Appendicular bone mass in children with a high prevalence of low dietary calcium intakes.

We have previously documented evidence of dietary calcium deficiency in black children living in a rural community in the eastern part of South Africa. The present study determined the bone mass of the distal one-third of the radius in a random sample of children living in the same community and compared their bone mass measurements with those of black children living in a similar rural community but without evidence of dietary calcium deficiency. Further, factors (weight, height, serum corrected total calcium, phosphorus, and alkaline phosphatase [ALP]) that might influence appendicular bone mass were assessed and correlated with the bone mass measurements. A random sample of 306 boys and 345 girls between the ages of 1 and 20 years were included in the study. Hypocalcemia was found in 6.5% of the boys and 5% of the girls, while elevated ALP values were recorded in 20 and 26% of the boys and girls, respectively. After adjusting for differences in age, weight, and height, bone mineral density (BMD) and bone mineral apparent density (BMAD) were significantly lower and bone width (BW) greater in study than control children. In a stepwise regression analysis, weight and/or height accounted for the majority of the observed variance in BMC, BW, and BMD; however, a significant effect of serum calcium (positively) and ALP (negatively) on BMC and BMD was also found. In boys, but not girls, serum ALP also had a positive effect on BW.BMAD was negatively correlated to ALP and positively correlated to serum calcium in both boys and girls. Those children with hypocalcemia or elevated ALP levels had significantly lower BMC, BMD, and BMAD and a trend toward greater BW than children with normal biochemistry. The findings suggest that low dietary calcium intake may have a detrimental effect on appendicular bone density in rural black children. Whether or not these effects are disadvantageous in the long-term is not known.

Metabolic bone disease in black teenagers with genu valgum or varum without radiologic rickets: a bone histomorphometric study.

Calcium deficiency in black (African) children can cause rickets and osteomalacia with severe limb deformities. It is not known whether black teenagers with genu valgum or varum but without radiologic rickets suffer from a related disorder. To examine this question we studied 26 such patients by iliac crest bone biopsy and serum and urine biochemistry: 12 patients (46%) had osteopenia with normal or low bone turnover, 5 (19%) mildly increased bone turnover, 4 (15%) histologic hyperparathyroidism, 2 (8%) preosteomalacia, and 3 (12%) osteomalacia (with features of hyperparathyroidism). Radiographs did not reflect the severity of the bone disease. Serum calcium levels correlated inversely with eroded mineralized surface (p < 0.001), osteoid surface (p < 0.01), osteoid thickness (p < 0.001), mineralization lag time (p < 0.001), and 1,25-(OH)2 vitamin D (p < 0.005), and 1,25-(OH)2 vitamin D correlated positively with osteoid surface (p < 0.05), osteoid thickness (p < 0.05), osteoid volume (p < 0.01), eroded surface (p < 0.05), and eroded mineralized surface (p < 0.0005). Tubular reabsorption of phosphate and 25-OH vitamin D levels were normal, and 1,25-(OH)2 vitamin D levels were normal to high. This suggests that calcium deficiency may have caused the increase in bone turnover and the mineralization defects. The most severe osteomalacia was found in males aged 16-19 years. We cannot explain the cause of the osteopenia. We conclude that all patients had bone disease.

Iliac bone biopsies at the time of periarticular stress fractures during fluoride therapy: comparison with pretreatment biopsies.

We attempted to establish whether systemic changes in trabecular bone explain the development of stress fractures in the lower limbs during fluoride therapy for osteoporosis. To this end we compared transiliac bone biopsies obtained before treatment with those taken around the time of stress fractures after 14.3 +/- 10.9 (SD) months of therapy in six patients (group A). Biopsies from a comparable group of six patients without stress fractures at the time of the second biopsy (after 11.9 +/- 2.7 months of treatment) served for comparison (group B). The biopsies were processed undecalcified and examined by routine histomorphometry. The second biopsies did not show any significant improvement in mean bone volume or trabecular architecture. Although the second biopsies in group A had increased erosion surfaces (p less than 0.05) and greater osteoid volume (p less than 0.05), group B biopsies showed no difference in erosion surfaces but an increase in all osteoid parameters: osteoid volume (p less than 0.05), osteoid surface (p less than 0.05), and osteoid seam thickness (p less than 0.01). We reached the following conclusions: (1) the combination of increased erosion and replacement of removed bone by as yet unmineralized osteoid in the stress fracture group must have weakened bone and allowed the development of stress fractures. (2) Stress fracture patients may have mounted a less vigorous osteoblast response to fluoride than non-stress fracture patients. Under these conditions microfractures are likely to heal poorly and propagate to develop into full stress fractures. (3) Renal failure is a contraindication to fluoride therapy.

