GREES recommendations for the registration of new drugs in the prevention and treatment of osteoporosis.
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Clinical Trials as Topic↗
Biomedical subjects
J Compston
Publications and source records attributed to J Compston.
An elderly woman with signs of osteoporosis.
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Aged↗
How to assess drug efficacy in osteoporosis.
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Bone Density↗
Generation and characterization of monoclonal antibodies to human type-5 tartrate-resistant acid phosphatase: development of a specific immunoassay of the isoenzyme in serum.
We have characterized four monoclonal antibodies (mAbs) to the purple ("tartrate-resistant," band 5) acid phosphatase of the human osteoclast (TRAP) and used these to develop a specific serum immunoassay. All four mAbs are of high affinity (Ka = 1-5 x 10(8) L/mol) with a very fast Kassoc (0.2-2.0 x 10(5) L mol-1 s-1) and a moderate Kdissoc (1-3 x 10(-3) s). Two of the mAbs were selected to develop a time-resolved fluorescence immunoassay to measure serum concentrations of TRAP. The mean serum immunoreactive TRAP in a group of healthy premenopausal women and men was 3.7 +/- 1.8 micrograms/L (mean +/- SD) and 3.5 +/- 1.6 micrograms/L, respectively. Significantly higher concentrations of TRAP were found in postmenopausal women (6.3 +/- 2.3 micrograms/L) and in eight patients with Gaucher disease (19.3 +/- 4.7 micrograms/L). Further studies are required to investigate the value of serum TRAP as a marker of bone resorption.
Acid Phosphatase↗
Systemic bone changes accompanying early rheumatoid arthritis in patients treated with nonsteroidal antiinflammatory drugs alone.
Seventeen patients suffering from early rheumatoid disease (mean duration, 3.5 years) and treated with nonsteroidal antiinflammatory drugs alone had evidence of systemic bone changes. Transiliac bone biopsies, compared with age and gender-matched controls, demonstrated reduced bone volume and increased eroded surface. In addition, the metacarpal indices were reduced in the rheumatoid patients and correlated with the iliac crest bone volume. These changes, found distal from sites of synovitis, suggest that in this group of rheumatoid patients there were systemic changes of bone metabolism. No biochemical abnormalities of calcium homeostasis were found. Collectively, present observations may be a reflection of the rheumatoid disease process itself.
Adult↗
Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women.
OBJECTIVE: To examine the relation between bone density and indices of calcium metabolism including parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. DESIGN: A cross sectional study. SETTING AND SUBJECTS: 138 women volunteers aged 45-65 with no known osteoporosis and unselected for disease status recruited for a dietary assessment study from the community using general practice registers. Volunteer rate was 20%. MAIN OUTCOME MEASURE: Bone mineral density measured with dual energy x ray absorptiometry. RESULTS: Bone density at the lumbar spine and neck and trochanteric regions of the femur was inversely related to serum intact parathyroid hormone concentrations and positively related to serum 25-hydroxyvitamin D concentrations. These associations were independent of possible confounding factors, including age, body mass index, cigarette smoking habit, menopausal status, and use of diuretics and postmenopausal hormone replacement therapy. These associations were apparent throughout the whole distribution of bone density and 25-hydroxyvitamin D and parathyroid hormone concentrations within the normal range, suggesting a physiological relation. CONCLUSIONS: The findings are consistent with the hypothesis that parathyroid hormone and 25-hydroxyvitamin D concentrations influence bone density in middle aged women. Findings from this study together with other work suggest that the role of vitamin D in osteoporosis should not be neglected. The associations with parathyroid hormone also indicate plausible biological mechanisms. The roughly 5-10% difference in bone density between top and bottom tertiles of serum 25-hydroxyvitamin D concentrations, though not large in magnitude, may have considerable public health implications in terms of prevention of osteoporosis and its sequelae, fractures.
25-Hydroxyvitamin D 2↗
Human osteoblasts in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines.
