Evidence of degraded BMD and geometry at the proximal femora in male patients with alcoholic liver cirrhosis.

UNLABELLED: We examined the association of alcoholic cirrhosis in 33 patients with areal bone mineral density (BMD) and the assessed bone geometric strength of their proximal femora. Lower areal BMD, cross-sectional area and section modulus, thinner cortex, and higher buckling ratio suggest that the alcoholic liver cirrhosis is associated with lower measures of bone strength. INTRODUCTION: Hepatic bone disease is an important complication of chronic liver disease and is associated with significant morbidity through fractures resulting in pain, deformity, and immobility. In this study, we examined the association of alcoholic cirrhosis and liver insufficiency stage with areal bone mineral density (aBMD) and additionally employed hip structure analysis (HSA) as an advanced method to assess bone geometric strength of the proximal femur in men with alcoholic liver cirrhosis. METHODS: The study included 33 male patients with alcoholic liver cirrhosis and a control group of 36 healthy patients. Laboratory testing included the following biochemical markers of bone turnover: serum levels of osteocalcin and C-telopeptide of type 1 collagen. Areal BMD was measured by dual x-ray absorptiometry on the proximal femora. Structural parameters were then derived from these scans using hip structure analysis software. RESULTS: After adjusting for age, body height, and weight, we found lower cross-sectional area (p = 0.005) and section modulus (p = 0.005), thinner cortex (p = 0.012), and higher buckling ratio (p = 0.043) in the neck region among patients with cirrhosis. The findings suggest that alcoholic liver cirrhosis is associated with lower measures of bone strength. These findings were consistent with decreased osteocalcin values and increased C-telopeptide of type 1 collagen in patients with cirrhosis, indicating reduction in bone formation and increased bone resorption. CONCLUSION: Our results emphasize that HSA-derived structural indices of proximal femoral structure may be an important index of greater fragility in patients with alcoholic cirrhosis.

A comparison of DXA and CT based methods for estimating the strength of the femoral neck in post-menopausal women.

UNLABELLED: The study goal was to compare simple two-dimensional (2D) analyses of bone strength using dual energy x-ray absorptiometry (DXA) data to more sophisticated three-dimensional (3D) finite element analyses using quantitative computed tomography (QCT) data. DXA- and QCT-derived femoral neck geometry, simple strength indices, and strength estimates were well correlated. INTRODUCTION: Simple 2D analyses of bone strength can be done with DXA data and applied to large data sets. We compared 2D analyses to 3D finite element analyses (FEA) based on QCT data. METHODS: Two hundred thirteen women participating in the Study of Women's Health Across the Nation (SWAN) received hip DXA and QCT scans. DXA BMD and femoral neck diameter and axis length were used to estimate geometry for composite bending (BSI) and compressive strength (CSI) indices. These and comparable indices computed by Hip Structure Analysis (HSA) on the same DXA data were compared to indices using QCT geometry. Simple 2D engineering simulations of a fall impacting on the greater trochanter were generated using HSA and QCT femoral neck geometry; these estimates were benchmarked to a 3D FEA of fall impact. RESULTS: DXA-derived CSI and BSI computed from BMD and by HSA correlated well with each other (R=0.92 and 0.70) and with QCT-derived indices (R=0.83-0.85 and 0.65-0.72). The 2D strength estimate using HSA geometry correlated well with that from QCT (R=0.76) and with the 3D FEA estimate (R=0.56). CONCLUSIONS: Femoral neck geometry computed by HSA from DXA data corresponds well enough to that from QCT for an analysis of load stress in the larger SWAN data set. Geometry derived from BMD data performed nearly as well. Proximal femur breaking strength estimated from 2D DXA data is not as well correlated with that derived by a 3D FEA using QCT data.

Hip bone geometry in HIV/HCV-co-infected men and healthy controls.

