FIBROGENESIS IMPERFECTA OSSIUM

S. L. BAKER, WOODBRIDGE, ENGLAND

Professor Emeritus of Osteopathology, University of Manchester

C. E. DENT, LONDON, ENGLAND

Professor of Human Metabolism, University College Hospital, London

M. FRIEDMAN, LONDON, ENGLAND

Research Fellow, Metabolic Unit, University College Hospital, Lo,zdo,z

LYAL WATSON, LONDON, ENGLAND

Honorary Consultant Physician, University College Hospital, London

In 1950 Baker and Turnbull in a short communication described the histological features
of a hitherto undescribed generalised bony abnormality which they had observed in necropsy
material from two patients. The histological examination appeared to demonstrate a
widespread defect in the formation of the collagen fibres of the newly laid down bone matrix.
As a result of this defect there was a partial failure to calcify normally, giving rise to wide
osteoid seams similar, at first sight, to those seen in osteomalacia. However, the cases
described were clearly different from osteomalacia, because they showed a specific and
striking histological abnormality of the collagen fibres when examined with a polarising
microscope and when stained by Gomori’s reticulin method. The abnormality was confined
to the bone collagen, affecting only lamellar bone, with no evidence of any collagen defect in
the subperiosteal bone or in any other connective tissues. In 1956 one ofus (S. L. B.) published
a comprehensive report on the histological findings in these two cases and named the disease
“ fibrogenesis imperfecta ossium.” No further cases of the condition have been reported.
Both the patients first described were elderly. The first, a woman aged fifty-six (a patient
of Dr R. F. Ferguson), died in 1938. The second was a man aged sixty-four (a patient of
Dr D. Hunter), who died in 1932. Both patients developed pains in the limbs and trunk some
years before death, and eventually became bedridden with numerous spontaneous fractures.
The essential abnormality was discovered by one of us (S. L. B.) when examining necropsy
material from the first patient in 1938, and the second one was diagnosed by Professor
Turnbull in 1942, ten years after the patient had died, during a review of necropsy material.
In 1962 a man aged fifty-six was referred to University College Hospital with bone pain
and multiple pathological fractures. The histological changes in his bones were identical to
those described by Baker and Turnbull (1950) and by Baker (1956). Moreover, a comparison
between the grossly abnormal appearance of his skeletal radiographs and those (as yet
unpublished) of the previous cases showed a characteristic and identical picture. We now
report the clinical progress, histological findings and metabolic investigations carried out on
this patient over a period of three years. We believe that this is the first time that fibrogenesis
imperfecta ossium has been confirmed during life. We also believe that we now have treatment
capable of greatly modifying, perhaps even of curing, the otherwise relentless course of the
disease. The details of this treatment seem to be of some theoretical interest in a wider field
of bone metabolism.

METHODS
Calcium and phosphorus balances were performed in the usual way (Dent, Harper and
Philpot 1961), and the balance data have been plotted for calcium by the conventional method
of Reifenstein, Albright and Wells (1945). The intake is measured downwards from the zero
line. The output of faecal and urinary calcium is measured upwards. The clear space below
the zero line represents the positive balance and, therefore, the retention of calcium in the
body.

804 THE JOURNAL OF BONE AND JOINT SURGERY

 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 805

The capsules of dihydrotachysterol were prepared as previously described (Dent and

Friedman 1964). The calciferol capsules (vitamin D2) were prepared by the same method
used in the preparation of the dihydrotachysterol, with the same spectrophotometric assays
for vitamin D content. The D2 used was pure crystalline material obtained from Glaxo
Laboratories Ltd., Greenford, Middlesex. One milligram of vitamin D2 is equivalent to
40,000 International units of vitamin D. The vitamin D activity in the plasma was kindly
measured for us by the rat bio-assay method by Dr W. F. J. Cuthbertson. Throughout this
paper the term vitamin “ D “ will be used to describe any drug with anti-rachitic activity.
The only ones available for clinical use are vitamin D2 (calciferol, ergocalciferol), vitamin D3
(cholecalciferol) and DHT (dihydrotachysterol, AT 10).
The total bound hydroxyproline was measured by the method of Prockop and
Udenfriend (1960).

CASE REPORT

The patient, a cattle drover born in 1906, was well until May 1960, when he fell on his
left elbow and sustained a fracture of the upper end of the radius. The degree of trauma which
produced this fracture was minimal. Up to this time he had led an active and strenuous life,
and had enjoyed good health apart from a perforated duodenal ulcer in 1928, which was
repaired by simple suture. He is the only child of unrelated parents, both of whom are now
dead. The cause of death of his father is unknown. His mother died during childbirth. He is
married and has seven children ranging in age between seventeen and thirty-one years. All
his children are well and there is no history of bone disease in the family.
In June 1960 he complained of generalised pains which predominantly affected his
shoulders, elbows and knees. These pains were brought on by movement and weight bearing,
but disappeared when he was at rest. In October 1960 he developed a painful left ankle and
was admitted to hospital. No fracture was found and the ankle was strapped. While in
hospital he bumped his knee against the edge of a bed and fractured the right patella, which
was removed. (This bone was later available for histological studies.) In December 1961 he
came under the care of Dr T. R. Littler. At the time he complained of increasing pains in
the limbs which interfered with walking. An extensive series of investigations was carried
out, all of which proved to be normal except the alkaline phosphatase which was 21 King-
Armstrong units, and the radiographic appearance of the bones which was grossly abnormal
(see later). He was treated with dianabol, phenylbutazone and calcium gluconate for varying
periods over the next nine months without any beneficial effect. In April 1962 he was given
1 25 milligrams of calciferol (vitamin D2) daily for seventeen days. Within six days of starting
therapy he developed an extremely severe exacerbation of pain in the thighs, knees and legs
which lasted for a week. On the tenth day of therapy he vomited repeatedly, was anorexic
and had polyuria and polydipsia. The plasma calcium was found to be l21 milligrams per
100 millilitres and the alkaline phosphatase had risen to 27 King-Armstrong units. After
the calciferol had been stopped the plasma calcium fell to 9l milligrams per 100 millilitres
and he recovered from the symptoms of vitamin D intoxication.
He was referred to University College Hospital in September 1962. At the time he
complained of pain in the elbows, knees, right ankle and some of the proximal interphalangeal
joints. The pains had gradually become worse since their onset in 1 960, and were particularly
troublesome at night, when the slightest movement in bed brought on the pain and interfered
with sleep. At the time he was almost completely bedridden, and was able to walk only a few
steps with the aid of a stick. Apart from the pain he was remarkably well and had no other
complaint.
On examination, his height was 178 centimetres (70+ inches). Crown-pubis length was
8l3 centimetres (32 inches), and pubis-heel length 889 centimetres (35 inches). Weight was
58 kilograms (l279 pounds), and the blood pressure was 140/90. There was no corneal

VOL. 48 B, NO. 4, NOVEMBER 1966

N
806 HARRY PLATT BIRTHI)AY VOLUME

Pelvis (November 7, 1962) shows the prominence of the bony trabeculae, with transradiant
areas in between the trabeculae.

