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Biomedical subjects

J E Compston

Publications and source records attributed to J E Compston.

At least 37 records · Page 2Linked to original sources
PubMed2001

High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation.

Osteoporosis is a common complication of liver transplantation. Its pathogenesis is multifactorial, but preexisting bone disease in patients with chronic liver disease is likely to play an important role. The aim of this study was to evaluate bone mineral density in adult patients with chronic liver disease prior to liver transplantation. A total of 243 consecutive patients (128 male, 115 female; mean age 51.1years) with chronic liver disease undergoing assessment for transplantation, were recruited over a 4-year period. BMD measurements were made using dual energy X-ray absorptiometry in the lumbar spine (L1-L4) and femoral neck (FN). Osteoporosis and osteopenia were defined by WHO criteria. Osteoporosis at either L1-L4 or FN was present in 36.6%, osteopenia in 48.1%, and normal BMD in only 15.2% of patients. There was no difference in prevalence of osteoporosis between males and females (P = 0.442). Women with osteoporosis were on average 10 years older (56.2 +/- 1.4 years) than those with normal bone density (46.4 +/- 2.3 years) P = 0.002; in men, no statistically significant age effect was found. Patients with osteoporosis had on average lower body weight than those with normal bone density (64.9 +/- 1.8 kg vs 74.2 +/- 2.2 kg) P = 0.003. T-scores in patients with cholestatic liver disease were lower than in non-cholestatic disease and the lowest BMD values were found in patients with cystic fibrosis. Logistic regression revealed that in women, increasing age (P = 0.004; OR = 1.12; CI 1.04-1.21) and lower body weight (P = 0.01; OR = 0.95; CI 0.91-0.99) were significant independent risk factors for osteoporosis but menopausal status (P = 0.1; OR = 0.24; CI 0.05-1.32) and presence or absence of cholestasis (P = 0.326; OR = 1.54; CI 0.65-3.67) were not. There were no independent risk factors in men. This study demonstrates a high prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation, men and women being equally affected. With the exception of increasing age and lower body weight in women, no independent risk factors were found, emphasizing the importance of BMD measurements in these patients and the need for prophylactic measures to optimize bone health.

Absorptiometry, Photon↗
PubMed2001

Tie2 ligands angiopoietin-1 and angiopoietin-2 are coexpressed with vascular endothelial cell growth factor in growing human bone.

Angiogenesis is essential for bone growth and repair. Recent studies have shown that the endothelial-specific mitogen vascular endothelial growth factor (VEGF) is a key regulator of vascular invasion into the growth plate in infant and adolescent animals. In order to identify mechanisms regulating VEGF-induced angiogenesis in growing bone, we have investigated the expression of the angiopoietins (Ang-1 and Ang-2) in human neonatal ribs. Ang-1 and Ang-2 exhibited similar patterns of staining in the growing rib. In the cartilage, expression of Ang-1 and Ang-2 increased with chondrocyte maturation. Ang-1, Ang-2, and VEGF were not detected in the resting zone except adjacent to vascular canals, and maximum expression was detected at the cartilage bone interface. In the cartilage, Ang-2 was more highly expressed than Ang-1 or VEGF, with staining observed in the proliferating, hypertrophic, and mineralized zones. In the bone, Ang-1, Ang-2, and VEGF were detected in modeling and remodeling sites. Ang-1 was detected in the majority of osteoblasts, osteoclasts, and in some marrow space cells. Ang-2 was expressed at variable levels by osteoblasts and osteoclasts in modeling and remodeling bone. VEGF was detected in cells at bone surfaces and in the marrow spaces. Strong staining for VEGF was observed in osteoblasts and osteoclasts in modeling and remodeling bone. In the perichondrium, Ang-1, Ang-2, and VEGF were most highly expressed adjacent to the hypertrophic zone and at sites of bone collar formation. In the periosteum, Ang-1, Ang-2, and VEGF expression colocalized with alkaline phosphatase expression. These observations provide the first evidence for the expression of the angiopoietins in growing human bone in vivo. The distribution of Ang-1, Ang-2, and VEGF indicate these factors may play key roles in the regulation of angiogenesis at sites of endochondral ossification, intramembranous ossification, and bone turnover in the growing human skeleton.

Angiopoietin-1↗
PubMed2001

Mechanisms by which high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women: role of locally produced growth factors.