UNLABELLED: People with both HIV and hepatitis C are more likely than those with HIV alone to have wrist, hip, and spine fractures. We compared hip strength between HIV/HCV-co-infected men and healthy men and found that HIV/HCV-co-infected men had decreased hip strength due to lower lean body mass. INTRODUCTION: Hepatitis C co-infection is a risk factor for fragility fracture among HIV-infected populations. Whether bone strength is compromised in HIV/HCV-co-infected patients is unknown. METHODS: We compared dual-energy x-ray absorptiometry (DXA)-derived hip geometry, a measure of bone strength, in 88 HIV/HCV-co-infected men from the Johns Hopkins HIV Clinic to 289 men of similar age and race and without HIV or HCV from the Boston Area Community Health Survey/Bone Survey. Hip geometry was assessed at the narrow neck, intertrochanter, and shaft using hip structural analysis. Lean body mass (LBM), total fat mass (FM), and fat mass ratio (FMR) were measured by whole-body DXA. Linear regression was used to identify body composition parameters that accounted for differences in bone strength between cohorts. RESULTS: HIV/HCV-co-infected men had lower BMI, LBM, and FM and higher FMR compared to controls (all p < 0.05). At the narrow neck, significant differences were observed between HIV/HCV-co-infected men and controls in bone mineral density, cross-sectional area, section modulus, buckling ratio, and centroid position. After adjustment for race, age, smoking status, height, and weight, only buckling ratio and centroid position remained significantly different between cohorts (all p < 0.05). Substituting LBM, FM, and FMR for weight in the multivariate model revealed that differences in LBM, but not FM or FMR, accounted for differences in all narrow neck parameters between cohorts, except buckling ratio and centroid position. CONCLUSION: HIV/HCV-co-infected men have compromised hip strength at the narrow neck compared to uninfected controls, which is attributable in large part to lower lean body mass.

Ethnic differences in femur geometry in the women's health initiative observational study.

SUMMARY: Participants in the observational study of the Women's Health Initiative (WHI) were studied to determine if ethnic differences in femur geometry can help to explain differences in hip fracture rates. Structural differences in femurs of African and Mexican-American women appear to be consistent with lower rates of hip fractures vs. whites. INTRODUCTION: Ethnic origin has a major influence on hip fractures, but the underlying etiology is unknown. We evaluated ethnic differences in hip fracture rates among 159,579 postmenopausal participants in the WHI then compared femur bone mineral density (BMD) and geometry among a subset with dual X-ray absorptiometry (DXA) scans of the hip and total body. METHODS: The subset included 8,206 non-Hispanic whites, 1,476 African-American (AA), 704 Mexican-American (MA), and 130 Native Americans (NA). Femur geometry derived from hip DXA using hip-structure analysis (HSA) in whites was compared to minority groups after adjustment for age, height, weight, percent lean mass, neck-shaft angle and neck length, hormone use, chronic disease (e.g., diabetes, rheumatoid arthritis, cancer), bone active medications (e.g., corticosteroids, osteoporosis therapies), and clinical center. RESULTS: Both AA and MA women suffered hip fractures at half the rate of whites while NA appeared to be similar to whites. The structural advantage among AA appears to be due to a slightly narrower femur that requires more bone tissue to achieve similar or lower section moduli (SM) vs. whites. This also underlies their higher BMD (reduces region area) and lower buckling ratios (buckling susceptibility). Both MA and NA women had similar advantages vs. whites at the intertrochanter region where cross-sectional area and SM were higher but with no differences at the neck. NA and MA had smaller bending moments vs. whites acting in a fall on the hip (not significant in small NA sample). Buckling ratios of MA did not differ from whites at any region although NA had 4% lower values at the IT region. CONCLUSION: Differences in the geometry at the proximal femur are consistent with the lower hip fracture rates among AA and MA women compared to whites.

Microwave based nanogenerator using the ratchet effect in Si/SiGe heterostructures.

