absorption could

pointed out: be so delicately

balanced by parathyroid overactivity that serum calcium concentration would be maintained at a normal level throughout life without any signs of hyperparathyroi(lism other than the increased phosphate excretion. Williams and associates 58 have critically and exhaustively reviewed the current theories of the pathophysiology of resistant rickets. The ubiquity of the action of vitamin D at the tissue level and the uniformity of its effect at the level of the mitochoncirion cellular level Iiitil such stitutive
Trealinciit

suggest that this disease will eventually arid thereby multiple tissue defects will knowledge is available therapy can, at
best,

be understood be included be only

at the subin its genesis. and sub-

empiric

Coordinated esseiitial for

and successful

highly

management.

individualized The

age

orthopaedic of the

and patient

medical treatment in relation to his

is po-

tential for growth, the severity of the skeletal caused by deformity or operative intervention, vitaminosis D are all factors determining the with
unit.

disease, the degree of immobilization and the susceptibility to hyperdegree of success obtained.

Vitamin-D therapy is most clearly frank rachitic changes and rapidly begun with 50,000 USP units of vitamin

and urgently indicated us younger children progressive deformity. Such treatment is D daily. Vitamin D2, available in 50,000-

capsules or as a water miscible concentrate, containing 50,000 units per cubic centimeter, is the preferred form of medication because of its general availability and low cost. The dosage is increased by 50,000-unit increments at monthly intervals until evidence of healing is apparent. The earliest indicator of healing is a decrease in the serum alkaline phosphatase or, in some patients, an increase in the serum phosphorus concentration. Changes in the latter parameter, however, should

be relied upon since healing and changes in the serum concentration

not

vitamin toxicity of phosphorus. lagging several

may appear with Roentgenographic weeks behind

no significant evidence change.

of

healing

is next such

to

appear,

usually

chemical

Roentgenograms change. On usually appear

of the wrist present the a schedule of vitamin-D in three to four months and

most sensitive administration, after a dosage

means of detecting evidence of healing level of 150,000 to

early will

200,000

units is attained. Once evidence of healing should be stabilized for two to three months proximately one-half the healing requirement. levels inevitably results in the appearance emphasized that this schedule of events

is obtained, the level of medication and then decreased in one step to apMore prolonged maintenance at high of vitamin-D toxicity. It should he to eiormous
JOURNAL OF BONE

is subject
THE

variation
ANI) JOINT

in time
SURGERY

TREATMENT

OF

VITAMIN-D

RESISTANT

RICKETS

985 at different in growth

ages. requires

and

dosage

level

from

patient

to patient age with its

and

in the

same

patient

In a general way increasing reduction in dosage. Throughout the phase serious and constant threat. and early
ties

coincident with as was

decrement

of active In many

treatment patients,

vitamin D, intoxication is a first emphasized by Pedersen range. larger In our quantimIentolsympof

McCarroll experience
of the

47,

the healing with vitamin-D were to the used point

and toxic treatment

doses are in the identical of resistant rickets, much here and the to determine that

tionally crated toms

acute

vitamin brought

than recommended of toxicity in order experience anorexia, of renal patients

patients were the maximum typical clinical

dose.
renal

However,
injury

subsequent

indicated

of toxicity, has

such as polyuria, with reduction occurred H., in some

and irritability, are function. Furthermore, without excessive elevation appearance of a positive study of these patients

manifestations the appearance of the Sulkowitch and more serum

of toxicity

calcium concentration (I\I. A. C. and W. knowledge

explain

and without the Table II). Clinical It

test recent

the day)

(one

concentrating -itamin-D

of the adverse effects apparent paradox. exposure of the kidney apparatus of the
intoxication occurred

of hypercalcuria upon kidney function adequately has been clearly demonstrated that \ery short to hypercalcuria induces structural changes in the kidney 9 Our clinical study of patients in whom has indicated that hyposthenuria was well estabThe of the total
calcinuria

lished twentytest

at
remained

the four

time hours studied

negative

symptoms was high

long

appeared. but
after

urinary of the
was

excretion urine, the

to

of calcium the Sulkowitch In most and

Repeated

in of the

because
excessive

dilution the
in six

established. azotemia,
a year.

the

patients
urea

the
resulted

ability
returned in

to

concentrate
to normal

urine,
months

decreased episodes,

clearance

however,

This
ill

occurred
series. episodes details

our

three
clinical

and irreversible loss of renal function. in two of the twelve patients (M. A. C. and W. II., Table II) followed In one of these (M. A. C.), persistent and severe hypertension followed of intoxication. Adequate follow-up and meticulous attention to
cumulative is essential to the prevention of these complications of therapy.

