Hypothalamic regulation of cortical bone mass: Opposing activity of Y2 receptor and leptin pathways

NeuropeptideY-, Y2 receptor (Y2)-, and leptin-deficient mice show similar anabolic action in cancellous bone but have not been assessed in cortical bone. Cortical bone mass is elevated in Y2(-/-) mice through greater osteoblast activity. In contrast, leptin deficiency results in reduced bone mass. We show opposing central regulation of cortical bone.

Sex- and race-related differences in cross-sectional geometry and bone density of the femoral mid-shaft in older adults

Background : Femoral shaft fracture incidence increases in older adults and is associated with low-energy trauma. Apart from bone density, the distribution and size of bone contributes to its strength. Aim : To examine if bone geometry and density of the femoral mid-shaft in older adults differs by sex and race, we studied 197 White women, 225 Black women, 242 White men, and 148 Black men aged 70-79 years participating in the Health, Aging, and Body Composition study; a prospective cohort study in the USA. A secondary purpose of the study was to examine the association of site-specific muscle and fat to bone geometry and density. Subjects and methods : Subjects were community-dwelling and reported no difficulty walking one-quarter of a mile or climbing stairs. Mid-femoral volumetric bone mineral density (vBMD, mg cm -3 ), total area (TA), cortical area (CA), medullary area (MA), cross-sectional moments of inertia (CSMI: I x , I y , J ), and muscle and fat areas (cm 2 ) were determined by computed tomography (CT; GE CT-9800, 10 mm slice thickness). Results : vBMD was greater in men than women with no difference by race ( p < 0.001). Bone areas and area moments of inertia were also greater in men than women ( p < 0.001), with Black women having higher values than White women for TA and CA. Standardizing geometric parameters for body size differences by dividing by powers of femur length did not negate the sex difference for TA and MA. Significant differences ( p < 0.05) among the four groups also remained for I x and J . Mid-thigh muscle area was an independent contributor to TA in all groups (Std beta = 0.181-0.351, p < 0.05) as well as CA in women (Std beta = 0.246-0.254, p < 0.01) and CSMI in White women (Std beta = 0.175-0.185, p < 0.05). Further, muscle area was a significant contributor to vBMD in Black women. Conclusion : These results indicate that bone geometry and density of the femoral diaphysis differs primarily by sex, rather than race, in older well-functioning adults. In addition, site-specific muscle area appears to have a potential contributory role to bone geometry parameters, especially in women.

A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: Benefit of the combination on total body and hip density

We report a prospective, randomized, multi-center, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d,- group HRT/D received HRT plus calcitriol 0.25 mug bd. All with a baseline dietary calcium (Ca) of < I g/d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P < 0.001) BNID increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, inter-trochanter and femoral shaft (% group mean Delta 4.2, 6.1, 9.3. 3.7. 3.3 and 3.3%, respectively). On HRT, at these significant Deltas were restricted to the trochanter and sites. si Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean Delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups Improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This Is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BNID at the hip, the major site of osteoporotic fracture.

Mechanical effects on the skeleton: Are there clinical implications?

The basic morphology of the skeleton is determined genetically, but its final mass and architecture are modulated by adaptive mechanisms sensitive to mechanical factors. When subjected to loading, the ability of bones to resist fracture depends on their mass, material properties, geometry and tissue quality. The contribution of altered bone geometry to fracture risk is unappreciated by clinical assessment using absorptiometry because it fails to distinguish geometry and density. For example, for the same bone area and density, small increases in the diaphyseal radius effect a disproportionate influence on torsional strength of bone. Mechanical factors are clinically relevant because of their ability to influence growth, modeling and remodeling activities that can maximize, or maintain, the determinants of fracture resistance. Mechanical loads, greater than those habitually encountered by the skeleton, effect adaptations in cortical and cancellous bone, reduce the rate of bone turnover, and activate new bone formation on cortical and trabecular surfaces. In doing so, they increase bone strength by beneficial adaptations in the geometric dimensions and material properties of the tissue. There is no direct evidence to demonstrate anti-fracture efficacy for mechanical loading, but the geometric alterations engendered undoubtedly increase the structural properties of bone as an organ, increasing the resistance to fracture. Like all interventions, issues of safety also arise. Physical activities involving high strain rates, heavy lifting or impact loading may be detrimental to the joints, leading to osteoarthritis; may stimulate fatigue damage leading with some to stress fractures; or may interact pharmaceutical interventions to increase the rate of microdamage within cortical or trabecular bone.

