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A Case of Adult-Onset Vitamin-D Resistant Osteomalacia with Elevated
Plasma Parathyroid Hormone Level
TAKUO FUJITA, KAZUTOSHI OKANO, HAJIME ORIMO, MASAHIRO OHATA and MASAKI YOSHIKAWA
J Bone Joint Surg Am. 1972;54:181-188.
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A Case of Adult-Onset Vitamin-D Resistant
Osteomalacia with Elevated Plasma Parathyroid
Hormone Level
BY TAKUO FUJITA, M.D. , KAZUTOSHI OKANO, M.D. , HAJIME ORIMO, M.D.
MASAHIRO OHATA, M.D. :;: AND MASAKI YOSHIKAWA, M.D. TOKYO, JAPAN
Franz tile Departnu’nt of Geriatrics, University of lokvo, Tokyo
Simple vitamin-D resistant osteomalacia with onset after adolescence is an cx-
tremely rare condition. Since the first report by McCance in 1947, less than thirty
cases have been documented in detail. As to the pathogenesis of this disease, a pni-
mary defect of renal tubular function leading to a phosphate leak was emphasized by
many investigators 5,20 whereas secondary parathyroid hyperfunction on account of
defective intestinal absorption of calcium was stressed by others 14. 21, We have re-
cently encountered a case of adult-onset vitamin-D resistant osteomalacia with hyper-
glycinuria and elevated plasma immunoreactive panathyroid hormone.
Case Report
S. S.. a sixteen-year-old high school girl. was admitted to the Department of Geriatrics.
University ofTokyo Hospital, on August 28, 1970. Her chiefcomplaints were pains in the knee
Posteroantenior roentgenogram of the pelvis. Decrease in roentgenographic density is evident
especially around the pubic bone, where tenderness against compression is especially pro-
nounced.
* Department ofGeriatrics, University ofTokyo. 3-1, Hongo 7-Chome, Bunkyo-Ku, Tokyo,
Japan.
VOL. 54-A,NO. 1.JANUARY 1972 181
182 TAKUO FUJITA AND ASSOCIATES
TABLE I
AMINO ACIDS IN URINE
(MIcRoMoLts PER TwErrrY-FouR HOURS)
Normal Control
Subject Patient
Threonine 198 189
Serine 177 182
Glutamic acid 182
Glycine 695 2373
Alanine 227 308
Cysteine 51 56
Tyrosine 102
Phenylalanine 63
Lysine 354 266
Histidine 442 833
* Amino acid in urine of the patient when compared with that of a normal control subject,
expressed in micromoles per twenty-four hours. The determination was carried out by Technicon
Amino Acid Auto Analyzer with one column system.
joints. lumbago. unstable gait. and shortening of statute. Her grandparents on her mother’s side
were cousins. No known members of the family had skeletal or other apparent abnormalities.
The patient was born at term after a normal gestation. Her subsequent growth was uneventful
under satisfactory nutritional conditions in a sunny part of central Japan. Her menstruation
started at the age of thirteen and remained regular. Her intelligence and achievement at school
were average.
Since 1969. the patient occasionally experienced pain in the knees and chest, and lumbago.
aggravated by exercise. The skin was free of hemangioma or other abnormalities. The gait be-
came unstable due to muscle weakness. In May 1970, out-patient investigation revealed de-
creased bone density. mild hypocalcemia and marked hypophosphatemia. and the patient was
hospitalized.
Anteroposterior roentgenogram of both knee joints. Decrease of roentgenographic density is
noted toward the end of the tibia.
THE JOURNAL OF BONE AND JOINT SURGERY
ADULT-ONSET VITAMIN-D RESISTANT OSTEOMALACIA 183
Physical examination revealed a well-developed. well-nourished. and normally proportioned
adolescent girl. 149 centimeters in height and 47 kilograms in weight. Blood pressure was I 10/78.
Sclerae and fundi were normal. Pelvis. femora, and tibiae were tender to compression. Moder-
ate muscle weakness was noted in the upper and lower extremities.
