European Journal of
Europ. J. Pediat. 125, 265--273 (1977)
Pediatrics 9 by Springer-Verlag 1977
A Case-Report of Idiopathic Juvenile Osteoporosis with Particular Reference to 47-Calcium Absorption D. L a c h m a n n 1, R. Willvonseder 2, R. H6fer 2, and H. E. Bugajer-Gleitmann 1 1Univ.-Kinderklinik, W/~hringer Gfirtel 74--76, A-1097 Vienna, Austria 2II. Med. Univ.-Klinik, Garnisongasse 13, A-1097 Vienna, Austria
Abstract. Calcium metabolism was studied in a 12-year old girl presenting with idiopathic juvenile osteoporosis. Absorption of orally administered 47-Ca was high. Serum calcium and phosphorus, serum immunoreactive P T H and CT and tubular phosphate reabsorption were found to be within normal limits. The data suggest that calcium malabsorption, nutritional calcium deficiency, hyperparathyroidism, a dysfunction related to sex hormones, and Cushing's syndrome cannot be implicated in the aetiology of the osteoporosis in this case who recovered spontaneously with sexual maturation. Key words: Pathophysiology - Malabsorption - Nutritional calcium deficiency - Hyperparathyroidism - Oestrogen deficit. Introduction Idiopathic juvenile osteoporosis is a rare disorder of childhood and adolescence, first reported by Schippers in 1938; Synonyms are osteopenia in adolescence (Berglund and Lindquist, 1960), transitory osteoporosis (Fanconi et al., 1966), "Pubert/~tsfischwirbelkrankheit" (Catel, 1954) and "juvenile Fischwirbelkrankheit" (Hammel, 1951). A m o n g m a n y aetiological factors, malabsorption of dietary calcium has been suggested as a cause of the disease (Dent and Friedman, 1964; Jowsey and Johnson, 1972). This study describes a case of idiopathic juvenile osteoporosis with particular reference to 47-Ca absorption.
Initial Investigations
History M.A. (born 1st April 1960) first presented on 2nd May 1972, because of low back pain of two months' duration. The history prior to admission was non-contributory. She had an excessive dietary intake which had not been restricted before admission to the hospital. No medication, in
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particular cortisone, had been administered. There was no family history of bone disease. Physical examination revealed an obese girl (69.9 kg, 160 cm) with kyphosis of the thoracic spine. She complained of pains in her lumbar spine on bending forward. Tenderness of the lumbar spine was observed on percussion. No secondary sex-characteristics or stigmata of Cushing's disease were present. The blood pressure was l l5/70mmHg.
Laboratory Findings T h e r e l e v a n t l a b o r a t o r y findings are listed in T a b l e 1. Results o f o t h er r o u t i n e b l o o d - c h e m i s t r y analyses (not i n c l u d e d in T a b l e 1) were n o r m a l an d ruled o u t r en al or h e p a t ic disease. T h e responsiveness o f the ad r en al cortex was tested by D e x a m e t h a s o n e . O n three successive days the 8.00 a.m. p l a s m a l l - O H corticosteroid c o n c e n t r a t i o n d e t e r m i n e d by f l u o r o m e t r y was f o u n d to range f r o m 7.4 to 7.7 ng/1. O n the t h i r d day 1 m g D e x a m e t h a s o n e was given by m o u t h at 9 p.m. an d 11 h later the p l a s m a l 1 - O H c o r t i c o s t e r o i d c o n c e n t r a t i o n h ad declined to 4.0 ng/1. U r i n a r y c a l c i u m e x c r e t io n at different levels o f dietary intake, with a n d w i t h o u t c a l c i u m s u p p l e m e n t a t i o n , were measured. T h e results are r e p o r t e d in T a b l e 2. Table 1. Laboratory findings Serum
Normal values
Calcium
mg/100ml
10.4" (10.0-- 10.8)
9.4-- 10.9
Inorganic phosphorus Alkaline phosphatase PTH c CT c
mg/100ml mU/ml ~tl eq/ml pg/ml
5.9a (4.4-- 6.3) 103a (76.6--130) 23 163
4.0-- 6.0 38--138 b 8-- 34 500
Total vitamin D3d Serum albumin
IU/100 ml 300 % of total protein 53.11
150--375 52.2-- 67.0
Urine Calcium Creatinine clearance Tubular phosphate reabsorption Phosphate excretion index Hydroxyprolinee 17-Ketosteroids 17-OH-Ketosteroids " b
Normal values mg/day 133 ml/min x 1;73 m 2 96 % 83 - 0.04 mg/day x m 2 60 mg/day 3.3a mg/day 4.7a
(1.5--4.3) (3.7--5.6)
< 200b 100 >85 - 0.18-- 0 25--80 b 1.8-- 5.0 2.4-- 6.7
Mean value; Normal range for age and weight; Immunoreactive PTH and CT (Arnaud et al., 1968, 1971) was determined by Drs. Glenn W. Sizemore and C. Arnaud, Mayo Clinic and Mayo Graduate School of Medicine; d Total serum vitamin D3 was determined in a semiquantitative manner by thinlayer chromatography (Weigenbacher et al., 1973) by Prof. Dipl.-Ing. DDr. J, Washfittl, Technische Hochschule, Vienna, Austria; e 24-h urine excretion of hydroxyproline was determined by the Hypronosticon| (Organon). All foods containing gelatine were excluded from the diet for the three days before collection of urine
267
Idiopathic Juvenile Osteoporosis Table 2. Urinary calcium excretion at various levets of calcium intake Date
Calories/day
Calcium intake (rag/day)
Urinary calcium excretion (nag/day)~
Hospitalization 18th--26th Sept. 1972 27th Sept.--17th Oct. 1972 18th Oct.--2nd Nov. 1972 3rd Nov.--3rd Dec. 1972d 9th--17th Dec. 1972
800 800 1000 1200--1500 1200--1500
150 150-- 620 600-- 810 780--1140 780--1140 + i000~
133 138
Outpatient 18th Dec. 1972--31st May 1973 low 1st June--23rd Aug. 1 9 7 3 1200--1500
Ca-rich 625--1210
Hospitalization 24th--26th Aug. 1973~ 31st Aug.--6th Sept. 1973
600-- 800 600-- 800 +
1000 1000
170
+ 1500 b
1500 b
206
" Two tablets Calcium-"Sandoz"-forte| One tablet contains 2.94 g calcium lactogluconate and 0.30 g calcium carbonate, equivalent to 500 mg calcium; b Three tablets Calcium-"Sandoz"-forte| c Mean values over 5-day period; a First administration of 47-Ca: 14th Nov. 1972; e Second administration of 47-Ca: 27th Aug. 1973
X-Ray of Skeleton T h e t h o r a c i c a n d l u m b a r spine (Fig. 1) were seriously affected by o s t e o p o r o s i s , the v e r t e b r a l b o d i e s h a v i n g a b i c o n c a v e a p p e a r a n c e with c o m p r e s s i o n at L1, L2 a n d L4 a n d the t r a b e c u l a r p a t t e r n being a l m o s t c o m p l e t e l y absent. T h e r e were no signs o f o s t e o p o r o s i s in the long bones. T h e b o n e age was e s t i m a t e d to be ! 3 years.