Bone disease in African children with slipped capital femoral epiphysis: histomorphometry of iliac crest biopsies.

African teenagers with slipped capital femoral epiphysis (SCFE) not infrequently also have genu valgum (knock-knee). Because we had previously demonstrated metabolic bone disease attributable to dietary calcium deficiency in black teenagers with genu valgum, we examined 29 black teenagers (15 male, 14 female) with SCFE for metabolic bone disease. Each patient had an iliac crest bone biopsy taken (after double tetracycline labeling) for routine histomorphometry, and blood and urine samples for bone biochemistry. Spinal bone mineral density was measured in 13 patients. Compared to reported data, we found our patients to be sexually more immature, older, at least as obese, and to have more severe and more frequently bilateral hip disease. Eighty percent of the children took dairy products only once or twice a week or less frequently, and 37.9% had genu valgum. Compared with race- and age-matched South Africans, bone biopsies in our patients showed lower bone volume (BV/TV, p = 0.0003), wall thickness (p = 0.0002), and trabecular thickness (Tb.Th, p = 0.0002), and a tendency to greater trabecular spacing (Tb.Sp, p = 0.053). Lower osteoid volume (OV/BV, p = 0.0001), osteoid surface (OS/BS, p = 0.0001), osteoid thickness (O.Th, p = 0.0002), double labeled surface (dLS/BS, p = 0.029), and bone formation rate (BFR/BS, p = 0.037) suggested poorer bone forming capacity in our patients. No evidence of hyperparathyroid bone disease or osteomalacia was found. BV/TV was below the reference range (14.2%) in 65.5% of cases; these patients had lower values for Tb.Th (p = 0.037) and Tb.N (p = 0.0003), greater Tb.Sp (p = 0.0002), a tendency to lower adjusted apposition rate (Aj.AR, p = 0.057), and had had less frequent intake of dairy products than those with normal BV/TV (p = 0.024). Furthermore, months since menarche correlated with histomorphometric variables BV/TV (r = 0.667, p = 0.009), Tb.Th (r = 0.745, p = 0.002), Tb.Sp (r = -0.549, p = 0.042), O.Th (r = 0.784, p = 0.0009), and Aj.AR (r = 0.549, p = 0.042). The correlation between Tb.Th and spinal bone mineral content (r = 0.656, p = 0.015) suggests that the reduced trabecular thickness reflected a generalized bone condition. A greater than normal proportion of patients had spinal bone mineral density values below -1 standard deviation (SD) of the mean (osteopenia) (p = 0.001). Patients tested for parathyroid hormone and 25-hydroxyvitamin D levels were found to have normal values. Parathyroid hormone correlated with Aj.AR (r = 0.661, p = 0.038) and serum phosphorus (r = -0.764, p = 0.010). We conclude that sexual immaturity and possibly past dietary calcium deficiency contributed to osteopenia, and that this, together with obesity, led to the development of more severe and more frequently bilateral SCFE in our patients than in reported series of black and white children.

Effect of oral cholecalciferol supplementation at physiological and supraphysiological doses in naturally vitamin D3-deficient subterranean damara mole rats (Cryptomys damarensis).

