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Biomedical subjects

Nicola L Fazzalari

Publications and source records attributed to Nicola L Fazzalari.

15 recordsLinked to original sources
PubMed2006

Structural and remodeling indices in the cancellous bone of the proximal femur across adulthood.

Fragility fractures, including fractures of the femoral neck, result from reductions in the amount, quality and architecture of bone. However, investigations of the underlying structural changes that might predispose to fracture have been largely limited to skeletal sites that do not fracture, such as the iliac crest (IC). The aim of this study was to use histomorphometry to map changes in the architecture and the static remodeling indices of cancellous bone, as a function of age and sex, in bone samples taken from the intertrochanteric (IT) region of the proximal femur at routine autopsy (18-88 years of age). Bone samples for histology were processed from 10-mm cubes of IT cancellous bone. Histomorphometry was performed using an ocular-mounted 10 x 10 graticule at a magnification of x100. An age-dependent decrease in trabecular bone volume was observed in both females and males, as expected (r=-0.75 and r=-0.63, p<0.001, respectively). The underlying mechanisms for bone turnover appeared to be different between males and females. Thus, while the static index of bone resorption (ES/BV) was positively age-dependent in males and females (p<0.001, p<0.03, respectively), the index of bone formation (OS/BV) correlated positively with age in the female group only (p<0.001 vs. NS). Perhaps reflecting an increase in bone formation in older females, the OS/ES ratio was greater in older females than younger females or males. Surprisingly, while resorption indices increased in older males compared with their younger counterparts, bone formation indices increased only in the older female cohort. The IT region in the proximal femur is adjacent to the site commonly involved in fragility fracture. With the limitation that these results describe cross-sectional data, they provide useful insights into changes in the cancellous bone structure and at the bone surface of females and males over the age range of 20-90 years, at a clinically relevant skeletal site.

Adolescent↗
PubMed2006

Evidence for reduced bone formation surface relative to bone resorption surface in female femoral fragility fracture patients.

Fragility fractures, including neck of femur fractures, result from reductions in the amount, quality and architecture of bone. The aim of this study was to compare the cancellous bone structure, and static indices of bone turnover, in female patients, who had sustained fragility fracture at the femoral neck, with age-matched females without fragility fracture. Bone samples were taken from the intertrochanteric region of the proximal femur of female patients undergoing hip arthroplasty surgery for a subcapital fragility fracture of the femoral neck (#NOF) or from age-matched female control individuals at routine autopsy. Contiguous bone samples were analyzed for undecalcified histomorphometry and for mRNA expression. The histomorphometric data, which were normally distributed, indicated no difference between the mean values for any of the structural parameters in control and fracture samples. In particular, the bone volume (BV/TV) values were not different and did not change significantly with age in these cohorts of individuals aged >65 years. The static indices of bone turnover, eroded surface (ES/BS) and osteoid surface (OS/BS), were positively correlated with age in the >65-year-old control group (p < 0.055 and p < 0.03, respectively). The median values for these indices were not different between the fracture and control groups. However, both the median and the range of OS/BS values were increased for >65-year-old controls compared with a group of younger females aged <65 years, suggesting an increase in bone formation surface in older females in the proximal femur after 65 years of age. When the data were further interrogated, a reduction in the percentage osteoid surface to eroded surface quotient (OS/ES) was found for the fracture group compared with the age-matched control group suggesting a reduced adaptive modeling drift capability in the fracture group. In contiguous bone samples, increased median values for receptor activator of nuclear factor kappa beta (RANK) and interleukin-6 (IL-6) mRNA expression were observed in the fracture group. Study of cultured human osteoblasts showed that recombinant human IL-6 (rhIL-6) inhibited osteoblast differentiation, as measured by an increase in the immature osteoblast marker, STRO-1 and concomitantly decreased expression of the osteoblast maturation marker, alkaline phosphatase. Importantly, cells cultured in the presence of IL-6 showed significantly less mineral deposition in vitro compared with control cultures. These data suggest that perturbations in bone formation surface, relative to resorption surface, are potentially important in producing bone in the proximal femur with increased propensity to fracture.