Failure
leading

of follow-up due to the development

to adverse of renal most We

social injury

conditions was in our patients.

the

most

frequent.

factor

the
tration

We believe that the single serum calcium concentration.

of eleven injury. for milligrams When per

valuable criterion of the onset of toxicity is have come to regard a serum calcium concenfor intensive and blood should be clinical for signs discon-

evaluation
of

in terms

of symptoms doubt

100 milliliters as an indication and examination of the urine exists

period.

renal

vitamin-D

administration been indicated, the presence

tmued

a one-to-two-month

in our
quantitative

experience,

is of little

value

As has in determining

the Sulkowitch test, of toxicity. Repeated

amount of calcium in the twenty-four-hour urine in the same child are useful but are not usually practicable in the general management of these children. The twenty-four-hour excretion of calcium varies widely in normal individuals and depends on the intake of calcium, body size, age, and many unknown variables. The degree of hypercalcinuria that leads to renal inj ury is unknown and appears to vary from patient to patient. For these reasons no established upper limits for the twenty-four-hour excretion for a given patient can be
evaluations

of the

given
viewed,

with When
it

any the

certainty.

long-term
to

efficacy
state

of vitamin-D

therapy

in resistant

rickets

is re-

tributed
growth

whether use of the vitamin to the final result. There is no doubt that, during of a child particularly, the roentgen and chemical
is impossible suppressed
NO. 5. JULY

has significantly conthe early phases of rapid evidence of the disease of deformities can

can
VOL.

be
46-A.

in some
1964

instances

and

the

rapid

progression

986 possibly
assess disease

D.

S. PIERCE,

\V.

M.

WALLACE,

AND

H.

HERNDON

the

be prevented. During slower value of such treatment. do as well without such vitamin of bone

phases of growth We do not know therapy. therapy mineral In severe

it becomes whether disturbances,

more difficult to mild cases of the such as those favorable rickets be that favorof bone of large

would

cited result. and such able mineral

here, it is possible that Since high turnover since high treatment roentgenographic

may lead to an over-all less is characteristic of resistant that action, it may the apparently removal by mouth

doses of vitamin accentuates the and important

D have skeletal

a parathyroid-like instability and represent

chemical
reported

changes

accelerated

from structurally Saville and associates

areas to areas of growth. that the administration

quantities of inorganic phosphate to patients with resistant rickets leads to healing and reversal toward normal of the metabolic defects. These authors also noted that such therapy appeared to reduce the amount of dihydrotachysterol needed to maintain regimen mental in man. therapy the twelve healing in these patients, but has been presented. Prolonged animals leads to extensive renal For
58

no long-term study of the results of such a administration of phosphate to experiinjury and presumably would act similarly have effects studies
been

this and patients

reason,
associates

most

investigators studied the Metabolic to increase resorption of treatment that not support that

reluctant calcium

to intakes

utilize

such of

Lafferty

of high

in four of calcium techniques.

reported

here.