The damara mole rat, Cryptomys damarensis, is a strictly subterranean dwelling herbivorous rodent that in its natural habitat has no access to any obvious source of cholecalciferol (D3). We examined the effects of D3 supplementation, at physiological and supraphysiological doses, on calcium metabolism, plasma concentrations of calcium and alkaline phosphatase (ALP) and D3 metabolites. Animals not receiving a D3 supplement maintained normal plasma calcium concentrations. In addition, they exhibited a high apparent fractional mineral absorption efficiency (91%) and maintained a positive mineral flux. The serum concentration of 25-(OH)D3 was undetectable (less than 5 nmol/l) and that of 1,25-(OH)2D3 was 41 +/- 10 pmol/l. Supplementation at a physiological dose of D3 resulted in increased plasma concentrations of D3 metabolites, food intake, apparent fractional absorption efficiency and apparent fractional retention efficiency. Despite the 1.8-fold increase in food intake, body mass remained constant suggesting that the enhanced energy intake was dissipated in catabolic processes. Plasma calcium and ALP concentrations were not significantly altered with physiological doses of D3. The group given supraphysiological doses of D3 exhibited hypercalcaemia, increased creatinine concentrations and markedly increased ALP levels. These data indicate that a pathological response to D3 intoxication occurred and that hepatic and renal excretory functions were impaired. It appears, therefore, that these animals function optimally at the low concentrations of D3 metabolites found naturally. Supplementation at both physiological and supraphysiological doses of D3 may disadvantage the damara mole rat.

Isoniazid pharmacokinetics in patients in chronic renal failure.

INH pharmcokinetics was studied in 2 groups of patients in chronic renal failure. In the group on conservative treatment, INH half life was prolonged, but was not related to the degree on renal impairement. In the hemodialysis group 73% of the INH given was removed by dialysis within 5 hours. If INH is to be used in the presence of renal failure, individual half life estimations should be performed in order to determine dosage frequency. In patients on hemodialysis, therapy should be given post dialysis. Alternatively, drugs not dependent on renal failure, e.g. rifampicin, may be preferable.

The micro-erythrocyte sedimentation rate in black neonates and children. Part II. A comparative study of the micro-erythrocyte sedimentation rate, C-reactive protein test and total white cell count.

The value of determination of the micro-erythrocyte sedimentation rate (ESR), testing for the presence of serum C-reactive protein (CRP) and the total white cell count (WCC) has been assessed in neonates and children, both healthy and in disease states. The results show that collective and maximum use of all three investigations aids diagnosis because these tests are simple, quick, cheap and easy to perform. Furthermore, the study has demonstrated that compared with a high ESR and WCC, the presence of CRP was the best single indicator of infection. The CRP test has the greatest predictive value and sensitivity in that it indicates the intensity of an infection as well as the patient's response to therapy.

The micro-erythrocyte sedimentation rate in black neonates and children. Part I. Its value in suspected neonatal infection.

The normal ranges for the micro-erythrocyte sedimentation rate (ESR) in neonates have been established. The use of the micro-ESR technique as an aid to the diagnosis of neonatal infection has been assessed. This test is both simple and quick, needs a heel prick only and appears to have considerable value in predicting the presence of infection in neonates.

Comparison of two commercial ionised calcium analysers, and values in South African blacks.

Although research on the ionised fraction of serum calcium (Ca++) started some 50 years ago, normal values and, above all, the methods of determination are still controversial. The use of calcium ion selective electrodes greatly enhanced and improved the measurement of Ca++. A study was carried out to: evaluate two Ca++ analysers (Radiometer ICA1 (Copenhagen, Denmark) and Orion SS-20 (Orion Biomedical, Cambridge, Mass., USA) ); correlate serum ionised calcium, total calcium and albumin levels in various normal and pathological states; and determine the values of Ca++ in healthy black subjects. The two analysers gave results showing very good correlation over a wide range (r = 0.986). Results for ionised Ca++ v. total calcium (TCa) showed a significant linear correlation (r = 0.956). Correcting TCa for variations in serum albumin concentrations did not improve this correlation (r = 0.9114). Reference normal values for Ca++ were established for healthy blacks, cord blood values being highest (mean 1.356 +/- 0.139 mmol/l) and adult values lowest (mean 1.159 +/- 0.04 mmol/l). Although the results obtained on the analysers were similar, the Radiometer ICA1 requires less blood and measures pH simultaneously. Correcting TCa for the variation in albumin within the normal range seemed to be of little value in assessing Ca++. The determination of TCa in most clinical situations is a good reflection of Ca++.