Conventional hormone replacement therapy acts primarily by preserving bone, but cannot restore lost bone in women with established osteoporosis. Studies in rodents have shown that high doses of estrogens have anabolic skeletal effects, and recent observations in a group of women treated long term with high doses of estrogen indicated that similar effects occur in humans. This study examines the hypothesis that locally produced growth factors, including transforming growth factor-beta (TGF-beta) and platelet-derived growth factors (PDGFs), are involved in mediating the anabolic effects of high-dose estrogen. Transiliac-crest bone biopsies were taken from ten women, aged 52-67 years (mean 58 years), who had been treated with high-dose estrogen for 15 years. Control samples were obtained from four age-matched postmenopausal women not receiving estrogen therapy. TGF-betas and PDGFs were analyzed for mRNA and protein expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Results showed both TGF-beta1 and -beta2 mRNA, expressed as a ratio to GAPDH, were increased in the estrogen-treated group with an eightfold increase for TGF-beta1 (0.258 +/- 0.246 [mean +/- SD] vs. 0.032 +/- 0.053 in the control group, p = 0.02) and a twofold increase for TGF-beta2 (p = n.s.). TGF-beta3 analysis showed only negligible amounts in both groups. Protein expression levels for TGF-beta1, -beta2, -betaRI and -RII were higher in the estrogen-treated group than in controls, the most marked effects being seen for TGF-beta1. PDGF-A protein expression was also significantly higher in osteoblasts and osteocytes in women treated with estrogen, whereas PDGF-B showed only modest differences. The percentage of bone surface occupied by osteoclasts, as determined by tartrate-resistant acid phosphatase (TRAP) staining, was significantly reduced in the estrogen-treated group (p = 0.001). These results demonstrate that high-dose estrogen therapy is associated with increased TGF-beta, TGF-betaR, and PDGF synthesis and decreased osteoclast activity, consistent with the hypothesis that these growth factors may mediate the actions of estrogen in bone.

Acid Phosphatase↗
PubMed2001

Treatments for Crohn's disease that minimise steroid doses are associated with a reduced risk of osteoporosis.

Crohn's disease is associated with an increased prevalence of osteoporosis. Corticosteroids, commonly used to control exacerbations, appear to be a major risk factor for subsequent development of osteoporosis. Exclusion diets, avoiding foods that precipitate symptoms, frequently allow control of the disease avoiding the use of corticosteroids and may thereby reduce the risk of osteoporosis. To investigate this we performed bone mineral density measurements of the proximal femur and spine in 95 patients, 31 treated predominately by corticosteroids, 33 by dietary manipulation with a low life-time corticosteroid dose and 31 by treatments other than diets but also with a low life-time corticosteroid dose. In both groups with a low life-time corticosteroid dose bone mineral density was comparable to that of age-matched normal controls, whereas bone mineral density was significantly reduced in those treated predominately by corticosteroids. We conclude that corticosteroid therapy is an independent risk factor for osteoporosis in patients with Crohn's disease and should be used as little as possible.

Absorptiometry, Photon↗
PubMed2001

Sex steroids and bone.

Sex steroids are essential for skeletal development and the maintenance of bone health throughout adult life, and estrogen deficiency at menopause is a major pathogenetic factor in the development of osteoporosis in postmenopausal women. The mechanisms by which the skeletal effects of sex steroids are mediated remain incompletely understood, but in recent years there have been considerable advances in our knowledge of how estrogens and, to a lesser extent androgens, influence bone modeling and remodeling in health and disease. New insights into estrogen receptor structure and function, recent discoveries about the development and activity of osteoclasts, and lessons learned from human and animal genetic mutations have all contributed to increased understanding of the skeletal effects of estrogen, both in males and females. Studies of untreated and treated osteoporosis in postmenopausal women have also contributed to this knowledge and have provided unequivocal evidence for the potential of high-dose estrogen therapy to have anabolic skeletal effects. The development of selective estrogen receptor modulators has provided a new approach to the prevention of osteoporosis and other major diseases of menopause and has implications for the therapeutic use of other steroid hormones, including androgens. Further elucidation of the mechanisms by which sex steroids affect bone thus has the potential to improve the clinical management not only of osteoporosis, both in men and women, but also of a number of other diseases related to sex hormone status.

Androgens↗
PubMed2000

Vertebral morphometry: repeat scan precision using the Lunar Expert-XL and the Hologic 4500A. A study for the 'WISDOM' RCT of hormone replacement therapy.