FIG. 2

Left elbow (January 21, l963)shows a fracture ofthe olecranon process ofthe ulna.

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 807

,,‘

.-

FIG. 3 FIG. 4
Figure 3-Right hand (January 22, 1963) shows a grossly abnormal trabecular pattern
affecting all the bones of the hand and the lower end of the radius and ulna. The
cortex is very narrow in some of the phalanges and completely absent in others.
A fracture is present at the base of the fourth proximal phalanx. Figure 4-Lumbar
spine (November 7, 1962) shows the pathological process involving the lumbar
vertebrae. Note the coarse trabecular pattern of the bone.

FIG. 5
Right foot (January 30, 1963). All the bones are abnormal. The
cortex of all the bones is reduced in thickness.

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808 HARRY PLATT BIRTHDAY VOLUME

calcification. Moderate bone tenderness was noted, particularly over the tibiae. There was
no inflammation or swelling of the joints. Extension of both elbow joints was limited. Gentle
movements-active or passive-of the knee or ankle joints did not cause pain, but rapid
movements produced some pain. A large abdominal incisional hernia was present in the
midline. No hepatomegaly, splenomegaly or lymphadenopathy was present. The
cardiovascular, respiratory and central nervous systems were normal. There was no clinical
evidence of scurvy.
Investigations-Plasma calcium was 94 milligrams per 100 millilitres (specific gravity of
plasma 1028-9). Plasma phosphorus was 38 milligrams per 100 millilitres. Twenty-four-hour
urinary calcium was 212 milligrams. Twenty-four-hour urinary phosphorus was 614 milligrams.

FIG. 7
Figure 6-Right tibia and fibula (March 28, 1963). There is marked abnormality of the trabecular pattern of
the lower ends of the long bones with decrease in cortical thickness. However, the bone structure and cortex
of the shaft appear to be normal. Figure 7-Knees (May 14, 1964). Note the grossly abnormal trabecular pattern
of the lower ends of the femurs and the upper end of the tibiae, merging into the shaft which appears normal
both with regard to cortical thickness and bone texture.

Plasma alkaline phosphatase was 17 King-Armstrong units. Acid phosphatase was 44

King-Armstrong units. Plasma sodium was 141, potassium 47, chloride 104 and bicarbonate
25 milli-equivalents per litre. Urea was 35 milligrams per 100 millilitres. Uric acid was 43
milligrams per 100 millilitres. Maximum urinary concentration was 1030 and maximum
dilution 1005. The urine contained no protein or cells and was sterile on culture. Amino-acid
chromatograph was normal. Haemoglobin was l56 grammes per 100 millilitres. Mean cell
diameter was 6#{149}9
t. Packed cell volume was 48 per cent and mean cell volume was 100 cubic 1u.
Mean corpuscular haemoglobin concentration was 35 per cent and red blood cells were 44
million per cubic millimetre. White blood cells were 5,600 per cubic millimetre. Erythrocyte

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 809

sedimentation rate was 13 millimetres per hour. In serum flocculation tests the colloidal red
gave a strong positive and the cephalin cholesterol a very weak positive. The thymol turbidity
was 2 units. Total protein was 82 grammes per 100 millilitres. The electrophoretic strip of the
plasma proteins showed an increase in alpha-2 and gamma globulins. The Rose-Waaler test
gave a serum titre of less than 8. The slide latex test was negative. The daily faecal fat output
was I .7 grammes measured over a six-day period and represented 98 per cent absorption of
dietary fat.
Radiographs ofthe skeleton (Figs. 1 to 8) showed a generalised increase in the prominence
ofthe bony trabeculae, because oftheir increase in size and because they were very well calcified.
The trabeculae appeared to have rather fuzzy outlines, and were less numerous than one would

Chest (February 29, 1964). The ribs show a coarse trabeculation.

expect in normal bone, with transradiant areas between the trabeculae. The general impression
of the radiographic changes was that of increased density. The pelvis, spine, long bones,
hands and feet all showed an abnormal bone structure superficially resembling generalised
Paget’s disease. In the long bones the part nearest to the joint was more affected by the
pathological process. There were incompletely healed fractures of the left olecranon process
and the base of the fourth right proximal phalanx. The skull was the only part of the entire
skeleton which appeared normal radiologically. There was no abnormality in the shape of
the bones including that of the vertebral bodies. The thickness of the cortex of the major
long bones was within normal limits, but the cortex was absent in the smaller long
bones, such as the phalanges. There were no radiological signs of hyperparathyroidism or

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810 HARRY PLATT BIRTHDAY VOLUME

osteomalacia. No Harris lines, indicating bone disease before epiphysial closure, were seen.
These radiographic findings were unlike those of any patient previously seen at our hospital.
The history of pathological fractures occurring in bones showing increased radiodensity
suggested the possibility of a bone matrix defect, for this situation also occurs in osteopetrosis
in both adult and child forms. Fibrogenesis imperfecta ossium came to mind as a possibility
and bone specimens were, therefore, obtained for histological examination in polarised light.
Metabolic investigations and subsequent progress-After five days on a constant diet matched
to his usual intake for both calcium and phosphorus content, stools and urine were collected
over three six-day control periods for both calcium and phosphorus balance. The average for
the whole period showed that he was in negative calcium balance of 1 18 milligrams a day.
During the same period his phosphorus balance was negative to the extent of 47 milligrams

700 I aaj I a a a a a a a a
VITA.1N C mi!Iiqrcm
per doy _____________________________
5.0
VITAMIN D2 2.5 :::...:.::::::::::::::::.::
mill!5rornC per day . l.........;..........;............... :#{149}.:.:...#{149}.:#{149}.#{149}:#{149}.:::#{149}...

