Hypogonadism induced by luteinising hormone releasing hormone agonist analogues: effects on bone density in premenopausal women.
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Publications and source records attributed to R Hesp.
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Bone formation and resorption have been measured in patients with idiopathic osteoporosis by histomorphometry of 7.5-mm trephine biopsies and in the whole body by 85Sr radiotracer methodology and calcium balances. The studies were synchronized and most were preceded by double in vivo tetracycline labeling. Correlations between histological and kinetic bone formation indices were better when better when based on the extent of double tetracycline labels than on measurements of osteoid by visible light microscopy. Correction of the kinetic data for long-term exchange, using 5 months' serial whole body counting of retained 85Sr, improved the fit of the kinetic to the histological data. A statistical analysis of the measurement uncertainties showed that the residual scatter in the best correlations (between exchange-corrected bone formation rates and double-labeled osteoid surface indices) could be attributed to measurement imprecision alone. The exchange-corrected resorption rate correlated fairly well with iliac trabecular resorption surfaces, and using a volume referent rather than a surface referent for the histological index improved the statistical fit when patients with therapeutically accelerated bone turnover were included. A much better correlation was obtained by including osteoid volume acting as an independent predictor of bone resorption in a bivariate regression with a resorption surface index. The residual errors could then be accounted for by known measurement uncertainties. Whereas osteoid taking a double label closely predicted the kinetic rate of bone formation, further analysis suggested that osteoid that took no label or a single label was more closely related to bone resorption, presumably as a secondary result of the coupling of bone formation to bone resorption. The idea that continued bone loss in some patients is associated with defective osteoblastic bone formation is supported by the low rates found in some patients by both techniques. Heuristically these studies validate both in vivo tetracycline labeling for dynamic histomorphometry and corrections for long-term exchange in kinetic studies of bone formation, providing a quantitative framework for the design and analysis of future studies of bone remodeling in the osteoporoses.
The accuracy of a combined test (75Se-HCAT + 58Co-B12) of ileal function by whole-body counting has been assessed with particular attention being paid to the reliability of the 100% retention measurements, the accuracy of the crossover of 58Co into the 75Se channel and the effects of variable counting geometry. A linear relationship between 58Co crossover and body weight improved the accuracy of determining the crossover value for individual patients. Non-geometrical errors such as those associated with counting statistics and crossover were found to be small, with a coefficient of variation usually less than +/- 2% except in cases of very low 75Se-HCAT retention in the presence of substantial amounts of 58Co. The main sources of error were due to problems of variable counting geometry but there was very good agreement between 75Se and 58Co retentions measured by whole body counting and by excreta analysis which suggested that the overall error of the test was unlikely to exceed +/- 10%. A protocol is presented for use of the combined test on an outpatient basis and includes retention measurements at 4, 7, and 10 d post administration.
In an attempt to achieve an anabolic response in both axial and peripheral bone, we treated twelve patients with osteoporosis using human 1-34 parathyroid peptide given discontinuously. The peptide was given as seven daily subcutaneous injections followed by 21 days' treatment with 0.25 mg calcitriol orally. This regime was repeated cyclically for at least sixteen cycles, of which the first four were at a lower dose of hPTH 1-34 than used subsequently. The results of treatment were monitored by kinetic, densitometric, histomorphometric and biochemical studies performed before and during treatment. Two patients developed hPTH 1-34 binding in their plasma during treatment: this was presumed to be due to the development of antibodies. The remainder, instead of increasing their indices of bone turnover as judged by iliac bone histomorphometry, were found to have consistent reductions in trabecular resorption surfaces. The other indices of bone formation and resorption measured showed no change or comparable reductions. The small increases seen in total body calcium were consistent with 'in-filling' of deleted basic multicellular units (BMUs). Because there is no evidence that calcitriol alone causes comparable reductions in activation of bone remodelling in osteoporosis, interruption of treatment with hPTH 1-34 after 7 days may have led to a failure of the activation mechanism to proceed to the resorption stage, with a consequent overall reduction in remodelling activity. This type of treatment regime, with its calcitonin-like effect, might be effective in reducing net bone loss due to imbalance between bone formation and resorption at the BMU level, particularly in patients with increased numbers of BMUs ('high turnover' osteoporosis).(ABSTRACT TRUNCATED AT 250 WORDS)
In a cross-sectional study of 70 early postmenopausal women, regional bone measurements were compared with total body calcium (TBCa). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P less than 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone, was weak (r less than 0.52, P less than 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.