On radiation safety grounds there is concern about the morbidity attributable to routine radiographs of the spine for the identification of new fractures in large-scale trials of fracture prevention. However, the role of the potentially safer low-radiation-dose technique of vertebral morphometry performed by third generation dual-energy X-ray absorptiometry equipment requires evaluation for use in clinical trials. We have therefore investigated the short-term inter-scan imprecision as well as the imprecision attributable to different-day analyses by the same operator and differences in analyses by different operators. The volunteer subjects were participants in a pilot study for a randomized controlled trial of hormone replacement therapy (Women's International Study of long Duration Oestrogen after Menopause, WISDOM). Each subject had two morphometric X-ray analysis scans separated by 2-4 weeks. Exclusions were women with densitometrically defined osteoporosis, as defined by the WHO criterion, and women with a body mass index exceeding 30.9 kg/m2. On average, the women were 58.7 years of age and had bone mineral density values in the lumbar spine which were about 0.7 SD units higher than a reference US female age-matched population. Scans were assessed from vertebrae T7 through L4. In the study there were no clinically significant differences in performance between the Hologic QDR 4500A and the Lunar Expert XL equipment. Between-scan imprecision was significantly worse than imprecision attributable to reanalysis of the same scan by a different operator or the same operator after an interval. Vertebral level had an effect on measurement uncertainty, especially at the level of the diaphragm and at T7. Coefficients of variation, expressed as percentages of mean values, were better for absolute height measurements than for height ratios, ranging from 1.75% to 3.40% for the three heights measured on three separate machines and from 2.34% to 4.11% for the two height ratios. These results compared favorably with the equivalent figures from a parallel study of morphometry precision undertaken using standard lateral radiographs of the thoracic and lumbar spine (3.1-3.6% and 3.8-3.9%, respectively). We conclude that in trials of prevention therapy in women (or men) selected for not having osteoporosis, low-dose vertebral morphometry using the Hologic 4500A, the Lunar Expert XL or similar equipment is preferable on safety grounds to the classical technique based on standard radiographs, although conventional radiology may still be required in those with prevalent or incident deformities to exclude causes other than osteoporosis. The place of this low-dose technique in trials performed on patients with osteoporosis requires further study.

Absorptiometry, Photon↗
PubMed2000

Megakaryocyte population in human bone marrow increases with estrogen treatment: a role in bone remodeling?

Skeletal effects of conventional hormone replacement therapy (HRT) are predominately antiresorptive, while high doses of estrogen have anabolic effects. The mechanisms mediating these effects are unclear but may involve cells in the bone marrow. We have investigated the in vivo effects of estrogen on the megakaryocyte (MK) population in bone marrow in 10 postmenopausal women before and after 2 years of conventional HRT, in 11 women after long-term, high-dose estradiol therapy, and in 2 premenopausal and 4 postmenopausal women who had received no previous estrogen treatment. Transiliac crest biopsies were halved and either decalcified and paraffin wax embedded for immunolocalization studies or dehydrated and embedded in LR White resin for histology. MKs were identified morphologically, and the bone marrow cell population and MK number quantified by cell counting in a defined area of view (1 mm(2)) from 5 randomly selected fields of bone marrow. Compared with pretreatment values, significantly higher MK numbers were found after conventional HRT treatment (before treatment, mean +/- SEM; 7.3 +/- 1.1 vs. after treatment, 18.0 +/- 1.6/5 mm(2); p < 0.0001), while the greatest MK number was associated with long-term, high-dose estradiol treatment (32.8 +/- 2.1/5 mm(2); p < 0.0001). Total bone marrow cell number did not differ significantly between groups. Immunolocalization studies revealed more intense estrogen receptor (ER)beta expression in MKs in the high-dose estradiol-treated group but similar levels of weak ERalpha staining in MKs in the control and high-dose estrogen-treated groups. Positive immunoreactivity for transforming growth factor (TGF)beta1, 2, and 3 and TGFbeta receptor I, II, and III was detected in MKs, with more intense staining being demonstrated in the high-dose estradiol-treated group, particularly for TGFbeta2 and TGFbetaRI and II. Our results demonstrate an increase in the MK population in bone marrow from women treated with estrogen. The ability of MKs to express ERs and synthesise TGFbeta, a potent mitogen in osteoblast differentiation, suggests that these cells may play a role in mediating estrogen-induced effects on bone.

Adult↗
PubMed2000

The localization of thyroid hormone receptor mRNAs in human bone.

