Judy Z. Miller

Calcium Supplementation and Increases in Bone Mineral Density in Children

BACKGROUND Increased dietary intake of calcium during childhood, usually as calcium in milk, is associated with increased bone mass in adulthood; the increase in mass is important in modifying the later risk of fracture. Whether the increase is due to the calcium content of milk, however, is not certain. METHODS We conducted a three-year, double-blind, placebo-controlled trial of the effect of calcium supplementation (1000 mg of calcium citrate malate per day) on bone mineral density in 70 pairs of identical twins (mean [+/- SD] age, 10 +/- 2 years; range, 6 to 14). In each pair, one twin served as a control for the other; 45 pairs completed the study. Bone mineral density was measured by photon absorptiometry at two sites in the radius (at base line, six months, and one, two, and three years) and at three sites in the hip and in the spine (at base line and three years). RESULTS The mean daily calcium intake of the twins given placebo was 908 mg, and that of the twins given calcium supplements was 1612 mg (894 mg from the diet and 718 mg from the supplement). Among the 22 twin pairs who were prepubertal throughout the study, the twins given supplements had significantly greater increases in bone mineral density at both radial sites (mean difference in the increase in bone mineral density: midshaft radius, 5.1 percent [95 percent confidence interval, 1.5 to 8.7 percent]; distal radius, 3.8 percent [95 percent confidence interval, 1.4 to 6.2 percent]) and in the lumbar spine (increase, 2.8 percent [95 percent confidence interval, 1.1 to 4.5 percent]) after three years; the differences in the increases at two of three femoral sites approached significance (Wards triangle in the femoral neck, 2.9 percent; greater trochanter, 3.5 percent). Among the 23 pairs who went through puberty or were postpubertal, the twins given supplements received no benefit. CONCLUSIONS In prepubertal children whose average dietary intake of calcium approximated the recommended dietary allowance, calcium supplementation increased the rate of increase in bone mineral density. If the gain persists, peak bone density should be increased and the risk of fracture reduced.

Influences on skeletal mineralization in children and adolescents: Evidence for varying effects of sexual maturation and physical activity

OBJECTIVE To establish rates of skeletal mineralization in children and adolescents, and to identify factors that influence these rates. DESIGN Three-year observational study. SETTING University hospital. SUBJECTS Ninety white children, aged 6 to 14 years. MEASUREMENTS Bone mineral density of the radius, spine, and hip was measured at baseline and 3 years later. Physical activity was assessed by questionnaires at 6-month intervals and dietary calcium intake by diet diary 1 day per month for 36 months. Sexual maturation (Tanner stage) was determined by an endocrinologist at 6-month intervals, as necessary to classify children as prepubertal, peripubertal, or postpubertal. RESULTS Skeletal mineralization accelerated markedly at puberty in the spine (0.077 vs 0.027 gm/cm2 per year, peripubertal vs prepubertal) and greater trochanter (0.050 vs 0.027 gm/cm2 per year), less markedly in the femoral neck (0.047 vs 0.030 gm/cm2 per year), and only slightly in the radius. Nearly one third (15 gm) of the total skeletal mineral in the lumbar spine of adult women (approximately 52 gm) was accumulated in the 3 years around the onset of puberty. Increases in height and weight were the strongest correlates of skeletal mineralization: weight changes were more strongly correlated with trabecular bone sites and changes in height with cortical bone sites. Increases in calf muscle area were strongly associated with mineralization, particularly in peripubertal children, and physical activity was associated with more rapid mineralization in prepubertal children. CONCLUSIONS Puberty has varying effects on skeletal mineralization depending on skeletal site; trabecular bone is apparently more sensitive to changing hormone concentrations. Physical activity and normal growth are also positively associated with skeletal mineralization, also depending on skeletal site and sexual maturation.

Concurrent sickle-cell anemia and α-thalassemia: effect on severity of anemia.

Abstract We studied 47 patients with sickle-cell anemia to determine the effect of α-thalassemia on the severity of their hemolytic anemia. We diagnosed α-thalassemia objectively by using α-globin-gene mapping to detect α-globin-gene deletions, studying 25 subjects with the normal four α-globin genes, 18 with three, and four with two. The mean hemoglobin, hematocrit, and absolute reticulocyte levels (±S.D.) were 7.9±0.9 g per deciliter (4.9±0.6 mmol per liter), 22.9±2.9 per cent, and 501,000±126,000 per cubic millimeter, respectively, in the non-thalassemic group; 9.8±1.6 g per deciliter (6.1±1.0 mmol per liter), 29.0±5.0 per cent, and 361,000±51,000 per cubic millimeter in the group with three α-globin genes; and 9.2±1.0 g per deciliter (5.7±0.6 mmol per liter), 27.5±3.0 per cent, and 100,000±15,000 per cubic millimeter in the group with two α-globin genes. Deletion of α-globin genes was also accompanied by a decreased mean corpuscular hemoglobin concentration (MCHC) in post-reticulocyte erythrocytes and...