02

02

URINE CALCIUM Q.4

FAECAL CALCIUM
qrommes per day
GE

08
OUT

10

a a a a a a a a i a . a a I a
29 5 11 17 23 29 4 10 15 22 28 31 b 12 18
62 DECEMBER ‘E3 JANUARY FEBR;ARy

FIG. 9
The results of control calcium balance studies and the positive calcium balance produced
by the administration of vitamin D2.

daily. A further six-day calcium balance was carried out while the patient was on 700
milligrams of ascorbic acid a day. The balance showed no change in the urine calcium
excretion, but the faecal calcium was decreased, giving an overall positive balance of 6
milligrams a day during the six-day period. However, during the three control balance
periods and the period on ascorbic acid, difficulty was experienced in separating the stools
belonging to the respective periods because of
poor faecal marking (Fig. 9). The small
change in the overall calcium balance while he was on the ascorbic acid was thought to be a
technical artefact. Unfortunately, we were not using an internal stool marker at that time.
He was then started on 2 milligrams a day of vitamin D2 while still on full balance. This
produced a rise in the urinary calcium and a larger fall in faecal calcium so that over the
next four six-day periods the calcium balance became positive to the extent of 1 1 7 milligrams
per day. Within five days of starting the vitamin D2 he developed a marked increase in his
bone pain similar to the episode of pain which occurred when he was given vitamin D2 in
April 1962. During this period his plasma calcium remained within normal limits. The
exacerbation of bone pain lasted about ten days and then passed off spontaneously. The
vitamin D2 was then increased from 2 milligrams a day to 5 milligrams a day, and after nine

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 811

days on this increased dose further calcium balances were carried out. These showed that he
was now in average positive balance of 325 milligrams of calcium per day. The balances once
again showed the expected effect of vitamin D with a further rise in the urinary calcium
and a fall in the faecal calcium (Fig. 9).
While the patient was having the increased dose of vitamin D2 there was further definite
decrease in his pain and bone tenderness. He was gradually mobilised and after a series of
exercises in bed was allowed to walk about with the aid of a stick. He had a number of minor
set-backs in hospital, where he developed pains in hands, feet and elbows at different times.
The history of these episodes strongly suggested new fractures, although we were able to
confirm this radiologically only in the case of the pain in his hands. During this period his
alkaline phosphatase fell from 17 to 15 King-Armstrong units.

FIG. 10
Left elbow (July 16, 1963). The fracture ofthe olecranon process which had beer,
present in January (see Fig. 2) has now healed. The trabecular pattern still remains
abnormal.

Over the course ofthe next three months his pains gradually returned and in July 1963 the
pains were as severe as they had been before starting therapy with vitamin D2. In particular he
complained of severe pains in the region of both knees. Radiographs of his knees revealed
avulsion of both tibial tuberosities. Radiographs of his hands and left elbow showed healing
of the fractures which had previously been present (Fig. 10). At this stage the vitamin D2
was increased to 10 milligrams a day (Fig. 1 1). Over the next four months there was no
improvement in his pain. He was readmitted to University College Hospital in November
1963. At this time his plasma calcium was 9 milligrams per 100 millilitres (specific gravity of
plasma 1026-7). Plasma phosphorus was 41 milligrams per 100 millilitres and twenty-four-
hour urinary calcium was I 53 milligrams. All these results indicated an absence of biochemical
response to the vitamin D2 which was puzzling in view of the previous response to a smaller
dose. At the same time his alkaline phosphatase had risen to 30 King-Armstrong units. We
suspected that the patient might possibly not have been taking his vitamin D2 in spite of repeated
assurances from him that he regularly took his capsules. That he had been taking them was

VOL. 48 B, NO. 4, NOVEMBER 1966

 812 HARRY PLATT BIRTHDAY VOLUME

r-.-’--I I I#{149}I#{149}’i#{149} I

U.C.H.admissions II II II II
VITAMIN D2 0 1:
hg msp dy 5

DI LR0TACHYSTE ROL1#{176}
milligrams per day 5

PAIN + ‘-:‘ + j;:i ±

PLA5II:

lOOm!
PLASMA PHOSPHORUS

ALKALINE
PHOSPHATASE
(K-A units)
!E
URNE CALCIUM
milligrams per
24 hours
E

Sept Dec May July Sept Dec May July Sept Dec Mcy July Sept
De(
62 ‘63 ‘b4

FIG. 11
The biochemical data, clinical assessment of the severity of the patient’s pain and treat-
ment given over the three years during which he was under observation at University
College Hospital. Between September and December 1964 the patient probably neglected
to take his dihydrotachysterol; this is represented in the Figure by the broken line.
For further explanation see text.

I I I
DIHYDROTACHYST EROL
2mslltqroms per day

02 -
DI HYDROTACHYSTEROL
I I I I I I

2 milliqrams per day

02

Q2 -

JT J......
URINE CALCIUM 02
FAECAL CALCIUM
-J-
grammes per day O#{149}6-
URINE CALCIUM fl 04
FAECAL CALCIUM
grammes per day
08 -

tzr
08 0t:S;:
ouT
jl.0- OUT ‘Ty0
j:
-I-
10
I I a
31 6 12
I I I I I
DEC JAN. 4 10 lb 22 28
‘63 64 JANUARY

FIG. 12 13
FIG.
Figure 12-The calcium balance picture in January 1964 two weeks after commencing dihydrotachysterol
at a dose of 2 milligrams daily. Figure 13-The calcium balance picture in January 1965 soon after restarting
dihydrotachysterol in hospital. Note the progressive rise in urinary calcium. For full explanation see text.

