Establishment of normative biometric data for body composition based on computed tomography in a North American cohort.

BACKGROUND & AIMS: Accurate and reproducible biomarkers are required to allow a more personalized approach to patient care. Body composition is one such biomarker affecting outcomes in a range of surgical and oncological conditions. The aim of this study is to determine the age and sex specific distribution of body composition data, based on information gathered from computed tomography (CT). METHODS: This prospective study used healthy subjects from the medical records linkage of the Rochester Epidemiology Project, based in Minnesota, USA. Each patient had a CT scan without intravenous contrast performed between 1999 and 2001. Quantification was performed using previously validated semi-automated in-house developed software for body composition analysis. Subcutaneous adipose tissue area, visceral adipose tissue area, intermuscular adipose tissue area and skeletal muscle area were measured and indexed to subject height. Generalized Additive Models for Location, Scale and Shape were used to assess the location, scale, and shape of each variable across age, stratified by sex. Z-scores specific to sex were assessed for each of the parameters analyzed. Age-specific z-scores were calculated using the formula: Z = (Index Variable - µ)/σ or Z = (√ (Index Variable) - µ)/σ. RESULTS: There were 692 subjects enrolled in the study. The fitted model equation was offered for each variable with values presented for µ and σ. Modelling with penalized splines was performed for VAT index, IMAT index and total adipose tissue index. Scatterplots of each variable were produced with lines of Z-scores as a visual representation. CONCLUSION: This study offers comparative data to allow comparison amongst multiple populations. This will form an important reference for future research and clinical practice.

Hip load capacity and yield load in men and women of all ages.

Quantitative computed tomography (QCT) based finite element (FE) models can compute subject-specific proximal femoral strengths, or fracture loads, that are associated with hip fracture risk. These fracture loads are more strongly associated with measured fracture loads than are DXA and QCT measures and are predictive of hip fracture independently of DXA bone mineral density (BMD). However, interpreting FE-computed fracture loads of younger subjects for the purpose of evaluating hip fracture risk in old age is challenging due to limited reference data. The goal of this study was to address this issue by providing reference data for male and female adult subjects of all ages. QCT-based FE models of the left proximal femur of 216 women and 181 men, age 27 to 90 years, from a cohort of Rochester, MN residents were used to compute proximal femoral load capacities, i.e. the maximum loads that can be supported, in single-limb stance and posterolateral fall loading (Stance_LC and Fall_LC, respectively) [US Patent No. 9,245,069] and yield load under fall loading (Fall_yield). To relate these measures to information about hip fracture, the CT scanner and calibration phantom were cross-calibrated with those from our previous prospective study of hip fracture in older fracture and control subjects, the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. We then plotted Stance_LC, Fall_LC and Fall_yield versus age for the two cohorts on the same graphs. Thus, proximal femoral strengths in individuals above 70 years of age can be assessed through direct comparison with the FE data from the AGES cohort which were analyzed using identical methods. To evaluate younger individuals, reductions in Stance_LC, Fall_LC and Fall_yield from the time of evaluation to age 70 years can be cautiously estimated from the average yearly cross-sectional decreases found in this study (108 N, 19.4 N and 14.4 N, respectively, in men and 120 N, 19.4 N and 21.6 N, respectively, in women), and the projected fracture loads can be compared with data from the AGES cohort. Although we did not set specific thresholds for identifying individuals at risk of hip fracture, these data provide some guidance and may be used to help establish diagnostic criteria in future. Additionally, given that these data were nearly entirely from Caucasian subjects, future research involving subjects of other races/ethnicities is necessary.

High rate of extrapair paternity in a human population demonstrates diversity in human reproductive strategies.

Among nonhuman species, social monogamy is rarely accompanied by complete fidelity. Evolutionary theory predicts that the rate of extrapair paternity (EPP) should vary according to socioecological conditions. In humans, however, geneticists contend that EPP is negligible and relatively invariable. This conclusion is based on a limited set of studies, almost all of which describe European-descent groups. Using a novel, double-blind method designed in collaboration with a community of Himba pastoralists, we find that the rate of EPP in this population is 48%, with 70% of couples having at least one EPP child. Both men and women were very accurate at detecting cases of EPP. These data suggest that the range of variation in EPP across human populations is substantially greater than previously thought. We further show that a high rate of EPP can be accompanied by high paternity confidence, which highlights the importance of disaggregating EPP from the notion of "cuckoldry."

Development and thyroid hormone dependence of skeletal muscle mitochondrial function towards birth.

KEY POINTS: Skeletal muscle energy requirements increase at birth but little is known regarding the development of mitochondria that provide most of the cellular energy as ATP. Thyroid hormones are known regulators of adult metabolism and are important in driving several aspects of fetal development, including muscle fibre differentiation. Mitochondrial density and the abundance of mitochondrial membrane proteins in skeletal muscle increased during late gestation. However, mitochondrial functional capacity, measured as oxygen consumption rate, increased primarily after birth. Fetal hypothyroidism resulted in significant reductions in mitochondrial function and density in skeletal muscle before birth. Mitochondrial function matures towards birth and is dependent on the presence of thyroid hormones, with potential implications for the health of pre-term and hypothyroid infants. ABSTRACT: Birth is a significant metabolic challenge with exposure to a pro-oxidant environment and the increased energy demands for neonatal survival. This study investigated the development of mitochondrial density and activity in ovine biceps femoris skeletal muscle during the perinatal period and examined the role of thyroid hormones in these processes. Muscle capacity for oxidative phosphorylation increased primarily after birth but was accompanied by prepartum increases in mitochondrial density and the abundance of electron transfer system (ETS) complexes I-IV and ATP-synthase as well as by neonatal upregulation of uncoupling proteins. This temporal disparity between prepartum maturation and neonatal upregulation of mitochondrial oxidative capacity may protect against oxidative stress associated with birth while ensuring energy availability to the neonate. Fetal thyroid hormone deficiency reduced oxidative phosphorylation and prevented the prepartum upregulation of mitochondrial density and ETS proteins in fetal skeletal muscle. Overall, the data show that mitochondrial function matures over the perinatal period and is dependent on thyroid hormones, with potential consequences for neonatal viability and adult metabolic health.