Radial bone mineral content (BMC) has been reported to be lower than normal in patients with hyperparathyroidism, but those measurements have been made with techniques which do not discriminate between trabecular and cortical bone. We have used a low radiation dose computed tomography technique to make differential measurements of trabecular and cortical bone in the radii of 18 out of 27 eligible female patients with surgically proven adenomata. Prior to parathyroidectomy there was a mean deficit of 40% (P less than 0.001) in trabecular bone density in the distal radius, and a deficit of 16% in cortical bone in the radius mid-shaft compared to normal values. Seventeen months after parathyroidectomy there was a small but significant increase in trabecular bone density in the distal radius in 13 of these patients, and no significant change in cortical bone. If these results represented the situation throughout the skeleton, it is possible that parathyroidectomy may provide some reduction in future risk of fracture in women with primary hyperparathyroidism.
The densities of trabecular and cortical bone in the radius were measured by computed tomography in 40 women with generalized osteoarthrosis (osteoarthritis, GOA), and the results were compared to normal values obtained from prediction equations. When age, weight and height were considered, no significant differences were observed between patients with GOA and normal controls. But when age only was considered, trabecular bone density in the distal radius was found to be 7% higher than predicted (p less than 0.05). Increased trabecular bone density is unlikely to be an etiopathogenetic factor in GOA although this cannot be completely excluded from our study.
Quantities related to the amount of trabecular bone in the distal radius and cortical bone in the radius mid-shaft have been measured in 262 normal adults of both sexes aged 21-89 years by computed tomography (CT). A special-purpose CT system (ISOTOM) which incorporated a source of 125I (29 keV) was used to make the measurements. The relationships between these quantities and age, weight, height and surface area have been evaluated, and the results have been used to draw conclusions on the significance of values measured in female patients with osteoporosis, Colles' fracture of the wrist and generalised osteoarthritis.
Biochemical, hormonal, and kinetic indexes of bone turnover were measured in 17 ambulant female patients with rheumatoid arthritis (RA) of recent onset (mean disease duration 14.2 months) and 19 controls. Mean serum osteocalcin concentration and 85Sr accretion rates were reduced and mean urinary hydroxyproline-creatinine ratios were increased in RA, but these differences were not significant compared with control values. Mean total body potassium (TBK), an index of skeletal muscle mass, was significantly reduced in RA, and the ratio of observed to predicted TBK correlated with indexes of bone formation. No abnormality of skeletal metabolism could be shown in early RA, but reduced rates of bone formation associated with diminished muscle mass may influence the development of osteopenia later in the disease.
Serial measurements of bone mineral in 17 ambulant female patients with rheumatoid arthritis (RA) of recent onset and 19 age matched female controls were made in the radius by computed tomography and in the vertebrae by dual photon absorptiometry. Loss of trabecular bone from the distal radius was more rapid in RA (p = 0.0014), but there was no difference in the rate of loss of bone mineral from the radial midshaft or lumbar spine compared with the controls. This study is consistent with the hypothesis that the predominant form of bone loss early in the disease is the vicinity of affected joints.
A comparison of computed tomography (CT) and dual photon absorptiometry (DPA) in the measurement of spinal bone mineral was made in 44 subjects of whom 26 had vertebral crush fractures. Although CT measures only trabecular bone within the vertebral body whilst DPA measures the whole vertebral segment, a good correlation was observed (r = 0.80) when these quantities were expressed in dimensionally similar units. Trabecular bone in the distal radius measured by CT correlated less well with vertebral CT (r = 0.65). Cortical bone in the radius correlated poorly with the spinal DPA measurement (r = 0.38).
Mean linear attenuation coefficients for trabecular bone (T) in the distal radius and total absorption coefficients (TA) in the radial mid-shafts of 22 patients with crush fracture osteoporosis were measured serially for a year by using computed tomography. After approximately 6 months, each patient was admitted to a metabolic ward for an 18-day calcium balance study. The rate of change (trend) in trabecular bone (T) in the distal radius was a better predictor of calcium balance than the trend in mid-shaft cortical bone (TA). The scatter in the regressions of the trends of T and TA on calcium balance could be accounted for by known methodological uncertainties.
Computed tomography measurements on the radii of 18 women with Colles' fracture of the radius have shown that compared to normal women of the same age they tended to have a smaller bone cross-sectional area in the radius midshaft, a small deficit of cortical bone, and a substantial deficit of trabecular bone in the distal radius.
