Effects of 25-hydroxycholecalciferol on calcium metabolism in chronic renal failure.
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Biomedical subjects
Publications and source records attributed to S H Cohn.
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The age-related changes in both skeletal mass and muscle mass were directly measured in normal black women ages 30-80 yr. The levels of total-body calcium (TBCa) were determined with the use of in vivo neutron activation. The muscle mass was measured by wholebody counting of 40K. In the same population, the bone mineral content of the radius was measured using a photon absorptiometric technique. Although there was no significant difference in stature, black women had a greater skeletal mass and bone mineral content of the radius than age-matched white female subjects. When the TBCa values were normalized for body size (i.e., corrected for height and lean body mass), the TBCa was still higher for the black women but not as high as the absolute TBCa values. Clearly, it is the larger muscle mass (as reflected by the 40K measure) in relation to weight and height that accounts for this difference. The lower prevalence of fracture and osteoporosis observed in black women relative to white women is due in part to this greater quantity of skeleton. American black women with a higher bone density (i.e., skeletal mass) maintain mechanical integrity of the skeleton longer than individuals with a lower bone density. It is suggested that the larger muscle mass in black women is, in part, a determinant of their increased skeletal mass and is partly responsible for their apparent resistance to osteoporosis and fracture of the skeleton.
The effect of therapy that simultaneously stimulates bone formation and inhibits bone resporption was evaluated in five patients with primary osteoporosis. The technique of in vivo neutron activation analysis was used to measure total body calcium (TB-Ca). The patients were treated with calcium supplements and salmon calcitonin combined with either a low or a high dose of growth hormond (hGH). There was no significant increase in skeletal mass (TB-Ca) during the low-dose hGH regimen. An increase in skeletal mass was observed in all patients following the high-dose regimen, except for one patient who developed secondary hyperparathyroidism. Although this study must be considered to be of a preliminary nature, the magnitude of the response in calcium balance suggests that skeletal mass can be increased in osteoporosis if combination therapy is employed.
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An in vivo method for the determination of Cd levels in human kidney and liver has been developed. The method allows detection of absolute quantities of Cd in the left kidney and Cd concentration in the liver. The limit of detection of cadmium is 2.5 mg for the left kidney and 1.8 microgram/g (wet weight) for the liver, for a localized dose of 670 mrem. The effects of patient positioning, organ geometry and liver-kidney interference on the measurement have been investigated using an Alderson phantom.
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The age-related changes in body chemical composition were measured in a normal black population ranging in age from 30 to 80 yr. The levels of total-body calcium, phosphorus, sodium, and chlorine were measured by in vivo neutron activation. In addition, the lean body mass (total-body potassium) was measured by whole-body counting of 40K. These data were compared with the same data obtained on a normal white population in a previous study. Although there were no significant differences in the height of the two groups, black men and women had significantly higher total-body calcium, phosphorus, sodium, chlorine, and potassium than the sex-and age-matched white population. The increased levels of total-body calcium and potassium when normalized for the weight and height of the subjects were reduced but still remained significantly higher than those of the white population. Clearly specific reference standards for skeletal and muscle mass as well as for sodium and chlorine need to be established for black populations.
During the 12 weeks following 5/6 nephrectomy in rats with moderate uremia (creatinine 0.7-1.2 mg/100 ml, BUN 53-89 mg/100 ml), no significant increases in total soft tissue calcification were observed. The calcium concentration of skeletal muscle remained unchanged at 4, 8, and 12 weeks after surgery. A slight but not significant increase in skin calcium was found. However, a significant decrease in cardiac calcium was found for the uremic animals. Total body calcium as determined by neutron activation analysis was significantly lower in the uremic rat when compared with the age-matched animal. However, when normalized for body weight, the total calcium content in uremic rats did not differ from the controls. Similar findings were observed for the absolute calcium content of the tibia and when normalized for weight. Furthermore, a highly significant linear relationship (r = 0.92, p less than 0.001) was established between absolute levels of total body calcium and tibia calcium which was identical for control and uremic groups.