in some by

of these absorption isotopic

patients

mdi-

cated that such and to decrease Final further evaluation definition metabolic extent

therapy appeared the rate of bone of this of the method possibility

the intestinal as measured must await all instances we recommend

long-term of resistant

evaluation rickets

and have on the a

common The

defect. of the brace

is dependent

severity of the disease. In mild forms of resistant rickets the application of corrective bow-leg braces at night only may be sufficient to prevent the development of deformity and we use this minimum support unless the deformities are increasing, in which case the braces are worn day and night except for short periods of freedom for exercise purposes. We have found that even in the relatively severe forms of the disease progressive deformity of the tibia and fibula can be arrested by this form of bracing, but we have been unable to arrest completely the anterolateral bowing of the femur or the coxa vara by any type of brace yet employed. It is recognized that surgical treatment of deformities should be avoided before puberty if possible since recurrence of the deformity or development of a secondary deformity in growing bone is a strong probability despite an adequate medical program and bracing after operation. There are instances, however, in which corrective osteotomy may be indicated before puberty even though recurrence may develop. We have had two patients (M.A.R. and W.H.) come under our not care who already out had until deformities satisfactory of such alignment severity of the that lower adequate extremities bracing had could been be carried

achieved. In other patients who discarded their braces, such severe deformities developed that osteotomy had to be performed prior to the resumption of bracing. We believe that if coxa vara develops to the point that it produces an adaptive obliquity should develops be in the roof of the acetabulum, corrective subtrochanteric osteotomy performed without further delay. Also, if genu valgum or genu varum to the extent that pain referable to the collateral ligaments of the knee we do not believe that osteotomy should be delayed. lower extremities are carefully evaluated and suitable At the time of osteotomies are If a related
JOINT

joint develops puberty, the

performed to achieve adequate alignment of hips, knees, and degree of bowing is allowed to persist, there is abnormal stress
THE JOURNAL OF BONE

ankles. on the
AND

serious

joint
SURGERY

TREATMENT
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VOL. 46-A, NO. 5, JULY 1964

c.:i

)S8

I).

5.

PiERCE,

W.

M.

WALLACE,

AND

C.

H.

HE1tNDON

anterior

A. H. Hoentgenogranis t.iI)ial bowing Ost(OtOHI\ an(l insertion

nlade recurred ill of Lottes

in

1962. nails

1963. After corrective An attempt was then in 1)0th tibiae.

ost eotomies were performed made to obtain correction

iii
by

1958, double

and

pathological zones)
operative
-

fractures
treatment

of the

shaft
is

of the

bone
either

at the
before at

points
or one

of maximum
after

stress
it is

(Loosers
When
essential

indicated, i)e discontinued

puberty.

that

vitarnin-D
The
effects

therapy

least
by

before and

operatioll.
hvpem-calcinuric

effect

of vitamin
of inactivity,

I)

superimposed

upon

month to six weeks the demineralizing in a plaster

augmented

immobilization

FIG.

4-A form the beeti

FIG.

4-B resistant condyles.

how-leg

4-A: L.T. at. three years of age with a relatiyel mild the feet together there was a six-inch spare between lower extremities were short in proportioll to the trunk. Fig. 4-B: L.T. at eight \e:1rs of age. His deformities had vit aIllinI ) therapy, and calcium supplement.
(HF:

Fig. With

of vitamin-i) medial femoral

colltrolled by

rickets. ihe
braces,

JOURNAl.

OF

BONE

AN!)

JOINT

SURGERY

TREATMENT

OF

VITAMIN-D

RESISTANT

RICKETS

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VOL.

46-A,

NO.

5,

JULY

1964

990

I).

S.

PIERCE,

W.

M.

WALLACE,

ANI)

C.

H.

HERNI)ON

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THE

JOURNAL

OF

BONE

AND

JOINT

SURGERY

TREATMENT

OF

VITAMIN-D

RESISTANT

RICKETS

991

FIG.

4-E when the boy was eight years in the form of calcium lactate. but there is persistent irregularity old. He was reThe radial and of the distal

Roentgenograms ceiving a daily til)ial epiphyseal

femoral epiphyseal

of the wrists and knees made supplement of 3.0 grams of calcium plates appear essentially normal, plate.

cast,
attendant

may

cause
depression

severe

or
of the

uncontrollable

hypercalcemia

and

hypercalciuiia

with

central

Although corrected,

the an

type of osteotomy attempt is made

nervous system and irreversible employed is dependent upon the to use techniques that will permit It is essential to reduce the without jeopardizing healing

renal damage. deformity to be the earliest pos-

sible postoperative mobilization. of inactivity as much as possible

Recently we have in one

demineralizing effects of the osteotomy. fractured simultanesimilar to that dewith osteogenesis the insertion of an immobilization in extremities
is encouraged

patient

(M.A.R.),

whose

tibiae

ously

at the point of maximum bowing, employed scribed by Sofield and Millar in the management imperfecta. This consisted in multiple osteotomies intramedullary nail, and early weight-bearing after long
initiated

a technique of patients of the tibia, postoperative to all uninvolved

weight-bearing

plaster
as

casts
soon as

(Fig.
possible

3).

