1. We studied the mechanism of action of the anabolic steroid, stanozolol, in 23 patients with osteoporosis, using a combination of biochemical and histomorphometric techniques. 2. Treatment with stanozolol (5 mg/day) for 1 year was associated with a marked and significant decrease in the fasting urinary excretion of calcium ( P < 0.01) but not with changes in the serum concentrations of calcium and phosphate, the serum activity of alkaline phosphatase, the renal tubular reabsorption of calcium or the urinary excretion of hydroxyproline. 3. Histological examination of trabecular bone showed an increase in bone turnover and the bone formation rate increased twofold ( P < 0.02). There were no significant changes in bone volume or wall thickness after treatment. Tetracycline labelling was used to discriminate bone structural units completed before and during treatment. Measurements of the wall thickness of those bone structural units formed during treatment showed no significant change. 4. Measurements made on the endocortical surface also showed an increase in bone turnover, but in contrast to trabecular bone, the bone structural units formed at endocortical sites during treatment had a significantly greater wall thickness than those formed before treatment ( P < 0.05). 5. We conclude that stanozolol increases the turnover of trabecular bone and increases the endocortical apposition of bone.

1. We have examined the relationship between the attenuation of broadband ultrasound in the os calcis in vitro and its bone mineral density measured by quantitative computed tomography and by physical density. 2. Broadband ultrasound attenuation was found to correlate closely with physical density ( r = 0.85, P < 0.0001), but the correlation was less than that observed between quantitative computed tomography and physical density ( r = 0.92, P < 0.0001). Measurements of broadband ultrasound attenuation and quantitative computed tomography were significantly correlated ( r = 0.80, P < 0.0001). 3. Partial correlation analysis showed a significant relationship between broadband ultrasound attenuation and bone density, but when the effect of physical density was taken into account no significant correlation was found between broadband ultrasound attenuation and quantitative computed tomography ( r = 0.08, not significant). 4. Broadband ultrasound attenuation in three prospective amputees showed a high degree of concordance between measurements in vivo and in vitro , with no interference by surrounding soft tissues. 5. The correlation between physical density and broadband ultrasound attenuation was independent of quantitative computed tomography, suggesting that the technique measures aspects of density which differ from its mineral density. Broadband ultrasound attenuation holds promise as a reproducible, rapid, radiation-free assessment of skeletal status.

1. We have examined the relationship between broadband ultrasound attenuation in the os calcis and measurements of bone mineral in the distal forearm and lumbar spine of normal and postmenopausal osteoporotic women. 2. Values of broadband ultrasound attenuation in postmenopausal women with vertebral osteoporotic fractures were significantly lower (35%) than in normal pre-and peri-menopausal women (55.4 ± 3.8 and 79.6 ± 0.8 dB/MHz, respectively). 3. Broadband ultrasound attenuation correlated significantly with bone mineral content measured in the distal forearm by single-photon absorptiometry ( r = 0.77, P < 0.0001) and with bone mineral content ( r = 0.66, P < 0.0001) and bone mineral density ( r = 0.72, P < 0.0001) measured in the lumbar spine by dual-photon absorptiometry. 4. Although significant, these correlations are not sufficiently close to be predictive. However, the accuracy of broadband ultrasound attenuation in discriminating between normal subjects and patients with vertebral fracture compared very favourably with direct measurements in the spine by dual-photon absorptiometry. 5. Broadband ultrasound attenuation, but not the other measurements, correlated significantly with age in the osteoporotic patients ( r = 0.50, P < 0.05). 6. These findings may reflect the partial dependence of broadband ultrasound attenuation on the intrinsic trabecular architecture of cancellous bone, the disruption of which contributes to an increase in fracture risk.

1. The effects of three intravenous diphosphonates (etidronate, clodronate and aminohexane diphosphonate) on phosphate homoeostasis were studied in 30 patients with Paget's disease of bone and in three patients with hypoparathyroidism. 2. In Paget's disease, all three diphosphonates induced significant increases in serum phosphate and renal tubular reabsorption of phosphate. This effect was most marked and persistent after etidronate, whereas in the clodronate- and aminohexane diphosphonate-treated patients the increases were less, of shorter duration and followed thereafter by significant decreases in serum phosphate and renal tubular reabsorption of phosphate. Unlike etidronate, both clodronate and aminohexane diphosphonate caused a significant reduction in serum and urinary calcium, with appropriate homoeostatic increases in immunoassayable parathyroid hormone. 3. Phosphaturic responses to infused parathyroid hormone were observed in two patients with etidronate-induced hyperphosphataemia. 4. In three hypoparathyroid patients, clodronate induced a more marked increase in serum phosphate and renal tubular reabsorption of phosphate than in Paget‘s disease, which was of comparable degree but of shorter duration than that after etidronate in Paget's disease. 5. These findings suggest that all three diphosphonates increase renal tubular reabsorption of phosphate, but that this effect is attenuated with those diphosphonates which induce secondary hyperparathyroidism.