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Measurements of bone mineral content and total-body calcium, normalized and expressed as ratios, were compared with radiographic morphometry in 45 women who had spinal osteoporosis. The radiographic indices examined included the femoral score, the femoral trabecular pattern, the biconcavity and metacarpal indices, and the total peripheral score. Both ratios and all the radiographic indices except the femoral trabecular pattern were found to be related to the number of dorsal spine fractures. The relationships observed support the following conclusions: (A) the femoral score and the metacarpal index are related to the degree of osteopenia; (B) the biconcavity index reflects the extraskeletal factors that are pathogenic in spinal osteoporosis; (C) a reduced femoral trabecular pattern index is associated with spinal osteoporosis, although this measurement is not related to the degree of osteopenia; and (D) it may be imprudent to diagnose osteoporosis from the presence of lumbar compression fractures.
The total-body retention of 127Xe, and its variation with time following short, nonequilibrium periods of inhalation, were measured in vivo so as to refine dosimetry calculations. Radioactivity in the chest region and in the recirculating xenon-air mixture was measured continuously during re-breathing of the gas mixture and in the first 5 min of the immediate gas-washout period using a scintillation camera and shielded NaI detector, respectively. Subjects were then counted in a whole-body counter at varying time intervals until background levels were reached, usually in 72 hr. Five components of Xe clearance from the entire body were measured; they had biologic half-times of 21.7+/-12.4 sec, 3.05+/-1.72 min, 0.04+/-0.11 hr, and 2.71+/-0.87 hr, and a long-term component varied between 7.59 and 17.04 hr. The half-time of the last component correlated highly with the percent of total-body fat. After 10-min inhalations of the xenon-air mixture, approximately one-third of the total xenon was transferred to the body tissues, extrapolated back to the start of gas washout. Of this amount, 13% was associated with the slowest component of clearance.
Absolute levels of total body sodium (TBNa) and total body chlorine (TBCl) were determined in 81 normal adults (39 males, 42 females) by means of total body neutron activation analysis (TBNAA). The ages of the subjects ranged from 30 to 90 yr. The mean values for both TBNa and TBCl remained relatively constant throughout the age span studied for males, but decreased slightly for females over 60 yr of age. In order for the absolute measurements of Na and Cl to be of clinical value, the values must be compared to a predicted value based on the sex and body habitus of the individual. Normalization of TBNa values relative to body dimensions (weight, height, body surface area) were evaluated. In addition, TBNa was related to total body calcium (TBCa), which reflects skeletal mass, and TBK, which reflects muscle, or lean body mass. Normalization in terms of a linear combination of the TBCa and TBK was found to be the most satisfactory of all those studied. Sodium excess, NaES, defined as the amount of body sodium (mEq) in excess of body chlorine (mEq) was determined. Sodium excess correlated well with total body calcium. Values for total body sodium and chlorine obtained in the present study were compared with values previously reported in the literature.
Total-body levels of calcium and phosphorus (reflecting skeletal mass) and total-body levels of potassium (reflecting muscle mass) were measured by neutron activation analysis in 39 men and 40 women ages 30-90 yr. In order to intercompare the total body calcium (TBCa) values in a heterogeneous population, such as this, it was necessary to normalize the data for skeletal size. The normalization consisted of dividing the absolute calcium level by the predicted calcium level for each individual matched to a set of critical parameters. The parameter used in the computation of normal values were age, sex, muscle mass, i.e., total body potassium (TBK) and height. For the calcium data of the women, it was necessary to add an age correction factor after the age of 55 yr. The calcium ratio(mean ratio of the predicted to measured TBCa) in men was 1.000 +/- 7.8% and in women 0.996 +/- 7.1%. The TBCa of normal males and females can thus be predicted to +/- 13% (at the 90% confidence level). An exception to this was found in males (70-90 yr) who exhibited a mean calcium ratio greater than 1.13. The derivative of TBCa with time was determined for this population of men and women by taking into account the dependency of calcium on three time dependent variables, height, TBK, and an explicit age correction factor in the case of the women. The mean rate of loss of TBCa in women was 0.37% and 1.1% per year before and after menopause (50 yr). In the males, the average rate of loss of TBCa was 0.7% per year after 50 yr of age. The pattern of total body phosphorus (TBP) loss with age paralleled that of TBCa as the ratio of TBP/TBCa was rather constant with age. The constancy of the ratio suggests that the mineral composition of bone does not change significantly with age. The rate of loss of TBK with age was also related directly to that of TBCa. The mean ratio of TBK/TBCa was 9.9 in females and 8.0 in males and this ratio remained relatively constant from 30-70 yr. Thus, the mechanism responsible for the loss of bone with age, whether nutritional deficiency or decreased gonadal function and physical activity may also be responsible for the loss of muscle mass with age.