In vitro heterogeneity of osteogenic cell populations at various equine skeletal sites

Bone cell cultures were evaluated to determine if osteogenic cell populations at different skeletal sites in the horse are heterogeneous. Osteogenic cells were isolated from cortical and cancellous bone in vitro by an explant culture method. Subcultured cells were induced to differentiate into bone-forming osteoblasts. The osteoblast phenotype was confirmed by immunohistochemical testing for osteocalcin and substantiated by positive staining of cells for alkaline phosphatase and the matrix materials collagen and glycosaminoglycans. Bone nodules were stained by the von Kossa method and counted. The numbers of nodules produced from osteogenic cells harvested from different skeletal sites were compared with the use of a mixed linear model. On average, cortical bone sites yielded significantly greater numbers of nodules than did cancellous bone sites. Between cortical bone sites, there was no significant difference in nodule numbers. Among cancellous sites, the radial cancellous bone yielded significantly more nodules than did the tibial cancellous bone. Among appendicular skeletal sites, tibial metaphyseal bone yielded significantly fewer nodules than did all other long bone sites. This study detected evidence of heterogeneity of equine osteogenic cell populations at various skeletal sites. Further characterization of the dissimilarities is warranted to determine the potential role heterogeneity plays in differential rates of fracture healing between skeletal sites.

Size-corrected BMD decreases during peak linear growth: Implications for fracture incidence during adolescence

Peak adolescent fracture incidence at the distal end of the radius coincides with a decline in size-corrected BMD in both boys and girls. Peak gains in bone area preceded peak gains in BMC in a longitudinal sample of boys and girls, supporting the theory that the dissociation between skeletal expansion and skeletal mineralization results in a period of relative bone weakness. Introduction: The high incidence of fracture in adolescence may be related to a period of relative skeletal fragility resulting from dissociation between bone expansion and bone mineralization during the growing years. The aim of this study was to examine the relationship between changes in size-corrected BMD (BMDsc) and peak distal radius fracture incidence in boys and girls. Materials and Methods: Subjects were 41 boys and 46 girls measured annually (DXA; Hologic 2000) over the adolescent growth period and again in young adulthood. Ages of peak height velocity (PHV), peak BMC velocity (PBMCV), and peak bone area (BA) velocity (PBAV) were determined for each child. To control for maturational differences, subjects were aligned on PHV. BMDsc was calculated by first regressing the natural logarithms of BMC and BA. The power coefficient (pc) values from this analysis were used as follows: BMDsc = BMC/BA(pc). Results: BMDsc decreased significantly before the age of PHV and then increased until 4 years after PHV. The peak rates in radial fractures (reported from previous work) in both boys and girls coincided with the age of negative velocity in BMDsc; the age of peak BA velocity (PBAV) preceded the age of peak BMC velocity (PBMCV) by 0.5 years in both boys and girls. Conclusions: There is a clear dissociation between PBMCV and PBAV in boys and girls. BMDsc declines before age of PHV before rebounding after PHV. The timing of these events coincides directly with reported fracture rates of the distal end of the radius. Thus, the results support the theory that there is a period of relative skeletal weakness during the adolescent growth period caused, in part, by a draw on cortical bone to meet the mineral demands of the expanding skeleton resulting in a temporary increased fracture risk.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood and adult-onset schizophrenia, bipolar disorder, attention-deficit/ hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages. (C) 2004 Published by Elsevier Inc.