1. We have studied the early effects of intravenously and orally administered etidronate on vitamin D metabolism and indirect indices of calcium and skeletal metabolism in 17 patients with Paget's disease of bone. 2. Administration of etidronate by mouth (700–1400 mg daily for 1 month) or its intravenous infusion (300 mg daily for 5 days) decreased bone resorption as judged by urinary excretion of hydroxyproline and significantly increased renal tubular reabsorption of phosphate. No significant change in serum activity of alkaline phosphatase was noted with either regimen. 3. When etidronate was given by mouth there was a progressive decrease in fasting urinary calcium excretion and a rise in serum 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ]. In contrast, intravenous etidronate decreased serum values of l,25-(OH) 2 D 3 and was associated with a progressive increase in fasting calcium excretion, suggesting a decrease in the net influx of calcium from the extracellular compartment to bone. Significant inverse correlations were noted between the change induced in 1,25-(OH) 2 D 3 values at 2 weeks and the changes in serum calcium, phosphate and fasting urinary excretion of calcium. 4. These observations suggest that the different effects of intravenous and oral etidronate on l,25-(OH) 2 D 3 values are a consequence of different doses of etidronate used and the different effects of these regimens on the accretion of calcium into bone.

1. In order to study the relationship between extracellular and intracellular concentrations of orthophosphate (P i ), phosphorus nuclear magnetic resonance spectra were recorded, at rest, from the flexor digitorum superficialis muscle of hypophosphataemic patients with vitamin D-resistant rickets, and patients with Paget's disease of bone before and after they had been made hyperphosphataemic by treatment with the drug ethylidene-1-hydroxy-1,1-bisphosphonate. Changes in intramuscular P i were estimated from the ratio of the areas of the P i to adenosine 5′-triphosphate peaks. Even though the plasma P i concentration in these patients spanned a fourfold range (0.5–2.0 mmol/l) the corresponding intramuscular P i concentration increased by only 70%. 2. A similar effect was observed in erythrocytes, from patients with these disorders, which were incubated in autologous plasma at 37°C, under an atmosphere of O 2 + CO 2 (95:5, v/v). However, chloride ions, which are transported passively across the cell membrane, showed no change in distribution between cells and plasma, indicating that there was no general effect on passive anion distribution. 3. When erythrocytes from normal subjects were incubated in autologous plasma (1.0 mmol of P i /l) and in plasma supplemented with P i (2.3 mmol of P i /l), the P i concentration in the cells, at steady state, increased only from 0.57 to 0.78 mmol/l cells, suggesting that the effect was not an artifact of disease or drug therapy. 4. It is concluded that, in human skeletal myocytes and erythrocytes, the percentage change in the concentration of cytoplasmic P i is lower than that in plasma. This implies that these cells can buffer or regulate cytoplasmic P i when the extracellular concentration is disturbed.

1. The metabolic clearance rate (MCR) of human calcitonin was measured in 12 normal subjects and four patients with Paget's disease by the infusion of synthetic human calcitonin (15–40 μg/h for 2–24 h), and in 10 additional patients with Paget's disease from the disappearance rate of immunoreactive calcitonin from plasma after the intravenous injection of large doses of synthetic human calcitonin (0·5–1·0 mg). 2. The estimated MCR during the infusion studies (range 531–1224 litres/day) was similar to that calculated from the disappearance of large doses of synthetic human calcitonin injected intravenously in patients with Paget's disease (mean = 1035 litres/day; range = 593–1408 litres/day). 3. An eightfold range in the basal values of plasma immunoreactive calcitonin, in spite of the presence of a relatively constant MCR, suggests that the variation in basal plasma calcitonin was due principally to variation in the endogenous secretion rate for calcitonin. 4. The results suggest that the endogenous secretion rate for calcitonin is low in normal subjects (mean 124 ± sem 24 μg/day), and give a basis for selecting the doses of calcitonin which can be considered physiological.

1. In subjects with normal renal function there was a strong positive correlation between serum concentrations of 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol, as measured by competitive protein-binding assay. 2. The 24,25-dihydroxycholecalciferol concentration was about 7% of the prevailing 25-hydroxycholecalciferol concentration. 3. In contrast, sera from anephric patients contained very low or undetectable amounts of 24,25-dihydroxycholecalciferol even after the serum 25-hydroxycholecalciferol concentrations in these patients had been elevated by oral administration of 25-hydroxycholecalciferol. 4. In a further group of anephric patients, all having normal serum 25-hydroxycholecalciferol concentrations, no radioactively labelled 24,25-dihydroxycholecalciferol was formed from an injected pulse dose of [ 3 H, 14 C]cholecalciferol. 5. These results indicate that in man the kidney is the major site of 24-hydroxylation of 25-hydroxycholecalciferol.

1. Plasma levels of immunoreactive calcitonin were measured in 22 patients with untreated Paget's disease of bone and in 22 control subjects matched for age and sex. 2. No significant differences in plasma calcitonin were found between patients and control subjects, and hormone levels did not correlate significantly with activity of plasma alkaline phosphatase. 3. These results suggest that Paget's disease of bone is not due to deficient secretion of endogenous calcitonin.