Sara B. Arnaud

Intestinal Calcium Absorption and Serum Vitamin D Metabolites in Normal Subjects and Osteoporotic Patients: EFFECT OF AGE AND DIETARY CALCIUM

Intestinal calcium absorption assessed by a double-isotope method, decreased significantly with aging in 94 normal subjects (r = -0.22, P < 0.025). In 52 untreated patients with postmenopausal osteoporosis, calcium absorption was significantly lower than normal when either age or habitual calcium intake was used as a covariable (P < 0.001). Serum 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) were measured in 44 normal subjects and 27 osteoporotic patients. For all normals, calcium absorption and serum 1,25(OH)(2)D were positively correlated (r = 0.50, P < 0.001). In nonelderly normal subjects (ages 30-65 yr), dietary calcium intake correlated inversely with both calcium absorption (r = -0.39, P < 0.01) and with serum 1,25(OH)(2)D (r = -0.50, P < 0.01). Both osteoporotic patients and elderly normal subjects (ages 65-90 yr) differed from nonelderly normals in that these correlations were not present. In addition although serum 25-OH-D was normal, serum 1,25(OH)(2)D was significantly decreased in both osteoporotic patients and elderly normals (P < 0.001). In osteoporotic patients, calcium absorption increased significantly (P < 0.001) after 7 d administration of a small dose (0.4 mug/d) of synthetic 1,25(OH)(2)D(3). In osteoporotics mean serum immunoreactive parathyroid hormone was either normal (COOH-terminal assay) or low (NH(2)-terminal assay) relative to age-matched controls, and mean serum phosphate was increased. The data suggest that inadequate metabolism of 25-OH-D to 1,25(OH)(2)D contributes significantly to decreased calcium absorption and adaptation in both osteoporotics and elderly normal subjects. In patients with osteoporosis this abnormality could result from a decrease in factors that normally stimulate 1,25(OH)(2)D production, such as the decreased parathyroid hormone secretion and increased serum phosphate demonstrated in this group. In elderly subjects a primary abnormality in metabolism of 25-OH-D to 1,25(OH)(2)D, analagous to that seen in aging rats, cannot be excluded.

Intestinal Calcium Absorption in Exogenous Hypercortisonism: ROLE OF 25-HYDROXYVITAMIN D AND CORTICOSTEROID DOSE

Pharmacologic doses of corticosteroids impair intestinal calcium absorption and contribute to negative calcium balance. However, the relationship between the impaired calcium absorption and a possible defect in the conversion of vitamin D to its physiologically active form, 1,25-dihydroxyvitamin D, is unknown. We compared fractional calcium absorption (double-isotope method, 100-mg carrier) and serum 25-hydroxyvitamin D (25-OH-D) (Haddad method) in 27 patients receiving pharmacologic doses of prednisone with 27 age-, sex-, and season-matched normal subjects. In patients receiving high daily doses of prednisone (15-100 mg/day), calcium absorption (P < 0.02) and serum 25-OH-D (P < 0.001) were decreased. However, in patients receiving low doses (8-10 mg/day) or high doses (30-100 mg) of prednisone on an alternate-day schedule, both of these parameters were normal. Calcium absorption in the patients treated with daily prednisone correlated inversely with the dose of corticosteroids (r = -0.52, P < 0.025) and, in all steroid-treated patients, correlated directly with serum 25-OH-D (r = 0.58, P < 0.01). In four patients who received high-dose corticosteroid therapy for an average of 4 wk, serum 25-OH-D decreased by 35.5% from pretreatment values. Administration of a physiologic or near-physiologic dose of synthetic 1,25-dihydroxyvitamin D(3) (0.4 mug daily for 7 days) to patients receiving high-dose corticosteroids led to an increase in calcium absorption in all patients. These results suggest that calcium malabsorption in the corticosteroid-treated patients is due to a dose-related abnormality of vitamin D metabolism and not to a direct effect of corticosteroids on depressing transmucosal intestinal absorption of calcium.

25-Hydroxyvitamin D3: Evidence of an Enterohepatic Circulation in Man

Summary Within 24 hr after intravenous administration of isotopic 25-hydroxyvitamin D3 to three normal adults for kinetic studies, one-third of the radioactivity was secreted into the lumen of the duodenum, probably with the bile. The subsequent intestinal reabsorption of over 85% of secreted radioactivity suggests that this major metabolite of vitamin D has a hitherto unrecognized enterohepatic circulation. Our observation of a dynamic hepatic secretion and intestinal reabsorption of radioactivity administered as 3H-labeled 25-hydroxyvitamin D3 to vitamin D-replete man is indicative of an enterohepatic circulation that may be of physiologic importance. It is conceivable that interruption in the recycling of 25-OH-D3 may be an important mechanism of acquired deficiency of vitamin D in gastrointestinal disease. This investigation was supported in part by Research Grants AM-69-2168, RR 585, and AM-6908 from the National Institutes of Health, Public Health Service. We gratefully acknowledge the technical assistance of Jane Bailey, Pamela A. Bonnes, Diane J. Brinck, Mary C. Matthusen, Garry V. Mussmann, and the nursing staffs of the Russell M. Wilder Clinical Study Unit and the Gastroenterology Unit.

