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.

Aging bone loss from the femur, spine, radius, and total skeleton.

In order to establish a comprehensive model for involutional bone loss, the following measurements were made of healthy white women: total body calcium by neutron activation analysis, bone density of the distal radius by single-photon absorptiometry, and dual-photon absorptiometry of the lumbar spine and femur (neck, Ward's triangle, and intertrochanteric areas). Longitudinal measurements were made for each of these skeletal sites except the femur. Evidence for a curvilinear component to the pattern of bone loss with aging was found for total body calcium and bone density of the radius, but not for the other measurements on analysis of cross-sectional data. Longitudinal studies confirmed that substantial bone loss begins only after menopause for the radius, whereas there is substantial premenopausal loss of bone from the lumbar spine. Prevention of vertebral osteoporosis requires maximizing bone mass before menopause. If longitudinal data confirm the model of linear rates of bone loss for the femur, there will be important implications for prevention of hip fractures.

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.

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.

Coherence treatment of postmenopausal osteoporosis with growth hormone and calcitonin.

Fourteen women with postmenopausal osteoporosis, all having at least one vertebral crush fracture, were randomly assigned to two treatment arms, each lasting 24 months. The coherence treatment group (7 patients) was treated in the following sequence: human growth hormone (hGH) 7 IU subcutaneously daily for 2 months, followed by 3 months of salmon calcitonin (CT), 100 MRC units every other day. After a 3 month rest period, this sequence was repeated twice. The contrast group (7 patients) was treated intermittently with salmon CT given in the same time periods and at the same dose as in the coherence treatment group. Bone mass was measured every 4 months by neutron activation analysis for total body calcium (TBCa) and by single photon absorptiometry for bone mineral content (BMC) of the distal radius. Although there were no significant differences between the two groups (two-way ANOVA), the rate of change in TBCa in the coherence treatment group was significantly different from zero (F = 3.8, P less than .05) and was +2.3%/year. The increase in bone mass appeared to be sustained throughout the 2 year study, in contrast with previous studies where a plateau effect was observed with calcitonin given alone or continuously with growth hormone. No significant change was found in bone histomorphometric values measured before and after treatment in 4 patients from each group.

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.

Serial measurements of body composition and total body mineral content in dialysis and nondialysis patients with renal failure.

Thirty-two patients with chronic renal failure, and 68 patients on maintenance hemodialysis underwent serial total body neutron activation over periods of time ranging from 23 to 159 months. Measurements of total body potassium (TBK), total body sodium (TBNa), total body calcium (TBCa), total body phosphorus (TBPhos), and total body chloride (TBC1) were performed. The results were normalized by lean body mass (LBM) or kilogram body weight (BW). The TBNa/LBM and TBC1/BW decreased during the first 36 months of measurements in the dialysis males, while there was no change in the nondialysis males. The TBNa/LBM, TBC1/LBM and TBC1/BW decreased during the first 36 months of monitoring the dialysis females, while a decrease in the LBM was the only change in the nondialysis females. In patients with an increasing K ratio (observed/predicted TBK), the TBNa/LBM and TBCa/LBM decreased and the LBM/BW increased. Similarly, in patients with an increasing Ca ratio (observed/predicted TBCa), the TBCa/LBM and TBPhos increased. The increasing K ratio in dialysis patients with a decreasing TBNa/LBM probably represents an improvement in nutritional status. The increasing TBPhos in dialysis patients with an increasing Ca ratio may represent an increase in skeletal tissue and/or soft tissue calcification. In dialysis females, the total body nitrogen is not different from controls. The total body fat, as a percentage of body weight, is greater in dialysis patients than in controls.

Noninvasive techniques for measuring body elemental composition : State of the art and future prospects.

In the past 20 yr, in vivo analysis of body elements by neutron activation has become an important tool in medical research. In particular, it provides a much needed means to make quantitative assessments of body composition of human beings in vivo. The data are useful both for basic physiological understanding and for diagnosis and management of a variety of diseases and disorders. This paper traces the development of the in vivo neutron activation technique from basic systems to the present state of the art facilities. A scan of some of the numerous clinical applications that have been made with this technique reveals the broad potentialities of in vivo neutron activation. The paper also considers alternative routes of future development and raises some of the questions now faced in making the technique more widely available to both medical practitioners and medical investigtors.In vivo neutron activation has opened a new era of both clinical diagnosis and therapy evaluation, and investigation into the modeling of body composition. The techniques are new, but it is already clear that considerable strides can be made in increasing accuracy and precision, increasing the number of elements susceptible to measurement, and reducing the dose required for the measurement.