Collagenase production by rodent osteoblasts in response to calciotropic hormones has led to the hypothesis that bone cells play a major role in bone resorption by degrading the surface osteoid layer, thereby exposing the underlying mineralized matrix to osteoclastic action. Many studies suggest, however, that this model might not apply to bone resorption in the human. Human osteoblasts have been shown to produce gelatinase-A (72 kDa) and TIMP-1 (tissue inhibitor of metalloproteinases), but previous investigators have been unable to demonstrate the synthesis of collagenase by human osteoblasts either constitutively or in response to bone resorptive agents. In the present study the ability of human osteoblasts to produce the matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, and their specific inhibitors TIMPs-1 and 2, was examined using highly sensitive and specific antisera and by zymography. Semi-quantitative histomorphometric data showed that cells cultured on either glass or a type I collagen substratum constitutively synthesized gelatinase-A and TIMP-1. On type I collagen, however, a small proportion of unstimulated cells produce both collagenase (7%) and gelatinase-B (95 kDa; 3%). Treatment of cells with either parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3), or partially purified mononuclear cell conditioned medium (MCM), stimulated the synthesis of collagenase, gelatinase-B and stromelysin; MCM was 2- to 3-fold more potent than either PTH or 1,25(OH)2D3. Zymography using SDS/PAGE on conditioned media from cells cultured on type I collagen films revealed the presence of active gelatinase-A and that MCM stimulated progelatinase-B synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Screening for vertebral osteoporosis using individual risk factors. The Multicentre Vertebral Fracture Study Group.
Osteoporosis is a major cause of ill health in postmenopausal women. Several risk factors for osteoporosis have been identified, and they have been widely recommended as a means of identifying subgroups of postmenopausal women who might benefit from prophylaxis and therapy. Evidence to support this use of risk factors is currently lacking, however. We have constructed and evaluated a profile of putative risk factors as a means of identifying women attending general practitioners who have sustained vertebral fractures. The overall prevalence of vertebral fractures in the 1012 women (mean age 64.4 years) studied was 7.8%. Women who had sustained vertebral fractures in this population were significantly (p less than 0.05) older and shorter than those without fractures. They reported a significantly (p less than 0.05) earlier menopause, lower parity and a greater prevalence of hyperthyroidism. However, the best screening instrument devised was not sufficiently predictive to warrant widespread use.
Aged↗
Quantitative microfocal radiography of children with renal osteodystrophy; comparison with laboratory and histological findings.
High definition microfocal radiography permitted the quantitative assessment of the radiographic features of renal osteodystrophy in the phalanges of 11 children in stable chronic renal failure, treated with phosphate binders for 1 year. The most consistent feature was subperiosteal cortical resorption, expressed as a ratio total length of resorbed subperiosteal bone/total length subperiosteal bone x 100. It was found that the extent of resorbed bone was significantly greater in the middle phalanx and on the ulnar surface of the phalanges. The radiological findings over the duration of the disease were compared with laboratory assessments and bone histomorphometry. The extent of the percentage of subperiosteal resorption at base line and its change during the study period correlated significantly with the level of serum parathyroid hormone levels and its change over the same period. No other significant correlations were found between radiographic features and laboratory assessments or with bone histomorphometry.
Adolescent↗
Bone turnover and 1,25-dihydroxycholecalciferol during treatment with phosphate binders.