Thyroid hormones have well-documented effects on the skeleton although the mechanism of their action on bone is poorly understood. We have recently reported the presence of different thyroid hormone receptor isoforms in human bone. However, there is evidence to suggest that the expression of thyroid hormone receptor (TR) protein may not necessarily correlate with its mRNA. In this study, we used specific digoxigenin-labeled ribo probes to investigate the expression of TRalpha1, variant TRalpha2, TRbeta1, and in particular TRbeta2 mRNA in human osteophytic bone and osteoclastoma tissue in situ. The number of positive cells was expressed as the percentage of the total number of cells of the same phenotype. In osteophytes, at sites of endochondral ossification, TRalpha1, variant TRalpha2, TRbeta1, and TRbeta2 mRNA were widely distributed in undifferentiated, proliferating, mature and hypertrophic chondrocytes. At sites of bone remodeling, TRalpha1 mRNA was expressed in the majority (> 90%) of osteoblasts. TRbeta1 and the variant TR-alpha2 mRNA were moderately expressed in approximately 75% of cells with only a few osteoblasts (< 25%) expressing TRbeta2 mRNA. All the TR transcripts were highly expressed in multinucleated osteoclasts in osteoclastoma tissue. The distribution of TR mRNAs was similar to TR receptor protein expression (as we have previously reported) in both osteophytic bone and osteoclastoma tissue except TRalpha1 mRNA that was highly expressed in osteoclasts and in undifferentiated, proliferating, mature, and hypertrophic chondrocytes in contrast to its receptor protein expression. This study highlights the importance of studying both TR mRNA and receptor proteins in triiodothyronine (T3) responsive tissues. This is also the first demonstration of the presence of TRbeta2 mRNA in bone. The role of TRbeta2 in mediating the actions of thyroid hormones in bone is not known and requires further investigation.

Aged↗
PubMed2000

Incidence of vertebral fractures in the first three months after orthotopic liver transplantation.

BACKGROUND AND OBJECTIVES: High rates of bone loss and increased fracture incidence have been reported in patients undergoing liver transplantation, mainly within the first post-operative year. The pathogenesis of post-transplantation bone disease has not been clearly established, but the high doses of glucocorticoids used for immunosuppression may contribute. The use of lower doses in recent years has been associated, in some studies, with lower rates of bone loss and decreased fracture incidence. The aim of this prospective study was to establish the incidence of vertebral fractures in the first 3 months in patients undergoing liver transplantation for chronic liver disease and to identify risk factors for fracture in these patients. DESIGN AND METHODS: Thirty-seven adults with end-stage liver disease were studied prospectively prior to and 3 months after liver transplantation. Vertebral fractures were assessed semi-quantitatively from lateral spine X-rays and bone mineral density measured using dual energy X-ray absorptiometry. RESULTS: Prior to transplantation, prevalent vertebral fractures were present in 13 patients (35%). New fractures developed after transplantation in 10 patients (27% of total) and were significantly more common in those with a prevalent vertebral fracture pre-operatively (P<0.02). Osteoporosis, defined as a bone mineral density T score below -2.5, was present in 39% of patients prior to transplantation, but bone mineral density was not helpful in predicting incident fracture, whether measured before or after transplantation. Over the 3-month study period, significant bone loss occurred in the femoral neck (P<0.05) but not the lumbar spine. CONCLUSIONS: Our results demonstrate a high incidence of vertebral fracture in the first 3 months after liver transplantation and indicate that prevalent vertebral fracture is an important risk factor for the subsequent development of fracture in these patients. Prevention of post-transplantation bone disease should focus both on optimizing bone mass prior to transplantation and preventing bone loss in the early post-operative period.

Absorptiometry, Photon↗
PubMed2000

The localization of the functional glucocorticoid receptor alpha in human bone.

Glucocorticoids have well-documented effects on the skeleton, although their mechanism of action is still poorly understood. The actions of glucocorticoids on bone cells are mediated, in part, directly via specific receptors. The presence of these receptors has been demonstrated in both rodent and human osteoblastic cells in vitro, but their presence in human bone in vivo has not been reported. In this study, we have used specific affinity purified polyclonal antibodies to the functional glucocorticoid receptor alpha (GRalpha) to investigate its expression in both developing and adult human bone using sections of neonatal rib, calvarial, and vertebral bones, tibial growth plates from adolescents, and iliac crest biopsies from adults who were to undergo liver transplantation. In the tibial growth plates, GRalpha was predominantly expressed in the hypertrophic chondrocytes within the cartilage. In the primary spongiosa, the receptor was highly expressed by osteoblasts at sites of bone modeling. Within the bone marrow, receptors were also detected in mononuclear cells and in endothelial cells of blood vessels. In the neonatal rib and vertebrae, GRalpha was widely distributed at sites of endochondral bone formation in resting, proliferating, mature, and hypertrophic chondrocytes. They were also highly expressed in osteoblasts at sites of bone modeling. At sites of intramembranous ossification in neonatal calvarial bone and rib periosteum, GRa was widely expressed in cells within the fibrous tissue and in osteoblasts at both the bone-forming surface and at modeling sites. In the iliac crests from adults, GRalpha was predominantly expressed in osteocytes. The receptors were not detected in osteoclasts. Our results show for the first time the presence of the functional GRalpha in human bone in situ and suggest that the actions of glucocorticoids on bone may be mediated, in part, directly via the GR at different stages of life. The absence of receptor expression in osteoclasts also suggests that the effects of glucocorticoids on bone resorption may be mediated indirectly.