Aged↗
PubMed2006

Trabecular rod buckling index in thoraco-lumbar vertebral bonedagger.

The need for improved mechanistic understanding of cancellous bone failure is at the core of important clinical problems such as osteoporosis, as well as basic biological issues such as bone formation and adaptation. Three-dimensional (3D) anaglyphs were produced from 15 T12 and L1 vertebral bodies, which encompass the adult life span in both sexes. The anaglyphs were viewed with red-green stereo glasses, using an image analyzer, and trabecular thickness and trabecular length were measured. From biomechanical principles, the strength of individual trabeculae can be estimated from measurement of trabecular rod thickness and trabecular rod length as the load to buckling index. The distribution of the load to buckling index was best described by a log normal curve. Trabecular rod thickness, trabecular rod length, and load to buckling index for males were consistently greater than for females. With aging, trabecular rod thickness, and the load to buckling index decrease for males while trabecular rod length increases for females. In this study, the load to buckling index for thoraco-lumbar vertebral trabecular rods potentially quantifies a greater risk of vertebral fracture for females. Decreased trabecular rod thickness or increased trabecular rod length result in the strength of trabeculae shifting closer to a putative fracture threshold. The corollary being that there is a reduced safety margin for resistance to mechanical loads for the vertebral bodies. The 3D anaglyph technique for measuring trabecular dimensions provides an accurate and precise methodology by which these morphological studies can be undertaken.

Adolescent↗
PubMed2006

Regional variations in the density and arrangement of elastic fibres in the anulus fibrosus of the human lumbar disc.

Elastic fibres are critical components of the extracellular matrix in dynamic biological structures that undergo extension and recoil. Their presence has been demonstrated in the anulus fibrosus of the human lumbar intervertebral disc; however, a detailed regional analysis of their density and arrangement has not been undertaken, limiting our understanding of their structural and functional roles. In this investigation we have quantitatively described regional variations in elastic fibre density in the anulus fibrosus of the human L3-L4 intervertebral disc using histochemistry and light microscopy. Additionally, a multiplanar comparison of patterns of elastic fibre distribution in the intralamellar and interlamellar zones was undertaken. Novel imaging techniques were developed to facilitate the visualization of elastic fibres otherwise masked by dense surrounding matrix. Elastic fibre density was found to be significantly higher in the lamellae of the posterolateral region of the anulus than the anterolateral, and significantly higher in the outer regions than the inner, suggesting that elastic fibre density in each region of the anulus is commensurate with the magnitude of the tensile deformations experienced in bending and torsion. Elastic fibre arrangments in intralamellar and interlamellar zones were shown to be architecturally distinct, suggesting that they perform multiple functional roles within the anulus matrix structural hierarchy.

Adolescent↗
PubMed2006

Differential gene expression of bone anabolic factors and trabecular bone architectural changes in the proximal femoral shaft of primary hip osteoarthritis patients.