Resistive
and protected

exercises
partial

are
as
in

soon resistant

as practicable. rickets to ensure

is reinstituted

Delayed and although adequate

as soon

union, the
after

however, program
operation

is not described

infrequent

after

osteotomy care must

is desirable,

be

exercised
therapy

of the osteotomy site. Vitamin-D as the patient can participate in an exercise program vigorous enough to combat the demineralizing effects of inactivity. In the prepubertal child, protective braces are worn t1fter the osteot.omies have healed and, as a rule, up to the age of puberty. In a child past puberty, braces are
WO1ll
osteotomy

immobilization

after

removal of the site is demonstrated.

postoperative

plaster

cast

until

Inature

healing

at

the

illustrative The teristic

relatively previously volved

Case illustrate

Reports the wide differences in severity charac-

following

two

case

reports

of the disease. Patient L.T. represents the group of patients who have a mild form of the disease which can be controlled by the plan of treatment described. Patient W. H. is representative of the group of severely inchildren whose disease D and in whom the
1 (Figs.

of vitamin
CASE

is never possibility
L. T.,
bow-leg There was cod-liver medication. revealed

adequately of vitamin-D
a boy, was first

controlled toxicity
examined in

even by huge doses is a constant danger.

April

4-A because entirely

through normal. and been given

4-E).

1958 Tile

when

he his

was early

three
to walk

years
at

old, was fourteen

of bilateral at given no other

deformities. no family months oil and At a well the

He history mother vitamin the

was

born noticed

at

full-term increasing

and bowing by Babies boy, the

development lower physician, drens

VOL.

of leg drops, time

deformities. as prescril)ed to

child

began of the family Chil-

months He had been physical

eighteen

extremities. but Hospital,

46-A. NO. 5,

had

of admission three-year-old

and

examination
1964

developed

somewhat

JULY

992
short the
femoral ment of

D. S. PIERCE,
in stature.

M.

WALLACE,

AND

C.

H.

HERNI)ON

The upper
Examination

extremities

demonstrable.

of

patient
the

was
condyles.

standing The range

with

and trunk were essentially normal; no rachitic rosary was the lower extremities revealed a severe bow-leg deformity ; when his feet together, there was a six-inch space between the medial

of motion

in all joints
power

was

normal was

and
findings

there
were

was 10

no palpable
within normal

enlargelimits. per and per at 100 100 globu-

metaphyses.
was within normal

Muscle
limits.

and

neurological

Urinalysis

Blood

urea

nitrogen

less phosphorus

than with

milligrams 5.60 milligrams

milliliters.
tin

The total
The calcium
moderate

serum
was

protein
10.8
flaring

was 7.45 grams

per 100 Bodansky epiphyses

per

100

milliliters,

albumin 3.2
of

1.82.

milliliters,
time revealed

and alkaline on
pattern

phosphatase
side
in

milligrams 13.8
of

milliliters,

units.
with some

Roentgenographic
widening

examination the
also
made

that

the
the

epiphvseal a rather
and the

plates coarse patient and

particularly
trabecular

the

medial
noted

of
the

distal
bones

femoral
examined.