Determination of ruthenium on DNA by XRF.

An X-ray fluorescence (XRF) technique is used to quantitate the binding of [H2O(NH3)5Ru(II)](2+) to DNA. This method is shown to be more sensitive, precise, and convenient than conventional optical absorption (OA) spectroscopy, differential pulse voltammetry (DPV), or atomic absorption (AA) techniques. X-ray fluorescence is insensitive to the oxidation state or coordination environment of Ru and so can be used to determine total Ru. The minimum detectable amount of Ru is 10 ng in 1 h of counting time, using a 100-mCi(125)I source. The specific advantages of the XRF method over the conventional methods are outlined.

Description of an XRF system for multielemental analysis.

An X-ray fluorescence (XRF) system that uses radioisotopes in an orthogonal configuration between the source, sample, and detector is described. The advantage of such a system is that for large (bulk) samples or in vivo measurements, the background caused by Compton scattering in the sample is minimized. High reproducibility for nonuniform samples is obtained by reducing the sample size and thus the effects of nonuniformity in the spatial response of such a system. Germane to any accurate analytical method is the use of proper mathematical algorithms for data evaluation. The problem is acute, in particular, when photopeaks with low counting statistics are to be analyzed. In the case of a single photopeak on flat background, optimal energy window size, which maximizes the signal-to-noise ratio, for trapezoidal intergration is described. The sensitivity and minimum detection limit at different energies together with background considerations are discussed.

Effects of elevated lead and cadmium burdens on renal function and calcium metabolism.

To assess the pathophysiologic significance of increased body burdens of lead and cadmium, detailed renal function studies and evaluation of calcium, phosphorus, and vitamin D metabolism were carried out in 38 industrial workers exposed to lead and cadmium for 11 to 37 yr. Body burden of lead, as assessed by x-ray fluorescence measurement of tibia lead content, was elevated in 58% of the men and, when assessed by excretion of lead after Ca-EDTA infusion, was elevated in 36%. Liver or kidney cadmium burden, as assessed by neutron activation analysis, was elevated in 31%. Creatinine clearance was normal in all workers. One worker was hyperuricemic and two were proteinuric; three had increased beta 2 microglobulin excretion and one had diminished urinary acidifying ability. Maximal urinary concentrating ability was abnormal in a significant fraction, i.e., 52% of the men. Individuals with a high lead burden had a slight decrease in mean serum phosphorus but no accompanying phosphaturia. There was no abnormality of serum calcium. Twenty-two percent of subjects were hypercalciuric and two had low vitamin D levels, but these abnormalities bore no relation to heavy metal burden. In this carefully characterized group of men with chronic lead and calcium exposure, definite, if subclinical, effects on renal function and serum phosphorus but not calcium or vitamin D metabolism were demonstrable.

Women at risk for developing osteoporosis: determination by total body neutron activation analysis and photon absorptiometry.

With stepwise multiple logistic regression (MLR), probabilistic classification equations were developed to identify asymptomatic women who are at risk for development of fracture of the spine. Clinically normal women with low TBCa/square root H ratios can be classified as at risk for osteoporosis prior to their developing spinal compression fractures. With receiver operating characteristic (ROC) analysis, it was possible to verify the accuracy of the MLR model to discriminate "normal" women at risk, with high sensitivity and specificity. With the MLR model, discrimination of osteoporotic women (50-59 years) was made correctly for 86.2% of the total osteoporotic subjects with the TBCa data. Similar models were derived from the photon absorptiometry data. From the spinal density (BDs) data, correct classification in the 50-59 year group was 55.6% of the total osteoporosis subjects; from the radius density (BMCr) data, the corresponding value was 31%. The highest probability of identifying osteoporosis in all age categories was, therefore, on the basis of TBCa data. Similar, but less accurate discrimination was achieved with the BDs and BMCr data. These conclusions were confirmed by the application of receiver operating characteristic (ROC) analysis. Correct identification of the population at risk permits the timely and efficient application of therapeutic programs prior to onset of fracture. In a serial study of 104 peri-menopausal women, for example, it was possible to determine the P value for individuals measured annually over a 3-10 year period and thus to predict normal individuals at risk for developing osteoporosis each year.

