Tadashi Nishioka

Nasal administration of salmon calcitonin for prevention of glucocorticoid-induced osteoporosis in children with nephrosis

To determine the effect of intranasal administration of salmon calcitonin on glucocorticoid-induced osteoporosis in children with nephrosis, we gave 100 U of calcitonin intranasally on alternate days with 1 alpha-hydroxyvitamin D3 to five children, 8 to 12 years of age, with frequently relapsing nephrosis. Four patients with osteoporosis, 10 to 14 years of age, were treated only with 1 alpha-hydroxyvitamin D3 and served as control subjects. Both groups were treated with an almost equal amount of glucocorticoids previously and during this study period. Bone mineral content of the spine was measured by a quantitative computed tomographic technique. The bone mineral content was preserved in both cortical and spongeous areas of the vertebrae during the 16-month period in the calcitonin-treated group but was decreased significantly in the control group. Urinary hydroxyproline and calcium excretion decreased significantly in the calcitonin-treated group. The serum calcium and phosphorus concentrations and the parathyroid function did not change significantly in either group. We conclude that calcitonin suppressed bone resorption and might be useful for the long-term treatment of osteoporosis, in combination with 1 alpha-hydroxyvitamin D3, in children with nephrosis requiring long-term glucocorticoid therapy.

Evidence that calcitonin plays a role in the postnatal increase of serum 1α, 25-dihydroxyvitamin D

To investigate the changes in the 1α, 25-dihydroxyvitamin D [1,25(OH)2D] level and the role of parathyroid hormone (PTH) and calcitonin (CT) during the early neonatal periods, we measure 1,25(OH)2D, 25-hydroxyvitamin D [25(OH)D], PTH specific for mid-regions (mPTH) and urinary cAMP (UcAMP) to evaluate the renal tubular responsiveness to intrinsic PTH and CT, as well as serum Ca and P in 28 mothers at term delivery and in their babies at birth and 5 days of age. Cord serum 1,25(OH)2D levels were low (28.8 ±9.2 pg/ml, means ±SD), while maternal serum 1,25(OH)2D levels were high (62.2±22.6 pg/ml). The low 1,25(OH)2D value increased 2.5 times (62.2±22.6 pg/ml) in 5-day-old infants, reaching a high normal adult value, concomitant with the increases in mPTH and urinary cAMP/creatinine ratio (UcAMP/Cr). The correlations between 1,25(OH)2D and UcAMP/Cr, and 1,25(OH)2D and mPTH in all paired samples of babies at birth and at 5 days of age were r=0.456, n=50, P<0.01 and r=0.341, n=50, P<0.05, respectively. These data suggest that the parathyroid activation after birth is a major factor in the rapid 1,25(OH)2D increment at that time. CT levels were high in all paired samples and in 5-day-old infants. CT vs 1,25(OH)2D showed a significant correlation (r=0.473, P<0.05, n=24) as well as the relative increase of 1,25(OH)2D (Δpg/ml) after birth vs CT at age 5 days (r=0.537, P<0.01, n=24). In the infants with low CT levels at 5 days the 1,25(OH)2D concentration failed to increase. These results suggest CT, in addition to PTH, may be important in the postnatal increase 1,25(OH)2 in term infants, though further direct evidence of the role of CT is necessary.

Infantile hypercalcemia with subcutaneous fat necrosis. Report of a case with studies on the pathogenesis of hypercalcemia.

ABSTRACT. A case of hypercalcemia in neonatal subcutaneous fat necrosis, which was successfully treated with a low Ca and vitamin D‐free formula, is described. Low l,25(OH)2D and severe calciuria, which were considered to result from hypercalcemia itself as well as parathyroid suppression, were noted during the hypercalcemic phase. The oral Ca load test was repeatedly normal, suggesting that intestinal hyperabsorprion of Ca was not a cause of the hypercalcemia. Later recurrence of calciuria without hypercalcemia was noted concomitant with softening of indurated calcified necrotic tissue. In this patient, cerebral infarction on the left side was detected by CT scanning.

Serum osteocalcin in normal children and children with glucocorticoid-induced osteoporosis

We have measured serum osteocalcin (OC) by radioimmunoassay in normal children, adults and patients with glucocorticoid-induced osteoporosis in childhood. And we have compared its concentration to the severity of osteoporosis evaluated by Jikei Medical College Classification.As the age increased up to 14 years, serum OC increased. However, no significant correlation with age was noted (r=0.244). In the controls serum OC was higher in children (11.00±2.10 ng/ml) than in adults (5.35±1.47 ng/ml) (p<0.005).Serum OC showed a cosiderable variation among patients with glucocorticoid-induced osteoporosis. Serum OC was significantly decreased in the patients with glucocorticoid-induced osteoporosis (9.09±3.32 ng/ml, vs. 11.00±2.10 ng/ml in age matched controls, p<0.02). Our data suggest that measurement of serum OC at regular intervals in patients requiring glucocorticoid therapy, might be useful to assess the early phase of osteoporosis and the therapeutic effects of drugs administered to osteoporosis.