Ratchet based microwave current generators and detectors were developed in Si/SiGe heterostructures for wireless communication with the possibility of extending the detection limit to the terahertz range. A microwave induced ratchet current was generated in the two-dimensional electron gas by patterning an array of semicircular antidots in hexagonal geometry. The spatial asymmetry created by the semicircular antidots forces the electrons under the influence of the microwave electric field to move preferentially towards the direction of the semidisc axis. A photovoltage of the order of few millivolts was observed. Such a photovoltage was completely absent in a symmetric system consisting of circular antidots. The induced photovoltage increased monotonically with microwave power and was found to be independent of the microwave polarization. This device opens the possibility of employing silicon based heterostructures for nanogenerators and other wireless communication devices using microwaves.

Hip structural geometry and incidence of hip fracture in postmenopausal women: what does it add to conventional bone mineral density?

SUMMARY: Hip geometry measurements of outer diameter and buckling ratio at the intertrochanter and shaft of the hip dual energy X-ray absorptiometry (DXA) scan predicted incident hip fracture in postmenopausal women. These associations, independent of age, body size, clinical risk factors, and conventional areal bone mineral density, suggest hip geometry plays a role in fracture etiology and may aid in improving identification of older women at high fracture risk. INTRODUCTION: This study examined whether hip geometry parameters predicted hip fracture independent of body size, clinical risk factors, and conventional femoral neck bone mineral density (aBMD) and whether summary factors could be identified to predict hip fracture. METHODS: We studied 10,290 postmenopausal women from the Women's Health Initiative. Eight thousand eight hundred forty-three remained fracture free during follow-up to 11 years of follow-up, while 147 fractured their hip, and 1,300 had other clinical fractures. Hip structural analysis software measured bone cross-sectional area, outer diameter, section modulus, average cortical thickness, and buckling ratio on archived DXA scans in three hip regions: narrow neck, intertrochanter, and shaft. Hazard ratios were estimated using Cox proportional hazards models for individual parameters and for composite factors extracted from principal components analysis from all 15 parameters. RESULTS: After adjustment for age, body size, clinical risk factors, and aBMD, intertrochanter and shaft outer diameter measurements remained independent predictors of hip fracture with hazard ratios for a one standard deviation increase of 1.61 (95% confidence interval (CI), 1.25-2.08) for the intertrochanter and 1.36 (95% CI, 1.06-1.76) for the shaft. Average buckling ratios also independently predicted incident hip fracture with hazard ratios of 1.43 (95% CI, 1.10-1.87) at the intertrochanter and 1.24 (95% CI, 1.00-1.55) at the shaft. Although two composite factors were extracted from principal components analysis, neither was superior to these individual measurements at predicting incident hip fracture. CONCLUSIONS: Two hip geometry parameters, intertrochanter outer diameter and buckling ratio, predict incident hip fracture after accounting for clinical risk factors and aBMD.

Women with hip fracture experience greater loss of geometric strength in the contralateral hip during the year following fracture than age-matched controls.

UNLABELLED: This study examined femur geometry underlying previously observed decline in BMD of the contralateral hip in older women the year following hip fracture compared to non-fractured controls. Compared to controls, these women experienced a greater decline in indices of bone structural strength, potentially increasing the risk of a second fracture. INTRODUCTION: This study examined the femur geometry underlying previously observed decline in BMD of the contralateral hip in the year following hip fracture compared to non-fractured controls. METHODS: Geometry was derived from dual-energy X-ray absorptiometry scan images using hip structural analysis from women in the third cohort of the Baltimore Hip Studies and from women in the Study of Osteoporotic Fractures. Change in BMD, section modulus (SM), cross-sectional area (CSA), outer diameter, and buckling ratio (BR) at the narrow neck (NN), intertrochanteric (IT), and shaft (S) regions of the hip were compared. RESULTS: Wider bones and reduced CSA underlie the significantly lower BMD observed in women who fractured their hip resulting in more fragile bones expressed by a lower SM and higher BR. Compared to controls, these women experienced a significantly greater decline in CSA (-2.3% vs. -0.2%NN, -3.2% vs. -0.5%IT), SM (-2.1% vs. -0.2%NN, -3.9% vs. -0.6%IT), and BMD (-3.0% vs. -0.8%NN, -3.3% vs. -0.6%IT, -2.3% vs. -0.2%S) and a greater increase in BR (5.0% vs. 2.1%NN, 6.0% vs. 1.3%IT, 4.4% vs. 1.0%S) and shaft outer diameter (0.9% vs. 0.1%). CONCLUSION: The contralateral femur continued to weaken during the year following fracture, potentially increasing the risk of a second fracture.