In vivo measurement of lithium in the body by a neutron activation analysis technique.

A technique has been developed for in vivo determination of lithium content in the head (and potentially in the whole body and in selected organs) of patients undergoing lithium therapy. It is based on the measurement of tritium induced by the 6Li(n,alpha)T nuclear reaction after neutron irradiation of the body. The fraction of tritium exhaled in the expired air in the form of HT is collected, separated from the other gases, and counted in a high-sensitivity beta counter. The feasibility of the technique was demonstrated by measurements of lithium in the head of a sheep and in the whole body of rats, following the administration of 6LiCl (enriched 6Li isotope, 95.46% abundancy). The precision of the technique is acceptable for clinical applications based on a maximum propagated error of 8.4%. The sensitivity is 1 count/d (from T activity) per 10 mSv (total dose) and 1 microgram of 6Li. This indicates that studies on patients under 6Li treatment can be performed successfully with a radiation dose to the head of 1-2 mSv.

In vivo bone lead measurements: a rapid monitoring method for cumulative lead exposure.

Lead concentrations (microgram/g wet weight) in human bone (tibia) were measured noninvasively in vivo employing an X-ray fluorescence technique. Forty-five workers who had been subjected to chronic industrial exposure were found to have a mean bone lead content of 52.9 micrograms/g wet weight (0 to 198 micrograms/g). In addition to bone lead content, blood lead, body burden of lead as assessed by urinary lead excretion after EDTA chelation, zinc protoporphyrin, and unstimulated urinary lead excretion were evaluated. The results suggest that the in vivo measurement of tibia lead content may serve as an acceptable indicator of body lead burden and provide a practical technique for lead screening purposes. The correlation coefficient between X-ray fluorescence findings and lead excretion following Ca-EDTA administration is 0.69; p less than 0.001.

A model for involutional bone loss.

Bone mass of the total skeleton and distal radius were measured by in vivo neutron activation analysis and single photon absorptiometry, respectively, in 403 healthy white women and 151 healthy white men. In addition, the density of L-2 to L-4 (bone mineral content of the spine [BMCs]) was measured by dual photon absorptiometry in 159 of these women and in 56 women with the vertebral crush fracture syndrome. The rate of loss of total body calcium (TBCa) and bone mineral content of the radius (BMCr) was linear in men and was slower than in women. The best fit for TBCa and the bone mineral content of the distal radius and spine as a function of age in women was with a two-phase regression. The TBCa and BMCr could be used as well as BMCs to identify women with crush fractures. The ratios of BMCs/TBCa, BMCs/BMCr, and TBCa/BMCr did not differ among women with crush fractures and age-matched normal individuals. Our data do not support the hypothesis that women with vertebral crush fractures have preferential loss of spinal bone.

A proposed method for in vivo determination of lithium in human brain.

A method for measuring Li in vivo in human brain is presented. The technique is based on the measurement of tritium gas exhaled by the subject following neutron irradiation of the organ of interest. The gas collection facility used to separate minute amounts of tritium from the breath is described. Methods for reducing the background levels of tritium were investigated. The limit of detection of the system is estimated to be 350 micrograms of Li for the whole brain for a dose of 10 mSv. This detection limit is sufficient for the study of patients treated with lithium compounds, but is too high to study 'normal' brain lithium content. The rate of elimination of tritium gas from the body was also investigated in animal studies. The method also appears suitable for the measurement of lithium levels in the kidney.

Polyacrylamide-based phantoms as tissue substitute in experimental radiation physics.

Polyacrylamide-based tissue-equivalent phantoms simulating cortical bone and muscle are described. The equivalency is based upon similar elemental composition and density, and partial similarity in the morphology of bone. Satisfactory results were obtained when the phantoms were tested at low (20 keV) and high (15 MeV) gamma radiation. Applicability of this phantom material to neutron transport is discussed. The material can be molded and shaped and its composition is easily modified by altering the proportions of the constituents. Trace elements or radionuclides are easily added. Details of the physical and radiation characteristics of the formulated systems are given together with the manufacturing procedures.