Cadmium: in vivo measurement in smokers and nonsmokers.

Absolute amounts of cadmium (in milligrams) in the left kidney and concentrations of cadmium (micrograms per gram) in the liver were measured in vivo in 20 healthy adult male volunteers. Organ cadmium levels of smokers were significantly elevated above those of nonsmokers. No relationship was evident between body stores of cadmium (liver and kidney) and cadmium or beta 2-microglobulin in urine or blood. The average total body burden of cadmium in man at age 50 is estimated to be 19.3 milligrams for nonsmokers and 35.5 milligrams for smokers (38.7 pack-year smoking history). Biological half-time for the whole body was, on average, 15.7 years (10- to 33-year range). Dietary absorption was 2.7 micrograms per day. Cigarette smoking resulted in the absorption of 1.9 micrograms per pack.

Premenopausal bone mass is related to physical activity.

The relationship between physical activity and bone mass was investigated in 24 healthy, white, premenopausal women (mean age [+/- SE], 39.0 +/- 1.39 years). Physical activity was determined by a sensor that measures movement of the trunk, and bone mineral levels were determined by means of single- and dual-photon absorptiometry and neutron activation analysis. Total physical activity levels were related both to bone mineral density of the spine (r = .41) and to total body calcium levels (r = .51). There was no significant relationship between the bone density of the distal portion of the radius and activity (r = .20). Nonparametric analysis and stepwise multiple regression analysis revealed negative correlations between cigarette smoking and bone density of the spine and radius. These data suggest that the level of physical activity in sedentary white women may be a determinant of peak total skeletal mass and bone density of the spine.

Determinants of bone mass in postmenopausal women.

Eighty white women, mean age 52 years, within one to six years postmenopausal, were studied to examine the relationship of various factors to bone mass. Forty-four of the women had annual measurements of bone mass, so that the rate of bone loss could be determined. Bone mass was measured by total body neutron activation analysis and photon absorptiometry of the distal radius (total body calcium [TBCa] and bone mineral content [BMC], respectively). Breast-feeding and pregnancy were noted to be associated with higher bone mass; those with lower BMC and/or TBCa tended to have higher serum alkaline phosphatase levels, lower testosterone levels, and more years since the cessation of menses. The rate of bone loss from the radius was greater in those with higher parathyroid hormone levels; those with reduced dietary intake of calcium and lower 25-hydroxyvitamin D levels had a greater rate of loss of TBCa.

Hydroxyproline peptides and bone mass in postmenopausal and osteoporotic women.

Total and nondialyzable hydroxyproline excretion was measured in 59 postmenopausal women and 68 women with spinal osteoporosis. Hydroxyproline excretion was similar in both groups of women and the hypothesis that hydroxyproline excretion is normally distributed could not be rejected for either group. No relationship was found between hydroxyproline excretion (total and percentage of nondialyzable) and body weight, height, body surface area, or total body calcium or bone mineral content of the radius, or these latter values normalized for age, sex, and body size. There was no difference in hydroxyproline excretion in osteoporotic women who took supplemental calcium as compared to those that did not. These data fail to provide any evidence that bone turnover in osteoporotic women differs from that in younger postmenopausal women, or that osteoporosis arises from a subpopulation of women with rapid bone loss.

Effects of growth hormone in osteoporosis.

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.

Serum osteocalcin and total body calcium in normal pre- and postmenopausal women and postmenopausal osteoporotic patients.