An fMRI study indicating increased cortical recruitment during a cognitive interference task in Huntington's disease patients

We used an event related fMRI design to study the BOLD response in Huntington’s disease (HD) patients during performance of a Simon interference task. We hypothesised that HD patients will demonstrate significantly slower RTs than controls, and that there will be significant differences in the pattern of brain activation between groups. Seventeen HD patients and 15 age and sex matched controls were scanned using 3T GE scanner (FOV = 24 cm2; TE = 40 ms; TR = 3 s; FA = 60°; slice thickness = 6 mm; in-plane resolution = 1.88x1.88 mm2). The task involved two activation conditions, namely congruent (for example, left pointing arrow appearing on the left side of the screen) and incongruent (for example, left pointing arrow appearing on the right side of the screen), and a baseline condition. Each stimulus was presented for 2500 ms followed by a blank screen for 500 ms. Subjects were instructed to press a button using the same hand as indicated by the direction of the arrow head and were given 3000 ms to respond. Data analysis was performed using SPM2 with a random effects analysis model. For each subject parameter estimates for combined task conditions (congruent and incongruent combined) were calculated. Comparisons such as these, based on block designs, have superior statistical power for detecting subtle changes in the BOLD response anywhere in the brain. The activations reported are significant at PFDR_corr

Age does not influence the bone response to treadmill exercise in female rats

Purpose: Because it is believed that bone may respond to exercise differently at different ages, we compared bone responses in immature and mature rats after 12 wk of treadmill running. Methods: Twenty-two immature (5-wk-old) and 21 mature (17-wk-old) female Sprague Dawley rats were randomized into a running (trained, N = 10 immature, 9 mature) or a control group (controls, N 12 immature, 12 mature) before sacrifice 12 wk later. Rats ran on a treadmill five times per week for 60-70 min at speeds up to 26 m.min(-1). Both at baseline and after intervention, we measured total body, lumbar spine, and proximal femoral bone mineral, as well as total body soft tissue composition using dual-energy x-ray absorptiometry (DXA) in vivo. After sacrificing the animals, we measured dynamic and static histomorphometry and three-point bending strength of the tibia. Results: Running training was associated with greater differences in tibial subperiosteal area, cortical cross-sectional area, peak load, stiffness, and moment of inertia in immature and mature rats (P < 0.05). The trained rats had greater periosteal bone formation rates (P < 0.01) than controls, but there was no difference in tibial trabecular bone histomorphometry. Similar running-related gains were seen in DXA lumbar spine area (P = 0.04) and bone mineral content (BMC; P = 0.03) at both ages. For total body bone area and BMC, the immature trained group increased significantly compared with controls (P < 0.05), whereas the mature trained group gained less than did controls (P < 0.01). Conclusion: In this in vivo model, where a similar physical training program was performed by immature and mature female rats, we demonstrated that both age groups were sensitive to loading and that bone strength gains appeared to result more from changes in bone geometry than from improved material properties.

Volumetric and areal bone mineral density measures are associated with cardiovascular disease in older men and women: The health, aging, and body composition study

