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Biomedical subjects

J E Compston

Publications and source records attributed to J E Compston.

At least 73 records · Page 4Linked to original sources
PubMed1997

The localization of androgen receptors in human bone.

Androgens have important effects on the human skeleton, and deficiency has been associated with bone loss in both males and females. The skeletal actions of androgens may be mediated directly via the androgen receptor (AR) or indirectly via the estrogen receptor after aromatization to estrogens. The presence of androgen receptors has been demonstrated in bone cells and chondrocytes in vitro, but their presence in human bone in situ has not been reported. In order to provide further evidence for a direct action of androgens on bone via androgen receptors, we have used specific monoclonal antibodies to investigate the expression of human AR in normal developing and osteophytic bone of both sexes. In the growth plates from the developing bone, androgen receptors were predominantly expressed in hypertrophic chondrocytes and in osteoblasts at sites of bone formation. They were also observed in osteocytes in the bone, and in mononuclear cells and endothelial cells of blood vessels within the bone marrow. In the osteophytes, androgen receptors were widely distributed at sites of endochondral ossification in proliferating, mature, and hypertrophic chondrocytes and at sites of bone remodeling in osteoblasts. They were also expressed in osteocytes and mononuclear cells within the bone marrow. The pattern and number of cells expressing the receptor was similar in both sexes. Our results show for the first time the presence and distribution of androgen receptors in normal developing human and osteophytic bone in situ and further provide evidence for a direct action of androgens on bone and cartilage cells.

Adenocarcinoma↗
PubMed1997

Cortical remodeling following suppression of endogenous estrogen with analogs of gonadotrophin releasing hormone.

The effects of estrogen suppression on osteonal remodeling in young women was investigated using transiliac biopsies (eight paired biopsies + four single pre; three single post biopsies) taken before and after treatment for endometriosis (6 months) with analogs of gonadotrophin releasing hormone (GnRH). Estrogen withdrawal increased the proportion of Haversian canals with an eroded surface (106%, p = 0.047), a double label (238%, p = 0.004), osteoid (71%, p = 0.002), and alkaline phosphatase (ALP) 116%, p = 0.043) but not those showing tartrate-resistant acid phosphatase (TRAP) activity (p = 0.25) or a single label (p = 0.30). Estrogen withdrawal increased TRAP activity in individual osteoclasts in canals with diameters greater than 50 microns (p = 0.0089) and also the number of osteons with diameters over 250 microns (p = 0.049). ALP activity in individual osteoblasts was increased but not significantly following treatment (p = 0.051). Wall thickness was significantly correlated with osteon diameter (p < 0.001). In a separate group of patients (four pairs + one post biopsy) on concurrent treatment with tibolone, there was no significant increase in the osteon density, cortical porosity, median canal diameter, or the markers of bone formation and resorption. Enzyme activities and numbers of active canals were also not increased with the concurrent treatment, but there was still an increase in the osteon diameter. As previously shown for cancellous bone, estrogen withdrawal increased cortical bone turnover. We have now shown that resorption depth within Haversian systems was also increased with treatment. The enhanced TRAP activity in individual osteoclasts supports the concept that osteoclasts are more active following estrogen withdrawal in agreement with theoretical arguments advanced previously. Understanding the cellular and biochemical mechanisms responsible for increased depth of osteoclast resorption when estrogen is withdrawn may allow the development of new strategies for preventing postmenopausal bone loss.

Acid Phosphatase↗
PubMed1997

Prevention and management of osteoporosis. Current trends and future prospects.

There has been significant progress in the management of osteoporosis in recent years, resulting in a greater choice of therapeutic interventions for the physician. Nearly all of the treatments currently available are antiresorptive agents, which prevent bone loss and, in some cases, have been shown to reduce fracture risk. Some of these agents appear to have site-specific effects in the skeleton and may therefore not protect against all types of osteoporotic fracture. However, other drugs, such as hormone replacement therapy and possibly bisphosphonates, appear to reduce fracture risk in both the spine and hip. The optimal timing and duration of therapy for osteoporosis remain to be defined and will differ between agents. There is increasing evidence that the changes in bone mass induced by treatment do not always predict the corresponding changes in fracture rate. Thus, significant reductions in fractures may occur with antiresorptive therapy despite very small changes in bone mass, while large increases in bone mass may be associated with reduced bone strength and unchanged or increased fracture rates. Finally, the demonstration that relatively short term interventions can substantially reduce fracture rates, even in the very elderly in whom bone mass is almost universally low, provides the rationale for a more aggressive approach to treatment in patients with established disease.