Previous studies have shown a generalised increase in bone mass in patients with osteoarthritis (OA). Using molecular histomorphometry, this study examined the in vivo expression of mRNA encoding bone anabolic factors and collagen type I genes (COL1A1, COL1A2) in human OA and non-OA bone. Bone samples were obtained from the intertrochanteric (IT) region of the proximal femur, a skeletal site distal to the active site of disease, from individuals with hip OA at joint replacement surgery and from autopsy controls. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed elevated mRNA expression levels of alkaline phosphatase (p < 0.002), osteocalcin (OCN) (p < 0.0001), osteopontin (p < 0.05), COL1A1 (p < 0.0001), and COL1A2 (p < 0.002) in OA bone compared to control, suggesting possible increases in osteoblastic biosynthetic activity and/or bone turnover at the IT region in OA. Interestingly, the ratio of COL1A1/COL1A2 mRNA was almost twofold greater in OA bone compared to control (p < 0.001), suggesting the potential presence of collagen type I homotrimer at the distal site. Insulin-like growth factor (IGF)-I, IGF-II, and transforming growth factor-beta1 mRNA levels were similar between OA and control bone. Bone histomorphometric analysis indicated that OA IT bone had increased surface density of bone (p < 0.0003), increased trabecular number (Tb.N) (p < 0.0003), and decreased trabecular separation (Tb.Sp) (p < 0.0001) compared to control bone. When the molecular and histomorphometric data were plotted, positive associations were observed in the controls for OCN/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) versus bone tissue volume (r = 0.82, p < 0.0007) and OCN/GAPDH versus Tb.N (r = 0.56, p < 0.05) and a negative association was observed for OCN/GAPDH versus Tb.Sp (r = -0.64, p < 0.02). These relationships were not evident in trabecular bone from patients with OA, suggesting that bone regulatory processes leading to particular trabecular structures may be altered in this disease. The finding of differential gene expression, as well as architectural changes and differences in molecular histomorphometric associations between OA and controls, at a skeletal site distal to the active site of joint degeneration supports the concept of generalised involvement of bone in the pathogenesis of OA.

Aged↗
PubMed2005

Antero-postero differences in cortical thickness and cortical porosity of T12 to L5 vertebral bodies.

OBJECTIVE: This study will investigate interrelationships between the cortical shell and cancellous bone trabecular thickness, in vertebral bodies. METHODS: One hundred and sixty vertebral bodies from T12 to L5 were obtained at autopsy. The average age of the cohort was 59.3+/-22.1 years (range = 20-94 years). Cortical thickness, cortical porosity and trabecular thickness from the adjacent cancellous bone were measured. RESULTS: At the mid-vertebral body anterior cortical thickness was significantly greater than posterior cortical thickness (524 +/- 352 vs. 370 +/- 283 microm, respectively, P < 0.0001) and mid-anterior cortical porosity was significantly less than mid-posterior cortical porosity (24 +/- 14% vs. 32 +/- 16%, respectively, P < 0.0001). There were no anterior/posterior differences in trabecular thickness of the cancellous bone adjacent to the cortical walls. CONCLUSION: This study provides a novel perspective of T12 to L5 vertebral body bone, where measurement of cortical thickness and cortical porosity in a cohort of skeletally normal individuals revealed structural differences between load bearing anterior and posterior cortical walls. The data suggest that modulators of change to vertebral body bone may affect the cortical and trabecular bone differently. The relationships between cortical and cancellous bone suggest that the middle sectors of the vertebral body play a critical role in load bearing.

Adult↗
PubMed2005

Stability of RNA isolated from human trabecular bone at post-mortem and surgery.

To determine the reliability of gene expression studies in human post-mortem bone, it is important to evaluate the stability of RNA isolated from such tissues as a function of the post-mortem interval. The stability of total RNA and bone-specific mRNA species was examined in bone samples obtained from routine autopsies and at surgery. The optimal temperature for any storage and transport of the bone before RNA isolation was shown to be 4 degrees C, and RT-PCR analysis is the preferred technique for the analysis of gene expression in post-mortem bone as it tolerates partial RNA degradation. For gene expression studies in bone, post-mortem cases, with a post-mortem interval of less than 48 h, should be selected, and the time that bone is stored after retrieval at autopsy or surgery should be kept to a minimum. Overall, our findings indicate that with appropriate storage and handling, RNA can be reliably isolated from human bone obtained at post-mortem and surgery to study ex vivo the pattern of gene expression in healthy individuals and in patients with musculoskeletal diseases such as osteoporosis and osteoarthritis.

Adult↗
PubMed2005

In vivo intrarater and interrater precision of measuring apparent bone mineral density in vertebral subregions using supine lateral dual-energy x-ray absorptiometry.