The associations of volumetric (vBMD) and areal (aBMD) bone mineral density measures with prevalent cardiovascular disease (CVD) and subclinical peripheral arterial disease (PAD) were investigated in a cohort of older men and women enrolled in the Health, Aging, and Body Composition Study. Participants were 3,075 well-functioning white and black men and women (42% black, 51% women), aged 68-80 years. Total hip, femoral neck, and trochanter aBMD were measured using dual-energy X-ray absorptiometry. Quantitative computed tomography was used to evaluate spine trabecular, integral, and cortical vBMD measures in a subgroup (n = 1,489). Logistic regression was performed to examine associations of BMD measures with CVD and PAD. The prevalence of CVD (defined by coronary heart disease, PAD, cerebrovascular disease, or congestive heart failure) was 29.8%. Among participants without CVD, 10% had subclinical PAD (defined as ankle-arm index < 0.9). Spine vBMD measures were inversely associated with CVD in men (odds ratio of integral [ORintegral] = 1.34, 95% confidence interval [CI] 1.10-1.63; ORtrabecular = 1.25, 95% CI 1.02-1.53; ORcortical = 1.36, 95% CI 1.11-1.65). In women, for each standard deviation decrease in integral vBMD, cortical vBMD, or trochanter aBMD, the odds of CVD were significantly increased by 28%, 27%, and 22%, respectively. Total hip aBMD was associated with subclinical PAD in men (OR = 1.39, 95% CI 1.03-1.84) but not in women. All associations were independent of age and shared risk factors between BMD and CVD and were not influenced by inflammatory cytokines (interleukin-6 and tumor necrosis factors-alpha). In conclusion, our results provide further evidence for an inverse association between BMD and CVD in men and women. Future research should investigate common pathophysiological links for osteoporosis and CVD.

The renal cortical fibroblast in renal tubulointerstitial fibrosis

Renal cortical fibroblasts have key roles in mediating intercellular communication with neighboring/infiltrating cells and extracellular matrix (ECM) and maintenance of renal tissue architecture. They express a variety of cytokines, chemokines, growth factors and cell adhesion molecules, playing an active role in paracrine and autocrine interactions and regulating both fibrogenesis and the interstitial inflammatory response. They additionally have an endocrine function in the production of epoetin. Tubulointerstitial fibrosis, the common pathological consequence of renal injury, is characterized by the accumulation of extracellular matrix largely due to excessive production in parallel with reduced degradation, and activated fibroblasts characterized by a myofibroblastic phenotype. Fibroblasts in the kidney may derive from resident fibroblasts, from the circulating fibroblast population or from haemopoetic progenitor or stromal cells derived from the bone marrow. Cells exhibiting a myofibroblastic phenotype may derive from these sources and from tubular cells undergoing epithelial to mesenchymal transformation in response to renal injury. The number of interstitial myofibroblasts correlates closely with tubulointerstitial fibrosis and progressive renal failure. Hence inhibiting myofibroblast formation may be an effective strategy in attenuating the development of renal failure in kidney disease of diverse etiology. (c) 2005 Elsevier Ltd. All rights reserved.

The Genetic Speciation of Archaeological Fish Bone: A Feasibility Study from Southeast Queensland

Current genetic methods enable highly specific identification of DNA from modern fish bone. The applicability of these methods to the identification of archaeological fish bone was investigated through a study of a sample from late Holocene southeast Queensland sites. The resultant overall success rate of 2% indicates that DNA analysis is, as yet, not feasible for identifying fish bone from any given site. Taphonomic issues influencing the potential of genetic identification methods are raised and discussed in light of this result.

Discourse priming of homophones in individuals with dominant subcortical lesions, cortical lesions, and Parkinson’s disease

An on-line priming experiment was used to investigate discourse-level processing in four matched groups of subjects: individuals with nonthalamic subcortical lesions (NSL) ( n =10), normal control subjects ( n =10), subjects with Parkinsons disease (PD) ( n =10), and subjects with cortical lesions ( n =10). Subjects listened to paragraphs that ended in lexical ambiguities, and then made speeded lexical decisions on visual letter strings that were: nonwords, matched control words, contextually appropriate associates of the lexical ambiguity, contextually inappropriate associates of the ambiguity, and inferences (representing information which could be drawn from the paragraphs but was not explicitly stated). Targets were presented at an interstimulus interval (ISI) of 0 or 1000ms. NSL and PD subjects demonstrated priming for appropriate and inappropriate associates at the short ISI, similar to control subjects and cortical lesion subjects, but were unable to demonstrate selective priming of the appropriate associate and inference words at the long ISI. These results imply intact automatic lexical processing and a breakdown in discourse-based meaning selection and inference development via attentional/strategic mechanisms.