Laboratory tests revealed a sedimentation rate of twenty-five millimeters per hour. C-reac-
tive protein negative, antistreptolysin titer less than 100, Wassermann reaction negative. hemo-
globin 12.9 grams per 100 milliliters, red cell count 395 X 10 4, platelet 25.6 X 10 , and white
cell count 4200 with normal differential count. Urinalysis was negative. Feces was of normal
color and consistency without conspicuous fat droplets. Serum total protein. albumin to globulin
ratio. blood urea nitrogen. creatinine. sodium. potassium. chlorine. total cholesterol. uric acid,
thymol turbidity, zinc sulphate test, serum glutamic oxaloacetic transaminase, serum glutamic
pyruvic transaminase, prothrombin time, serum protein electrophoresis, arterial blood pH,
PCO2, P02, 02 saturation, buffer base, standard bicarbonate, actual bicarbonate, phenolsulfonph-
thalein excretion, fasting blood sugar, and blood sugar thirty, sixty, ninety, and 120 minutes after
oral loading offifty grams glucose were all within normal limits.
Serum calcium was 8.6 and 8.7 milli-
grams per 100 milliliters, serum inorganic
phosphorus 1.8 and 1.2 milligrams per 100
milliliters, alkaline phosphatase sixteen and
twenty-two King-Armstrong units, and tubular
reabsorption of phosphorus (per cent tubular
resorption of phosphorus) 48 per cent. After
oral loading of six grams ammonium chloride,
pH of the urine fell to 4.47. Analysis of amino
acid content of urine revealed a definite in-
crease of glycine and a slight increase of histi-
dine but other amino acids in normal concen-
trations, as shown in Table I. Calcium absorp- isi .‘
.
tion rate was 0.10, compared with the normal
range (0.30 to 0.50) according to the method
of Nordin and associates. On the day of intra-
venous infusion of fifteen milligrams per kilo-
gram of body weight of calcium, urinary cal-
cium excretion showed scarcely any increase
from the level in control day, indicating a
marked avidity of the skeleton to infused cal-
cium. Basal metabolic rate was - I per cent,
serum protein-bound iodine 3.2 alpha per
cent, urinary 17-hydroxycorticosteroid 1.5
milligrams per twenty-four hours, and urinary
17-ketosteroids 3.2 milligrams per twenty-four
hours. Bone density was generally decreased
especially in the pelvis and proximal end of the
tibia (Figs. I and 2). Wedge-shaped deformity
of the thoracic and lumbar vertebrae was
noted (Fig. 3). Thickness of the clavicular cor- FIG. 3
tex was 40 per cent, compared with the normal Lateral roentgenogram of the lower tho-
racic and upper lumbar vertebrae. Decrease of
range at this age of 56 ± 5 per cent.
roentgenographic density and wedging de-
Radio-immunoassay of parathyroid hor- formity are noted.
mone in plasma was carried out using guinea
pig antibodies to partially purified parathyroid
hormone with biological activity of 250 international units per milligram (supplied by Wilson
Laboratories, Chicago) and highly purified bovine parathyroid hormone with biological activity
of 3000 international units per milligram (supplied by Wilson Laboratories, Chicago) labeled
with 1251 by the method of Hunter and Greenwood. Bound and free hormones were separated
by dextran-coated charcoal 22 Standard human serum obtained from a patient with uremia
arbitrarily defined to contain 1000 microequivalents per milliliter, and unknown serum samples
were incubated with antibodies at the final concentration of one to 1 5,000 at 4 degrees centi-
grade for seventy-two hours. ‘251-parathyroid hormone was then added and the incubation was
continued for another forty-eight hours, at the end of which dextran-coated charcoal was added.