Peripubertal estrogen levels and physical activity affect femur geometry in young adult women.

UNLABELLED: The growing skeleton is particularly responsive to exercise around the time of puberty, suggesting a possible role for estrogen in mechanical adaptation in young women. We assessed femoral neck strength index at age 17 in young women with varying adolescent physical activity levels and E2 levels in the first 3 years after menarche. The results indicate that both E2 levels in the first year after menarche and adolescent physical activity are positively associated with bone strength in young adulthood, such that hormone levels may modify human osteogenic responses to exercise. INTRODUCTION: It is well established that physical activity contributes to bone strength in young females, but less is known about how peripubertal estrogen affects skeletal responses to exercise. METHODS: We used data from 84 participants in the Penn State Young Women's Health Study to test the prediction that young women who (1) had higher E2 levels during the first year after menarche or (2) were more physically active in adolescence will have greater bone strength at the end of adolescence. Subjects were divided into tertiles of physical activity and of E2 level in the first, second, and third postmenarchal years, and femoral strength was calculated from dual-energy X-ray absorptiometry scans of the proximal femur using hip structure analysis. RESULTS: At age 17, subjects with the highest E2 levels in year 1 after menarche had 5-14% greater strength in the narrow neck and intertrochanteric region, and the most active subjects had 10-11% greater strength in the femoral narrow neck vs. less active girls. CONCLUSIONS: This study suggests that both physical activity and peripubertal estrogen have important influences on young adult bone strength and that hormone levels may be mediators of human osteogenic responses to exercise.

DXA-based hip structural analysis of once-weekly bisphosphonate-treated postmenopausal women with low bone mass.

SUMMARY: DXA-based hip structural analysis from 947 individuals completing two large osteoporosis clinical trials was pooled and analyzed. Treatment with once-weekly (OW) ALN or OW RIS resulted in significant improvements from baseline in geometric parameters at all three HSA ROIs. Improvements were generally greater with OW ALN than OW RIS. INTRODUCTION: BMD can be altered by changes in distribution and quantity of bone and changes in mineralization. These effects cannot be distinguished with conventional measurements of BMD. Currently, tissue composition is evaluated only by invasive means. Structural geometry of the proximal femur, however, can be measured in vivo by several methods, including dual energy X-ray absorptiometry (DXA) using specialized hip structure analysis (HSA) software. METHODS: DXA-based HSA was obtained and analyzed in a subset of 947 subjects participating in the Fosamax Actonel Comparison Trials. Data were pooled to evaluate treatment effects on the structural geometry of the proximal femur by once-weekly alendronate (ALN) 70 mg and risedronate (RIS) 35 mg in postmenopausal women with low bone mass. RESULTS: Both ALN and RIS treatment over 2 years resulted in improvements in HSA-derived geometry at all three HSA regions of interest (ROI). The largest treatment effects were seen at the intertrochanteric ROI. Consistently greater treatment effects were seen with ALN compared with RIS at all three HSA-ROIs. CONCLUSIONS: HSA offers insight into the potential mechanisms of fracture risk reduction from pharmacologic intervention. In the current study, treatment with once-weekly bisphosphonates resulted in significant improvements in hip geometric parameters.

Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans.