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Total-body calcium was measured in 40 adult women by total-body neutron activation analysis (TBNAA). Procedures for normalizing the absolute calcium measurements for the parameters of size and age were developed in order to effect a direct comparison of women of age 30-78 yr. The normal total-body calcium (TBCa) for an individual can be predicted by a formula developed in the present study to within +/- 11% (1.62 SD) at the 90% confidence level. The TBCa loss can be characterized by two components: one with a slower rate, 0.37%/yr, and the other with a faster rate, 1.08%/yr. The latter, a more rapid postmenopausal loss, started at 50-60 yr and was superimposed on the slower rate of loss that started in the fourth decade and continued throughout life. The bone mineral content (BMC) of the radius, measured by the absorptiometric technique, correlated well with the total-body skeletal calcium in this population (r = 0.813, P less than .001). However, for intercomparisons of the BMC values of individuals, normalization of the BMC values for size and age is required, as it is for the TBCa data. Normalization provided by the ratio of BMC to radius width is not adequate for comparative studies.
Male rats with an average body weight of 250 g were injected (sc) daily for 4 wk with 0.05, 0.20, 0.75, or 3.00 mg of cortisol acetate. Intact and adrenalectomized control animals were injected daily with 0.1 ml of vehicle (corn oil). Total body calcium (TBCa) was measured weekly in each rat by in vivo neutron activation analysis. The gain is body weight of rats treated with 0.75 mg cortisol was significantly less than controls, and the animals treated with 3.00 mg cortisol lost weight. In spite of these differences in body weight, the TBCa of all rats increased to an equal degree from an average of 1.93 g to 2.81 g in 4 wk. In addition, there were no significant differences in tibial ash calcium. However, calcium (mg) per unit length (mm) of tibia was increased in rats treated with the higher doses of cortisol; thus bone density was increased. These results demonstrate that the TBCa increases even when rats are subjected to cortisol. This is explained in part by the normal rate of intestinal calcium absorption in cortisol-treated rats.
The effect of chronic administration of growth hormone (GH) to osteoporotic patients was studied using the techniques of total body neutron activation analysis, whole body counting, calcium tracer kinetics, photon absorptiometry, quantitative microradiography, and urinary hydroxyproline. Two dosage schedules were utilized for six months each: 2 units daily and 0.2 w3/4 units of GH daily (where W represents body weight expressed in kg). The lower dosage (2 units) did not produce any appreciable change in the indices studied. Following the higher dose, no evidence of any anabolic effect was apparent in most patients (i.e., no increase in total body levels of Ca, Na, K, P, or Cl). Increases were noted in the urinary calcium excretion rate and in the urinary hydroxyproline excretion. Bone mineral content decreased. The bone biopsies displayed an increase in bone formation and resorption surfaces in response to treatment, but these changes were not statistically significant. It may be concluded that under the conditions of this study, GH administration did not result in an increment in skeletal mass. Several side effects that are characteristic of acromegaly were observed, including hyperglycemia, hypertension, arthralgia, and the carpal tunnel syndrome. Because of the lack of demonstrated benefit and the associated complications of therapy, GH administration does not appear to be of value in the treatment of osteoporosis.