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 813

fully confirmed later when we found that his plasma contained between 50 and 120 International
units of vitamin D per millilitre, which is a very high level (normal is less than 2 units per
millilitre) and ofthe order to be expected for that dosage (Cuthbertson and Dent-unpublished
work). It was obvious that the patient had become resistant to vitamin D2 and it was therefore
discontinued, 10 milligrams of dihydrotachysterol daily being substituted. Within two weeks of
starting dihydrotachysterol the plasma calcium rose to l29 milligrams per 100 millilitres (specific
gravity of plasma 10267) and the urinary calcium to 1220 milligrams per twenty-four hours.
The dihydrotachysterol was discontinued for two weeks, during which time the plasma calcium
fell to normal limits. The dihydrotachysterol was then restarted at a dose of2 milligrams daily
and a further calcium balance was carried out in January 1964. This again showed a high
urinary calcium (between 500 and 600 milligrams per day) and a low faecal calcium so that the
overall calcium balance was positive to the extent of 216 milligrams a day (Fig. 12). His
plasma vitamin D level during the balance was 14 International units per millilitre. While
dihydrotachysterol was being taken there was once again a significant decrease in bone pain,

Pelvis (January 1 , I 965). There has been a considerable increase in thickness of the cortex
of the pubic ramus in comparison with the radiographs taken in November 1962 (Fig. I).

but the patient now complained of a severe pain over the right supraorbital region.
Radiographs of the supraorbital foramen and the adjacent frontal sinus did not reveal any
abnormality. A detailed neurological examination showed no abnormality. Injection of the
supraorbital nerves with procaine produced immediate but temporary relief. In view of the
troublesome nature of the pain 1 .5 millilitres of an oily solution of proctocaine was injected
into the supraorbital nerve, which completely and permanently relieved the pain, and produced
a small anaesthetic area in the region of the distribution of the supraorbital nerve. The
patient was discharged home in January 1964 taking 1 milligram of dihydrotachysterol daily.
When seen in May 1964 he was completely pain-free and was able to walk up to a mile
without any pain. However, in August 1964 he once more gradually started to develop pains
in the knees, ankles and elbows on walking. The alkaline phosphatase was 7 King-Armstrong
units at this stage. The dihydrotachysterol was increased to 2 milligrams a day. This increase
in the dose of dihydrotachysterol produced a temporary lessening of the pain, but within two
months the pain recurred. Because of this he was readmitted in December 1964. He was
given 2 milligrams of dihydrotachysterol daily, the dose he was supposed to have taken at
home for the preceding three months. While this dose was being taken there was a gradual
increase in the urine calcium excretion from 272 milligrams in twenty-four hours to 773
milligrams in twenty-four hours. At the same time there was a gradual rise in the plasma

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814 HARRY PLATT BIRTHDAY VOLUME

phosphorus. Within ten days of the patient’s admission there was a marked exacerbation of
pains III the limbs, particularly severe in the left knee. This increase in pain lasted a week and
then he gradually became pain-free over the course of the next week. This episode of increase
in pain was similar to that which he had experienced in April and December 1962, when, on
each occasion, he was given vitamin D after a period without therapy.
After ten days in hospital on 2 milligrams of dihydro-
tachysterol calcium and phosphorus balance studies were
carried out. He was in positive phosphorus balance of 100
milligrams a day over twenty-four days. Initially he was in
positive calcium balance to the extent of 238 milligrams a
day, but the balance became less positive as the study
proceeded and by the end of the fourth six-day period he
was in approximate balance with urinary and faecal calcium
equal to intake. Throughout the period of the balance
studies faecal calcium remained practically constant at
between 248 and 265 milligrams a day, whereas the urinary
calcium rose progressively from 447 milligrams to 773
milligrams in twenty-four hours (Fig. 13). At the end of
the balance period his plasma contained 5 International
units of vitamin D per millilitre. The progressive rise in
the urinary calcium together with a further temporary
increase in bone pain strongly suggested that the patient
had not been taking the prescribed dose of dihydro-
tachysterol in the three months before admission.
Radiographs of the skeleton taken in January 1965
showed a definite improvement. This was particularly
marked in the pelvic bones where there was considerable
thickening of the cortex of the pubic rami (Fig. 14) in
comparison with the appearances in November 1962 (Fig. I).
The cortex of the phalanges which was practically absent
in the earlier radiographs (Fig. 15) had become thickened
and prominent and had a sharp outer margin.
The patient was discharged in February 1965 on a
decreased dose of dihydrotachysterol, namely 1 milligram
daily. In October 1965 he was almost free from pain and
was able to walk two miles with the aid of a stick. The

FIG. 15 biochemical findings and treatment during the three years

Radiological appearances of bones for which the patient was followed are shown in Figure 1 1.
of fourth
digit of right hand in When seen next in February and June 1966 his plasma
January 1963 compared with those . . . .

in July 1965 (right). The cortex of levels remained normal and he continued in good cllnlcal
the phalanges which was practically condition.
absent in the earlier radiographs is . . .

now thickened with a sharp outer The hydroxyproline output in the urine during
margin. The fracture of the base of treatment with 1 milligram of dihydrotachysterol daily
the proximal phalanx present in .

1963 has healed. was measured by Dr R. Smith. On June 23, 1965, it was
21 milligrams in twenty-four hours, while on October 17,
1965, it was 25 milligrams in twenty-four hours. Both these values are within the normal
range for this method (13-39 milligrams in twenty-four hours).

PATHOLOGY
The right patella (preserved in formol saline) and two specimens from the iliac crest
were available for histological examination.

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 815

Patella-Naked eye inspection of the surface of a transverse slice through the patella showed a
markedly abnormal architecture with irregular masses of tissue replacing most of the normal
trabeculae (Fig. 16). This tissue showed a mottled appearance caused by many irregular
rather ill-defined pale areas (these are patches ofcoarsely granular calcification in the abnormal
bone matrix). The greater part of this tissue is calcified and shows up well in the fine grain
radiograph ofa thin slice ofthe bone (Fig. 17). In comparison with a similar preparation of a
normal patella from an individual of approximately the same age (Fig. 1 7) most of the normal
trabecular pattern is blotted out by thick columns of calcified tissue which follow the main
direction of the normal trabeculae.
Abnormal bone is also found in the anterior and posterior cortical zones of the patella
where it adds to and partly replaces the normal bone. It can be seen that the anterior cortical
zone is widened and its structure blurred. The well defined compact cortex supporting the
articular surface in the normal bone has been partly replaced by an ill-defined zone with much
loss of structural detail.