Serum osteocalcin was measured in 51 normal pre- and 114 postmenopausal women and in 41 postmenopausal osteoporotic patients. Total body calcium (TBCa) was determined in the same individuals by neutron activation analysis. Many of the perimenopausal nonosteoporotic women had increased serum osteocalcin values, but 15 yr or more after the menopause most of the women had serum osteocalcin levels in the normal range. Comparing normal women before and after menopause, the mean serum osteocalcin levels [7.8 +/- 4.7 (+/- SE) and 10.1 +/- 9.4 ng/mL] were not significantly different; however, the TBCa values (898 +/- 99 and 806 +/- 111 g) were significantly different (P less than 0.001). When the normal postmenopausal women were regrouped according to high vs. low osteocalcin values, TBCa and phosphorus content as well as forearm linear bone density were significantly lower in the high osteocalcin group, even though most of the other variables, including urinary hydroxyproline excretion, serum alkaline phosphatase, age, height, and weight, were not different. Osteoporotic women had a mean serum osteocalcin concentration of 17.4 +/- 8.6 ng/ml and a TBCa of 657 +/- 83 g, both significantly different from the respective values in normal and pre- and postmenopausal women (P less than 0.001 for both variables in comparison to each group). These data suggest that high serum osteocalcin levels, at least on a group basis, are an index of low skeletal mass.

Relationship of menopause to skeletal and muscle mass.

Cross-sectional and longitudinal changes in body composition with age were examined in white women to determine the relationship of body cell mass to menopause and of body fat to bone mass. There was statistical evidence for a curvilinear component to loss of total body potassium with negligible rates of loss before menopause. Longitudinal measurements also indicated a relationship between the proximity to menopause and the rate of loss of potassium. Total body potassium was significantly related to total body calcium and bone density of the spine, radius, and femoral neck. Total body fat was not related to any of these measurements. We found no evidence that adiposity plays a major role in protecting against bone loss.

Evaluation of body composition and nitrogen content of renal patients on chronic dialysis as determined by total body neutron activation.

Total body protein (nitrogen), body cell mass (potassium), fat, and water were measured in 15 renal patients on maintenance hemodialysis (MHD). Total body nitrogen was measured by means of prompt gamma neutron activation analysis; total body water was determined with tritium labeled water; total body potassium was measured by whole body counting. The extracellular water was determined by a technique utilizing the measurement of total body chloride and plasma chloride. When compared with corresponding values of a control group of the same age, sex, and height, the protein content, body cell mass, and total body fat of the MHD patients were within the normal range. The only significant change was an increase in the extracellular water/body cell mass ratio in the male MHD patients compared to the controls. The lack of significant difference of the nitrogen values of the MHD patients compared to matched controls suggests that dialysis minimizes any residual effects of uremic toxicity or protein-calorie malnutrition. These findings further suggest that there is a need to reevaluate the traditional anthropometric and biochemical standards of nutritional status for MHD patients. It was concluded that it is particularly important to measure protein stores of MHD patients with low protein intake to ascertain nutritional status. Finally, in vivo measurement of total body nitrogen and potassium for determination of body composition provides a simple, direct, and accurate assessment of the nutritional status of MHD patients.

Improved models for determination of body fat by in vivo neutron activation.

In the present study, two different models of body composition, based on data obtained by nuclear techniques are used. Total body nitrogen, calcium, and chlorine were obtained by total body neutron activation. Total body chlorine was used to estimate extracellular water, and total body calcium to determine bone mineral and extracellular solids. Total body potassium was measured by whole body counting to obtain the body cell mass. In addition, total body water was measured by the tritium dilution technique. It was found that either model can be used equally well to measure total body fat in normal subjects. Estimation of body fat as the difference between body weight and the sum of total body nitrogen (protein), total body water, and bone ash (model 1) appears to have an advantage over model 2, which uses body cell mass, extracellular water, and extracellular solids, particularly for patients with metabolic disorders. This advantage is partly due to the fact that the parameter protein (total body nitrogen) is less affected in metabolic disorders than the more labile total body potassium. The closely correlated results obtained with the two models based on nuclear measurements support the conclusion that these techniques provide reliable measurements of total body fat.

Comparison of methods of estimating body fat in normal subjects and cancer patients.

Total body fat can be indirectly estimated by the following noninvasive techniques: determination of lean body mass by measurement of body potassium or body water, and determination of density by underwater weighing or by skinfold measurements. The measurement of total body nitrogen by neutron activation provides another technique for estimating lean body mass and hence body fat. The nitrogen measurement can also be combined with the measurement of total body potassium in a two compartment model of the lean body mass from which another estimate of body fat can be derived. All of the above techniques are subject to various errors and are based on a number of assumptions, some of which are incompletely validated. These techniques were applied to a population of normal subjects and to a group of cancer patients. The advantages and disadvantages of each method are discussed in terms of their ability to estimate total body fat.