Serum Parathyroid Hormone and Blood Minerals: Interrelationships in Normal Children

Extract: Simultaneous measurements of immunoreactive parathyroid hormone (iPTH), calcium, magnesium, phosphorus, and alkaline phosphatase in serum were performed in 120 normal subjects who ranged from 6 months to 20 years of age. When plotted as a function of age, these extracellular indices of calcium homeostasis showed changes throughout the growth period and differences in their interrelationships in early childhood, middle childhood, and adolescence. Mean serum concentration of minerals was highest during early childhood and decreased parallel to decreases in iPTH and alkaline phosphatase. Between the ages of 6 and 12 years, calcium, magnesium, and phosphorus tended to plateau, iPTH was lower, and alkaline phosphatase increased. During adolescence, calcium, phosphorus, and alkaline phosphatase decreased to adult values, magnesium showed no change, and iPTH increased to adult values.Plasma ionized calcium, which was higher in middle childhood (mean, 4.59 mg/100 ml) than at ages 12 to 20 years (mean, 4.33 mg/100 ml), showed the expected negative correlation with iPTH (P < 0.005). Total serum calcium did not correlate with iPTH; however, the pattern of decrease of serum calcium with age was similar to growth velocity curves, especially in girls, in whom mean serum calcium was higher (9.93 mg/100 ml) between 8 and 16 years than in boys (9.75 mg/100 ml).Speculation: Parathyroid hormone is important in maintaining the concentration of plasma ionized calcium in normal children, but the regulation of total serum calcium is different from that in adults. The total serum calcium or factors regulating it may have a direct or indirect influence on the growth process.

The frequency of bone abnormality in patients on anticonvulsant therapy.

Biochemical and bone morphometric measurements were evaluated in 12 patients who were on long-term anticonvulsant therapy with barbiturates. Half of the patients had no symptomatic bone disease, and half presented with bone disease and pain. Serum biochemical values were normal except for a few patients who had an elevated serum level of parathyroid hormone; the concentration of serum 25-hydroxy vitamin D was decreased in the majority of patients in whom it was measured. Bone absorptiometric values were normal but proved to be misleading: the Singh Index and videodensitometric measurements indicated that bone mass was below normal in all patients. Bone morphometric data indicated that bone resorption was 3 times greater than normal, and there was no evidence of osteomalacia. Vitamin D and possibly calcium have been suggested as potentially useful agents in the treatment of the bone disease associated with chronic anticonvulsant therapy.

388 PRIMARY HYPERPARATHYROIDISM (HPT) IN INFANCY

Hypercalcemia (↑Ca) due to HPT in infancy is rare and its laboratory diagnosis difficult. We report a case with unusual features in which the assay of parathyroid hormone (iPTH) aided in the diagnosis and in the evaluation of the novel therapeutic technique of autotransplantation. An 18 mo old female was noted to have ↑Ca (16.7 mg/d1) and hypophosphatemia (2.5 mg/dl) during evaluation for retardation. She was the first child of 5th cousins, both of whom had asymptomatic ↑Ca (11.4 and 10.4 mg/dl) and ‘normal’ levels of iPTH (31 and 35 μ1 eq/m1). The infants head circumference was small (44 cm) and skeletal films showed little evidence of increased bone resorption in spite of high serum iPTH (125 u1 eq/m1, normal, < 56). Treatment with dietary calcium restriction, saline, furosemide, phosphate, and calcitonin decreased serum calcium to 12 mg/d1; steroids did not influence the course. At surgery, 3 hyperplastic and one normal sized parathyroid glands were removed (140 mg, total wt). Portions of one gland were implanted into the brachial muscle. Normocalcemia was maintained by decreasing doses of Dihydrotachysterol postoperatiVely. This is the first known instance of HPT due to parathyroid hyperplasia in infancy in which both parents were affected with milder forms of the disease and, we believe, the youngest in whom the disease was treated by autotransplantation.

Recent Developments in Vitamin D Research

Correspondence to S. B. Arnaud, M.D., c/o Section of Publications, Mayo Clinic, 200 First Street SW, Rochester, Minn. 55901. admissions between 1956 and 1960;~ this prevalence probably reflects the use of breast feeding without supplementary vitamins, plus the use of unfortified milk. The lack of appropriate public health measures in developing countries and the peculiarities of local diets or local customs (such as shielding infants from sunlight) account for the continued prevalence of &dquo;nutritional rickets 113.4 in many countries. The importance of health education and of periodic examinations of high-risk populations is evident from the experience of physicians in Glasgow, who recognized a rise in the number of cases of rickets as recently