Biopsy of the Iliac Crest T h e t r a b e c u l a r p a t t e r n o f the iliac crest was h o m o g e n e o u s l y s t a i n e d ~ ( h e m a toxilin-eosin, M a l l o r y ) . T h e r e were n o signs o f increased o s t e o b l a s t i c or osteoclastic activity. Q u a n t i t a t i v e e v a l u a t i o n o f the b i o p s y was n o t p o s s i b l e b e c a u s e o f l a c k o f facilities for m i c r o r a d i o g r a p h y or m o r p h o m e t r y .
Bone Scintigraphy O n e h o u r after i n t r a v e n o u s injection o f 2 m C i 87 m - S r there was a well defined u p t a k e o f the nuclide in the spine a n d in the l o n g b o n e s (Fig. 2). I n a d d i t i o n , there was a c o n s i d e r a b l e u p t a k e in the epiphyses as expected for a p a t i e n t o f this age. 1
Doz. Dr. H. Czitober, Head, II. Med. Poliklinik, Vienna, Austria
268
D. Lachmann et al.
Fig. 1. Lateral X-ray of the spine (May, 1972), showing severe osteoporosis with biconcave appearance of vertebral bodies and compression of L1, L2 and L4. The trabecular pattern is completely absent
Total Body 47-Ca Retention (Method: see Appendix) While the patient was on a diet containing 780--1140 mg calcium per day, the total body retention of 47-Ca from an oral test dose containing 100 mg CaCI2.6 H20 was 89 _+3% at 7 days, and 81 + 3% at 14 days.
47-Ca Absorption By adding the cumulative urinary excretion of 6.5% during days 0--7 to the retention of 89 _+3% measured at day 7, the lower limit of 47-Ca absorption was
Idiopathic Juvenile Osteoporosis
1
269
2
Fig. 2. Gamma-camera bone scintigrams (87m-Sr; Searle, Pho-Gamma III, HP) in the patient M.A. (1) and in a normal 12-year old girl of comparable weight and height (2). Lumbar spine and sacroiliac joints 30 000 cts (a); right humeral diaphysis 15 000 cts (b). Note increased uptake in the patient
calculated to be 95 + 3%. Estimation of true absorption would require the further addition of cumulative endogenous faecal excretion. However, this quantity, possibly in comparable magnitude to that of urinary excretion (Heany, 1964), is obscured by concurrent excretion of unabsorbed 47-Ca.
Course of the Disease and Follow-Up Examinations
Treatment consisted primarily of support with a corset to relieve the spine, and this resulted in freedom from discomfort within a few days. A weight loss of 12 kg was achieved within 3 months by a low caloric diet. X-ray and scintigraphic examinations of the skeleton were repeated after an interval of 10 months, during the last three of which 1.5 g calcium had been given daily. These did not reveal any improvement. Three days after termination of this calcium supplement, 47-
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D. Lachmann et al.
Fig. 3. Lateral X-ray of the spine in the patient (April, 1975). Absence of radiologic evidence for osteoporosis. Biconcave appearance of vertebral bodies L 1, L2 and L4 still visible. Reappearance of the trabecular pattern in all vertebral bodies
Ca was again administered in a test dose containing 100 mg CaC12 6 H20. The total 47-Ca retention at 7 days was 7 4 + 3% and the cumulative urinary 47-Ca excretion 7.5%, indicating an absorption of at least 8 2 + 3 % of the dose. Radiological evidence of severe osteoporosis of the spine could be demonstrated until February 1974. A slight improvement was evident by October 1974. In April 1975 at the age of 15 the patient presented in good health. The radiograph of the spine (Fig. 3) clearly showed a trabecular pattern in all vertebral bodies. However, the biconcave appearances in the lumbar vertebrae were still visible. She had her menarche in February 1974 at the age of 14.