epiphysis. mild
this

There severity was 11.5

was was

all of

A diagnosis
was liters; started on
abdominal

of vitamin-D 100,000 3.2 toxicity which

braces The anterolateral

resistant vitamin
On

rickets July

of relatively

discomfort

units of developed.
milligrams
dosage was

D daily.
3, 1958,

On

dosage

polyuria,

nocturia, per

mild
milli-

his

calcium

milligrams

100

phosphorus,

units.
been

The
fitted

vit.amin-D

symptoms
twice daily

of

disappeared

with
during

bilateral
the

bow-leg
time they

per 100 milliliters; and alkaline phosphatase, 14.2 Bodansky dropped to 50,000 units every second day. On this dosage the and did not recur. At the time of admission the patient had braces which were worn day and night, except for one hour were removed femur 100 for exercise with purposes. Following was
per

a)plicatiOfl
occurring

of over

these
in

corrective tibia. two

bow-leg
bowing

deformity
of the per

improved
persisted.

most
This

of the correction
continued 100

the next

treatment
milligrams

the

years

with
3.1
units.
to

serum
4.5

calcium

ranging

from
milliliters;

9.4

to

9.8
and

milliliters;
from that. patient braces

phosphorus, from to 20.6 Bodansky

Urinalyses impairment of

milligrams
urea nitrogen

alkaline this time he

to

phosphatase, period did

be

9.5
no was and tibiae night given use

and
renal

blood
function

determinations

during

indicated The not bowing worn

and

had
1960 to

resulted March

from 1961, in March

braces

the during 1961

vitamin-D which revealed

reapplied,

intoxication. increased units

controlled

lost

to
not

follow-up
take vitamin

from medial daily On was

April D. torsion. exercise this

wear day by
early

did
except

Re-examination

of both and D was 1962 had and

lactate

associated
for

with
two

The
periods the

bow-leg
of one bow-leg only. on

were

hour

each, deformities

and

50,000 were at

of Vitamin

every of the

other braces Since

day. metabolic

regimen, to night

reduced studies

wear

conducted

other

patients

University
in

Hospitals

shown

positive
slowing

calcium
of

and phosphorus
turnover
in

balance

associated

with reduction
the

bone resorption
supplements,
of calcium

skeletal
given

was ment

discontinued was

May
.

following administration of high 1962 and three grams of calcium in

patient that time end sides. was of the still showed femora
was

calcium
form

gradual vitamin D

supplein October of marked bowing the on of

daily
at on

The at

taking a

calcium coarse and still proximal

when trabecular end

he was patiern of the severe

last

examined with widening more

196.1. epiphyseal the

Roentgenograms plates than the the medial

distal lateral

tibiae, anterolateral

There

moderately

both
Moderate the

femora,
medial

milligrams
phatase,

minimum coxa vara, and considerable improvement in the bowing of both tibiae. medial tibial torsion persisted; but, with the patient standing and his feet together femoral condyles were separated by only three centimeters. Serum calcium was 9.0 per 100 milliliters; phosphorus, 2.9 milligrams per 100 milliliters; and alkaline phos_
units.

1 1 Bodansky

Discnssion
rIClhis

patient vitamin-D

illustrates resistant

the

problems rickets.

encountered It should evidence satisfactory by means

in treating be noted that the

a child patients

with

relarickets

tively

mild

never completely It was possible, ing deformity tinue carry this out
CASE
weighing

healed nor was there however, to maintain of the lower extremities until after osteotomies
5-D). fourteen he did lower not

of healing on high calcium control and to prevent of bracing. It is planned tibial torsion alignment. old,
until thereafter.
OF BONE

intake. increasto conto

program derotation
2 (Figs.
three

puberty and to achieve

W. H., a man
ounces at birth.

then, if medial more normal

twenty-one
His motor

persists,

5-A through
pounds

years
and

was he was The

a premature development nineteen family

JOINT

baby, were months physician

SURGERY

and

physical

essentially old. Increasing

normal

although bowing

begin extremities

to walk was

independently noted
THE

of both

soon
JOURNAL

AND

TREATMENT

OF

VITAMIN-I)

RESISTANT

RICKETS

993

FIG.

5-A
resistant severe give!) coxa high rickets, vara, doses at four femoral of vitamin

FIG.
years
bowing,

5-B
of age
and in

Fig. 5-A: \V. H., a boy with severe vitamin-I) was moderately severe bowing of 1)0th femora. Fig. 5-B: At twelve years of age, there was on the left even though the patient had been

1946.
genu

There yalgum

I).