Analysis of apparent bone mineral density (BMD) in the lumbar spine is commonly based on anteroposterior (AP) scanning using dual-energy X-ray absorptiometry (DXA). Although not widely used, clinically important information can also be derived from lateral scanning. Vertebral bone density, and therefore strength, can may vary in different subregions of the vertebral body. Therefore, subregional BMD measurements might be informative about fracture risk. However, the intrarater and interrater precision of in vivo subregional BMD assessments from lateral DXA remains unknown. Ten normal, young (mean: 24 yr) and 10 older (mean: 63 yr) individuals with low BMD were scanned on one occasion using an AP/lateral sequence. Each lateral scan was reanalyzed six times at L2 by three raters to determine the intrarater and interrater precision in selecting seven regions of interest (subregions). Precision was expressed using percentage coefficients of variation (% CV) and intraclass correlation coefficients (ICC). Intrarater precision ranged from ICC(1,1) 0.971 to 0.996 (% CV: 0.50-3.68) for the young cohort and ICC(1,1) 0.934 to 0.993 (% CV: 1.46-5.30) for the older cohort. Interrater precision ranged from ICC(2,1) 0.804 to 0.915 (% CV: 1.11-2.35) for the young cohort and ICC(2,1) 0.912 to 0.984 (% CV: 1.85-4.32) for the older cohort. Scanning a subgroup of participants twice with repositioning was used to assess short-term in vivo precision. At L2, short-term in vivo precision ranged from ICC(1,1) 0.867 to 0.962 (% CV: 3.38-9.61), at L3 from ICC(1,1) 0.961 to 0.988 (% CV: 2.02-5.57) and using an L2/L3 combination from ICC(1,1) 0.942 to 0.980 (% CV: 2.04-4.61). This study demonstrated moderate to high precision for subregional analysis of apparent BMD in the lumbar spine using lateral DXA in vivo.

Absorptiometry, Photon↗
PubMed2004

A review of anatomical and mechanical factors affecting vertebral body integrity.

Background: The aetiology of osteoporotic vertebral fracture is multifactorial and may be conceptualised using a systems framework. Previous studies have established several correlates of vertebral fracture including reduced vertebral cross-sectional area, weakness in back extensor muscles, reduced bone mineral density, increasing age, worsening kyphosis and recent vertebral fracture. Alterations in these physical characteristics may influence biomechanical loads and neuromuscular control of the trunk and contribute to changes in subregional bone mineral density of the vertebral bodies. Methods: This review discusses factors that have received less attention in the literature, which may contribute to the development of vertebral fracture. A literature review was conducted using electronic databases including Medline, Cinahl and ISI Web of Science to examine the potential contribution of trabecular architecture, subregional bone mineral density, vertebral geometry, muscle force, muscle strength, neuromuscular control and intervertebral disc integrity to the aetiology of osteoporotic vertebral fracture. Interpretation: A better understanding of factors such as biomechanical loading and neuromuscular control of the trunk may help to explain the high incidence of subsequent vertebral fracture after sustaining an initial vertebral fracture. Consideration of these issues may be important in the development of prevention and management strategies.

Journal Article↗
PubMed2004

Effectiveness of AutoPap system location-guided screening in the evaluation of cervical cytology smears.

Location-guided screening is a feature of the AutoPap primary screening software. Areas of the smear most likely to contain an abnormality are identified for prompt review by the cytotechnologist, thereby facilitating diagnostic accuracy and reducing laboratory workload. A two-armed retrospective study comprising 6,000 conventional smears was undertaken to compare this approach with the current practice of full manual screening of conventional smears. Discrepant diagnoses between the two study arms were subject to an internal discrepancy review process to determine the final truth diagnosis. Analysis of the results show that AutoPap location-guided screening is at least equivalent to current practice when detecting high-grade or suspected high-grade smears. However, the device does not detect low-grade abnormalities, unsatisfactory smears, an endocervical component or organisms, as well as standard screening. The device also assigns a numerical score to each slide, with abnormal smears allocated a higher rank. Slide ranking was found to be of value in triaging abnormal smears for prompt screening and reporting. The performance of the primary screening software was found to be comparable to previous studies, with the majority of abnormal smears being selected by the instrument for manual review.