Idiopathic Juvenile Osteoporosis
271
Discussion
Malabsorption of calcium has been considered the primary cause of idiopathic juvenile osteoporosis by several authors (Dent and Friedman, 1964; Jowsey and Johnson, 1972; Lapatsanis et al., 1971). As we were unable to use non-radioactive nucleides to estimate intestinal calcium absorption, radiocalcium studies were performed in our patient. The absorption of orally administered 47-Ca in the presence of 100 mg CaC12. 6 HzO exceeded 95% and the total body retention at 7 days was 89%. These values are high in comparison with data reported in the literature for normal subjects, even after allowing for the youth of our patient and the negative linear correlation which Alavizaki et al. (1973) found between the log. of intestinal absorption and age. Thus there is no evidence that calcium malabsorption was the cause of the disease in our patient. Although the calcium absorption seems to be abnormally high, the levels of vitamin D and PTH, two hormones which regulate calcium absorption, were normal in our case. However, the more relevant metabolite of cholecalciferol, 1.25-DHCC, was not determined. Despite the high percentage absorption of calcium demonstrated in our case, it might still be suggested that her condition simply reflected nutritional calcium deficiency. This seems unlikely, as there was no improvement of the disease after sufficient and controlled calcium intake for more than an eight-month period of observation (Table 2: 9th Dec. 1972--6th Sept. 1973): Also, there is no evidence of excessive calcium avidity as urinary calcium excretion increased steadily with increasing calcium intake while she was on a calcium-rich diet. Hyperparathyroidism has been suggeste d as another cause of idiopathic juvenile osteoporosis (Fanconi et al., 1966). In our patient we found the level of immunoreactive P T H and CT, the tubular phosphate reabsorption and the phosphate excretion-index to be within the normal range. Also, we did not find an increase in serum alkaline phosphatase, an index of increased osteoblastic activity in hyperparathyroidism. Jowsey and Johnson (1972) were unable to demonstrate an increase in these parameters in any of their patients. However, by means of microradiography they demonstrated increased bone resorption, indicating increased osteoclastic activity as expected in hyperparathyroidism. In our patient, examination of bone histology gave no evidence of increased osteoclastic activity. However, its absence was not proved by microradiography or morphometry. On the other hand, although the urinary hydroxyproline was normal for the patient's age, when allowance is made for the probable reduction of skeletal mass it can be considered high, suggesting that the bone turnover rate was increased. Our bone scintigraphy findings, indicating increased osteoblastic or osteoclastic activity, could also be consistent with the microradiography findings of Jowsey and Johnson (1974). Another hypothesis as to the cause of the disease is some disturbance related to sex hormones. Noting its onset in childhood and spontaneous recovery with sexual maturation, Albright et al. (1940) postulated that the primary cause of the disease was a dysfunction of hormone homeostasis, resulting in inadequate formation of bone matrix due to decreased osteoblastic activity. A decrease in osteoblastic activity has also been demonstrated by bone biopsies in postmeno-
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D. Lachmann et al.
p a u s a l o s t e o p o r o s i s (Vitalli, 1970). It is r e c o g n i z e d t h a t o e s t r o g e n deficit with a relative p r e p o n d e r a n c e o f steroids results in increased b o n e r e s o r p t i o n ( A l b r i g h t , 1940). T h e o b s e r v a t i o n o f an increase in s e r u m c a l c i u m a n d u r i n a r y excretion o f h y d r o x y p r o l i n e in femals f o l l o w i n g o v a r i e c t o m y c o r r e s p o n d s well with increased b o n e r e s o r p t i o n in p o s t m e n o p a u s a l o s t e o p o r o s i s . These p h e n o m e n a c a n be r e v e r s e d b y o e s t r o g e n t h e r a p y in p o s t m e n o p a u s a ! females ( G a l l a g h e r et al., 1972). W e d i d n o t f i n d an increase in the s e r u m calcium or a c o m p e n s a t o r y increase in s e r u m i m m u n o r e a c t i v e CT, o r a n increased u r i n a r y excretion o f h y d r o x y p r o l i n e in o u r p a t i e n t . A s o e s t r o g e n t h e r a p y in p a t i e n t s with i d i o p a t h i c juvenile o s t e o p o r o s i s ( D e n t a n d F r i e d m a n , 1 9 6 4 ) is ineffective, increased b o n e r e s o r p t i o n due to o e s t r o g e n deficit seems u n l i k e l y to be the p r i m a r y cause o f the disease. T h e incidence o f o s t e o p o r o s i s in C u s h i n g ' s s y n d r o m e due to i m p a i r e d neogenesis o f b o n e a n d cartilage is well k n o w n ( A l b r i g h t , 1940). T h e u r i n a r y excretion o f 17-ketosteroids a n d 17-OH k e t o s t e r o i d s , a n d the r e s p o n s e to D e x a m e t h a s o n e , exclude C u s h i n g ' s s y n d r o m e in o u r patient. H e r o b e s i t y can be e x p l a i n e d b y excessive f o o d intake.
Conclusion O u r s t u d y o f the a b s o r p t i o n o f r a d i o a c t i v e calcium in a subject with this rare d i s o r d e r d i d n o t give evidence for m a l a b s o r p t i o n o f calcium as the cause o f the disease as the a b s o r p t i o n o f 4 7 - C a was high. N u t r i t i o n a l calcium deficiency, h y p e r p a r a t h y r o i d i s m , o r a d y s f u n c t i o n r e l a t e d to sex h o r m o n e s or C u s h i n g ' s s y n d r o m e , which have p r e v i o u s l y been suggested as p r i m a r y causes o f this t r a n s i t o r y disease, seem v e r y u n l i k e l y causes a n d its a e t i o l o g y r e m a i n s obscure.