FIG. Fig. 5-C:

5-C

FIG. made plates, on

5-D
January a coarse 16, 1947, trabecular wIle!! pattern, tile ioy severe

of the lower extremities was five is widening of the epiphyseal anterolateral bowing of the femora, and coxa vara. Fig. 5-D: Roentgenograms of the femora, pelvis, thirteen \cears old. The coxa vara had been corrected I)o\%ing had been improved by supracondylar osteotomies. in the pelvis, sacrum, and ribs.

Roentgenogram years old. There

and lumbar spine by subtrochanteric Note the coarse

made when the boy was osteotomies and felnoral widely spaced t.rabeculae

established
percomorphum medication,

a diagnosis
supplement,

of rickets
one

in full

1944 to at

when Babies the age made Serum

the twice and

patient a day. Childrens in time

was

two

years of the

old failure for

and

gave

him and

oleum to this treatrachitic bowing widened

dropper

Because Hospital 1946, showed was phosphatase, vitamin-I) rise remained

to evaluation had and

respond typical lateral and 100

the On femora admission

patient to tibiae. milligrams was

was the pigeon

referred hospital breast,

ment. deformities of the epiphyseal

of four, groove, at this and

patient wrists, coarse

including and plates

2.5

Harrisons of rickets.

thickening

of the

Roentgenograms per 100 by of vitamin After plates.

1964

trabeculae

characteristic
demonstrated

calcium alkaline and

9.0 milligrams
23 tolerance in serum on large

per
Bodansky tests. showed

milliliters; units. The patient to 3.6 evidence of vitamin of No

phosphorus, malabsorption was healing

VOL.

milliliters; means four D a day months 1946 to

of glucose with 1951,

placed

on 50,000 per 100 epiphyseal

5, JULY

unit-s milliliters.

a subsequent the patient

phosphorus doses

milligrams

of treatment,

roentgenogra!ns

at the
46-A, NO.

From

994
D except for temporary

D.

S. PIERCE, withdrawal developed.

W.

M. WALLACE, of intoxication

AND

C. W in 1947.

HERNDON Braces were bilateral not used during

because In 1951,

this
rickets,

period

and, was
units 3.39

although
bowing

roentgenograms and
evidence

of the
when

epiphyseal
he
was

plates
nine years

showed
old,

no evidence a day.
and per

of active osteotomies

increasing roentgenographic

supracondylar

osteotomy

performed
of vitamin milligrams

vitamin
started,

D was

increased
in eight to calcium

to 500,000
ten weeks. was and for 10.0 the

units
Four

The
100

showed
the patient Because time time the medial hospital otomies the phosphorus,

of healing 100
and

a half

months

after The which per at that control bilateral to the osteagain

500,000 now

D was
per

serum

milligrams vitamin

milliliters;

milliliters;
abdominal

and
not seen per 13.9
reinstituted

alkaline
again

phosphatase,
approximately

had

mild
follow-up, calcium

nausea

discomfort

6.4 Bodansky units. D was discontinued.

six months, milligrams made This consisting was did not of femoral was at 3.16

of loor serum

the was alkaline

patient 9.23 phosphatase,

was

milligrams D was

100

milliliters;
units.
at

phosphorus,
Roentgenograms units recurred, the left. He a day.

100 milliliters;
revealed rickets tibial in were operation and April

and active the torsion,

the

Bodansky

rickets. deformities bilateral at

Vitamin in coxa years correct genu at 9.28

50,000 rapidly on

the
vara, the

lower and of age. coxa

extremities genu At vara The this and vitamin valgum time

readmitted

1954

twelve to

bilateral

subtrochanteric osteotomy

performed and

a left

supracondylar

performed
after
mm per

to correct calcium

recurrent increased remained

valgum. milligrams

progressively

D the
100

D was increased to 100,000 units daily to 500,000 units a day. Even on 500,000 units of vitaper 100 milliliters, the phosphorus at 3.6 milligrams

milliliters,
of toxicity,

of fear

and the alkaline phosphatase the dosage was reduced to

healed without
deformity

at
100,000 on

25.4 units this

Over

Bodansky a occasion,

units.