The effect of dietary phosphate restriction with high-dose aluminum hydroxide or calcium carbonate on bone disease assessed by histomorphometry and on the plasma levels of 1,25-dihydroxycholecalciferol was investigated in 12 children with chronic renal failure (GFR 8 to 45 ml/min/1.73 m2, age 5 to 15 years) over a one year period. Prior to treatment patients had biochemical and histological hyperparathyroidism with greatly increased bone formation rates. During treatment, plasma phosphate levels decreased from the upper to the lower limit of normal for age (pre, 1.69 +/- 0.06 mmol/liter; 6 months, 1.28 +/- 0.06 mmol/liter; 1 year, 1.34 +/- 0.06 mmol/liter; P less than 0.01). Circulating 1,25-dihydroxycholecalciferol rose to supranormal levels within three months and remained high throughout the period of study (pre, 96 +/- 32 pmol/liter; 6 months, 144 +/- 46 pmol/liter; 1 year, 169 +/- 53 pmol/liter; P less than 0.001). Significant falls in bone formation rate at tissue and cellular levels (P less than 0.005) and in total resorption surface (P less than 0.005) were observed. A mild mineralization defect present before treatment worsened, with a decrease in mineral appositional rate (P less than 0.01) and increase in mineralization lag time (P less than 0.01). Staining for aluminum in post-treatment biopsies was positive in 9 of 11 cases. Phosphate restriction produced suppression of biochemical and histological hyperparathyroidism and sustained elevation of circulating 1,25-dihydroxycholecalciferol. The adverse changes in bone mineralization may be related to aluminum hydroxide therapy; calcium carbonate is therefore recommended.
Adolescent↗
Lack of osteomalacia in chronic cholestatic liver disease.
Assessment of osteomalacia using rigorous histologic definition was carried out in 36 unselected patients with chronic cholestatic liver disease, 33 with primary biliary cirrhosis, and 3 with primary sclerosing cholangitis. Disease duration varied from 1 to 11 years. The mean values for total trabecular bone volume, osteoid volume, osteoid surface, and mineralization appositional rate were all decreased when compared to age-matched and sex-matched controls. There was a highly significant decrease in the mean osteoid seam width in both females (P = 0.001) and males (P = 0.02), and a significant prolongation of the mineralization lag time was found in females (P = 0.05), but failed to reach significance in males. These results excluded osteomalacia but were more indicative of osteoporosis. Biochemical evidence of osteomalacia was also absent, with serum calcium, serum phosphorus, and mean 25-hydroxyvitamin D levels not significantly different from control values, although there was a nonsignificant decrease in the mean value of 25-hydroxyvitamin D in patients with elevated serum bilirubin levels, and all patients with levels below 20 nmol/L had avoided sunlight exposure. The present results suggest that osteoporosis is the major type of metabolic bone disease in patients with chronic cholestatic liver disease.
Adult↗
Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy.
To determine the frequency of osteoporosis in patients with autoimmune chronic active hepatitis who are maintained on corticosteroids, both cortical and trabecular bone loss were studied in a group of 36 patients. A significant decrease in both the total trabecular bone volume (p = 0.005) and cortical plate thickness (p = 0.01) of iliac crest biopsy specimens was found in the patients with chronic active hepatitis. Bone mineral content of the radial metaphysis, a site composed of both cortical and trabecular bone, was found to be significantly decreased (p = 0.05). However, no statistical reduction in cortical bone mass of the radial diaphysis and second metacarpal was detected. Altogether, 47% of patients had evidence of either excessive trabecular or cortical bone loss, or both, as judged by histologic and radiologic criteria. The presence of cirrhosis at the time of diagnosis or subsequently did not appear to lead to greater loss of bone mass. However, a weak inverse correlation was found between the product of mean dose and duration of corticosteroid therapy and both the trabecular bone volume and the cortical plate thickness of the iliac crest biopsy specimens. Based on these results, patients with autoimmune chronic active hepatitis on low doses of prednisolone therapy may need to be treated with calcium and vitamin D at an early stage of their disease.
Adrenal Cortex Hormones↗
Osteoporosis in chronic cholestatic liver disease.