Automation↗
PubMed2004

Increased expression of IL-6 and RANK mRNA in human trabecular bone from fragility fracture of the femoral neck.

Previous studies have implicated pro-inflammatory cytokines in the bone loss of estrogen deficiency. The aim of this study was to investigate the expression of key regulatory molecules of bone remodeling in the trabecular bone microenvironment in osteoporosis. Bone samples were taken from the intertrochanteric region of the proximal femur of patients undergoing total hip arthroplasty for a subcapital fragility fracture of the femoral neck (#NOF). For comparison, samples were taken from age-matched control individuals at routine autopsy. Expression of RANKL, RANK, osteoprotegerin (OPG), IL-6, IL-11, osteocalcin (OCN), and calcitonin receptor (CTR) messenger RNA (mRNA) species were analyzed and the data were nonparametrically distributed. The median expression of the proresorptive genes, RANK and IL-6, were significantly elevated in the fracture group compared to an age-matched control group (2.2 [1.9-2.9; 25th-75th percentiles] > 1.0 [0.4-2.1], P < 0.03; 3.9 [1.8-6.2] > 0.8 [0.7-1.5], P < 0.002, respectively). In contrast, there were no significant differences in expression of RANKL, OPG, CTR, or OCN mRNA between the #NOF and control groups. The median RANKL/OPG mRNA ratio was significantly greater in hip fracture bone than in bone from controls (4.8 [3.8-7.6] > 3.2 [2.1-4.0], P < 0.05). IL-6 mRNA levels associated strongly with RANKL mRNA levels in the #NOF group (r = 0.77, P < 0.001), but not in the control group. A strong positive association was found between IL-11 mRNA levels and RANKL mRNA levels in the #NOF group (r = 0.81, P < 0.001), consistent with the apparent coordinated regulation of IL-6 and IL-11 in bone samples from the #NOF group (r = 0.93, P < 0.0001). These data suggest a relative increase in the expression of the molecular promoters of osteoclast formation and activity in #NOF bone, which may lead to the imbalance between bone formation and resorption associated with fragility fracture.

Aged↗
PubMed2003

Trabecular rod thickness by direct measurement from 3D SEM anaglyphs.

This study presents a methodology for measuring the thickness of trabecular rods directly from anaglyphs. Macerated sagittal slices of T12 vertebral bodies from 15 subjects were examined by scanning electron microscopy (SEM). Two digital images (the second image tilted 5 degrees ) were recorded, and a 3D anaglyph was created. The thickness of the trabecular rods (Tb.Th((rods))), and the anatomical orientation of the trabecular rods were measured using an image analyser. Conventional 2D histomorphometry was performed on adjacent bone slices. A total of 1559 rod measurements were made from the 15 vertebral bone slices, with a mean Tb.Th((rods)) of 123 +/- 36 microm. The rod thickness in males (128 +/- 34 microm) was significantly greater than that in females (119 +/- 37 microm, P < 0.001). Tb.Th((rods)) changed significantly with age in the males: the thicker rods in the younger men reduced with age to a thickness similar to that in women. 3D measurements were significantly larger than the 2D estimates, and there was no correlation between the two methods of measurement. An inverse correlation was found between the number of rods and the bone volume fraction (BV/TV), indicating that decreased BV/TV is associated with an increased number of rods. The vertical rods (132 +/- 39 microm) were significantly thicker than the horizontal rods (116 +/- 33 microm, P < 0.001). The determination of rod numbers, and their orientation and individual thicknesses enables a greater understanding of cancellous bone architecture in both individuals and populations, and will allow more reliable finite element modelling. Direct measurements from 3D anaglyphs of intact specimens provide new data that show previously unrecognised age- and sex-related changes.

Adolescent↗
PubMed2003

Interrelationships between structural parameters of cancellous bone reveal accelerated structural change at low bone volume.