After

two
change

months
in

because applied was

day, with little

a knock-knee

blood values.
was

The
to

osteotomies
prevent recurrent

difficulty
at

and,

brace

the left knee.

D to a level
The
toxicity.

the next
would
was

several
result

months
increased of bone

an attempt
of the
again structure

made
would units was 5.88 250,000 definite grams
7.77

to adjust
be daily. again low At

the
enough

dosage
to

of vitamin
prevent

that

in healing

rickets
to at

but
the

dosage

gradually improvement

500,000

this

level

roentgenograms

demonstrated calcium at 13.07

epiphyseal

plates,
evidence

but after
of toxicity

being
with

on this dosage
and alkaline

for a period
milligrams phosphatase

of approximately
per at 6.87 1954 reduced 100 and milliliters, Bodansky then dosage,

two months
phosphorus units. gradually the patient Accordingly, down

there
at to

milligrams D
units

per
was

100 by

milliliters, March 1955.

the vitamin

reduced

to 350,000

units
However, 3.80 was

daily
even

in November on this

daily

showed

evidence of toxicity with per 100 milliliters; phosphorus,

nausea,

vomiting,

and

nocturia.

milligrams
roentgenographic

per

Serum 100 milliliters; had evidence been of

calcium was 14.68 milliand alkaline phosphatase, satisfactorily active rickets controlled although by

Bodanskv
of brace but

units.

The were
a dose left was

deformity
There

of his lower An attempt

extremities

means

protection. such of the was

symptoms
of toxicity, the the valgus 1955,
deformity

of toxicity

present
not recurred.

was made
to control

to maintain

the dosage

just

below
bowing in

levels
of July

sufficient.

the rickets,

and even with brace

protection and the

Postopera-

knee present

At this

tibia

associated
strain that age

with medial
of thirteen, vitamin and
in

torsion.
at the derotation

Because
knee, from the

time the deformit,v was primarily due to of the rather rapid increase in deformity
patient was of the to 300,000 evidence 16, three times of 1956, the daily readmitted left healing tibia of vitamin
was

to

the

hospital

at the he

and

osteotomy 100,000 showed

performed.

tively
without
no

received difficulty

D ranging
roentgenograms

units

daily.
the

The
rickets, 1) was

osteotomy
but discontinued there

healed
was and

improvement patient was

blood

chemistry. I .0 gram
of

On February
phosphate

the

given

but

with no effect

on his blood

. After a period of six weeks, the calcium remained at 10.4 milligrams per 100 milliliters, phosphorus at 2.9 milligrams per 100 milliliters, and alkaline phosphatase at 16.5 Bodansky units. At that time 500,000 units of vitamin D was added to the therapeutic regimen with no appreciable

chemistry

effect vitamin-I)

on

his

blood intoxication,

chemistry the the

after vitamin calcium

a period D was

of two reduced

months. to

In 50,000

order units

to avert daily

the and was per since

development the still 100 phosphorus no evident

of

increased
change the no range beneficial

progressively
in blood chemistry,
in

up to 7 grams
the

a day.
milligrams The

Alter
per

a period
in the 100 was

of four
range then

months

there

remaining phosphorus

of 10.4

milligrams

milliliters,

the phosphorus

range
and the

of

2.7

milliliters,

and the alkaline

discontinued

phosphatase
it had produced

in

of 24. 1 Bodansky effects

units. vitamin

the

left

tibia

gradually
was age of no

developed. There coxa vara remained

Hospitals

recurred moderately
of fifteen healing he and was

well corrected.

D was increased to 100,000 units a day. The deformity in and moderate medial bowing and rotation of the right tibia severe persistent anterolateral bowing of both femora but the In August 1957 the patient was again readmitted to University
a second derotation osteotomy was performed on
as

at treated

the

the

left

tibia.

He patient

was

postoperatively vitamin

with

100,000 placed in

units
a brace

of vitamin
and the

D, but
vitamin

as soon
D was

the

osteotomy

showed

evidence received

discontinued.

The
when
SURGERY

D after

that

time.

