N J Garrahan

Cardiff University, Cardiff, Wales, United Kingdom

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Publications (49)195.16 Total impact

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    ABSTRACT: Investigations of the actions of estrogen on the skeleton have mainly focused on cancellous bone and there are no reported histomorphometric studies of the effects of oestrogen on cortical bone in humans. The aim of this study was to investigate the effects of both conventional hormone replacement therapy (HRT) and high-dose oestradiol on cortical bone in postmenopausal women. Transiliac biopsies were obtained from nine postmenopausal women aged 54-71 yr before and after 2 yr (mean, 23.5 months) of conventional HRT and in seven postmenopausal women aged 52-67 yr after long-term, high-dose oestradiol implant therapy (at least 14 yr). Indices of bone turnover, remodeling, and cortical structure were assessed by image analysis. Cortical width was highest in the women treated with high-dose oestrogen therapy (2.29 +/- 0.78 mm; mean +/- SD) and lowest in untreated women (1.36 +/- 0.60 mm; P=0.014). The proportion of canals with an eroded surface was significantly lower in the high-dose oestrogen group than in women before or after conventional HRT (3.03 +/- 3.7% vs. 11.1 +/- 7.1% and 10.5 +/- 8.6%; P=0.017 and 0.05, respectively). Bone formation rate (microm2/microm/day) in untreated women was significantly higher than in the high-dose oestrogen group (0.121 +/- 0.072 vs. 0.066 +/- 0.045, respectively; P=0.05), values in women treated with conventional HRT being intermediate. Our results provide the first histomorphometric evidence in postmenopausal women of dose-dependent oestrogen-induced suppression of bone turnover in iliac crest cortical bone. There was also a trend toward higher wall width with increasing dose of oestrogen, consistent with the previously reported anabolic effect in cancellous bone.
    Bone 10/2003; 33(3):330-4. · 3.82 Impact Factor
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    ABSTRACT: This study reports the results of quantitative analysis of iliac bone histology in adults with cystic fibrosis (CF) and low bone mineral density (BMD). Twenty patients with CF had bone biopsies taken after double tetracycline labeling. Histomorphometric measurements were made by image analysis, and data were compared with those of healthy control subjects. Cancellous bone area was lower in the patients with CF (p = 0.003), and there was a trend towards a decrease in cancellous bone connectivity. Bone formation rate at tissue level was significantly lower in patients with CF (p = 0.0002). Wall width, representing the amount of bone formed within individual remodeling units, was decreased (p < 0.0001), as was mineralizing perimeter and mineral apposition rate. Analysis of resorption cavities revealed lower cavity area, reconstructed surface lengths, and cavity depths (p < 0.003) in patients with CF, whereas eroded surface area was higher (p = 0.0004). Our results demonstrate low cancellous bone volume in adult patients with CF with low BMD, the main cause of which appears to be low bone formation at tissue and cellular level. Osteomalacia was diagnosed in one patient. This condition should be excluded as a cause of low bone mineral density in patients with CF and vitamin D insufficiency corrected.
    American Journal of Respiratory and Critical Care Medicine 12/2002; 166(11):1470-4. · 11.04 Impact Factor
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    ABSTRACT: Osteoporosis is a common and serious complication of solid organ transplantation. Effective therapeutic regimens have not been established but evidence that increased bone turnover is responsible for bone loss early after transplantation provides a rationale for the use of anti-resorptive agents in the peri-operative period. We have examined the effects of a single pre-operative infusion of pamidronate, 60 mg, on bone remodelling and turnover in a prospective study of 12 patients, four male and eight female aged 19-61 years, with chronic liver disease, who formed a subgroup of a larger randomised controlled single-blind study. Iliac-crest biopsies were obtained before and 3 months after liver transplantation and histomorphometry performed using image analysis. In untreated patients ( n=5) a significant increase in bone formation rate at tissue level was demonstrated at 3 months in comparison to pre-operative values (0.035+/-0.013 vs. 0.161+/-0.12 microm(2)/microm/day; mean +/- SD, P=0.003). In patients treated with pamidronate ( n=7) no significant increase in bone formation rate was demonstrated at 3 months, although there was a trend towards an increase in indices of bone turnover. In this group there was also a significant reduction in erosion cavity length (210.4+/-63.8 vs. 179.8+/-67.5 microm; P=0.03) and non-significant reductions in other indices of erosion cavity size. These results indicate that pre-operative administration of pamidronate in patients with chronic liver disease prevents, at least in part, the increase in bone turnover which occurs in untreated patients after transplantation.