Appendix Determination of Total-Body 47-CA Retention After a 24 h fast, 3 pCi 47-Ca as the chloride was administered by mouth in 30 ml distilled water with 100 mg CaC12.6 H20 as carrier. The cup was rinsed twice with 30 ml distilled water and the washings were also administered. Fasting was then continued for another 4 h, as recommended by Kinney et al. (1965). The counting rate attributable to the 47-Ca in the body was recorded at various times after oral administration by means of a whole body counter consisting of a 20 cm x 10 cm NaI (TI) crystal inside a steel room. The patient, reclining first prone and second supine, was measured in scanning geometry with the crystal face 35 cm above the bed surface and with a scan length of 235 cm. Counts were summed over the spectral band 0.22--1.39 MeV. Also, an aliquot of the administered dose was similarly measured when positioned in a simple unit-density phantom of the human trunk. The fractional retention was determined from the ratio of the respective counting rates, after a correction for the small differences in counting efficiency between skeletally deposited 47-Ca in the body and 47-Ca in the phantom, as previously established in extensive studies on persons with known burdens of skeletally deposited 47-Ca. These techniques, described in detail elsewhere (Dudley and ben Haim, 1968), give fractional retention of orally administered 47-Ca within an error (standard deviation) of 2--3%. This calibration procedure uses as the basic reference a known activity of 47-Ca deposited in the skeleton of another person of similar size, rather than a known percentage of the dose (i.e. 100%) located in the same subject's intestine immediately after administration, thus making irrelevant questions regarding possible changes in counting efficiency with redistribution of the
Idiopathic Juvenile Osteoporosis
273
nucleide in the body. However, such effects are of no consequence ~r the measurement technique adopted and using this system of calibration a measurement 1.5 hr after administration yielded a value of 100 + 3% for retention. Urinary excretion was measured by counting pooled 24-hour urinary samples made up to standard volume with the 20• 10cm NaI (TI) crystal and normalizing the results against measurements of aliquots of the dose. Acknowledgement. The authors are grateful to Dr. Robert A. Dudley and Mr. F. Gordon Mason of the International Atomic Energy Agency for performing and interpreting the whole-body counting measurements of 47-Ca retention.
References Albright, F., Bloomberg, E., Smith, P. H.: Postmenopausal Osteoporosis. Trans. Ass. amer. Phycus. 55, 298 (1940) Alavizaki, C. C., Ikkos, D. G., Inghelakis, P.: Progressive decrease of true intestinal calcium absorption with age in normal man. J. Nucl. Med. 14, 760 (1973) Arnaud, C. D., Littledike, E. T., Tsao, H. S., Kaplan, E. L.: Radioimmunoassay of Calcitonin: a preliminary report. Mayo Clin. Proc. 43, 496 (1968) Arnaud, C. D., Tsao, H. S., Littledike, E. T.: Radioimmunoassay of human parathyroid hormone in serum. J. Clin. Invest. 50, 21 (1971) Belcher, E. H., Dudley, R. A.: Whole body counting of 47Ca. In: Medical uses of 47Ca: Second Panel Report. Technical Reports Series Nr. 32, 9--12 IAEA, Wien, 1964 Berglund, G., Lindquist, B.: Osteopenia in adolescence. Clin. Orthop. 17, 269 (1960) Bronner, F., Harris, R. S., Maletskos, C. J., Benda, C. E.: Studies in calcium metabolism. The fate of intravenously injected radiocalcium in human beings. J. Clin. Invest. 35, 78 (1956) Catel, W.: Pubert~ttsfischwirbelkrankheit. Kinderhrztl. Praxis 22, 21 (1954) Dent, C. E., Friedman., M.: Idiopathic juvenile osteoporosis. Quart J. Med. N. S. 134, 177--210 (1964) Dudley, R. A., ben Haim, A.: Comparison of techniques for whole body counting of ?-ray emitting nuclides with Na I (TL) detectors. II: Distributed sources in phantoms and humans. Phys. Med. Biol. 13, 194 (1968) Fanconi, A., Illig, R., Poley, R. J., Prader, A., Francillon, M., Labhart, A., Uehlinger, E.: Transitorische Osteoporose im Puberthtsalter. Helv. paediat. Acta 6, 531 (1966) Gallagher, J. C., Young, M. M., Nordin, B. E. C.: Effects of artificial menopause on plasma and urine calcium and phosphate. Clin. Endocrinology 1, 57 (1972) Gallagher, J. C., Nordin, B. E. C.: Treatment with oestrogens of primary hyperparathyroidism in postmenopausal women. Lancet 1972 I, 503 Hammel, H.: Ober die Osteoporose der Wirbelshule unklarer Ursache (Fischwirbelkrankheit). Arch. orthop. Unfall-Chir. 44, 412 (1951) Heany, R. P.: Normal calcium kinetics: application of a newly derived composite reference standard. In: Medical Uses of 47Ca: Second Panel Report. Technical Reports Series No. 32, 57. IAEA, Vienna, 1964 Jowsey, J., Johnson, K. A.: Juvenile osteoporosis: Bone findings in seven patients. J. Pediat. 81, 511 (1972) Kinney, V. R., Tauxe, W. N., Dearing, W. H.: Isotopic tracer studies of intestinal calcium absorption. J. Lab. Clin. Med. 66, 187 (1965) Lapatsanis, P., Kawadias, A., Vretos, K.: Juvenile osteoporosis. Arch. Dis. Childh. 46, 66 (1971) Schippers, J. C.: Over een geval van (spontane) algemeene osteoporose by een klein meisje. Maandschr. Kindergeneesk. 8, 108--117 (1939) Swoboda, W.: Das Skelett des Kindes, S. 86. Stuttgart: Thieme 1956 Vitalli, H. P.: Knochenerkrankungen. Sandoz 1970 WeiBenbacher, G., Washtittl, J., Gemeiner, M.: Klinische Anwendung einer semiquantitativen dtinnschichtc~omatographischen Vitamin D-Bestimmung im Blut. Wien. klin. Wschr. 85, 809 (1973) Received October 4, 1976