FIG. 16
Cut surface of a transverse slice through the patella mounted in gelatine. ( x 2 and x 6 (right).) Irregular
thick columns of abnormal bone replace the normal trabecular pattern. The irregular pale areas are patches of
coarsely granular calcification in the abnormal bone matrix. They are shown better with the higher magnification.

Some fine vertical trabeculae can be seen crossing open spaces in the upper figure; these
are the visible remains of the normal trabeculae; others are concealed inside the abnormal
bone, as became apparent microscopically.
Histology-The essential abnormality in this material is, as in the two earlier cases (Baker and
Turnbull I 950), the production of a bone matrix markedly deficient in normal collagen fibres.
The easiest way of recognising this defect is by the use of the polarising microscope. Collagen,
like many other fibres, is birefringent and can be made to shine up in the dark field produced
by setting the axes of polarisation of the polariser and the analyser at right angles to one
another. To get the maximum luminosity the object must be set so that its fibre direction is at
the correct angle to the polarised beam-which is usually done by rotating the microscope
stage. The result of this is that if the fibre direction of an object varies much from place to
place only a part of it can be seen at one time-the stage has to be rotated so that the other
part can be seen. This is not much of a disadvantage visually but a photograph will as a rule
show only part of an irregular refractile object such as a bone trabecula. Figures 1 8 and I9
show some of the thickened trabeculae from the central area of the patella. In Figure 19 with
polarised lighting the section has been orientated so that most of the normal lamellar bone
trabeculae show up and it is seen that these lie within the more recently formed thick irregular
trabeculae composed of abnormal fibre-deficient bone which is for the most part non-refractile.

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816 HARRY PLATT BIRTHDAY VOLUME

In Figure 18 two different appearances of the abnormal bone can be seen-a lightly
staining substance mainly on the surfaces, but sometimes around small vascular spaces and
rather darker spotted areas. The lighter staining substance is uncalcified fibre-deficient
osteoid tissue; the spotted areas are the calcified defective bone.
Figures 20 and 21 with normal and polarised lighting show a field in the same region
with higher magnification. The details can be seen more clearly here and letters mark the
different types of bone structure. Two fragments of lamellar bone trabeculae (A) are seen
embedded in the abnormal bone which is for the most part calcified (B). The dark dots seen

A fine grain radiograph ofa thin transverse slice through the abnormal patella (above)
compared with a radiograph of a similar slice of normal patella. ( 2).)

in Figure 1 8 are seen here to be the cell spaces which have a dark outline because of granular
calcification which stains more intensely with haematoxylin than does the more diffuse
calcification of the surrounding area. The lighter stained fibre-deficient osteoid tissue (C) is
mostly on the outer surfaces, but some is around vascular spaces (C’). Very dark narrow
zones of coarsely granular calcification separate the osteoid tissue from the diffusely calcified
matrix.
In the region (D) and covering an area to the left ofit a fine lamellar structure is visible in
Figure 21 . The fibres are less compactly arranged than in normal lamellar bone and are
limited to the small area seen here, but it represents an attempt to produce lamellar bone.

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 817

Figure 18-Section from the central part of the patella showing thickened irregular trabeculae composed of
calcified and uncalcified abnormal bone surrounding partly eroded lamellar bone trabeculae. (Haematoxylin
and eosin, x 27.) Figure 19-The same section as in Figure 18 with polarised light. The illuminated birefringent
trabeculac of lamellar bone can be seen in the interior of the abnormal non-refringent bone tissue.

Figure 20-Part of a thickened trabecula similar to those

in Figure 18. (A) marks the remains of eroded
lamellar bone trabeculae; (B) is calcified fibre-deficient (C) is uncalcified
bone; fibre-deficient bone matrix.
(Haematoxylin and eosin, x 100.) Figure 21-The same field as that shown in Figure 20 with polarised light.
(D) marks the right hand side of an area showing localised lamellation of groups of collagen fibres in the
defective matrix.

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818 HARRY PLATT BIRTHDAY VOLUME

This was found in various places in sections of the patella and is an indication that the defect
is not so complete as in the two earlier cases where very few signs of lamellar structure
were found, though much more material was examined than is available here.

DEVELOPMENT OF THE BONE DEFECT

The clinical radiographs show that the condition is widespread in the skeleton and
appears to involve virtually all the bones. The skull, however, shows no radiographic changes

FIG. 22

,- ‘T’! w::’:

-.-..-

. -,t- .
i #{149}*.C

. .

FIG. 23
Early deposit of fibre-deficient osteoid tissue on the surface of a small lamellar-bone
trabecula. Surface erosion of the lamellar bone with shallow bays and small pits is well
seen in Figure 22. In the polarised light (Fig. 23) the non-refringent osteoid contrasts
with the refractile Iamellar bone. (Haematoxylin and eosin, 400.)

and if the defect is present there it must be in an early stage. In neither of the two earlier
cases was there radiographic evidence of skull changes, but in Case 1 in which the skull was
examined histologically well marked early changes were found.
The mode of advance of the bone changes in the patella in this case follows the same
histological pattern as seen in the two earlier cases. Since the radiographic appearance of

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 819

the patella slice (Fig. 17) shows thickened calcified columns corresponding with appearances
in the clinical radiographs at other sites it seems safe to assume that it is a fair sample of the
bone changes as a whole.

FIG. 24
Osteoclastic erosion of lamellar bone and calcified cartilage at the cartilage-bone
junction beneath the articular surface of the patella. (A) and (B) are irregular
erosion spaces with flattened osteoclasts on their walls (or pulled away by
shrinkage oftissue); (C)iscalcified cartilage; (L) is lamellar bone; (D) is an irregular
piece of partly calcified abnormal bone, the eroded remains of a larger piece which
occupied part of the site of the large erosion space below it. (V) is a small vascular
canal. (Haematoxylin and eosin, x 110.)

At the start of the process the new abnormal bone is seen to be deposited on the surfaces
of the normal lamellar bone. It is deposited on the surfaces of trabecular bone and also on
the walls of spaces in the compact bone.
Figures 22 and 23 show a small trabecula with the early changes. This consists ofa core of
normal lamellar bone on the surface of which is a layer of fibre-deficient osteoid tissue. Before
this osteoid was deposited the lamellar bone
surface had suffered some osteoclastic erosion V

leaving a rough surface with many small shallow ‘‘

mi’;’.
pits (Fig. 24). This process advances in many ‘S

places by the continued addition of layers of

abnormal bone until the lamellar bone trabeculae
are buried in irregular masses of fibre-deficient
bone as seen in Figures 18 and 19. - ...