Serum calcium and phosphate disturbances during rehydration in acute dehydrating gastroenteritis.

Alterations in serum ionized and total calcium, magnesium, and phosphate concentrations, during recovery from acute dehydrating gastroenteritis, were studied. Fifteen children with acute dehydrating gastroenteritis had serum concentrations of ionized and total calcium, magnesium, phosphate, sodium, potassium, chloride, urea, creatinine, and albumin, as well as acid-base status, evaluated during rehydration and up to 72-h postadmission. The total serum calcium corrected for albumin did not change significantly during rehydration and remained within the normal range. Although serum ionized calcium fell significantly at 24 and 72 h, its concentration was not sufficiently decreased to cause symptomatic hypocalcemia. Serum ionized calcium correlated significantly with pH (r = -0.57), bicarbonate (r = -0.63), and albumin (r = +0.65), but not with total serum calcium, magnesium, and phosphate. Serum magnesium remained within the normal range during the study period. Serum phosphate was increased on admission (2.64 +/- 0.77 mmol/L), decreased by 12 h (to 0.84 +/- 0.32 mmol/L), and then followed by a gradual increase. This study suggests that changes in serum ionized calcium in dehydrating gastroenteritis are not of clinical significance. However, changes in serum phosphate concentration need further evaluation.

Serum osteocalcin has limited usefulness as a diagnostic marker for rickets.

UNLABELLED: Serum alkaline phosphatase (AP), the bone fraction of which is secreted by osteoblasts, is elevated in rickets. Both normal and elevated levels of serum osteocalcin (OC), a bone-specific marker secreted by osteoblasts, have been reported in rickets. Expression of the OC gene is enhanced by 1,25-dihydroxyvitamin D (1,25(OH)2D) in experimental models. This study assessed serum OC levels in 14 controls and 41 patients with active rickets divided into a phosphopenic (n = 20) and a calciopenic (n = 21) group. Phosphopenic subjects were older (9.5 versus 5.7 years, P = 0.03) with higher median serum calcium level (2.35 versus 2.16 mmol/l, P = 0.0002) and serum 25-hydroxyvitamin D level (15.4 versus 10.4 ng/l, P = 0.003); and lower serum phosphate (0.80 versus 1.51 mmol/l, P = 0.0001), serum 1,25(OH)2D (43.0 versus 95.6 pg/ml, P = 0.0001) and intact serum parathyroid hormone level (45.0 versus 141.5 ng/l, P = 0.01) than calciopenic subjects. There were no differences in median serum AP (774 versus 1430 IU/l, P = 0.17) and OC (14.5 versus 13.4 ng/ml, P = 0.6) between the two groups. The mean OC value for the 41 rickets subjects was 15.1 +/- 6.2 ng/ml and 17.4 +/- 7.8 ng/ml for the 14 control subjects. In the face of markedly elevated serum AP levels in the rickets subjects, all of the serum OC values in the study fell within two standard deviations of the mean for normals. There was no association between serum OC and 1,25-(OH)2D in either the phosphopenic or the calciopenic group. CONCLUSION: These results show that serum osteocalcin levels are not elevated in all forms of active rickets and that, unlike serum alkaline phosphatase, serum osteocalcin cannot be used in the diagnosis of rickets.

Acquired hypophosphataemic vitamin D resistant rickets in black children.

The case histories of five black children aged between 4 1/2 and 9 years, with acquired hypophosphataemic vitamin D resistant rickets are presented. Muscle weakness was a striking feature clinically, while radiographically all had marked osteopenia in association with classical florid rickets. Biochemically, they were normocalcaemic and hypophosphataemic, with normal parathyroid hormone concentrations. In three of the children 1,25-dihydroxyvitamin D concentrations were low. One child responded to no specific therapy, while three required continuous 1 alpha-hydroxyvitamin D and oral phosphate supplementation, and the fifth 1 alpha-hydroxyvitamin D therapy alone before the clinical, biochemical and radiographic picture responded. The features in three of the children resemble oncogenous rickets, but the features of the other two do not fit any known aetiology. Although the group as a whole may be heterogeneous, until the pathogenetic mechanisms are determined, the authors believe they should be grouped together as acquired hypophosphataemic vitamin D resistant rickets.