Plasma parathyroid hormone in this case was 310 and 280 microequivalents per milliliter, defi-
nitely higher than 45 ± 45 (mean ± standard deviation) in 107 normal controls. Intravenous in-
jection of four milligrams per kilogram of body weight of calcium in the form of gluconate over
VOL. 54-A, NO. I, JANUARY 1972
184 TAKUO FUJITA AND ASSOCIATES Serum Ca
PTH n#{128}cml
6CC #{149}
Before Treatment After Treatment mg#{176}l
t
400
/\ 10
8
6
200
4
2
V BeforeAfter 1h 2h 3h
Before After 1h 2h 3h
FIG. 4
Changes of serum and plasma immunoreactive parathyroid hormone levels in response to
intravenous injection of four milligrams per kilogram of body weight of calcium. before and
after treatment. Dark bars represent plasma immunoreactive parathyroid hormone levels. Cross
signs represent serum calcium in milligrams per 100 milliliters.
a period of ten minutes definitely suppressed the plasma parathyroid hormone level as shown in
Figure 4. Intravenous infusion of twenty milligrams per kilogram Na2-ethylenediamine tetra-
acetic acid over a period of ten minutes resulted in an increase of plasma parathyroid hormone
as shown in Figure 5. Rapid calcium infusion according to the method of Goldsmith and For-
land gave rise to normal response of the suppression of urinary phosphorus excretion as shown
in Figure 6. Renal phosphorus threshold measured by the method of Bijvoet and associates was
0.8 milligram per deciliter, which was well below normal. Microradiography of the bone biopsy
specimen obtained from the iliac crest revealed a layer of insufficiently calcified bone with vague
outline compatible with the diagnosis of osteomalacia.
Changes of serum calcium and plasma immunoreactive parathyroid hormone levels in re-
sponse to infusion of twenty milligrams per kilogram of body weight of Na2-ethylenediamine
tetra-acetic acid over a period of twenty minutes. Dark bars represent plasma immunoreactive
parathyroid hormone levels. Cross signs represent serum calcium in milligrams per 100 milli-
I iters.
THE JOURNAL OF BONE AND JOINT SURGERY
ADULT-ONSET VITAMIN-D RESISTANT OSTEOMALACIA 185
Urinary P
rnglhr
Control day
60
40
Test day
20
(I 9-10 10-il 11-12 am.
FIG. 6
Fall of urinary phosphorus excretion in response to intravenous injection of four milligrams
per kilogram of body weight of calcium. Unlike the control day without such injection with a
rise of urinary phosphorus excretion, urinary phosphorus excretion fell in response to intra-
venous injection of calcium.
Under the diagnosis of adult-onset vitamin-D resistant osteomalacia. 100.000 units of vita-
mm D2 was started and increased to 300,000 units in two weeks. As shown in Figures 4. 5. and
7, serum phosphorus. per cent tubular reabsorption of phosphate. and plasma parathyroid hor-
mone returned to normal after one month of treatment. The pains in the bones and joints rapidly
diminished and the muscle weakness rapidly improved. Renal phosphorus threshold also in-
creased to 3.2 milligrams per 100 milliliters.
Vitamin 02
1O’tj.
mg/dl ________ 15luu.
,
3Oitl0’j.
10 . . jSerumca
. . . TRP%)
I U_
:
“
.__:::,__._.__.._..._.__m_.I___r
2 i2 1215 9 26 5 9
Sep. Oct. Nov.
FIG. 7
Clinical course of patient S. S.. a sixteen-year-old girl. In response to increasing doses of vita-
mm D2 in doses up to 30 x l0 units. serum phosphorus and tubular reabsorption of phosphate
returned to normal range.
VOL. 54-A, NO. I, JANUARY 1972
1 86 TAKUO FUJITA AND ASSOCIATES
Discussion
Osteomalacia, hypophosphateni ia, elevated alkaline phosphatase, phosphate
leak, and hyperglycinuria in the absence ofglycosunia, and with normal kidney func-
tion and ability to acidify the urine, provide the basis for the diagnosis ofsiniple vi-
taniin-D resistant osteomalacia (Dent Type II). Uneventful growth and development in
childhood and absence of marked skeletal deformity indicates the onset after ado-
lescence.