UNLABELLED: This study shows that change to cancellous bone structure is bone volume-dependent in a nonlinear manner. At low bone volume (< 15%), trabecular thickness and trabecular separation change at a much greater rate than at higher bone volume. This suggests that the structural integrity of the cancellous bone may become rapidly compromised when bone volume falls below a critical value. INTRODUCTION: While bone mass is the major determinant of bone strength, this mass-based paradigm does not fully account for the contribution of the bone microstructure to mechanical efficiency. Geometric models of cancellous bone structure have been formulated based on stylized representations of the trabecular elements, where the relationships between bone volume and bone surface of cancellous bone are complex and reflect the modulating effect on the cancellous bone structure of bone remodeling at the trabecular surfaces. Using the plate model of cancellous bone structure, the interrelationships between parameters of cancellous bone structure have been studied. MATERIALS AND METHODS: Two hundred eighty histological sections of human cancellous bone from eight skeletal sites were analyzed. The structural parameters of cancellous bone (BV/TV, BS/TV, BS/BV, Tb.Th, Tb.Sp, Tb.N, and TBPf) were obtained. RESULTS AND CONCLUSIONS: This study shows that change to cancellous bone structure is bone volume-dependent in a nonlinear manner. At low bone volume (< 15%), structural parameters of cancellous bone, such as trabecular thickness and trabecular separation, change at a much greater rate than at higher bone volume. This suggests that the structural integrity of the cancellous bone may become rapidly compromised when bone volume falls below a critical value. These data describe the complex relationships between bone mass and structure in cancellous bone that are often overlooked in the mass-based paradigm of bone strength. Histomorphometric descriptors of cancellous bone structure highlight the potential for accelerated deterioration of the structure with low bone volume, which leads to increased risk of fracture. From a clinical viewpoint, estimation of an individual's fracture risk is constrained to noninvasive techniques, which only provide bone mineral density or bone mineral content. Therefore, there is a need to better correlate measurement of bone mass with measurements of structural parameters.

Bone Density↗
PubMed2002

The effect of hydration on the stiffness of intervertebral discs in an ovine model.

OBJECTIVE: To determine the hydration-over-time behaviour of ovine intervertebral discs and intact joints in a saline bath at body temperature and the effect this has on their stiffness compared to air at ambient temperature. DESIGN: The hydration-over-time behaviour and stiffness of the ovine functional spinal unit and disc were quantified. BACKGROUND: The fluid content of an intervertebral disc is not constant but varies with external load and load history. The stiffness of ovine functional spinal units in a hydrated environment and how this compares to testing in air have not been quantified. METHODS: Intervertebral discs and functional spinal units were weighed and soaked in a saline water bath at 37 degrees C and reweighed each hour for 6 h. They were then allowed to stand in air at room temperature while the time to return to initial weight was recorded. Functional spinal units were randomly assigned to two groups. Axial compression, flexion, extension, lateral bending and axial torsion tests were performed on both the intact functional spinal unit and isolated disc. Group 1 was tested in air then in a saline water bath at 37 degrees C with the testing order reversed for Group 2. RESULTS: Hydration of the disc reached a plateau after an average 3-4 h of soaking with the largest increase seen in the first hour. Four hours, standing in air at room temperature, was required to return specimens to their initial weight. The functional spinal unit stiffness was significantly lower for those specimens tested in the bath compared to air. CONCLUSIONS: Ovine intervertebral discs show similar hydration-over-time behaviour when compared to human discs. Stiffnesses in different modes of loading were significantly different when tested in a hydrated environment compared with the standard method of testing in air. RELEVANCE: It has been shown that there are biomechanical and biochemical similarities between sheep and human intervertebral discs. Despite these similarities, no studies have looked at how ovine intervertebral discs behave over time in a hydrated environment. In humans, hydration levels are an important aspect of intervertebral disc degeneration. There is also a relationship between decreased hydration levels and increased stiffness. This study demonstrates the similarities between human and ovine hydration-over-time behaviour. The importance of intervertebral disc hydration and its effects on stiffness under different modes of loading were also demonstrated and have not been previously shown using the ovine model. In this context, the results from this study provide further support for the use of the ovine model.

Analysis of Variance↗