Measurements of body composition were made on 104 women aged 14-60 years whose fat content varied from 6 per cent to 60 per cent of body weight. Estimates of fat content were systematically lower when based on a measurement of body density than when based on body water, and were higher still when based on total body potassium. When body weight and body fat were corrected for stature by dividing by height squared there was a coefficient of correlation between these two variables of 0.936, 0.921 and 0.938 for estimates of fat based on density, water and potassium respectively. When the mean of all three estimates of fat was used the correlation was 0.955. Neither the slope of the regression line nor the strength of the correlation was affected if gross body weight was correlated with total body fat without correction for stature. It is concluded that differences in weight between women of similar height is attributable to tissue which is 70-78 per cent fat and 22-30 per cent lean, and that in the treatment of obese patients it is desirable that no more than 22 per cent of the weight loss should be lean tissue.
In 18 patients with idiopathic crush fracture syndrome, iliac trabecular bone volume measured in 8 mm trephine biopsies correlated well with trabecular bone density as estimated in low thoracic or high lumbar vertebrae by computed tomography (CT). The CT of trabecular bone in the radius correlated poorly with the other two measurements, but it discriminated fairly well between patients and age-matched controls. These results suggest that abnormally low trabecular bone density values in the radius may be useful in predicting some patients at risk for crush fractures, but ranking patients in order of severity of axial bone loss after they have acquired a fracture requires measurements on the spine or iliac crest.
In order to assess whether impairment of cell-mediated immunity in cancer was due to the presence, site and stage of malignant disease or to associated undernourishment, 48 patients with gastrointestinal cancer were compared to 27 patients with benign gastrointestinal disease. Cell-mediated immunity (CMI) was assessed by delayed hypersensitivity (DHS) skin test response to recall antigens and lymphocyte mitogenic response to phytohaemagglutinin (PHA). Patients were grouped according to nutritional status assessed from a history of weight loss and changes in the ratio of total body potassium (TBK mmol) to total body water (TBW kg). The results showed that, whilst cancer patients as a whole had significantly worse DHS response, there were no significant differences between benign and malignant groups of equivalent nutritional status and in both types of disease response decreased significantly with worsening nutritional status (chi 2(2) = 6.83 cancer, 6.11 benign, p less than 0.05). PHA response was significantly worse in the worst nourished cancer patients than in those with normal nutritional status (p less than 0.05, Wilcoxon). Disease site and stage had no significant effect on either test. The results suggest that depression of CMI response in gastrointestinal cancer is due to undernutrition and is not a cancer specific effect.
In 21 women with crush fracture osteoporosis quantities related to trabecular bone density in lumbar vertebrae and in the distal radius were significantly correlated (r = 0.50, P less than 0.05). When the group was enlarged to include data from other patients without osteoporosis, a higher coefficient of correlation was obtained (r = 0.69, P less than 0.001). Total body calcium, measured by in vivo neutron activation analysis, was significantly correlated to quantities related to cortical bone mass in the radius and femur. Thus, these quantities could be used to make estimates of total body calcium in osteoporotic patients. There was no significant correlation between total body calcium and quantities related to trabecular bone density, measured by computed tomography, in vertebrae or in the distal radius.
1. The effect of 5 consecutive days of hill walking on electrolyte balance, fluid homeostasis, plasma renin activity and plasma aldosterone concentration was studied in five male subjects. 2. The 5-day exercise period was preceded by a 4-day control period and followed by a 4-day recovery period. Throughout the 13-day study subjects ate a fixed diet. 3. After 5 days of exercise subjects had retained a mean of 264 mmol (SD 85) of sodium. Plasma sodium concentration remained constant at 142.0 mmol/l (SD 5.4). This indicates an expansion of the extracellular space by 1.84 litres. 4. By the end of the exercise period there was a positive water balance of about 0.9 litre. Thus there was a net movement of 0.94 litre of fluid from the intracellular to the extracellular space. 5. Packed cell volume decreased from a mean of 43.5% to 37.9% after 5 days of exercise, indicating that about 0.9 litre of the extracellular fluid entered the vascular compartment. The remaining fluid may be responsible for the significant increase in lower leg volume. 6. During the exercise period plasma aldosterone concentration and plasma renin activity rose, and there was a highly significant correlation between these values and the sodium retention. There was also a significant correlation between sodium retention and the increase in leg volume, which suggests that oedema may be the result of prolonged exercise of this type.