Europ. J. Pediat. 125, 265--273 (1977)
Pediatrics 9 by Springer-Verlag 1977
A Case-Report of Idiopathic Juvenile Osteoporosis with Particular Reference to 47-Calcium Absorption D. L a c h m a n n 1, R. Willvonseder 2, R. H6fer 2, and H. E. Bugajer-Gleitmann 1 1Univ.-Kinderklinik, W/~hringer Gfirtel 74--76, A-1097 Vienna, Austria 2II. Med. Univ.-Klinik, Garnisongasse 13, A-1097 Vienna, Austria
Abstract. Calcium metabolism was studied in a 12-year old girl presenting with idiopathic juvenile osteoporosis. Absorption of orally administered 47-Ca was high. Serum calcium and phosphorus, serum immunoreactive P T H and CT and tubular phosphate reabsorption were found to be within normal limits. The data suggest that calcium malabsorption, nutritional calcium deficiency, hyperparathyroidism, a dysfunction related to sex hormones, and Cushing's syndrome cannot be implicated in the aetiology of the osteoporosis in this case who recovered spontaneously with sexual maturation. Key words: Pathophysiology - Malabsorption - Nutritional calcium deficiency - Hyperparathyroidism - Oestrogen deficit. Introduction Idiopathic juvenile osteoporosis is a rare disorder of childhood and adolescence, first reported by Schippers in 1938; Synonyms are osteopenia in adolescence (Berglund and Lindquist, 1960), transitory osteoporosis (Fanconi et al., 1966), "Pubert/~tsfischwirbelkrankheit" (Catel, 1954) and "juvenile Fischwirbelkrankheit" (Hammel, 1951). A m o n g m a n y aetiological factors, malabsorption of dietary calcium has been suggested as a cause of the disease (Dent and Friedman, 1964; Jowsey and Johnson, 1972). This study describes a case of idiopathic juvenile osteoporosis with particular reference to 47-Ca absorption.
Initial Investigations
History M.A. (born 1st April 1960) first presented on 2nd May 1972, because of low back pain of two months' duration. The history prior to admission was non-contributory. She had an excessive dietary intake which had not been restricted before admission to the hospital. No medication, in
266
D. Lachmann et al.
particular cortisone, had been administered. There was no family history of bone disease. Physical examination revealed an obese girl (69.9 kg, 160 cm) with kyphosis of the thoracic spine. She complained of pains in her lumbar spine on bending forward. Tenderness of the lumbar spine was observed on percussion. No secondary sex-characteristics or stigmata of Cushing's disease were present. The blood pressure was l l5/70mmHg.
Laboratory Findings T h e r e l e v a n t l a b o r a t o r y findings are listed in T a b l e 1. Results o f o t h er r o u t i n e b l o o d - c h e m i s t r y analyses (not i n c l u d e d in T a b l e 1) were n o r m a l an d ruled o u t r en al or h e p a t ic disease. T h e responsiveness o f the ad r en al cortex was tested by D e x a m e t h a s o n e . O n three successive days the 8.00 a.m. p l a s m a l l - O H corticosteroid c o n c e n t r a t i o n d e t e r m i n e d by f l u o r o m e t r y was f o u n d to range f r o m 7.4 to 7.7 ng/1. O n the t h i r d day 1 m g D e x a m e t h a s o n e was given by m o u t h at 9 p.m. an d 11 h later the p l a s m a l 1 - O H c o r t i c o s t e r o i d c o n c e n t r a t i o n h ad declined to 4.0 ng/1. U r i n a r y c a l c i u m e x c r e t io n at different levels o f dietary intake, with a n d w i t h o u t c a l c i u m s u p p l e m e n t a t i o n , were measured. T h e results are r e p o r t e d in T a b l e 2. Table 1. Laboratory findings Serum
Normal values
Calcium
mg/100ml
10.4" (10.0-- 10.8)
9.4-- 10.9
Inorganic phosphorus Alkaline phosphatase PTH c CT c
mg/100ml mU/ml ~tl eq/ml pg/ml
5.9a (4.4-- 6.3) 103a (76.6--130) 23 163
4.0-- 6.0 38--138 b 8-- 34 500
Total vitamin D3d Serum albumin
IU/100 ml 300 % of total protein 53.11
150--375 52.2-- 67.0
Urine Calcium Creatinine clearance Tubular phosphate reabsorption Phosphate excretion index Hydroxyprolinee 17-Ketosteroids 17-OH-Ketosteroids " b
Normal values mg/day 133 ml/min x 1;73 m 2 96 % 83 - 0.04 mg/day x m 2 60 mg/day 3.3a mg/day 4.7a
(1.5--4.3) (3.7--5.6)
< 200b 100 >85 - 0.18-- 0 25--80 b 1.8-- 5.0 2.4-- 6.7
Mean value; Normal range for age and weight; Immunoreactive PTH and CT (Arnaud et al., 1968, 1971) was determined by Drs. Glenn W. Sizemore and C. Arnaud, Mayo Clinic and Mayo Graduate School of Medicine; d Total serum vitamin D3 was determined in a semiquantitative manner by thinlayer chromatography (Weigenbacher et al., 1973) by Prof. Dipl.-Ing. DDr. J, Washfittl, Technische Hochschule, Vienna, Austria; e 24-h urine excretion of hydroxyproline was determined by the Hypronosticon| (Organon). All foods containing gelatine were excluded from the diet for the three days before collection of urine