Nitric oxide (NO), produced by endothelial cells, is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOS). NO is known to reduce the ratio of receptor activator of nuclear factor KappaB (RANKL)/osteoprotegerin (OPG), leading to decreased osteoclastogenesis and a reduction in bone resorption. Endothelial nitric oxide synthase (eNOS or NOS3) is the predominant constitutive isoform of nitric NOS within bone. Recently, a NOS3 polymorphism, Glu298Asp, previously implicated in osteoporosis, failed to demonstrate an association with bone mineral density (BMD), although there was some indication of an association with selected geometry indices. Since a single polymorphism does not capture all of the potential variants in a given gene, we investigated a broader coverage of the NOS3 gene with bone density/ultrasound and geometry indices in a sample of unrelated individuals from the Framingham Offspring Study. Our results indicated that the Glu298Asp polymorphism was not associated with BMD but suggested some haplotype-based associations in the linkage disequilibrium (LD) region that included the Glu298Asp polymorphism with several geometry indices. Although our findings exhibited several associations with selected bone density/ultrasound and geometry indices, the nominally significant associations are regarded as primarily hypothesis generating and suggest that replication in other samples is needed. Thus, NOS3 genetic variation does not appear to be a major contributor to adult bone density/ultrasound and geometry in our sample.

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish.

INTRODUCTION: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. MATERIALS AND METHODS: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age+/-SD=49.8+/-16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. RESULTS: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD=2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD>2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. CONCLUSIONS: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.

Does a novel school-based physical activity model benefit femoral neck bone strength in pre- and early pubertal children?

UNLABELLED: The effects of physical activity on bone strength acquisition during growth are not well understood. In our cluster randomized trial, we found that participation in a novel school-based physical activity program enhanced bone strength acquisition and bone mass accrual by 2-5% at the femoral neck in girls; however, these benefits depended on teacher compliance with intervention delivery. Our intervention also enhanced bone mass accrual by 2-4% at the lumbar spine and total body in boys. INTRODUCTION: We investigated the effects of a novel school-based physical activity program on femoral neck (FN) bone strength and mass in children aged 9-11 yrs. METHODS: We used hip structure analysis to compare 16-month changes in FN bone strength, geometry and bone mineral content (BMC) between 293 children who participated in Action Schools! BC (AS! BC) and 117 controls. We assessed proximal femur (PF), lumbar spine (LS) and total body (TB) BMC using DXA. We compared change in bone outcomes between groups using linear regression accounting for the random school effect and select covariates. RESULTS: Change in FN strength (section modulus, Z), cross-sectional area (CSA), subperiosteal width and BMC was similar between control and intervention boys, but intervention boys had greater gains in BMC at the LS (+2.7%, p = 0.05) and TB (+1.7%, p = 0.03) than controls. For girls, change in FN-Z tended to be greater (+3.5%, p = 0.1) for intervention girls than controls. The difference in change increased to 5.4% (p = 0.05) in a per-protocol analysis that included girls whose teachers reported 80% compliance. CONCLUSION: AS! BC benefits bone strength and mass in school-aged children; however, our findings highlight the importance of accounting for teacher compliance in classroom-based physical activity interventions.

Realistic CT simulation using the 4D XCAT phantom.

The authors develop a unique CT simulation tool based on the 4D extended cardiac-torso (XCAT) phantom, a whole-body computer model of the human anatomy and physiology based on NURBS surfaces. Unlike current phantoms in CT based on simple mathematical primitives, the 4D XCAT provides an accurate representation of the complex human anatomy and has the advantage, due to its design, that its organ shapes can be changed to realistically model anatomical variations and patient motion. A disadvantage to the NURBS basis of the XCAT, however, is that the mathematical complexity of the surfaces makes the calculation of line integrals through the phantom difficult. They have to be calculated using iterative procedures; therefore, the calculation of CT projections is much slower than for simpler mathematical phantoms. To overcome this limitation, the authors used efficient ray tracing techniques from computer graphics, to develop a fast analytic projection algorithm to accurately calculate CT projections directly from the surface definition of the XCAT phantom given parameters defining the CT scanner and geometry. Using this tool, realistic high-resolution 3D and 4D projection images can be simulated and reconstructed from the XCAT within a reasonable amount of time. In comparison with other simulators with geometrically defined organs, the XCAT-based algorithm was found to be only three times slower in generating a projection data set of the same anatomical structures using a single 3.2 GHz processor. To overcome this decrease in speed would, therefore, only require running the projection algorithm in parallel over three processors. With the ever decreasing cost of computers and the rise of faster processors and multi-processor systems and clusters, this slowdown is basically inconsequential, especially given the vast improvement the XCAT offers in terms of realism and the ability to generate 3D and 4D data from anatomically diverse patients. As such, the authors conclude that the efficient XCAT-based CT simulator developed in this work will have applications in a broad range of CT imaging research.