Body composition and skeletal metabolism following pituitary irradiation in acromegaly.

The change in body composition in acromegaly that resulted from pituitary irradiation was examined using the technic of total body neutron activation analysis. Before treatment, increased ratios of total body P:Ca, P:K and Na:K were noted. After pituitary irradiation, the total body levels of P, Na and K were reduced in a proportion that indicated restoration of body composition towards normal. Skeletal mass (total body calcium) decreased into the range observed in osteoporosis in several patients. Trabecular bone mass, as reflected by the Singh Index, was consistently reduced, and two patients had vertebral compression fractures. Local bone mass as determined by photon absorptiometry was reduced when the values were normalized for age, sex and body size. It is postulated that in untreated acromegaly there is differential bone remodelling with an increase in cortical bone accompanied by a reduced trabecular bone mass. When reduction of hGH levels is accomplished with treatment, cortical apposition may decrease. Since the increased cortical bone mass probably aids in preventing vertebral compression fractures, the treated acromegalic patient may incur an increased risk of fractures. This risk may be increased further by the hypogonadism which may arise secondary to pituitary irradiation or surgery. It would be prudent to ensure that the hypogonadal acromegalic patient receives an adequate calcium intake and sex hormone replacement therapy.

Calcitriol in the treatment of postmenopausal osteoporosis.

Calcitriol was compared with placebo in the treatment of postmenopausal osteoporosis in a double-blind, randomized, parallel clinical trial of 24 months' duration. Adjustment was made in dietary calcium to maximize the dose of calcitriol. The study was completed by 15 patients who received placebo and 12 patients who received calcitriol. The calcitriol group had positive slopes (compared with negative slopes for the placebo group) for total body calcium, bone mineral content of the radius, bone mineral density of the lumbar spine, and radiographic absorptiometry of the middle phalanges. The difference between the two groups was statistically significant for each of these measurements. The fracture rate in the treatment group was 250 per 1,000 patient-years as compared with 333 for the placebo group. The mean dose of calcitriol was 0.8 micrograms per day. Hypercalcemia, hypercalciuria, and perhaps nephrolithiasis were observed as complications of treatment. Calcitriol increased bone mineral density by decreasing bone resorption, but not by increasing bone formation. Future studies should concentrate on treatment with oral calcitriol in lower doses. It would also be of interest to examine parenteral administration of calcitriol. It is possible that bone formation can be increased by achieving higher serum levels of the drug, whereas complications may be avoided by using a non-oral route of administration.

Risk factors for postmenopausal osteoporosis.

Fifty-eight women with postmenopausal osteoporosis (crush fracture of the spine) were compared with 58 age-matched normal women. The osteoporotic women had lower total-body calcium levels and bone mineral content of the radius, had undergone an earlier menopause, smoked cigarettes more, and had breast-fed less often. They also had lower levels of estrone, estradiol, and testosterone and reduced levels of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D. These findings suggest the presence of changeable risk factors for the development of osteoporosis. Smoking should be discouraged. An adequate intake of calcium and vitamin D should be ensured. It is the opinion of the authors that those women who have had an early menopause or who have a low bone mass at the time of menopause should be given the choice of medically supervised replacement therapy with estrogen and progesterone.

In vivo measurement of body nitrogen by analysis of prompt gammas from neutron capture.

A method for the in vivo determination of body nitrogen by prompt gamma photons from neutron capture is described. An 85-Ci 238Pu-Be source provides the neutrons. The gamma detection system consists of two 15.24 x 15.24 cm Nal(TI) detectors placed above the patient. Absolute value of body nitrogen is determined using body hydrogen as an internal standard. The reproducibility of the method is +/- 3% for a body dose of 26 mrem.

Phonton absorptiometry and skeletal mass in the treatment of osteoporosis.