Aged↗
PubMed1996

Bone mineral mass consolidation in young British adults.

Forty males and 40 females, ages 18-21 years, were recruited into a prospective study to investigate the consolidation of bone mineral after cessation of linear growth and the influences of calcium intake, lifestyle factors, physical activity, and body composition on bone. Three sets of bone measurements were made annually at the spine, hip, and whole body (dual-energy X-ray absorptiometry) and at the wrist and midshaft radius (single photon absorptiometry). At baseline, the bone mineral content (BMC) was significantly greater in males than females at all sites (p < 0.004). After adjustment for scan area (BA), height, weight, and age, male BMC was significantly greater than female BMC at the midshaft radius (+7.4%; p < 0.01) but lower at the spine (-10.9%; p < 0.001) with no difference at the wrist, hip, or whole body. Positive effects of leanness on bone were observed in females but not in males. Dietary calcium, nutrient intakes, and physical activity levels were not size-independent determinants of BMC at any site. Significant increases in whole-body BMC were observed within individuals over the study period of 670 (SD 51) days, +1.3% in males and +2.1% in females (p < 0.01), mirrored by increases in BMC and BA at most skeletal sites. After allowing for changes in BA, significant increases (p < 0.01) were observed in adjusted BMC for the whole body (males, +1.1%; females, +0.6%), lumbar spine (males, +1.5%; females, +1.1%), and midshaft radius (males, +1.9%; females, +2.0%). No lifestyle or anthropometric factors were identified that influenced these longitudinal increases in bone mineral.

Adolescent↗
PubMed1996

Assessment of cancellous bone structure: comparison of strut analysis, trabecular bone pattern factor, and marrow space star volume.

Cancellous bone architecture is an important determinant of bone strength. Recently, several approaches to the assessment of bone structure in histological sections have been described; however, no comparative studies of these different methods have been reported. We have developed computerized methods for the simultaneous assessment of several indices of bone structure, including trabecular bone pattern factor, marrow space star volume, node-to-terminus ratio, trabecular number, and trabecular separation. The relationships between these variables has been examined in iliac crest cancellous bone obtained from 41 healthy subjects, 17 male and 24 female, aged 20-80 years (mean 47.9 years). All structural indices assessed showed significant correlations with cancellous bone area (p < 0.0001). Values for trabecular bone pattern factor and marrow space volume were highly correlated (r = 0.789; p < 0.0001). A comparison of indices obtained by strut analysis with trabecular bone pattern factor and marrow space star volume also revealed significant relationships, especially for the terminus-to-terminus strut length (r = 0.704 and r = 0.634, respectively; p < 0.0001) and node to terminus ratio (r = -0.947 and r = -0.788, respectively; p < 0.0001). The node-to-terminus ratio and trabecular bone pattern factor showed significant relationships with age which were independent of sex, cancellous bone area and trabecular width (p < 0.01 and p < 0.005, respectively). Our results demonstrate strong correlations between the different two-dimensional indices of bone structure in cancellous bone from healthy subjects. Trabecular penetration is likely to be an important determinant of all these variables, which may therefore reflect connectivity; however, direct comparison of these methods with three-dimensional techniques is required to establish their true relationship to bone structure.

Adult↗
PubMed1996

Production of collagenase by human osteoblasts and osteoclasts in vivo.