Pseudohypoaldosteronism: decreased aldosterone levels with age without significant change in urinary sodium excretion.

To clarify age‐related changes in the plasma renin activity (PRA)‐aldosterone (ALDO) system in relation to urinary sodium (Na) excretion in pseudohypoal‐dosteronism type I (PHA), we followed a patient with PHA serially by measuring the hormonal balance and urinary electrolyte excretion for 5 years. The patient was diagnosed as PHA mainly on the basis of extremely high PRA (170 ng/ml/h) and ALDO (1670 ng/dl) despite massive urinary Na excretion, a normal ALDO/PRA ratio (mean value = 11), and the ineffectiveness of 9a‐fluorocortisol (Florinef) to reduce urinary Na excretion and PRA‐ALDO. The pattern of reduction in PRA‐ALDO with age in this patient was almost identical with that of normal infants and children and was most remarkable during the first 18 months of life. During this period, there were statistically significant correlations between age and each of the following values: PRA (r=−0.753, n= 9, P<0.05), ALDO (r=−0.736, n= 11, P<0.01) and urinary ALDO excretion (r=−0.840, n= 9, P<0.01). But the reduction of PRA‐ALDO in this patient was not the result of increased urinary Na excretion with age. Although PRA and ALDO values in this patient did decrease with age, they were still high compared with age‐matched controls, suggesting a marginal state of Na balance. Thus, we conclude that PRA‐ALDO levels in PHA decrease with age in the same pattern as in normal infants and children without a significant change in urinary Na excretion, possibly through increased renal conservation of Na, the mechanism of which should be clarified in a future study.

A Discordant Movement in Urine Calcium Excretion in Relation to Serum Calcium and Parathyroid Function Occurring Immediately after Birth

ABSTRACT. We studied the relationship between serum calcium and urinary calcium excretion in association with the parathyroid function in 28 neonates at birth and at five days of age. At birth, the urine calcium was low in spite of high cord serum calcium and a low parathyroid hormone level. On the fifth day of birth, urinary calcium excretion increased despite the reduction in serum calcium and an increase in the parathyroid hormone. These results suggest that the large increase in renal blood flow and the consequent increase in calcium load on the immature renal tubule occurring after birth may be the main cause for the change in this serum calcium‐urinary calcium relationship. This finding can in part explain the temporary hypocalcemia during this period.

Two Siblings with Complete Carbamyl Phosphate Synthetase I Deficiency

A female infant, who showed hyperammonemia in the neonatal period, died on 43rd postnatal day. Her female sibling also died on 42nd day after birth with an identical clinical picture and hyperammonemia. Urinary organic acids were negative in both cases. Their blood amino acids showed no specific pattern, and urinary orotic acid excretion was normal. The first two urea cycle enzymes and N‐acetyl L‐glutamate synthetase of the liver tissues of these two infants obtained at autopsy were assayed. They revealed a selective deficiency of carbamyl phosphate synthetase I.

Demonstration of blood calcium-related parathyroid function in the diurnal variation of blood and urine calcium and phosphorus in healthy individuals

The circadian changes in blood and urine minerals and parathyroid function assessed by nephrogenous cyclic AMP (NcAMP) and a highly sensitive midregion specific parathyroid hormone (PTH) radioimmunoassay (RIA) were investigated for 26 hours in ten healthy 23 to 53-year-old males (group 1) with normal food intakes. Also, we studied another six male and four female adults between 600 and 1200 h as fasting controls (group 2). The blood calcium (Ca) levels were the highest at 630 h in both groups and decreased thereafter, and the diurnal variation of NcAMP reflected that of serum Ca, showing a low value in the morning. There were significant negative correlations between total Ca and NcAMP in both groups 1 and 2 (r=−0.323, n=130, p<0.01; r=−0.525, n=60, p<0.01), suggesting that the blood Ca level is the major determinant of parathyroid function and that NcAMP is a good indicator of blood Ca related PTH secretion in healthy individuals. This last relationship was not seen between Ca and midregion PTH levels presumably owing to slow clearance of PTH fragments from the circulation. However, midregion PTH perhaps because of its long half life, not NcAMP, shows a significant inverse relation to urinary Ca excretion (mg/dIGF) in the diurnal variation in healthy individuals (r=−0.560, n=130, p<0.01). The circadian pattern (s) of serum phosphate (P) consisted of a minium level at 900–1100 h followed by two peaks, at 1400–1600 h and 2200–2400 h. Thus, this study conducted in healthy individuals under physiologic condition clearly demonstrated that the NcAMP level reflects blood Ca related PTH secretion and that urinary Ca excretion seems to be determined by the sum of PTH secretion.