In the more compact bone the process starts FIG. 25

by the deposition of the abnormal bone on the Osteoclastic erosion of lamellar bone and calci-
fled cartilage at the cartilage-bone junction
walls of irregular cavities produced by osteoclastic beneath the articular surface of the patella.
erosion. As in other types of erosion of compact Enlargement of spindle-shaped osteoclasts on
right hand wall of cavity (A) in Figure 24.
bone such cavities start by the osteoclastic (Haematoxylin and eosin, . 300.)
erosion of the walls of the small vascular
channels in the bone. Two such spaces are seen in Figure 24 at (A) and (B); they are
at the bone-cartilage junction beneath the articular surface of the patella. Space (A) lies
partly in lamellar bone and partly in the calcified zone ofthe articular cartilage; and space (B)

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820 HARRY PLATT BIRTHDAY VOLUME

is in lamellar bone, but also encroaches below on an irregular piece of partially calcified
abnormal bone (D) containing two vascular channels. All these erosion spaces contain a fine
reticular tissue with some thin-walled vessels and numerous osteoclasts in relation to their
walls. These are seen well in cavity (A) where they form a line of elongated flattened cells on
the right hand wall. These small osteoclasts have from 2 to 6 nuclei (Fig. 25); they
may be as much as 40 p long, but only about 10 1u thick and produce shallow depressions,
undulating surfaces and small pits (Fig. 24) on wall of cavity (A) which are not so easily
recognised as the typical more deeply cut Howship’s lacunae produced by the larger more
spherical osteoclasts commonly found in active types of bone erosion.
Erosion of both lamellar bone and the abnormal bone continue in various places. Figure
24 shows at (D) an area of partly calcified abnormal bone with irregular surfaces on which
some osteoclasts are seen ; this is clearly the remains of a larger deposit which probably
occupied much of the space below it now filled by reticular tissue. This alternation of
erosion and deposition gives rise to the complicated mosaic patterns seen in Figures 18
and 19.
Reaction of the abnormal bone matrix to stresses-There can be little doubt that the abnormal
thickening of the defective bone trabeculae is largely determined by stresses. This is well seen
in the bone thickening along stress lines seen in the clinical radiographs and also in the
arrangement of the thickened calcified columns seen in the radiograph of the patella slice. It
can be seen in Figure 17 that in the patella the columns follow the same general direction as
the normal trabeculae, being arranged to resist the stresses within the bone produced by
compression of the patella against the femoral trochlea when the quadriceps is in action
with the knee bent.
Calcification of the abnormal bone matrix-The wide osteoid seams on bone surfaces and
surrounding the small vessels in the vascular canals in the bone show that calcification of the
abnormal bone matrix is much delayed, but calcification of most of this tissue eventually
takes place. In the two earlier cases calcification was much less complete. This can be seen in
Figure 9 of the earlier publication (Baker 1956) showing thickened trabeculae in the femoral
condyle rather like those seen in the patella in this case, but largely composed of osteoid
tissue, so that the calcified tissue is in irregular patches and tenuous lines and would not give
the radiographic appearance of solid trabeculae. In the radiographs of these earlier cases the
striking trabecular pattern seen in most of the bones of the present case is largely replaced by
an ill-defined spotted appearance, the result of the less complete and focal calcification.
Calcium content of the abnormal matrix-Dr H. A. Sissons very kindly prepared some
microradiographs of 70-micron ground sections of the patella and by further grinding a
20-micron section of the same area so that the microscopic appearances could be compared
with the microradiographs as seen in Figures 26 and 27. Figure 26, in which polarised light
was used, shows in the upper haifa luminous lamellar bone trabecula; attached to it are three
irregular pieces of darker material-these are calcified abnormal bone matrix. In Figure 27,
the corresponding microradiograph, it is seen that the abnormal bone is considerably lighter
(more opaque radiographically) than the normal bone.
Dr Sissons also made micro-densitometer tracings of the microradiographs and worked
out the mineral content of different areas in terms of hydroxyapatite. The normal lamllear
bone gave a figure of 1 2 grammes of hydroxyapatite per cubic centimetre (in good agreement
with his findings on other samples of lamellar bone which gave l0-U3 grammes per cubic
centimetre); the calcified abnormal bone gave at least 15 grammes per cubic centimetre, an
increase of about 25 per cent.
A probable explanation of the increased amount of calcium salt in the abnormal bone
is the greatly reduced collagen fibre content ofthe matrix. In normal lamellar bone the collagen
fibres form a closely packed mass and the amount of space available for the calcium salt
deposited at the time of its formation seems to be a limiting factor. In the abnormal bone the

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 821

r4 .r.,.
S. : ‘

. .-4 .. . ‘ -4.

Fio. 26
Identical fields in a microradiograph and in a ground section from the same block. The ground section (Fig. 26)
with the polarised light shows part of a birefringent lamellar bone trabecula with three irregular non-refractile
dark masses of calcified fibre-deficient bone attached to it. In the microradiograph (Fig. 27) it can be seen that
the abnormal bone is paler (more opaque radiographically) than the normal lamellar bone. ( x 45.)

collagen fibres are greatly reduced with a very openwork structure. (An estimation of the
calcium : nitrogen ratio in a piece of calcified abnormal matrix in one of the earlier cases
indicated that the protein content was not more than one-fifth of that in normal lamellar
bone.)
In support of this explanation is the fact that woven bone, in which the fibres are loosely
packed, is more opaque than lamellar bone in microradiographs.
Biopsy specimens-The first biopsy, taken November 16, 1962, shows a mixture ofnormal and
abnormal bone rather irregularly distributed, there being a central area composed largely of
lamellar bone with some areas of abnormal bone and thickened trabecula similar to those in
the patella extending into the marrow space. The defective bone partly calcified and partly
osteoid tissue shows rather more collagen fibre than that in the patella.
The second biopsy, taken on May 15, 1964, is very small and composed largely of lamellar
bone with some small areas of defective bone. lts structure resembles parts of central area of
the first biopsy, but it is too small a sample on which to base conclusions about the surrounding
bone. This was most unfortunate in the light of the clinical and radiological improvement
being noted at this time.
Remarks-The histology of this case differs from that of the first two in that the collagen
defect is rather less severe and the calcification of the defective matrix is more complete. The
first two cases were, of course, in the terminal stage with multiple fractures and we do not
know how long the disease had taken to develop. In this case one would think it would take
some years to reach its present stage and there appear to have been only relatively small
changes in the radiographs since he has been under observation. Healing could come about
only by osteoclastic removal of the abnormal bone and its replacement by normal bone. No
change is possible in the collagen of calcified bone matrix.