Thirty-six osteoporotic patients who underwent several therapeutic regimes were studied on two occasions by photon absorptiometry and total-body neutron activation analysis (TBNAA). These determinations were made at a mean interval of 8.9 plus or minus 0.8 months. The 8-cm radial site was chosen for the photon absorptiometry which was performed with the Norland-Instruments Densitometer. Mean initial bone mineral content (BMC) was 0.724 plus or minus 0.069 gm/cm and mean bone width was 1.235 plus or minus 0.072 cm. The mean percent change in BMC (%deltaBMC) was 1.02 plus or minus 4.2. The initial total-body calcium (TBCa) as determined by TBNAA was reduced when compared with values that would be expected from empirically derived formulas. The mean percent change in TB-Ca (%deltaTB-Ca) was -3.2 plus or minus 4.7. Most patients displayed a change in BMC and TB-Ca that was at least 2 s.d. greater than the precision of the methods used (%deltaTB-Ca greater than 2). No relationship was found between the deltaBMC and the deltaTB-Ca (r = 0.17). These findings suggest that changes in the radical BMC at the 8-cm site cannot be extrapolated to indicate changes in skeletal mass in response to treatment of osteoporosis. Whether photon absorptiometry at other sites or at multiple sites provides a closer relationship to changes in skeletal mass (TB-Ba) remains to be determined.

Total-body sodium and sodium excess.

Total-body levels of sodium (TBNa), chlorine (TBCl), calcium (TBCa), and potassium (TBK) were measured by neutron activation and analysis of results by whole body counting in 66 postmenopausal women. The relationship between TBNa, and TBCl, TBK, and TBCa on the one hand, and height and weight on the other, were found to compare with those previously reported. The hypothesis that TBNa and TBCl are distributed normally could not be rejected. The sodium excess (Naes) is defined as the sodium that is present in excess of that associated with the extracellular fluid (chlorine) space; the Naes approximates nonexchangeable bone sodium. In these 66 postmenopausal women, and in patients with different endocrinopathies previously described, the values of Naes did not differ from the normal values except in the thyrotoxicosis patients, where they were decreased. A close relationship between Naes and TBCa was maintained in the endocrinopathies studied. This relationship was found in conditions accompanied by either an increment or a loss of skeletal mass. It appear

Radiographic morphometry and osteopenia in spinal osteoporosis.

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.

Whole-body retention of radioxenon.

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.

Combination therapy for osteoporosis with estrogen, fluoride, and calcium.

Nine women with postmenopausal spinal osteoporosis were treated with combination therapy consisting of estrogen, fluoride, and calcium. Their data were compared with those of a control group treated with fluoride, and calcium without estrogen. Bone mass was measured about every six months by photon absorptiometry (bone mineral content/bone width (BMC/BW)] and total-body neutron activation analysis [total-body calcium (TB Ca)]. Time-trend analysis revealed positive slopes for TB Ca (P = 0.002) and BMC/BW (P = N.S.) for the combination therapy group. The change in BMC/BW in the combination therapy group was significantly different from the response in the fluoride - calcium group. These data suggest that combination therapy may be successful in increasing bone mass in postmenopausal osteoporosis. A clinical trial to establish efficacy and examine risk/benefit ratios should be performed.

Absence of an effect of chronic administration of growth hormone on serum lipids.

Human growth hormone (hGH) was administered to a group of osteoporotic patients at two dosage levels for a period of 6 mo each. The first dose employed was 2 units subcutaneously daily, and the second dose was 0.2W-3/4 units (where W is body weight expressed in kg) daily. There was no significant change in serum-cholesterol or triglyceride concentration despite the production of hyperglycemia and soft-tissue swelling on the higher dosage regimen. A number of factors may account for the conflict between our findings and a previous report in which hGH administration had a lypocholesterolemic, hyperglyceridemic effect. These factors include differences in sex, age, dosage, and duration of treatment. Nonetheless, it is clear that from a therapeutic vantage, even if hGH were readily available, it would not be a useful hypocholesterolemic agent.