267
Idiopathic Juvenile Osteoporosis Table 2. Urinary calcium excretion at various levets of calcium intake Date
Calories/day
Calcium intake (rag/day)
Urinary calcium excretion (nag/day)~
Hospitalization 18th--26th Sept. 1972 27th Sept.--17th Oct. 1972 18th Oct.--2nd Nov. 1972 3rd Nov.--3rd Dec. 1972d 9th--17th Dec. 1972
800 800 1000 1200--1500 1200--1500
150 150-- 620 600-- 810 780--1140 780--1140 + i000~
133 138
Outpatient 18th Dec. 1972--31st May 1973 low 1st June--23rd Aug. 1 9 7 3 1200--1500
Ca-rich 625--1210
Hospitalization 24th--26th Aug. 1973~ 31st Aug.--6th Sept. 1973
600-- 800 600-- 800 +
1000 1000
170
+ 1500 b
1500 b
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" Two tablets Calcium-"Sandoz"-forte| One tablet contains 2.94 g calcium lactogluconate and 0.30 g calcium carbonate, equivalent to 500 mg calcium; b Three tablets Calcium-"Sandoz"-forte| c Mean values over 5-day period; a First administration of 47-Ca: 14th Nov. 1972; e Second administration of 47-Ca: 27th Aug. 1973
X-Ray of Skeleton T h e t h o r a c i c a n d l u m b a r spine (Fig. 1) were seriously affected by o s t e o p o r o s i s , the v e r t e b r a l b o d i e s h a v i n g a b i c o n c a v e a p p e a r a n c e with c o m p r e s s i o n at L1, L2 a n d L4 a n d the t r a b e c u l a r p a t t e r n being a l m o s t c o m p l e t e l y absent. T h e r e were no signs o f o s t e o p o r o s i s in the long bones. T h e b o n e age was e s t i m a t e d to be ! 3 years.
Biopsy of the Iliac Crest T h e t r a b e c u l a r p a t t e r n o f the iliac crest was h o m o g e n e o u s l y s t a i n e d ~ ( h e m a toxilin-eosin, M a l l o r y ) . T h e r e were n o signs o f increased o s t e o b l a s t i c or osteoclastic activity. Q u a n t i t a t i v e e v a l u a t i o n o f the b i o p s y was n o t p o s s i b l e b e c a u s e o f l a c k o f facilities for m i c r o r a d i o g r a p h y or m o r p h o m e t r y .
Bone Scintigraphy O n e h o u r after i n t r a v e n o u s injection o f 2 m C i 87 m - S r there was a well defined u p t a k e o f the nuclide in the spine a n d in the l o n g b o n e s (Fig. 2). I n a d d i t i o n , there was a c o n s i d e r a b l e u p t a k e in the epiphyses as expected for a p a t i e n t o f this age. 1
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Fig. 1. Lateral X-ray of the spine (May, 1972), showing severe osteoporosis with biconcave appearance of vertebral bodies and compression of L1, L2 and L4. The trabecular pattern is completely absent
Total Body 47-Ca Retention (Method: see Appendix) While the patient was on a diet containing 780--1140 mg calcium per day, the total body retention of 47-Ca from an oral test dose containing 100 mg CaCI2.6 H20 was 89 _+3% at 7 days, and 81 + 3% at 14 days.
47-Ca Absorption By adding the cumulative urinary excretion of 6.5% during days 0--7 to the retention of 89 _+3% measured at day 7, the lower limit of 47-Ca absorption was
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Fig. 2. Gamma-camera bone scintigrams (87m-Sr; Searle, Pho-Gamma III, HP) in the patient M.A. (1) and in a normal 12-year old girl of comparable weight and height (2). Lumbar spine and sacroiliac joints 30 000 cts (a); right humeral diaphysis 15 000 cts (b). Note increased uptake in the patient
calculated to be 95 + 3%. Estimation of true absorption would require the further addition of cumulative endogenous faecal excretion. However, this quantity, possibly in comparable magnitude to that of urinary excretion (Heany, 1964), is obscured by concurrent excretion of unabsorbed 47-Ca.
Course of the Disease and Follow-Up Examinations
Treatment consisted primarily of support with a corset to relieve the spine, and this resulted in freedom from discomfort within a few days. A weight loss of 12 kg was achieved within 3 months by a low caloric diet. X-ray and scintigraphic examinations of the skeleton were repeated after an interval of 10 months, during the last three of which 1.5 g calcium had been given daily. These did not reveal any improvement. Three days after termination of this calcium supplement, 47-
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Fig. 3. Lateral X-ray of the spine in the patient (April, 1975). Absence of radiologic evidence for osteoporosis. Biconcave appearance of vertebral bodies L 1, L2 and L4 still visible. Reappearance of the trabecular pattern in all vertebral bodies
Ca was again administered in a test dose containing 100 mg CaC12 6 H20. The total 47-Ca retention at 7 days was 7 4 + 3% and the cumulative urinary 47-Ca excretion 7.5%, indicating an absorption of at least 8 2 + 3 % of the dose. Radiological evidence of severe osteoporosis of the spine could be demonstrated until February 1974. A slight improvement was evident by October 1974. In April 1975 at the age of 15 the patient presented in good health. The radiograph of the spine (Fig. 3) clearly showed a trabecular pattern in all vertebral bodies. However, the biconcave appearances in the lumbar vertebrae were still visible. She had her menarche in February 1974 at the age of 14.