DISCUSSION
The final diagnosis in this patient was from the histological examination. The appearance
of the abnormal “ osteoid “ is so characteristic as to leave no doubt that he suffers from
fibrogenesis imperfecta ossium. We believe this is the first case to be described during the
life of the patient. The clinical, radiological and other features seem now to be characteristic

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0
822 HARRY PLATT BIRTHDAY VOLUME

enough to enable diagnosis from these findings alone. We hope this description will enable
more cases to be identified ; indeed we already believe, from reports posted to us, that the
disease is commoner than one might expect from the existence so far of only three cases in
the literature. Most cases are likely to be mistaken for Paget’s disease, if fibrogenesis imperfecta
ossium is not considered.
We are especially interested to comment on the significance of the patient’s great clinical
and partial radiological improvement with vitamin D treatment. One action of vitamin D
(often considered to be its main action) is to promote the absorption of calcium from the
gastro-intestinal tract (Albright and Sulkowitch 1938, Nicolaysen and Eeg-Larsen 1953).
Vitamin D also at the same time increases the absorption of phosphorus (Carlsson 1954).
This latter action is probably not a direct one, but depends on the simultaneous increased
absorption of calcium (Nicolaysen 1956). Another effect of the vitamin is to increase the
urinary excretions of calcium and phosphorus. With large doses, 1-10 milligrams daily, a
rise in the plasma calcium to abnormally high levels can also occur seemingly by a direct
action favouring bone dissolution-sometimes described as its parathormone-like action. “ “

Vitamin D also appears to be necessary for the normal calcification of bone. When vitamin D
is absent or deficient in the diet, rickets or osteomalacia develops in both man and animals.
The quantity of vitamin D required to prevent or heal dietary rickets is extremely small,
only a few micrograms a day being necessary. Vitamin D action has been reviewed by
Nicolaysen and Eeg-Larsen (1956) and Neuman and Neuman (1958). The response of our
patient with fibrogenesis imperfecta ossium to vitamin D suggests that vitamin D may possibly
have a further specific action, namely on the abnormal protein matrix. We have noted great
improvement in this patient while he was having vitamin D as the sole treatment, an effect
unlikely to have been spontaneous in view of the unrelenting course of the disease in the
two other known cases. The cortex of many of the phalangeal bones appears to have re-formed
(Fig. 15) and in the larger bones the cortical thickness has increased (Fig. 14) during treatment
with vitamin D. His clinical improvement has been closely related to the current dose of
vitamin D, except during the period in late 1963 when he developed biochemical as well as
clinical evidence of resistance to the effects of vitamin D9.
What then is the action of vitamin D in this disease, where the defect appears to be an
isolated and highly specific matrix abnormality ? There is at present no clinical or experimental
evidence that vitamin D action is concerned in the formation of the protein matrix. Its action
in classical rickets, however, suggests strongly that it somehow promotes calcification in
osteoid tissue and in metaphysial cartilage, and it is of interest that work with labelled vitamin
D (Kodicek and Thompson 1965) has shown concentration of the label in as yet uncalcified
rachitic cartilage as if its first action were closely related to matrix formation. In view of the
quite unexpected finding of a normal complexed-hydroxyproline output in the urine in a
bone disease of this nature, an obvious and plausible speculation is that the newly laid down
bone collagen lacks the necessary ability to oxidise its peptide proline to hydroxyproline, and
that the vitamin D therapy was subsequently concerned in remedying this defect. Such
deficient hydroxylation could grossly affect hydrogen bond cross-linking in the collagen
molecules, could prevent its normal partly crystalline molecular structure and thus lead to
loss of the ability doubly to refract polarised light, the cardinal feature of the histology.
Further chemical and physical study of biopsy or necropsy material is clearly needed here.
We have been unable yet to secure clear histological evidence of cure of bone disease since the
iliac crest biopsies obtained have been insufficiently representative of the whole skeleton.
This may be possible later if healing continues for some years longer. It must be relevant as
further evidence of bone healing to stress the changes in plasma alkaline phosphatase which
mirrored well the other signs and symptoms.
The development of a severe exacerbation of bone pain when the patient was first given
vitamin D2 in April 1962 for a short period and again after further treatment with the same

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 823

drug at University College Hospital in December 1962, is of considerable interest. We have