Assessment for both trabecular and cortical osteoporosis was carried out in 36 unselected patients with chronic cholestatic liver disease of whom a number had received corticosteroids during the course of their illness. Symptoms suggestive of osteoporosis were present in 42 per cent of patients of whom 11 per cent had evidence of one or more wedged or collapsed vertebrae. There was a highly significant decrease in the cortical area (total area ratio of the second metacarpal (p = 0.05), bone mineral content at the metaphyseal site of the radius (p = 0.01) and the total trabecular bone volume of the iliac crest biopsies (p = 0.005) in the 31 female patients when compared with age and sex-matched healthy controls). There was a nonsignificant decrease in total trabecular bone volume of the iliac crest and bone mineral content of the radial metaphysis in the males compared with age and sex-matched controls but the cortical plate thickness of the iliac crest (p = 0.005) and bone mineral content of the radial diaphysis (p = 0.02) were significantly higher. In total, 42 per cent of patients had evidence of either excessive cortical (28 per cent) and/or trabecular (36 per cent) bone loss as judged by radiological and histological criteria. Only the total trabecular bone volume of the iliac crest, of all the parameters measured was significantly (p = 0.02) lower in patients with backache compared with those without back pain. Significantly greater bone loss was demonstrated at all sites measured in those patients that were receiving or had received corticosteroids in the past.
Adrenal Cortex Hormones↗
Enterohepatic circulation of vitamin D.
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Bile↗
Calcium metabolism in subjects living with a permanent ileostomy.
Several indices of calcium metabolism have been studied in 39 subjects living with a permanent ileostomy after proctocolectomy for ulcerative colitis, and in a control group of 39 healthy volunteers, matched for age and sex. No significant differences were found in plasma levels of calcium, phosphate, magnesium, parathyroid hormone, calcitonin and 25-hydroxy-vitamin D nor in the urinary excretion of calcium and phosphate, but the alkaline phosphatase was raised in the ileostomists. The bone density of the ileostomists was rather low, but the difference from the control subjects was not statistically significant. The absorption of calcium was measured by means of a total body counter. The ileostomists retained significantly more calcium than expected. It is suggested that this may represent the correction of a state of calcium deficiency at the time of proctocolectomy, due to the effects of the colitis and its medical treatment with corticosteroids.
Alkaline Phosphatase↗
Low bone turnover state in primary biliary cirrhosis.
To determine whether bone loss in patients with chronic cholestatic liver disease is the consequence of a high or low bone turnover state, 30 female patients with biopsy-proven primary biliary cirrhosis underwent iliac crest biopsy following double tetracycline labeling. The mean trabecular bone volume was decreased as a result of trabecular plate thinning in both the premenopausal (p less than 0.02) and postmenopausal (p less than 0.05) patients, compared to age- and sex-matched controls. Indications that osteoblastic function was impaired included a significantly lower mean wall thickness (p less than 0.01) and mean osteoid seam width (p less than 0.05), and this in association with a decreased mineral appositional rate and prolonged mineralization lag time was suggestive of a defect in matrix synthesis. Further evidence of impaired osteoblastic activity was the significantly lower bone formation rate at both tissue (p less than 0.001) and basic multicellular unit levels (p less than 0.05) in the postmenopausal patients. Total resorption surfaces and fasting urinary calcium/creatinine ratios were significantly increased (p less than 0.005 and 0.05, respectively) in the premenopausal patients and mean interstitial bone thickness reduced in both pre- and postmenopausal patients, suggesting that increased resorption may also contribute to bone loss in primary biliary cirrhosis.
Adult↗
Measurements of total body calcium by prompt-gamma neutron activation analysis using a 252Cf source.
A clinical neutron activation instrument has been developed for in vivo elemental analysis. Utilizing the prompt-capture gamma ray technique, simultaneous total body (TB) measurements of primarily Ca, but also Cl, N, C, and H are routinely performed. This paper describes a technique for the measurement of TBCa (g) that relies on the use of TBCl as an internal standard. The method has been tested with four anthropomorphic phantoms covering a range of body habitus. The mean discrepancy between the measured and known Ca contents was 3.6%. The technique has been applied to two patient groups, and encouraging results were obtained.
Body Composition↗