    Transplant International 07/2002; 15(6):290-5. · 3.16 Impact Factor
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    ABSTRACT: Organ transplantation is associated with increased bone loss and high fracture risk, but the pathophysiological mechanisms responsible have not been established. We have performed a histomorphometric analysis of bone remodeling before and 3 months after liver transplantation in 21 patients (14 male, 7 female) aged 38-68 years with chronic liver disease. Eight-micrometer undecalcified sections of trans-iliac biopsies were assessed using image analysis. Preoperatively, bone turnover was low with a tendency toward reduced wall width and erosion depth. The bone formation rate increased from 0.021 +/- 0.016 (mean +/- SD) to 0.067 +/- 0.055 microm2/microm/day after transplantation (p < 0.0002) and activation frequency from 0.24 +/- 0.21/year-1 to 0.81 +/- 0. 67/year-1 (p < 0.0001). No significant change was observed in wall width, but there was a trend toward an increase in indices of resorption cavity size. There was a small increase in osteoid seam width postoperatively (p< 0.02) and decrease in mineralization lag time (p < 0.001). No significant changes in indices of cancellous bone structure were observed in the postoperative biopsies. These results demonstrate a highly significant and quantitatively large increase in bone turnover in the first 3 months after liver transplantation. Although no significant disruption of cancellous bone structure was demonstrated during the time course of the study, the observed changes in bone remodeling predispose to trabecular penetration and may thus result in long-term adverse effects on bone strength.
    Journal of Bone and Mineral Research 03/1999; 14(2):281-7. · 6.13 Impact Factor
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    ABSTRACT: Although bone mass is a contributory risk factor for intracapsular hip fracture, its distribution and porosity within the femoral neck is also important for bone strength. In femoral neck biopsies from 13 women with intracapsular hip fracture (mean +/- SEM: 75.4+/-2.1 years, OP) and 19 cadaveric samples (9 men and 10 women [control], aged 79.4+/-1.7 years), a segmental analysis was used to quantify circumferential variations in the characteristics of cortical bone haversian systems. In female control femoral necks, there was an increasing porosity gradient between the inferior (I) (7.7+/-0.6%) and superior regions (S) (16.05+/-1.8%,p < 0.005). In walking, these regions undergo compression and tension, respectively. In men, a similar trend was observed, but the differences were not significant (I: 11.1+/-1.2%; S: 14.1+/-1.7%; p = 0.133). This porosity gradient was not maintained in the fracture group (I: 10+/-1%; S: 12.65+/-1.2%). In contrast, porosity in the fracture group was greatest in the anterior cortex, being 41% higher in that quadrant than in controls (p = 0.06). The areal density of haversian canals ranged from 16.7 to 21.3 canals/mm2 with no significant differences between fractures and controls. In the control women, mean canal diameter was highest in the superior region (60+/-2.8 microm), and these canals were significantly larger than those in the inferior region (49.4+/-1.4 microm, p < 0.05). This difference was less marked in the fracture cases (I: 53.21+/-2.5 microm; S: 59.1+/-2.8 microm; p = 0.0878). Although the mean canal diameter in the anterior quadrant of the fracture cases was higher than in the control women this did not reach significance (OP/F: 59.5+/-3 microm; control/F: 52.7+/-2.6 microm; p = 0.106). However, the proportion of "giant" canals with diameters >385 microm (defined as the top 0.5% in the controls) was doubled in the anterior region of the fracture cases (OP/F: 1.28%; control/F: 0.69%; p < 0.005). Porosity is related to the square of the canal radius; therefore, such canals make a substantial contribution to cortical porosity. Previous work has shown that the elastic modulus of bone decreases approximately as the square root of porosity. Therefore, the increased porosity and the higher prevalence of "giant" canals have a markedly negative influence on the ability of the cortical shell to withstand stresses associated with a fall. The mechanisms responsible for the localized generation of "giant" haversian canals, and ultimately the "trabecularization" of the cortex, require further investigation.
    Bone 02/1999; 24(1):57-64. · 3.82 Impact Factor