As to the cause of simple vitamin-D resistant osteomalacia, Albnight and asso-
ciates originally proposed that the primary defect was diminished calcium absorption
from the gastrointestinal tract. Secondary parathyroid hyperfunction is responsible
for the increased renal phosphate clearance according to these authors. Primary de-
feet in renal tubules was also suggested 20.23 In order to decide whether primary
tubular defect or secondary panathyroid hyperfunction plays a dominant role in the
augmented phosphatunia in this disease, calcium infusion to suppress parathyroid
function has been carried out repeatedly. Falls and associates conducted calcium in-
fusion in six patients. While standard four-hour calcium infusion failed to enhance
phosphate reabsorption except in one case, more prolonged infusion strongly aug-
mented renal reabsorption of phosphate. These authors drew a conclusion that these
patients had no secondary hyperparathyroidism. In view of the clear-cut enhance-
ment of phosphate reabsorption by similar calcium infusion in the reports of others,
these authors suggested the presence of two varieties within the category of simple
vitamin-D resistant osteomalacia. Different degrees of parathyroid autonomy might
offer another explanation for such discrepancy. Abundant evidence is available for
the hyperfunction of parathyroid gland in rickets. Highman and Hamilton demon-
strated parathyroid hormone-like activity in serum of patients with rickets. Exoge-
nous parathyroid hormone caused little increase in phosphate excretion probably
due to the already elevated plasma parathyroid hormone level . However, hypo-
calcemia sufficient to stimulate the parathyroid gland seldom occurs in vitamin-D re-
sistant osteomalacia. In many cases of resistant osteomalacia, hypophosphatemia
persisted even during administration of a large dose of vitamin D or along with hy-
percalcemia. Riggs and associates performed total parathyroidectomy in a twenty-
seven-year-old man with adult-onset vitanii n-D resistant osteomalacia, suggesting a
causal or permissive role of parathyroid hormone in this disease. Glanville and
Bloom reported a case of adult-onset vitamin-D resistant rickets in which autono-
mous hyperparathyroidism developed on the basis of secondary hyperparathy-
roidism.
Although the increased phosphate conservation in response to calcium infusion
has been regarded as evidence for secondary hyperparathynoidism in vitamin-D re-
sistant osteomalacia elevation of serum calcium by itself niay act directly on the
kidney to increase the net tubular reabsorption of phosphate . 16, In the case of Kall-
meyer and associates, calcium infusion caused a fall of phosphate clearance to nor-
mal range. but such change might be accompanied by a fall in glomerular filtrate rate.
Direct measurement of parathyroid hormone would therefore provide a much more
definite evidence secondary
for parathyroid hyperfunction than the changes of phos-
phatunia. One of us (T. F.) reported a case of adult-onset vitamin-D resistant osteo-
malacia with increased parathyroid hormone-like activity in urine according to a bio-
assay method 25, Salassa and associates reported two cases of adult-onset hypophos-
phatemic osteonialacia associated with benign scierosing hemangionias. In the second
case, removal of the tumor increased serum inimunoreactive parathynoid hormone
to a normal level from the undetectable level before operation. ln the present case,
definitely elevated plasma i mmunoreactive parathyroid hormone readily suppressed
by intravenous calcium infusion provides a direct evidence for secondary hyperpara-
THE JOURNAL OF BONE AND JOINT SURGERY
ADULT-ONSET VITAMIN-D RESISTANT OSTEOMALACIA I 87
thynoidism. Normalization of plasma parathyroid hormone along with other biochem-
ical abnornialities such as serum phosphorus, per cent tubular reabsorption of phos-
phate and phosphorus excretion threshold after treatment with vitamin D2 provides
further evidence for the connectable abnormality of panathyroid function apart from
congenital tubular abnormality in this case. However, the cause of the secondary hy-
perparathyroidism is obscure in this case. Calcium absorption was apparently im-
paired but no other manifestations of malabsonption were noted.
Summary
A sixteen-year-old girl with adult-onset vitamin-D resistant osteomalacia had an
elevated plasma immunoneactive panathyroid hormone level which was readily sup-
pressed by intravenous calcium infusion. Treatment with 300,000 units of vitamin D2
normalized the high plasma immunoreactive parathyroid honnione level as well as
augmented phosphatunia. Parathyroid hormone appears to play an important role in
the development of vitamin-D resistant rickets in this case.
NOTE: The Central Research Institute, Sankyo Co., Ltd., measured the amino acid content in urine, and Dr.
Seizo Yoshikawa, Associate Professor ofOrthopedic Surgery, University ofTokyo, aided with the study.
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