Adolescent↗
PubMed1999

Bone remodeling and structure in postmenopausal women treated with long-term, high-dose estrogen therapy.

Conventional hormone replacement therapy preserves bone mass predominantly by reducing bone turnover but does not exert significant anabolic skeletal effects. In contrast, high doses of estrogen have been shown to increase bone formation in animals and we have recently reported high bone mineral density values in women treated long-term with estradiol implant therapy. The aim of this study was to investigate the mechanisms by which high doses of estrogen may increase bone mass in postmenopausal women. Iliac crest biopsies were obtained from 12 women who had received long-term treatment with estradiol implants (at least 14 years), on demand, following hysterectomy and bilateral salpingo-oophorectomy. Indices of bone turnover, remodeling balance and cancellous bone structure were assessed by image analysis and compared with those of premenopausal women. Mean wall width was significantly higher in women treated with estradiol therapy than in premenopausal women (44. 8 +/- 4.8 vs 38.8 +/- 2.8 mm; mean +/- SD; p = 0.001) and eroded cavity area was significantly lower in the implant-treated women (3612 +/- 956 vs 5418 +/- 1404 mm(2); p = 0.001). Bone formation rate at tissue level and activation frequency were lower in the women treated with implants, although the differences were not statistically significant. Indices of cancellous bone structure were generally similar between the two groups. These results provide the first direct evidence that high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women and indicate that these are achieved by stimulation of osteoblastic activity.

Aged↗
PubMed1999

Does estrogen stimulate osteoblast function in postmenopausal women?

How estrogen therapy influences bone metabolism in postmenopausal women has previously been studied using several approaches, including bone densitometry, measurement of biochemical markers of bone turnover, and histomorphometry. Taken together, these investigations suggest that conventional doses of estrogen protect from bone loss predominantly through suppression of bone resorption, with little evidence to suggest that a stimulatory action on osteoblasts is also involved. In contrast, studies of patients treated with estradiol implants suggest that, following prolonged exposure to relatively high estrogen levels, an additional stimulatory effect on osteoblast function is observed. The suggestion that estrogen stimulates osteoblast activity in postmenopausal women under certain circumstances is consistent with other evidence that estrogen is an important physiological regulator of osteoblast activity. Furthermore, these findings raise the possibility that it may be useful to develop strategies for treating postmenopausal osteoporosis that aim to reproduce the stimulatory action of relatively high estrogen levels on bone formation in postmenopausal women.

Aged↗
PubMed1999

Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) distribution in normal and pathological human bone.

Degradation of skeletal connective tissue is regulated, at least in part, by the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs), their natural inhibitors. The balance between MMPs and TIMPs may therefore be a determinant of normal bone turnover, and imbalance could thus lead to reduced organization of bone structure. To test this hypothesis, the cellular expression of MMPs and TIMP-1 was investigated by immunohistochemistry in human neonatal rib and osteophytic and heterotopic bone; these differ in their structure, with heterotopic bone showing the least and normal rib the most organized development. In all samples, high levels of MMPs were expressed. Collagenase and stromelysin-2 were detected in chondrocytes, osteoblasts, and osteoclasts, whereas gelatinase-B was confined to osteoclasts and mononuclear cells. Matrix-associated stromelysin-1 was present in fibrous tissue and osteoid. In contrast, the expression of TIMP-1 varied markedly between the three types of bone. In heterotopic bone only occasional low level TIMP-1 expression was detected in chondrocytes and osteoblasts. Osteophytic bone showed varying levels of TIMP-1, which was matrix-bound in fibrous tissue and cell-associated in osteoblasts, chondrocytes, and occasional mononuclear cells. In both types of bone, expression of TIMP-1 by osteoclasts was absent despite large numbers of these cells. Neonatal rib bone showed consistent expression of TIMP-1, particularly in chondrocytes, osteoblasts, and lining cells. In contrast to pathological bone, many osteoclasts were TIMP-1 positive. These results suggest that, in heterotopic and osteophytic bone, the low levels of TIMP-1, and in particular its absence in osteoclasts, may partly explain the more poorly organized bone formation in these pathological bone samples. Furthermore, TIMP-1 may play a role in the regulation of bone modeling and remodeling in normal developing human bone.

Adult↗