Studies in some animal species have demonstrated the production of metalloproteinases by bone cells, suggesting that they may play a role in bone modeling and remodeling. The aim of the present study was to investigate the expression of collagenase in human bone in situ, using heterotopic and osteophytic bone. Immunohistochemistry was performed on chilled sections of bone, using well characterized polyclonal antibodies to human collagenase. The heterotopic and osteophytic bone exhibited high turnover and both bone modeling and remodeling were evident. Collagenase expression by osteoblasts was demonstrated in cells synthesising matrix and in lining cells; the strongest signal was seen in areas of de novo matrix formation, where bridges of woven bone were being formed between areas of mineralized bone. Collagenase was also present in some osteoclasts associated with eroded bone surfaces and in some mononuclear cells that were present in resorption cavities and in the bone marrow. Our results provide the first demonstration, in situ, of collagenase in human bone and suggest that it may play a role in human bone modeling and remodeling. Production of collagenase by active osteoblasts and lining cells suggest that it may be involved both in matrix formation and activation of bone remodeling. The presence of collagenase in osteoclasts provides further evidence that metalloproteinases may play a role in bone resorption.

Acid Phosphatase↗
PubMed1996

Effects of hormone replacement therapy on cancellous bone microstructure in postmenopausal women.

Menopausal bone loss is associated with disruption of cancellous bone architecture which has adverse mechanical effects and is believed to be irreversible. The aim of this study was to examine the effects of long-term hormone replacement therapy on cancellous bone structure in women with postmenopausal osteoporosis. Iliac crest biopsies from 22 women with osteopenia or osteoporosis were obtained before and after hormone replacement therapy (mean duration 23.5 months). Cancellous bone architecture was assessed by strut analysis, trabecular bone pattern factor, and marrow star volume. Post-treatment biopsies showed no significant changes in any of the structural indices assessed. Our results suggest that hormone replacement therapy preserves existing cancellous bone structure but provide no evidence that this treatment is able to reverse structural disruption in women with postmenopausal osteopenia or osteoporosis.

Adult↗
PubMed1996

Early increase in plasma parathyroid hormone levels following liver transplantation.

BACKGROUND/AIMS: The pathogenesis of post-transplantation bone loss is poorly understood, although glucocorticoid therapy is believed to play an important role. In the present study we have measured plasma parathyroid hormone concentrations in the first few months after orthotopic liver transplantation, in order to examine the potential contribution of hyperparathyroidism to bone disease. PATIENTS AND METHODS: Twenty-seven patients aged 32-54 years, 12 male, undergoing liver transplantation were studied prospectively before and for 3 months after operation. Plasma parathyroid hormone and serum 25-hydroxyvitamin D concentrations were measured by radioimmunoassay. RESULTS: Plasma parathyroid hormone levels were normal in all but two patients prior to transplantation. There was a highly significant increase in plasma parathyroid hormone concentrations at 1 and 2 months (p < 0.0005 and 0.001, respectively, versus baseline); by 3 months, values were close to those obtained preoperatively. Serum 25-hydroxyvitamin D concentrations showed no significant change over the study period. However, 74% of the patients had subnormal values at baseline. CONCLUSIONS: An early and transient increase in plasma parathyroid hormone after liver transplantation may be responsible for the high rates of bone loss which occur during the first few post-operative months. Prevention of post-transplantation bone disease is most likely to be achieved by peri-operative intervention with an anti-resorptive agent.

Adult↗
PubMed1996

Distribution of platelet-derived growth factor (PDGF) A chain mRNA, protein, and PDGF-alpha receptor in rapidly forming human bone.

Platelet-derived growth factors (PDGFs) are potent bone cell mitogens which stimulate the proliferation of osteoblastic cells, may also be involved in the regulation of osteoclastic bone resorption, and indirectly induce vascular endothelial cell proliferation and angiogenesis. In view of the established relationship between angiogenesis and osteogenesis, the production of PDGFs by both osteoblastic and vascular endothelial cells suggests that they may play a role in bone formation during skeletal development. We have used two human models of rapid bone formation, heterotopic bone and osteophytic bone, to investigate the expression of PDGF-A mRNA and protein and the PDGF-alpha receptor protein in vivo using in situ hybridization and immunohistochemistry. PDGF-A mRNA and protein were widely distributed throughout heterotopic and osteophytic bone. Within the cartilaginous tissue PDGF-A mRNA and protein were most strongly expressed by mature chondrocytes with decreased expression in the hypertrophic zone and almost no staining in the mineralizing and mineralized zones. PDGF mRNA and protein were also expressed in cells of small blood vessels within fibrous and cartilaginous tissue. In contrast, PDGF-alpha receptor expression was restricted to a minority of hypertrophic chondrocytes and sites of vascular invasion. Within the bone and fibrous tissue the growth factor and the receptor were widely distributed, being detected on most cells at sites of bone formation or in remodeling sites; no receptor was detected on osteoclasts. These data demonstrate the widespread expression of PDGF-A and its receptor in forming human bone and indicate that this growth factor may exert autocrine and paracrine effects to regulate osteogenesis during skeletal development.