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    ABSTRACT: Although bone mass is a contributory risk factor for hip fracture, its distribution about the femoral neck is also important. Femoral neck biopsies were obtained from 13 females with intracapsular hip fracture (fracture: mean age 74.3 +/- 2.3 years [SEM]) and 19 cadaveric samples (control: 9 males and 10 females 79.4 +/- 1.7 years) and the areas of cortical and cancellous bone were quantitated in octants. In the control group, although males had larger bones than females, the proportions of cortical and cancellous bone were not different (p > 0.05) between the genders. The total amount of bone, as a proportion of bone + marrow, was significantly reduced in the fractures compared with the female controls (%Tt.Ar: fracture 27.83 +/- 1.18, female control 33.62 +/- 1.47; p = 0.0054). Reductions in cortical bone area occurred in all regions but particularly in the inferior, inferoanterior, and anterior octants (p < 0.05). There were no differences between cases and controls in the regional amount of cancellous bone (all regions, p > 0.178). Marked reductions in mean cortical bone width between the fracture and female control group occurred in the anterior, inferoanterior (31%), and superoposterior (25%) regions. Representing cortical widths as simple Fourier functions of the angle about the center of area (R2adj = 0.79) showed in the cases that there was preservation of the cortical bone in the inferior region, with the proportional loss of cortical bone being greatest in the inferoanterior and superoposterior regions. It is concluded that loss of cortical, rather than cancellous, bone predominates in cases of femoral neck fracture. This loss occurs primarily along the inferoanterior to superoposterior axis. As this axis bears the greatest strain during a fall, it is hypothesized that specific thinning of the cortex in these regions leads to an exaggerated propensity to fracture in those so affected, above that resulting from an equivalent general decrease in bone mass.
    Journal of Bone and Mineral Research 01/1999; 14(1):111-9. · 6.13 Impact Factor
  • Bone 01/1999; 24(1). · 3.82 Impact Factor
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    ABSTRACT: 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.
    Journal of Bone and Mineral Research 08/1997; 12(8):1231-40. · 6.13 Impact Factor
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    ABSTRACT: An interactive image analysis package was developed to examine whole cross-sections from the femoral neck. The package quantifies cortical width (Ct.Wi), cortical porosity (Ct.Po), and proportions of cortical, cancellous bone as a percentage of bone plus marrow area. Segmental analysis was used to quantify circumferential variations in bone distribution within the femoral cross-section. To evaluate reproducibility of data four independent operators analyzed previously prepared femoral neck sections from a 2000 BC population. Differences in total and circumferential distributions of cortical and cancellous bone with respect to gender and age of samples were demonstrated. Reproducibility was assessed using coefficients of variation (CV). Analysis of sections using a variable magnification, giving largest possible image size, rather than a set magnification reduced variation between operators for all measurements. Use of a calculated threshold significantly decreased variation between operators for the proportions of cortical and cancellous bone (p < or = 0.026). Dividing the image into 8 rather than 16 segments also improved reproducibility. There was little agreement between operators in the determination of cortical porosity. The mean CV for the other quantitative indices such as cortical width and proportions of cortical and cancellous bone ranged from 4.87% to 13.52%. The genders showed similar patterns in circumferential distribution of bone. Cortical width was significantly greater in the inferior region compared to the other areas, whereas percent cortical bone was lowest at the superior region. The center of mass (COM) for the younger age group was located anteriorly, whereas in the older samples the COM was located posteriorly of the center of area (p = 0.041). Basic data relating to cortical and cancellous bone of acceptable reproducibility in comparison with current standards in iliac histomorphometry can now be provided at modest cost in operator time and resources.
    Bone 11/1996; 19(5):541-8. · 3.82 Impact Factor
  • S Vedi, P I Croucher, N J Garrahan, J E Compston
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    ABSTRACT: 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.
    Bone 08/1996; 19(1):69-72. · 3.82 Impact Factor
  • P I Croucher, N J Garrahan, J E Compston
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    ABSTRACT: 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.
    Journal of Bone and Mineral Research 08/1996; 11(7):955-61. · 6.13 Impact Factor
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    ABSTRACT: Without Abstract
    Osteoporosis International 01/1996; 6:196-196. · 4.04 Impact Factor
  • Bone 01/1996; 19(3):131-131. · 3.82 Impact Factor
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    ABSTRACT: 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.
    Bone 03/1995; 16(2):261-7. · 3.82 Impact Factor
  • P I Croucher, N J Garrahan, J E Compston