Sex hormone status may modulate rate of expansion of proximal femur diameter in older women alongside other skeletal regulators.

CONTEXT: Little is known of associations between hip geometry and skeletal regulators. This is important because geometry is a determinant of both hip function and resistance to fracture. OBJECTIVE: We aimed to determine the effects of sex hormone status and other candidate regulators on hip geometry and strength. SUBJECTS AND METHODS: A random sample of 351 women aged 67-79 had two to four hip dual-energy x-ray absorptiometry scans performed over 8 yr of follow-up. Hip structural analysis software was used to measure subperiosteal diameter (PD) and the distance from the center of mass to the lateral cortical margin (d-lat) on three 5-mm-thick cross-sectional regions: narrow neck, intertrochanter, and shaft. Section modulus (Z), bone mineral density (grams per centimeter squared), and an index of bone mineral content (cross-sectional area) were calculated as estimators of bone strength. Serum analytes measured at baseline included SHBG, estradiol, PTH, creatinine, albumin, vitamin D metabolites, and glutamate- and gamma-carboxyglutamate-osteocalcin (OC). A linear mixed model was used to model associations with predictor variables, including testing whether the predictors significantly modified the effect of aging. RESULTS: Aging was associated with increasing PD and d-lat, and higher baseline SHBG significantly modified this effect, in the case of PD, increasing the rates of change at the narrow neck region by 19% for SHBG level 2 sd higher than population mean (P = 0.026). Higher baseline creatinine was independently associated with faster increases in PD and d-lat with aging (P < 0.041). Z declined faster with aging if baseline PTH was higher, and higher albumin had a contrary effect. Z was positively associated with free estradiol and inversely associated with SHBG and glutamate-OC. CONCLUSION: These results show large effects of SHBG on the regulation of proximal femur expansion and bending resistance, probably acting as a surrogate for low bioavailable estrogen. Potentially important effects for fracture resistance in old age were also revealed for PTH, markers related to renal function and the nutritional markers albumin and undercarboxylated OC.

Effects of physical activity on evolution of proximal femur structure in a younger elderly population.

INTRODUCTION: For a fixed weight, a wider bone of standardised length is stiffer. But moving the cortices away from the centre of mass risks creating structural (elastic) instability, and hip fractures have been postulated to occur as a consequence of buckling of the thinned supero-lateral femoral neck cortex during a fall. We hypothesised that stereotyped physical activity (e.g., walking) may help conserve bending resistance (section modulus, Z) through redistribution of bone tissue, but it might be at the expense of supero-lateral cortical stability. METHODS: Hip structural analysis (HSA) software applied to DXA scans was used to derive measurements of section modulus and distances of a cross-section's centre of mass from the supero-lateral cortical margin (lateral distance, in cm). DXA scans were obtained on 1361 men and women in the EPIC-Norfolk population-based prospective cohort study. Up to 4 repeat DXA scans were done in 8 years of follow-up. Weight, height and activities of daily living were assessed on each occasion. A detailed physical activity and lifestyle questionnaire was administered at baseline. The lateral distance was measured on three narrow cross-sections with good precision: narrow neck (NN, coefficient of variation 2.6%), intertrochanter (IT) and shaft (S). A linear mixed model was used to assess associations with predictors. RESULTS: Ageing was associated with medial shifting of the centre of mass, so that lateral distance increased. Both greater weight and height were associated with greater lateral distance (P<0.0001). Among physical activity-related variables, walking/cycling for >1 h/day (P=0.025), weekly time spent on moderate impact activity (P=0.003), forced expiratory volume in 1 s (NN and IT, P<0.026) and lifetime physical activity (IT, P<0.0001) were associated with higher lateral distance. However, after adjusting for these variables, activities of daily living scores (NN, P<0.0001) and weekly time spent on low impact hip flexing activities were associated with shorter lateral distance (P=0.001). Greater baseline lateral distance was significantly associated with increased risk of subsequent hip fracture (n=26) in females (P<0.05, all regions) independently of age, height and bone mineral content. CONCLUSION: The age-related shift medially of the centre of mass of the femoral neck and trochanter may have adverse effects on fracture resistance in the event of a fall, so compromising the beneficial effects of walking on fitness, strength and risk of falling. The role of more diverse physical activity patterns in old age that impose loading on the supero-lateral cortex of the femur, involving for example hip flexion and stretching, needs investigation for their ability to correct this medial shifting of the centre of mass.