Bone Development↗
PubMed1996

The effects of long-term hormone replacement therapy on bone remodeling in postmenopausal women.

Hormone replacement therapy prevents menopausal bone loss and reduces the risk of fragility fracture, but its effects on bone remodeling have not been clearly established. We studied the effects of long-term hormone replacement therapy on bone turnover and remodeling balance in 22 postmenopausal women with osteopenia or osteoporosis. Iliac crest biopsies were obtained before and after treatment (mean 23.5 months) after double tetracycline labeling and subjected to histomorphometric analysis. Post-treatment biopsies showed a significant reduction in bone formation rate at tissue level and activation frequency (p = 0.002 and 0.01, respectively). There was also a reduction in mineral appositional rate (p = 0.0002) and osteoid seam width (p = 0.01), but no significant change in mineralization lag time or osteoid maturation period. Wall width showed a significant decrease after treatment (p = 0.03) and there was a consistent trend toward a reduction in resorption cavity dimensions with a statistically significant decrease in the resorption cavity length (p = 0.03). These results confirm the previously reported reduction in bone turnover in postmenopausal women treated with hormone replacement therapy. Post-treatment biopsies also showed a reduction in resorption cavity size and a decrease in wall width, the latter possibly reflecting a compensatory change in response to the reduction in erosion depth. Our data do not provide any evidence that conventional hormone replacement therapy has anabolic effects at the level of the bone remodeling unit and indicate that its beneficial skeletal effects result from suppression of bone turnover and a reduction in the size of resorption cavities.

Adult↗
PubMed1996

Rates of bone loss in peri- and postmenopausal women: a 4 year, prospective, population-based study.

1. Age-related bone loss is well established but reported rates of bone loss in the spine and femur vary widely. The aim of the present study was to investigate changes in bone mineral density in the lumbar spine and proximal femur in healthy postmenopausal women. 2. One hundred and thirty-eight population-based women, aged 45-65 years, recruited from general practice registers in 1990, were assessed at baseline; 108 returned for repeat assessment 4 years later, of whom 31 had taken hormone replacement therapy for 12 months or more of the 4-year study period. Bone densitometry of the lumbar spine and proximal femur was performed by dual-energy X-ray absorptiometry. Serum 25-hydroxyvitamin D and oestradiol were measured by RIA and serum intact parathyroid hormone by radio-immunometric assay. 3. The mean age at follow-up was 62 years (mean of 13.6 years after menopause). Lumbar spine bone mineral density was significantly higher in women who had received hormone replacement therapy for more than 12 months during the study period than in those who had not (P < 0.01). There was no difference between these two groups in the femoral neck or trochanteric bone mineral density. In the lumbar spine, the annual change in bone mass in untreated women was -0.39% (95% confidence intervals -0.60 to -0.09; P < 0.02) whereas there was a small gain in women receiving hormone replacement therapy [+0.36% (-0.12 to 0.84; P not significant)]. The annual change in bone mass in the femoral neck and trochanter was -0.51 and -0.45 respectively in untreated women (P < 0.01 and P < 0.02), and -0.16 and -0.15 in those receiving hormone replacement therapy (P not significant). 4. Our results demonstrate relatively low rates of bone loss in the spine and proximal femur in these healthy, population-based peri- and postmenopausal women. Hormone replacement therapy appeared to be associated with a significant protective effect on spinal, but not femoral, bone mineral density.

Absorptiometry, Photon↗
PubMed1996

Vertebral deformity in the thoracic spine in post-menopausal women: value of lumbar spine bone density.