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    ABSTRACT: Osteoporosis is characterised by reduced bone mass and disruption of cancellous bone architecture; however, it is unknown whether these changes arise from a specific disease process or represent one extreme of physiological bone loss. We have quantitatively assessed cancellous structure in 35 patients with primary osteoporosis and 41 normal subjects. Cancellous microstructure was assessed by computerised strut analysis and by calculation of trabecular width, separation and number. Node to terminus ratio, node to node and node to loop strut length were significantly decreased in patients with osteoporosis when compared to normal subjects (P < 0.001), whereas terminus count and terminus to terminus strut length were significantly increased (P < 0.001). When two subgroups were matched for age these differences remained highly significant (P < 0.005). However, when two subgroups were matched for cancellous area, no significant differences were observed in any of the structural indices except terminus count (P < 0.05). Mean trabecular width and number were significantly lower and trabecular separation significantly higher in the patients with osteoporosis before and after age-matching but their differences disappeared after matching for cancellous area. Multiple regression analysis confirmed highly significant correlations between cancellous bone area and structural indices after adjustment for age, sex and disease status (P < 0.001). Our data demonstrate that for a given cancellous area, structural changes in primary osteoporosis are similar to those observed during age-related bone loss in normal subjects. These findings support the hypothesis that primary osteoporosis is the result of greater biological ageing rather than a specific disease process and are consistent with evidence from other sources that low bone mass is associated with increased mortality from diseases unrelated to osteoporosis.
    Bone and Mineral 05/1994; 25(2):111-21.
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    ABSTRACT: To examine whether changes in cancellous bone turnover and resorption cavity depth contribute to bone loss in patients with non-steroid treated rheumatoid arthritis. Iliac crest biopsies were obtained from 37 patients with non-steroid treated rheumatoid arthritis, 13 male and 24 female, aged 37-71 years. Bone turnover and resorption cavity characteristics were quantitatively assessed using semiautomated computerised techniques. When compared with age- and sex-matched control values, there was a significant reduction in bone formation rate at tissue level and activation frequency (P < 0.001) in the patient group. The eroded perimeter, mean and maximum eroded depth and cavity area were also significantly reduced (P < 0.01, < 0.005, < 0.01 and < 0.005 respectively). These results demonstrate low bone turnover in non-steroid treated rheumatoid arthritis and indicate that the reduced bone mass in these patients is due mainly to a negative remodelling balance.
    Annals of the Rheumatic Diseases 03/1994; 53(3):163-6. · 9.11 Impact Factor
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    ABSTRACT: The effects of long-term tamoxifen therapy on bone remodeling were studied in 41 women with breast cancer, 22 treated with tamoxifen for a minimum of 15 months (mean 33) and 19 untreated. Transiliac crest bone biopsies were obtained and a comprehensive histomorphometric analysis performed using a semiautomatic image analysis system. There were no statistically significant differences between the two groups in bone area, osteoid perimeter and area, or osteoid width. Mineral appositional rate, adjusted appositional rate, and mineralization lag time were also similar in the two groups; however, tissue-based bone formation rate was significantly lower in the tamoxifen-treated women (p = 0.05) and the remodeling period significantly longer (p < 0.05). Mean and maximum resorption cavity depth and cavity area were significantly reduced in the tamoxifen-treated patients compared to the untreated patients (p < 0.01, p < 0.01, and p < 0.03, respectively). Calculated and directly measured indices of cancellous bone structure were similar in the two groups, although the data indicated a trend toward greater connectedness in the tamoxifen-treated group. These data indicate that tamoxifen does not exert an antiestrogenic effect on bone remodeling in the human and are consistent with a weak estrogenic effect.
    Journal of Bone and Mineral Research 02/1994; 9(2):153-9. · 6.13 Impact Factor
  • Bone 01/1994; 15(1):124. · 3.82 Impact Factor
  • Bone 01/1994; 15(2):243-243. · 3.82 Impact Factor
  • Bone 01/1994; 15(4):450-450. · 3.82 Impact Factor

Publication Stats

1k Citations
195.16 Total Impact Points

Institutions

  • 1993–2003
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 1985–2002
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 1996–1999
    • University of Cambridge
      • Department of Medicine
      Cambridge, ENG, United Kingdom