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Discussion
Malabsorption of calcium has been considered the primary cause of idiopathic juvenile osteoporosis by several authors (Dent and Friedman, 1964; Jowsey and Johnson, 1972; Lapatsanis et al., 1971). As we were unable to use non-radioactive nucleides to estimate intestinal calcium absorption, radiocalcium studies were performed in our patient. The absorption of orally administered 47-Ca in the presence of 100 mg CaC12. 6 HzO exceeded 95% and the total body retention at 7 days was 89%. These values are high in comparison with data reported in the literature for normal subjects, even after allowing for the youth of our patient and the negative linear correlation which Alavizaki et al. (1973) found between the log. of intestinal absorption and age. Thus there is no evidence that calcium malabsorption was the cause of the disease in our patient. Although the calcium absorption seems to be abnormally high, the levels of vitamin D and PTH, two hormones which regulate calcium absorption, were normal in our case. However, the more relevant metabolite of cholecalciferol, 1.25-DHCC, was not determined. Despite the high percentage absorption of calcium demonstrated in our case, it might still be suggested that her condition simply reflected nutritional calcium deficiency. This seems unlikely, as there was no improvement of the disease after sufficient and controlled calcium intake for more than an eight-month period of observation (Table 2: 9th Dec. 1972--6th Sept. 1973): Also, there is no evidence of excessive calcium avidity as urinary calcium excretion increased steadily with increasing calcium intake while she was on a calcium-rich diet. Hyperparathyroidism has been suggeste d as another cause of idiopathic juvenile osteoporosis (Fanconi et al., 1966). In our patient we found the level of immunoreactive P T H and CT, the tubular phosphate reabsorption and the phosphate excretion-index to be within the normal range. Also, we did not find an increase in serum alkaline phosphatase, an index of increased osteoblastic activity in hyperparathyroidism. Jowsey and Johnson (1972) were unable to demonstrate an increase in these parameters in any of their patients. However, by means of microradiography they demonstrated increased bone resorption, indicating increased osteoclastic activity as expected in hyperparathyroidism. In our patient, examination of bone histology gave no evidence of increased osteoclastic activity. However, its absence was not proved by microradiography or morphometry. On the other hand, although the urinary hydroxyproline was normal for the patient's age, when allowance is made for the probable reduction of skeletal mass it can be considered high, suggesting that the bone turnover rate was increased. Our bone scintigraphy findings, indicating increased osteoblastic or osteoclastic activity, could also be consistent with the microradiography findings of Jowsey and Johnson (1974). Another hypothesis as to the cause of the disease is some disturbance related to sex hormones. Noting its onset in childhood and spontaneous recovery with sexual maturation, Albright et al. (1940) postulated that the primary cause of the disease was a dysfunction of hormone homeostasis, resulting in inadequate formation of bone matrix due to decreased osteoblastic activity. A decrease in osteoblastic activity has also been demonstrated by bone biopsies in postmeno-
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p a u s a l o s t e o p o r o s i s (Vitalli, 1970). It is r e c o g n i z e d t h a t o e s t r o g e n deficit with a relative p r e p o n d e r a n c e o f steroids results in increased b o n e r e s o r p t i o n ( A l b r i g h t , 1940). T h e o b s e r v a t i o n o f an increase in s e r u m c a l c i u m a n d u r i n a r y excretion o f h y d r o x y p r o l i n e in femals f o l l o w i n g o v a r i e c t o m y c o r r e s p o n d s well with increased b o n e r e s o r p t i o n in p o s t m e n o p a u s a l o s t e o p o r o s i s . These p h e n o m e n a c a n be r e v e r s e d b y o e s t r o g e n t h e r a p y in p o s t m e n o p a u s a ! females ( G a l l a g h e r et al., 1972). W e d i d n o t f i n d an increase in the s e r u m calcium or a c o m p e n s a t o r y increase in s e r u m i m m u n o r e a c t i v e CT, o r a n increased u r i n a r y excretion o f h y d r o x y p r o l i n e in o u r p a t i e n t . A s o e s t r o g e n t h e r a p y in p a t i e n t s with i d i o p a t h i c juvenile o s t e o p o r o s i s ( D e n t a n d F r i e d m a n , 1 9 6 4 ) is ineffective, increased b o n e r e s o r p t i o n due to o e s t r o g e n deficit seems u n l i k e l y to be the p r i m a r y cause o f the disease. T h e incidence o f o s t e o p o r o s i s in C u s h i n g ' s s y n d r o m e due to i m p a i r e d neogenesis o f b o n e a n d cartilage is well k n o w n ( A l b r i g h t , 1940). T h e u r i n a r y excretion o f 17-ketosteroids a n d 17-OH k e t o s t e r o i d s , a n d the r e s p o n s e to D e x a m e t h a s o n e , exclude C u s h i n g ' s s y n d r o m e in o u r patient. H e r o b e s i t y can be e x p l a i n e d b y excessive f o o d intake.
Conclusion O u r s t u d y o f the a b s o r p t i o n o f r a d i o a c t i v e calcium in a subject with this rare d i s o r d e r d i d n o t give evidence for m a l a b s o r p t i o n o f calcium as the cause o f the disease as the a b s o r p t i o n o f 4 7 - C a was high. N u t r i t i o n a l calcium deficiency, h y p e r p a r a t h y r o i d i s m , o r a d y s f u n c t i o n r e l a t e d to sex h o r m o n e s or C u s h i n g ' s s y n d r o m e , which have p r e v i o u s l y been suggested as p r i m a r y causes o f this t r a n s i t o r y disease, seem v e r y u n l i k e l y causes a n d its a e t i o l o g y r e m a i n s obscure.