Racial Differences in Aldosterone Excretion and Plasma Aldosterone Concentrations in Children

Blacks are more likely to have hypertension, have lower levels of plasma renin activity, and typically consume less potassium than whites. Whether blacks and whites secrete different amounts of aldosterone is less clear. We estimated aldosterone secretion indirectly in 715 children, 249 of whom were black, by measuring their nocturnal rates of urinary excretion of aldosterone. Dietary sodium and potassium intakes were estimated from their excretion rates. The mean (+/- SE) aldosterone-excretion rate was lower in the black children than in the white children (0.045 +/- 0.003 vs. 0.078 +/- 0.004 nmol per micromole of creatinine per kilogram of body weight; P less than 0.001). The potassium-excretion rate was also lower in the black children than in the white children (0.13 +/- 0.01 vs. 0.18 +/- 0.01 mmol per micromole of creatinine per kilogram; P less than 0.001). Aldosterone excretion was highly correlated with potassium excretion (P less than 0.001), but the lower aldosterone-excretion rate in blacks was explained only in part by their lower dietary intake of potassium. Systolic blood pressure was higher in black children (P less than 0.001), as was diastolic pressure (P = 0.037). In a second study of 99 children, the plasma aldosterone level was found to be significantly lower in black children than in white children (230 +/- 30 vs. 400 +/- 30 pmol per liter; P less than 0.001). Plasma renin activity and plasma cortisol levels were the same in both groups. In summary, we found that black children secrete about 40 percent less aldosterone than white children. The role of the lower aldosterone-secretion rate in the genesis of the higher blood pressures observed in black children is not known.

Effects of age on renal sodium homeostasis and its relevance to sodium sensitivity

Age-related changes in blood pressure, renal function, and sodium homeostasis suggest that sodium sensitivity of blood pressure may also be influenced by age. Blood pressure was measured in 378 normal volunteers and 198 patients with essential hypertension after an intravenous infusion of normal saline and after sodium and volume depletion. Those whose mean arterial blood pressure decreased more than 10 mm Hg after sodium and volume depletion were considered sodium-sensitive, whereas those with a decrease of less than 5 mm Hg were considered sodium resistant. The normal and hypertensive subjects were divided into groups of those above and those below 40 years of age. The blood pressure responses of both older and younger groups were normally distributed, indicating that blood pressure could either decrease or increase following volume depletion. Older hypertensive and normotensive subjects are more likely to be sodium sensitive. They usually have lower renin values than do younger subjects, but substantial heterogeneity is found. Age and renin status do not reliably predict sodium sensitivity. Volume contraction and dietary sodium restriction are more likely to decrease blood pressure in older than in younger subjects, but regimens must be tailored individually.

Association of haptoglobin with sodium sensitivity and resistance of blood pressure.

Sodium sensitivity and resistance of blood pressure were examined in 117 normotensive and 85 hypertensive subjects by means of a protocol using rapid extracellular fluid volume expansion with intravenously administered saline (2 L over 4 hours) followed by a day of low dietary sodium intake (10 mEq) and volume contraction induced by a diuretic (furosemide, 120 mg orally). Genetic markers were also examined. Both hypertensive and normotensive subjects with haptoglobin 1-1 phenotype were significantly more (p less than 0.05) likely to be sodium-sensitive than were those with 2-1 or 2-2 phenotypes, and subjects with 2-2 phenotypes were more apt to be sodium-resistant. A second population was examined in which both adults and children with haptoglobin 1-1 phenotype were found to have significantly (p less than 0.05) higher casual systolic and diastolic blood pressures. These two studies independently confirm a relationship between haptoglobin phenotypes and blood pressure and suggest an environmental factor (sodium) as well.

The effects of age, race and heredity on glomerular filtration rate following volume expansion and contraction in normal man

To elucidate racial and age differences in natriuretic responses following volume expansion, we studied GFR, as reflected by endogenous creatinine clearance, in 446 normal persons including 99 blacks and 44 pairs of mono-and dizygotic twins. GFR was measured day and night, under basal conditions, following volume expansion with 2 L intravenous normal saline and volume contraction with 120 mg oral furosemide. Volume expansion and contraction altered GFR to similar degrees in whites and blacks. White exhibited a diurnal variation in GFR (day>night) under all conditions, which was not observed in blacks. Following saline, whites excreted more sodium during the day, but less sodium during the night, than blacks (p<0.05). In whites, UnaV and GFR were correlated only during the day, while in blacks the correlation persisted throughout the night. When the white population was divided into subjects < 40 years and ≥40 years, the responses of the older whites resembled those of blacks. The inverse relationship between GFR and age was steeper in blacks than whites. A twin analysis demonstrated that plasma creatinine, urinary creatinine excretion and creatinine clearance are heritable. The failure of GFR to decrease at night in blacks and older whites may be related to an altered natriuretic capacity. Decreases in GFR with aging are greater in blacks than whites. GFR is partially under the influence of genetic variance.