Dietary calcium content, calcium balance and mode of uptake in a subterranean mammal, the Damara mole-rat.

Calcium flux and mode of uptake were investigated in an underground dwelling mole-rat, Cryptomys damarensis, fed diets of varying Ca content. The amount of dietary Ca positively influenced the amounts ingested, absorbed and retained. The linear relationship between ingested and absorbed Ca was significantly (P less than 0.001) correlated, implying that this process is nonsaturable. When mole-rats were fed a diet low in Ca, apparent fractional absorption of Ca was high (85.88%). This increased still further when the diet was changed to a food of greater Ca content (96.13%, carrots; 96.97%, gemsbok cucumber). Mineral homeostasis is regulated at the intestinal level in most mammals. Regardless of dietary Ca content, uptake of 45Ca (examined via the everted gut sac technique) was passive, confirming that absorption is via a nonsaturable process. Plasma Ca concentrations were not tightly regulated, yet when fed the diet with the highest Ca content, mole-rats were not hypercalcemic. Regardless of diets, Ca apparent fractional retention was positive, and approached physiological maxima (greater than 97%). Cryptomys damarensis, in using highly efficient modes of mineral uptake and retention, is therefore capable of fully exploiting the limited food resources of their arid ecotope.

Differences in mineral homeostasis, volumetric bone mass and femoral neck axis length in black and white South African women.

In South Africa, appendicular and lumbar spine bone mineral density (BMD) have been found to be similar in black and white women. However, femoral BMD has been found to be higher in black than in white women. Two different techniques were used to recalculate BMD to eliminate the possible confounding influence of ethnic differences in height on areal BMD measurements. Volumetric bone mineral apparent density (BMAD) values were calculated and bone mineral content (BMC) was corrected for body and bone size. This report analyses differences in BMD (corrected for height and weight), BMAD, BMC (corrected for body and bone size), femoral neck axis length (FNAL), mineral homeostasis and bone turnover (BT) in a group of 20 to 49-year-old premenopausal (105 whites and 74 blacks) and 45 to 64-year-old postmenopausal (50 whites and 65 blacks) female South African nurses. The corrected BMD and BMC findings were congruous, showing that both pre- and postmenopausal blacks and whites have similar distal radius and lumbar spine bone mass but that whites have lower femoral neck bone mass than blacks. In contrast, BMAD findings suggest that pre- and postmenopausal whites have lower bone mass at the lumbar spine and femoral neck than blacks but similar bone mass at the distal radius to blacks. There is a greater rate of decline in BMD in postmenopausal whites than in blacks. BMD at the femoral neck was 12.1% lower in premenopausal whites and 16.5% lower in postmenopausal whites than in blacks. There was a positive association between femoral neck BMD and weight in premenopausal blacks (R2 = 0.5, p = 0.0001) but not in whites. Blacks had shorter FNAL than whites in both the pre- and post-menopausal groups. Blacks had lower serum 25-hydroxyvitamin D (25-(OH)D) and higher 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels than whites. There were no ethnic differences in biochemical markers of bone formation (serum alkaline phosphatase and osteocalcin) or bone resorption (urine hydroxyproline and pyridinoline), or in dietary calcium intake in either the pre- or postmenopausal groups. In the postmenopausal group, whites had higher ionized serum calcium (p = 0.003), similar serum albumin, lower serum parathyroid hormone (p = 0.003) and higher urinary calcium excretion (p = 0.0001) than blacks. These results suggest that the higher peak femoral neck BMD in South African blacks than in whites might be determined by greater weight-bearing in blacks and that the significantly lower femoral neck BMD in postmenopausal whites than in blacks is determined by lower peak femoral neck BMD and a faster postmenopausal decline in BMD in whites. The higher incidence of femoral neck fractures in South African whites than in blacks is probably determined by the lower femoral neck BMD and longer FNAL in whites. The greater rate of decline in BMD in postmenopausal whites than in blacks is associated with an increase in urinary calcium excretion in whites. Measurement of biochemical markers of BT has not contributed to the understanding of ethnic differences in BMD and skeletal metabolism in our subjects.