Proximal hip geometry is linked to several chromosomal regions: genome-wide linkage results from the Framingham Osteoporosis Study.

INTRODUCTION: Femoral geometry contributes to bone strength and predicts hip fracture risk. The purpose of this study was to evaluate heritability (h(2)) of geometric indices of the proximal hip and to perform whole-genome linkage analyses of these traits, adjusted for body size. METHODS: DXA scans of the proximal femur from 1473 members of 323 pedigrees (age range 31-96 years) from the population-based Framingham Osteoporosis Study were obtained. Using the hip structural analysis program, we measured femoral neck length (FNL, cm) and neck-shaft angle (NSA); subperiosteal width (WID, cm), cross-sectional area (CSA, cm(2)); and section modulus (Z, cm(3)) at the narrowest section of the neck (NN), intertrochanteric (IT) and femoral shaft (S) regions. Linkage analyses were performed for the above indices with a set of 636 markers using variance components maximum likelihood method. RESULTS: Substantial genetic influences were found for all geometric phenotypes, with h(2) values between 0.28 (NSA) and 0.70 (IT_WID). Adjustment for height and BMI did not alter h(2) of NSA and FNL but decreased h(2) of the cross-sectional indices. We obtained substantial linkage (multipoint LOD >3.0) for S_Z at 2p21 and 21q11 and S_WID at Xq25-q26. Inclusion of height and BMI as covariates resulted in much lower LOD scores for S_Z, whereas linkage signals for S_Z at 4q25, S_CSA at 4q32 and S_CSA and S_Z at 15q21 increased after the adjustment. Linkage of FNL at 1q and 13q, NSA at 2q and NN_WID at 16q did not change after the adjustment. CONCLUSION: Suggestive linkages of bone geometric indices were found at 1q, 2p, 4q, 13q, 15q and Xq. The identification of significant linkage regions after adjustment for BMI and height may point to QTLs influencing femoral bone geometry independent of body size.

A cortical-bone structural geometry phantom: dental plaster as a convenient and radiologically similar fabrication material.

Areal bone mineral density (aBMD), derived from dual-energy X-ray absorptiometry (DXA) scanners is used routinely to infer bone strength. With DXA hip scans there is growing acceptance of the advantages of also measuring bone structural geometric variables, that complement conventional aBMD to improve understanding of bone modelling, remodelling and processes of metabolic bone disease. However, phantoms for assessing structural geometric variables from DXA scans are not widely available, unlike those for aBMD. This study describes the development of such a phantom, simulating the cortical shell of the human femoral neck, using dental plaster as a material radiologically similar to cortical bone. The mass attenuation coefficient of the dental plaster differed by < 1% from cortical bone, over the relevant energy range. Performance testing was carried out with DXA, to determine accuracy and precision of the phantom structural geometry, using its dimensions and composition as 'gold standards'. Accuracy and precision of cortical structural geometry were poor when measured in a simulated 1 mm-thick osteoporotic cortex (5.5% precision and 50% accuracy errors), but improved with increasing cortical thickness. This study demonstrates the limitations of DXA-based Hip Structure Analysis when applied to femora with thin cortices, and indicates improvements in the design of a phantom to better simulate such cortical structures.

Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women.

TNFalpha is a proinflammatory cytokine that promotes osteoclastic bone resorption. We evaluated the association between a G-308A polymorphism (rs1800629) at the TNFA locus and osteoporosis phenotypes in 4306 older women participating in the Study of Osteoporotic Fractures. Femoral neck bone mineral density (BMD) and structural geometry were measured using dual-energy x-ray absorptiometry and hip structural analysis. Incident fractures were confirmed by physician adjudication of radiology reports. Despite similar femoral neck BMD, women with the A/A genotype had greater subperiosteal width (P = 0.01) and endocortical diameter (P = 0.03) than those with the G/G genotype. The net result of these structural differences was that there was a greater distribution of bone mass away from the neutral axis of the femoral neck in women with the A/A genotype, resulting in greater indices of bone bending strength (cross-sectional moment of inertia: P = 0.004; section modulus: P = 0.003). Among 376 incident hip fractures during 12.1 yr of follow-up, a 22% decrease in the risk of hip fracture was seen per copy of the A allele (relative risk 0.78; 95% confidence interval 0.63, 0.96), which was not influenced by adjustments for potential confounding factors, BMD, or bone strength indices. The G-308A polymorphism was not associated with a reduced risk of other fractures. These results suggest a potential role of genetic variation in TNFalpha in the etiology of osteoporosis.

Examining the developing bone: What do we measure and how do we do it?

The clinical tools available to evaluate bone development in children are often ambiguous, and difficult to interpret. Unfortunately bone densitometry methods (i.e., dual energy X-ray absorptiometry, DXA) which have a relatively straightforward application in adult osteoporosis, are far more difficult to evaluate in the growing skeleton. Even with adequate "adjustment" for bone size or maturity, bone "density" (areal or volumetric) alone often gives an inaccurate assessment of bone strength--especially in children. Ideally, we would like to measure both material and geometric properties of bone to accurately estimate "strength". Mechanically meaningful measures of bone geometry (bone cross-sectional area, cortical thickness) and estimates of bending strength (section modulus, or SSI) are available with non-invasive techniques such as (p)QCT and some DXA software. With new technology it might be possible to also measure bone material properties, which will be especially important in some pediatric disorders. In children, we also need to know something about the loads imposed on a child's bone and consider not only absolute bone strength, but also the strength of bone relative to the physiologic loads. Interpreting bone strength in light of the loads imposed (particularly muscle force) is critical for an accurate diagnosis of the developing bone.

Does body size account for gender differences in femur bone density and geometry?

The extent to which greater bone strength in men is caused by proportionately greater bone mass versus bigger bone size is not clear, primarily because the larger overall body size of men has made direct comparisons of skeletal measures difficult. We examined gender differences in femur neck (FN) areal bone mineral density (BMD) values collected from 5,623 non-Hispanic whites aged 20+ years in the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) before and after correction for measured height and weight. We supplemented the conventional areal BMD data (Hologic QDR 1000) with measurements of areal BMD and geometric properties (subperiosteal width, section modulus, and cortical thickness) made at narrow "cross-sectional" regions traversing the FN and the proximal shaft using a structural analysis program. Before body size adjustment, men had significantly higher values than women for all variables at the three measurement sites (p < 0.0001). Adjustment for body size reduced the differences between the sexes for all variables but had a greater effect on BMD (1-8% higher in men) than on geometry (5-17% higher in men). When examined by age, the sex discrepancy was significantly greater in the older group for all variables except subperiosteal widths. We conclude that although body size difference may account for most of the areal BMD difference between men and women, male bones are still bigger in ways that suggest greater bone strength. These differences may contribute importantly to lower fracture risk in men.