RACE AND GENDER INFLUENCE HEMODYNAMIC RESPONSES TO PSYCHOLOGICAL AND PHYSICAL STIMULI

To evaluate factors influencing hemodynamic responses to psychological and physical stress, 117 normotensive college students were studied. The standardized tests included arithmetic, Stroop word-color, mirror draw, isometric handgrip and cold pressor challenges. The responses of blood pressure and pulse during the tests were compared to the baseline measurements. All the challenges produced a significant (P less than 0.01) increase in systolic and diastolic pressure and pulse rate, with the greatest increase being seen with the isometric handgrip test. The increases in the systolic and diastolic pressure and the heart rate to the psychological stressors were highly correlated (P less than 0.001). The responses to the physical stressors were correlated for the diastolic pressure (P less than 0.01) and the heart rate (P less than 0.001), but not for the systolic pressure. The responses of the systolic and diastolic pressure, but not the heart rate, to the isometric handgrip correlated with the responses to the psychological stressors. The responses of the diastolic pressure and the heart rate, but not the systolic pressure, to the cold pressor stimulus correlated with the responses to the psychological stressors. The gender influenced the response to all the stressors with males having a greater (P less than 0.05) blood pressure response and a lesser (P less than 0.001) heart rate response than females. Black subjects had greater blood pressure responses to the cold pressor test and a greater diastolic pressure response to the handgrip, but there were no observed racial differences in the responses to the psychological stressors.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic influences on renin, aldosterone, and the renal excretion of sodium and potassium following volume expansion and contraction in normal man.

SUMMARY To investigate the influence of heredity on plasma renin activity (PRA), plasma aldosterone concentrations (PAC), blood pressure, and the renal excretion of sodium and potassium following volume expansion and contraction in normal man, we studied 37 pairs of monozygotic (MZ) and 18 pairs of dizygotic (DZ) twins. Volume expansion was achieved by the intravenous infusion of 2L normal saline; volume contraction was accomplished by a low-sodium diet and 120 mg oral furosemide. The presence of genetic variance was tested by calculating the within pair and among component estimates of genetic variance.Outpatient 24-hour-urine collections suggested that MZ and DZ twins ingested diets similar in sodium and potassium content, and failed to reveal genetic influences on the dietary preferences for these electrolytes. The PRA values suggested heritable influences during both the volume expanded and contracted state with the added stimulus of upright posture. Heritable influences were observed on PAC and were most apparent in the basal state on the day of volume expansion. An influence of heredity on blood pressure was most apparent during volume contraction. Urinary sodium excretion (UNaV), urinary potassium excretion (UKV), fractional excretion of sodium (FENa), and fractional excretion of potassium (FEK) revealed evidence of significant genetic variance under the condition of volume expansion. In that state, systolic blood pressure was directly correlated with PRA, PAC, and inversely with FENa. The data suggest that the renal regulation of sodium and potassium excretion is in part influenced by heritable factors that may in turn contribute to the development of hypertension in some individuals.

Blood pressure response to dietary sodium restriction in normotensive adults.

Sixteen healthy, normotensive husband-wife pairs participated in a study to investigate the effect of reduction of dietary sodium intake (goal less than or equal to 60 mEq/day) on blood pressure. Sodium excretion decreased from a control average of 152.7 +/- 10.1 (SE) mEq/day to 69.5 +/- 4.5 mEq/day (p less than 0.001). Results indicated significant decreases in both systolic (p less than 0.001) and diastolic (p less than 0.001) blood pressure after a period of sodium restriction. In the entire group, there was no significant change in potassium excretion (58.4 +/- 3.2 vs 54.6 +/- 3.5 mEq/day) or body weight (76.0 +/- 2.8 vs 75.3 +/- 2.7 kg). Although there was variability in the blood pressure response, the decrease in blood pressure was significantly correlated with the magnitude of sodium restriction (r = 0.36, p less than 0.03). These results indicate that the blood pressure response to sodium restriction may not be limited to individuals with hypertension and that the response is heterogeneous in normotensive subjects.