A laboratory investigation into bilirubin binding in neonates.

The presence of free bilirubin the serum of 59 Black neonates was studied at the time of exchange transfusion with an electrophoretic technique. It was observed that 32 infants had detectable free bilirubin in their serum and that these infants had a significantly greater bilirubin/albumin ratio that infants without free serum bilirubin.

Artificial feeding of Black infants.

Analysis of milk formula feeds in a community where infant malnutrition is common, showed that overdilution of feeds is less frequent than expected. Many feeds were too concentrated. Modified and 'humanised' milks were more often and more seriously too strong than unmodified milks. An inadequate number and volume of milk feeds per day was probably more important in causing malnutrition than the strength of the feeds.

Is craniotabes a pathognomonic sign of rickets in 3-month-old infants?

Fifty-eight well Black infants between the ages of 10 and 15 weeks were examined for the presence of craniotabes and investigated for the presence of vitamin D deficiency and rickets. Thirty-five infants were found to have craniotabes and 5 of these had radiological evidence of rickets. No difference in dietary history, birth weight, weight gain, length or skull circumference was found between those with and those without craniotabes. Significantly more females than males had craniotabes. The majority of infants with craniotabes had normal biochemical values. Craniotabes is a common finding in 3-month-old infants and is of no help in diagnosing rickets in this age group.

Serum levels of anticonvulsants and haematological sequelae in black epileptics.

Serum levels of phenytoin and phenobarbitone were studied in a group of Black adult epileptics. Therapeutically satisfactory levels of phenytoin were observed in only 11,3% of patients, and of phenobarbitone, in 63,9%. An overall non-compliance rate of about 50% was noted. The possible reasons for this are discussed. Folate deficiency was not a major problem in this group of patients.

Endemic skeletal fluorosis in children: hypocalcemia and the presence of renal resistance to parathyroid hormone.

Although endemic skeletal fluorosis has been reported in children, hypocalcemia has not been previously noted. In a prevalence study of 260 schoolchildren living in an endemic fluorosis area in South Africa (water fluoride content 8-12 ppm), hypocalcemia was documented in 23%. Furthermore in a separate study of nine children with skeletal symptoms due to endemic fluorosis, hypocalcemia was found in six. 1,25-Dihydroxyvitamin D levels were elevated in the seven children in whom it was measured. Parathyroid hormone (PTH) stimulation tests on admission revealed evidence of impaired phosphaturic responses, typical of acquired pseudohypoparathyroidism type II, and a direct correlation between serum calcium values and the degree of phosphaturia was noted. Repeat tests performed in two of the children after correction of the hypocalcemia by dietary means, revealed a return of normal renal responsiveness. Serum calcium values also correlated inversely with the degree of osteomalacia on iliac crest bone histomorphometry. It is suggested that low dietary calcium intakes might exacerbate the severity of the bone lesions in children living in areas of endemic fluorosis.

Mineral homeostasis in very low birth weight infants fed either own mother's milk or pooled pasteurized preterm milk.

As part of a randomised controlled study to assess the effect of pasteurization of breast milk on the growth of very-low-birth-weight infants, the longitudinal changes in serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, and bone-gla-protein concentrations were investigated. Infants fed untreated own mother's milk grew more rapidly than those fed pasteurized pooled preterm milk and had higher serum alkaline phosphatase and lower phosphorus values. Serum calcium and 25-hydroxyvitamin D (25-OHD) concentrations were similar in the two groups. Despite the provision of 750 IU vitamin D daily from the 2nd week of life, serum 25-OHD values remained low in a number of infants in both groups, suggesting that either malabsorption of vitamin D or hepatic immaturity might be responsible for the persistently low values. Bone-gla-protein rose significantly after birth and was correlated with alkaline phosphatase values, but not with 25-OHD or phosphorus values. The study supports previous work that indicates that the low phosphorus content of breast milk is probably responsible for biochemical evidence of inadequate bone mineralization and that despite vitamin D supplementation, 25-OHD values do not rise adequately. Thirty-six infants were reexamined between 4 and 11 months after birth. The 25-OHD values had risen significantly in all infants except one who had vitamin D deficiency rickets.