The

epiphyseal
THE JOURNAL

plates
OF

closed
BONE

after
AND

puberty
JOINT

TREATMENT he last lateral was seen about

,

OF VITAMIN-I)

RESISTANT

RICKETS
thereaft.e:. \Vhen he

995
was

extremities

fifteen years old and there was no increase in deformity the patient had a short stature, the trunk being essentially were short; the upper extremities were essentially normal. of the femora, right. alignment a mild Both of recurrent knees the genu showed extremities valgum moderate was on the ligamentous acceptable.

normal

whereas

tile

lower
antero-

There
left, and

was
laxity

residual

bowing

moderntely with

severe increased osteotomy

medial tibial torsion on the mobility, but the over-all

of the right tibia was

A derotation

indicated

but

the patient

refused

further

surgery.

Discussion This case demonstrates the difficulties encountered patient with severe vitamin-D resistant rickets. At times ment there was no roentgenographic evidence of healing
epiphyseal plates on doses of vitamin

in the nrnnagement of a during the course of treatof the rachitic lesion at the to be toxic. At other periods
on on This con-

D which

proved was
to

healing siderably

of the rachitic lesion shown smaller dosages of vitamin

roentgenographically D. At no time

was there time

accomplished

consistent
the patient

correction
a con-

in the blood-chemistry pattern. stant vitamin-D dosage, as the

dosage demonstrates closure of the required to control the

It was impossible toxic level varied

rachitic lesion varied

maintain from time is not

from

to time,
to

and,
time.

also,

the
case

the

relative

futility
plates when

of

performing
the rachitic

corrective
lesion

epiphyseal

osteotomies prior to well controlled. Re-

current deformity is to be anticipated under such circumstances with the necessity of repeating the osteotomies. We believe that it is preferable to control the deformities by means of brace correction through the age of puberty, at which time definitive
provement.

osteotomies II presents follosed. numerator the same age of the

can

be performed

with

greater of the

assurance pertinent is calculated

of permanent clinical according normal shows was made. data

OH

imthe Wil-

Table twelve
kins would n

a summary The

of certain height-age

patients The
attain

column

to

represents the age height as the patient patient at the time

at which the average and the denominator the measurement

individual the actual Inspection degree of of fluctunumber

of

chronological

of the table indicates deviation of the serum atioii

episodes

the wide spectrum of intensity of the disease. The concentrations from the normal range, the degree with treatment, the
and,

of these
of

values
vitamin-D

severity
in many

of the

deformities,
the

the
frequency

of
op-

intoxication,

instances,

erative correction of deformity, all correlate with the t.urbance as indicated by the height-age index. Pain in the severity of the deformity and to the severity of the lem and is shown in the table as a manifestation of the in the individual patient. It is caused either by fatigue the ligaments caused by angulation deformities in the ber of osteotomies that were required in each patient the severity of the process. Conclusions 1. The clinical course and response to medical and

severity of the growth disthese patients is related to underlying metabolic probseverity of the total process

fracture or by stretching of lower extremities. The numis recorded also to indicate

orthopaedic

treatment

of

a group of patients with vitamin-D resistant rickets is described. in clinical severity of the disease is emphasized. Some patients may be managed successfully with combined orthopaedic and while in others the disease progresses despite meticulous attention treatment. 2. The Patients evidence episodes. of Such hazards vitamin events of therapy healing lead of the intoxication with process should large doses not and be of vitamin by subjected renal

The wide variation with mild disease medical treatment to the details of D to are emphasized. followed similar by

in whom

is accompanied irreversible

or quickly repeated
injury.

to cumulative

996
3. A rigorous

D.

S. PIERCE,

W.

M.

WALLACE,

AND

C.

H.

HERNDON

program

of bracing

is of definite

value

in checking

the

progression

of deformity, nitude of the

NOTE: Requests

especially corrective
for reprints

in the surgery
should

tibia, prior to puberty, to be performed.

be addressed to Dr. C.

thereby

minimizing

the

mag-

H.

Herndon,

2065

Adelbert

Road,

Cleveland

6, Ohio.

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VOL.

JULY

1964