frequently observed this phenomenon of temporarily increased bone pain in patients with
osteomalacia soon after starting treatment with loading doses of vitamin D. The explanation
for this is obscure, but it is so common that we now warn all our patients with osteomalacia
that there may be an increase in bone pain soon after starting treatment with vitamin D. We
regard the increased pain as a sign that the vitamin is in some way acting on the bones and
rapidly calcifying the matrix, and have rather unscientifically referred to this phenomenon as
a “ stirring up “ process. We think that the occurrence of the two episodes of increased bone
pain within days of starting therapy with vitamin D is additional evidence that it is acting
directly on the bone. Another similar situation occurred in January 1965. Obviously therapy
must not be stopped in such circumstances in the mistaken view that the patient is being
harmed. The recognition of the significance of such a process is of great clinical help in
managing the patient for it enables a happy outcome of treatment to be anticipated even
before corresponding biochemical data can appear from the laboratory. Indeed it was this
that enabled us to stay our hand in difficult clinical circumstances, and limit the long-term
treatment to one type of drug only, that is, vitamin D.
A remarkable feature of this case has been the development of resistance to very large
doses of vitamin D2. When the patient was first given vitamin D2 in December 1962 the
calcium balances obtained showed the characteristic effect produced by vitamin D : a rise in
the urinary calcium and fall in faecal calcium. Associated with the change in partition between
the urine and faecal calcium he went into positive calcium balance (Fig. 9). This was followed
some months later by considerable improvement in his clinical condition. His bone pain
decreased considerably and he was once more able to work. However, it soon became apparent
that the clinical remission was only temporary and by December 1963 his pains were almost
as bad as before beginning treatment with vitamin D2. At this time, in spite of taking very
large doses, namely 10 milligrams of vitamin D2 daily, his urine calcium was only 160
milligrams in twenty-four hours and his plasma calcium 9 milligrams per 100 millilitres.
Both the biochemical and clinical evidence were highly suggestive that resistance to the
vitamin D2 had developed since the start of treatment. The resistance to D action occurred in
spite of a markedly elevated plasma vitamin D level which indicated that the patient was
certainly taking the drug and that there was no defect either in the absorption ofthe vitamin D
from the gastro-intestinal tract or in the potency ofthe preparation administered. Furthermore,
the resistance to vitamin D2 action was manifest on the bones, as evidenced by increased bone
pain as well as loss of the expected hypercalcuric and hypercalcaemic effects of the very large
doses administered. When the vitamin D2 was changed to an approximately equivalent dose
(10 milligrams a day) of dihydrotachysterol there was a rapid increase in the urinary calcium
to 1220 milligrams in twenty-four hours and at the same time the patient became
hypercalcaemic and developed symptoms of vitamin D intoxication (Fig 1 1). Further calcium
balances performed in January 1964 on the reduced dose of2 milligrams of dihydrotachysterol
daily once again showed the characteristic vitamin D action (Fig. 12). Associated with this
there was a marked improvement in the clinical condition, and by March 1964 the patient
became completely pain-free for the first time since the onset of his illness. Later in the year
when we had reduced his dose to 1 milligram daily there was a slight recurrence of his pain
and the dose of dihydrotachysterol had to be raised. This once again produced a lessening of
his pain and his good condition is maintained until the time of writing.
The phenomenon of the development of resistance to vitamin D2 has been reported by
Dent, Harper, Morgans, Philpot and Trotter (1955). They studied four patients with tetany
after operation who were initially sensitive to vitamin D2 in the usual dosages, but eventually
became insensitive to even large doses of vitamin D2. When they were then given normal
doses of AT 10 or pure vitamin D3 there was a rapid disappearance of the signs and symptoms
of tetany, a rise in plasma and urinary calcium and a fall in plasma phosphorus. This work

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824 HARRY PLATT BIRTHDAY VOLUME

was done using a tablet preparation of calciferol of whose stability on storage we subsequently
had some doubts. We have, therefore, now made up capsules, which we regularly assay to
confirm their content, which has been found to be stable over long periods. With this safe
preparation we are confirming our earlier work and our patient with fibrogenesis imperfecta
ossium represents a further example of acquired vitamin D resistance. It will be interesting to
note if further patients with fibrogenesis imperfecta ossium show similar response to continued
calciferol administration and if they later respond similarly to dihydrotachysterol. The
acquired resistance phenomenon is without parallel as far as other vitamins are concerned
(Lancet annotation 1955). There are, however, many other situations in which a permanent
state ofresistance to all forms ofvitamin D seems to occur, sometimes in hereditary, sometimes
in acquired, disease. In osteomalacia accompanying gluten-sensitive steatorrhoea there is
such a state of vitamin D resistance, for the bone disease heals only with milligram doses of
calciferol while classical dietary osteomalacia responds to microgram doses. Of especial
interest is that in this particular instance, treatment with a gluten-free diet restores normal
vitamin D sensitivity while the steatorrhoea and other signs of malabsorption are correcting
themselves. Whatever the mechanism of the vitamin D resistance in our patient with
fibrogenesis imperfecta ossium it was not related to malabsorption of the vitamin, nor to its
excessive destruction after absorption, for very high concentrations of anti-rachitic activity
were discovered in the plasma by biological assay when the patient himself was showing no
other signs of vitamin D activity. His immediate response to dihydrotachysterol, which
differs from vitamin D2 (calciferol) in having a methyl instead of a methylene group at carbon
atom 10 in the steriod ring, represents a remarkable form of molecular specificity, for
dihydrotachysterol and vitamin D2 under other circumstances have very similar biological
activities. We are watching the patient closely to see if he later becomes resistant to
dihydrotachysterol.
SUMMARY
1 . A clinical, radiological and histological description of a patient with fibrogenesis imperfecta
ossium is given. We think that this is the first case in which diagnosis has been made during
the life of the patient.
2. The disease is characterised by a defect in the formation of the collagen fibres of the bone
matrix. There is also a failure of normal calcification of the matrix, giving rise to the
appearance of wide “ osteoid “ seams. When examined with the polarising microscope and
when stained with Gomori’s reticulin stain the collagen fibres can be seen to be grossly
deficient and abnormal.
3. The patient presented at the age of fifty-four years with bone pain and multiple fractures.
The only biochemical abnormality detected in the plasma was an elevated alkaline phosphatase.
He was also in negative calcium balance.
4. Treatment with vitamin D2, later changed to dihydrotachysterol, appears to have produced
clinical, biochemical and radiological improvement. It appears that a direct action of the
vitamin on the abnormal bone collagen must be postulated, in addition to its known actions
on the calcifying mechanisms.
5. An unusual feature of the case was the slow development of a total unresponsiveness to
large doses of vitamin D9, in spite of a markedly elevated level of vitamin D in the plasma.
There was later a response to a much smaller dose of dihydrotachysterol, which is being
maintained to date.

We wish to thank the nurses, biochemists and dietitians of the metabolic ward for their help during the
investigation ofthis patient. We are most grateful to Dr T. R. Littler for referring the case to us. We are indebted
to Dr H. A. Sissons of the Institute of Orthopaedics for the radiographs and microradiographs of the patella
and for his microdensitometric investigations as well as for sections prepared in his department: also to Dr
J. Bull for sections of the biopsy specimen prepared in his department. Dr D. Hunter kindly allowed us to
examine radiographs of the bones of the two original cases of fibrogenesis imperfecta ossium for comparison
with those of our case. One of us (L. W.) is indebted to the British Empire Cancer Campaign for a generous
grant held during the course of this work.

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 S. L. BAKER, C. E. DENT, M. FRIEDMAN AND L. WATSON 825

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