Differential bone loss in the thoracic and lumbar spine is known to occur in some patients with osteoporosis. However, the discriminant value of lumbar spine bone densitometry in the detection of thoracic spine fractures in healthy, population-based women has not been established. The relationship between lumbar spine bone mineral density and thoracic spine vertebral deformities in a prospective study of 79 post-menopausal population-based women aged 45-65 years has been investigated. Lumbar spine bone mineral density was measured using dual energy X-ray absorptiometry, and vertebral morphometry was assessed from lateral thoracic spine radiographs. Seven women (9%) were found to have one or more vertebral deformities in the thoracic spine (reduction in anterior or posterior height > 25%). Only one of these had a lumbar spine bone mineral density T score below -2.5, whilst the T score was between -1 and -2.5 in three and greater than -1 in three. Two of these women also had lumbar spine vertebral deformity but lumbar spine radiographs were normal in the remaining five. There were no significant differences in age, height, weight, hormone replacement therapy use or bone mineral density between women with and without thoracic spine fractures. These results demonstrate that vertebral deformities in the thoracic spine occur in a proportion of healthy post-menopausal women in the absence of densitometric or radiographic evidence of osteoporosis in the lumbar spine. Although often asymptomatic, the significance of these fractures lies in the increased risk of further fractures. In the future, morphometric X-ray absorptiometric techniques may prove valuable in the detection of these fractures and avoid the need for conventional radiography.

Absorptiometry, Photon↗
PubMed1995

Evidence for interrupted bone resorption in human iliac cancellous bone.

Bone resorption and formation are coupled both in time and space and may occur simultaneously in the same remodeling unit. A number of studies have shown that the formative phase of the remodeling sequence may undergo temporary interruptions prior to completion and it is possible that bone resorption may be subject to similar interruptions. We have investigated this hypothesis by studying the distribution of eroded depth in resorption cavities in human cancellous bone. Eroded depth was assessed in iliac crest cancellous bone from 41 normal healthy subjects using a cubic spline curve fitting technique. The distribution of mean eroded depths was skewed to the right. Comparison of the observed distribution with an expected distribution, which was calculated from previously published data and assumes resorption begins rapidly and slows as it approaches completion, showed a significantly greater proportion of shallower cavities than expected (p<0001). Similarly, comparison of observed and uniform distributions, which assumes a constant rate of resorption throughout the erosion period, also showed a significantly greater proportion of smaller cavities (p<0.01). In subjects aged less than 39 years, there were fewer small cavities than in those aged 40-59 years. In addition, there was some evidence that females of 40-59 years had a proportionately greater number of smaller cavities than males; however, there were no differences in other age groups. Our results demonstrate a significantly greater proportion of smaller resorption cavities than would be expected from current models of bone remodeling and are consistent with the hypothesis that resorption undergoes temporary interruptions and/or permanent arrest during the process of bone remodeling.

Adult↗
PubMed1995

The effects of gonadotrophin-releasing hormone agonists on iliac crest cancellous bone structure in women with endometriosis.

The administration of gonadotrophin-releasing hormone (GnRH) analogs to premenopausal women causes hypoestrogenism and bone loss, but the effects on cancellous microstructure have not been determined. In this study we have assessed bone structure in transiliac biopsies obtained from women before and after treatment for endometriosis with GnRH analogs. Twenty-one premenopausal women were studied, paired biopsies being obtained in 13; five women received both GnRH analogs and Org OD 14 (Tibolone, Livial). Comparison of pre- and post-treatment biopsies in women treated only with GnRH analogs showed a reduction in indices related to connectivity (node-to-terminus ratio, node-to-loop strut length, p < 0.02) and increase in inversely related indices (terminus-to-terminus and node-to-terminus strut length, p < 0.03). No significant changes were seen in any of the structural indices in women receiving both GnRH and Org OD 14 therapy. Activation frequency and bone formation rate at tissue level increased in women treated with GnRH agonists alone, although this change was not statistically significant. Our results suggest that bone loss induced by GnRH analogs may be associated with adverse effects on cancellous microstructure which are unlikely to be reversed following cessation of therapy. Concurrent treatment with Org OD 14 appears to prevent these changes.

Adult↗