Appendix Determination of Total-Body 47-CA Retention After a 24 h fast, 3 pCi 47-Ca as the chloride was administered by mouth in 30 ml distilled water with 100 mg CaC12.6 H20 as carrier. The cup was rinsed twice with 30 ml distilled water and the washings were also administered. Fasting was then continued for another 4 h, as recommended by Kinney et al. (1965). The counting rate attributable to the 47-Ca in the body was recorded at various times after oral administration by means of a whole body counter consisting of a 20 cm x 10 cm NaI (TI) crystal inside a steel room. The patient, reclining first prone and second supine, was measured in scanning geometry with the crystal face 35 cm above the bed surface and with a scan length of 235 cm. Counts were summed over the spectral band 0.22--1.39 MeV. Also, an aliquot of the administered dose was similarly measured when positioned in a simple unit-density phantom of the human trunk. The fractional retention was determined from the ratio of the respective counting rates, after a correction for the small differences in counting efficiency between skeletally deposited 47-Ca in the body and 47-Ca in the phantom, as previously established in extensive studies on persons with known burdens of skeletally deposited 47-Ca. These techniques, described in detail elsewhere (Dudley and ben Haim, 1968), give fractional retention of orally administered 47-Ca within an error (standard deviation) of 2--3%. This calibration procedure uses as the basic reference a known activity of 47-Ca deposited in the skeleton of another person of similar size, rather than a known percentage of the dose (i.e. 100%) located in the same subject's intestine immediately after administration, thus making irrelevant questions regarding possible changes in counting efficiency with redistribution of the
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nucleide in the body. However, such effects are of no consequence ~r the measurement technique adopted and using this system of calibration a measurement 1.5 hr after administration yielded a value of 100 + 3% for retention. Urinary excretion was measured by counting pooled 24-hour urinary samples made up to standard volume with the 20• 10cm NaI (TI) crystal and normalizing the results against measurements of aliquots of the dose. Acknowledgement. The authors are grateful to Dr. Robert A. Dudley and Mr. F. Gordon Mason of the International Atomic Energy Agency for performing and interpreting the whole-body counting measurements of 47-Ca retention.
References Albright, F., Bloomberg, E., Smith, P. H.: Postmenopausal Osteoporosis. Trans. Ass. amer. Phycus. 55, 298 (1940) Alavizaki, C. C., Ikkos, D. G., Inghelakis, P.: Progressive decrease of true intestinal calcium absorption with age in normal man. J. Nucl. Med. 14, 760 (1973) Arnaud, C. D., Littledike, E. T., Tsao, H. S., Kaplan, E. L.: Radioimmunoassay of Calcitonin: a preliminary report. Mayo Clin. Proc. 43, 496 (1968) Arnaud, C. D., Tsao, H. S., Littledike, E. T.: Radioimmunoassay of human parathyroid hormone in serum. J. Clin. Invest. 50, 21 (1971) Belcher, E. H., Dudley, R. A.: Whole body counting of 47Ca. In: Medical uses of 47Ca: Second Panel Report. Technical Reports Series Nr. 32, 9--12 IAEA, Wien, 1964 Berglund, G., Lindquist, B.: Osteopenia in adolescence. Clin. Orthop. 17, 269 (1960) Bronner, F., Harris, R. S., Maletskos, C. J., Benda, C. E.: Studies in calcium metabolism. The fate of intravenously injected radiocalcium in human beings. J. Clin. Invest. 35, 78 (1956) Catel, W.: Pubert~ttsfischwirbelkrankheit. Kinderhrztl. Praxis 22, 21 (1954) Dent, C. E., Friedman., M.: Idiopathic juvenile osteoporosis. Quart J. Med. N. S. 134, 177--210 (1964) Dudley, R. A., ben Haim, A.: Comparison of techniques for whole body counting of ?-ray emitting nuclides with Na I (TL) detectors. II: Distributed sources in phantoms and humans. Phys. Med. Biol. 13, 194 (1968) Fanconi, A., Illig, R., Poley, R. J., Prader, A., Francillon, M., Labhart, A., Uehlinger, E.: Transitorische Osteoporose im Puberthtsalter. Helv. paediat. Acta 6, 531 (1966) Gallagher, J. C., Young, M. M., Nordin, B. E. C.: Effects of artificial menopause on plasma and urine calcium and phosphate. Clin. Endocrinology 1, 57 (1972) Gallagher, J. C., Nordin, B. E. C.: Treatment with oestrogens of primary hyperparathyroidism in postmenopausal women. Lancet 1972 I, 503 Hammel, H.: Ober die Osteoporose der Wirbelshule unklarer Ursache (Fischwirbelkrankheit). Arch. orthop. Unfall-Chir. 44, 412 (1951) Heany, R. P.: Normal calcium kinetics: application of a newly derived composite reference standard. In: Medical Uses of 47Ca: Second Panel Report. Technical Reports Series No. 32, 57. IAEA, Vienna, 1964 Jowsey, J., Johnson, K. A.: Juvenile osteoporosis: Bone findings in seven patients. J. Pediat. 81, 511 (1972) Kinney, V. R., Tauxe, W. N., Dearing, W. H.: Isotopic tracer studies of intestinal calcium absorption. J. Lab. Clin. Med. 66, 187 (1965) Lapatsanis, P., Kawadias, A., Vretos, K.: Juvenile osteoporosis. Arch. Dis. Childh. 46, 66 (1971) Schippers, J. C.: Over een geval van (spontane) algemeene osteoporose by een klein meisje. Maandschr. Kindergeneesk. 8, 108--117 (1939) Swoboda, W.: Das Skelett des Kindes, S. 86. Stuttgart: Thieme 1956 Vitalli, H. P.: Knochenerkrankungen. Sandoz 1970 WeiBenbacher, G., Washtittl, J., Gemeiner, M.: Klinische Anwendung einer semiquantitativen dtinnschichtc~omatographischen Vitamin D-Bestimmung im Blut. Wien. klin. Wschr. 85, 809 (1973) Received October 4, 1976