Quantifying Rome symptoms for diagnosis of the irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, diagnosed on symptom-based criteria. Many have reported discrepancies between formal Rome criteria and diagnoses made in clinical practice. The aim of the study was to explore whether a quantitative version of the Rome criteria would better represent a clinical diagnosis of IBS than the current dichotomous criteria for symptom measure. METHODS: As part of a large, case-control study, participants completed a validated bowel disease questionnaire. Rome criteria were analyzed based on 15 individual symptoms. Penalized logistic regression model with stepwise selection was used to identify significant symptoms of IBS which were independently associated with case-control status. KEY RESULTS: In cases with a clinical diagnosis of IBS, 347 (70%) met Rome criteria for IBS. Increasing number of Rome symptoms were found related to the odds of being diagnosed with IBS. Nearly half of the Rome-negative case group experienced infrequent symptoms suggesting milder disease. Five of 15 Rome symptoms were associated with predicting case-control status in the final model, with 96% correctly classified among Rome-positive cases, 76% for Rome-negative cases, and 91% for controls. CONCLUSIONS AND INFERENCES: Irritable bowel syndrome appears to be a spectrum disorder. Quantifying individual symptoms of Rome criteria has greater utility than the current application in representing the degree of IBS affectedness and appears to better reflect a clinical diagnosis of IBS applied by physicians. The use of a quantitative diagnostic Rome "score" may be helpful in clinical practice and research studies to better reflect the degree an individual is affected with IBS.

Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice.

OBJECTIVE: To investigate whether osteocytic connexin 43 (Cx43) is required for the bone response to intermittent PTH administration, and whether the connexin is involved in maintaining the bone matrix. METHODS: Human PTH(1-34) was injected to adult male mice expressing (Cx43(fl/fl)) or not osteocytic Cx43 (Cx43(fl/fl);DMP1-8kb-Cre) daily (100 µg/kg/d) for 14 days. RESULTS: Cx43(fl/fl);DMP1-8kb-Cre mice have no difference in body weight and BMD from 1 to 4 months of age. Intermittent PTH administration increased BMD and BV/TV and induced a similar increase in type I collagen, alkaline phosphatase, runx2, osteocalcin, and bone sialoprotein expression in mice from both genotypes. On the other hand, osteocytic deletion of Cx43 did not alter mRNA levels of glycosaminoglycans, proteoglycans, collagens and osteoblast-related genes. In addition, expression of collagens assessed by immunohistochemistry was not affected by deleting osteocytic Cx43. However, PTH administration increased type II collagen only in Cx43(fl/fl) control mice, whereas hormone increased type I collagen expression only in Cx43(fl/fl);DMP1-8kb-Cre mice. Furthermore, PTH increased maturity of collagen fibers in control, but not in Cx43-deficient mice. CONCLUSION: Expression of Cx43 in osteocytes is dispensable for bone anabolism induced by intermittent PTH administration; but it can modulate, at least in part, the effect of PTH on the bone matrix environment.

Prediction using hierarchical data: Applications for automated detection of cervical cancer.

Although the Papanicolaou smear has been successful in decreasing cervical cancer incidence in the developed world, there exist many challenges for implementation in the developing world. Quantitative cytology, a semi-automated method that quantifies cellular image features, is a promising screening test candidate. The nested structure of its data (measurements of multiple cells within a patient) provides challenges to the usual classification problem. Here we perform a comparative study of three main approaches for problems with this general data structure: a) extract patient-level features from the cell-level data; b) use a statistical model that accounts for the hierarchical data structure; and c) classify at the cellular level and use an ad hoc approach to classify at the patient level. We apply these methods to a dataset of 1,728 patients, with an average of 2,600 cells collected per patient and 133 features measured per cell, predicting whether a patient had a positive biopsy result. The best approach we found was to classify at the cellular level and count the number of cells that had a posterior probability greater than a threshold value, with estimated 61% sensitivity and 89% specificity on independent data. Recent statistical learning developments allowed us to achieve high accuracy.

Crop rotational diversity enhances belowground communities and functions in an agroecosystem.

Biodiversity loss, an important consequence of agricultural intensification, can lead to reductions in agroecosystem functions and services. Increasing crop diversity through rotation may alleviate these negative consequences by restoring positive aboveground-belowground interactions. Positive impacts of aboveground biodiversity on belowground communities and processes have primarily been observed in natural systems. Here, we test for the effects of increased diversity in an agroecosystem, where plant diversity is increased over time through crop rotation. As crop diversity increased from one to five species, distinct soil microbial communities were related to increases in soil aggregation, organic carbon, total nitrogen, microbial activity and decreases in the carbon-to-nitrogen acquiring enzyme activity ratio. This study indicates positive biodiversity-function relationships in agroecosystems, driven by interactions between rotational and microbial diversity. By increasing the quantity, quality and chemical diversity of residues, high diversity rotations can sustain soil biological communities, with positive effects on soil organic matter and soil fertility.

A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease.

BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2-2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7-0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls.

A case-control study of childhood trauma in the development of irritable bowel syndrome.

BACKGROUND: The etiology of irritable bowel syndrome (IBS) is not been fully elucidated, but childhood trauma may disturb the brain-gut axis and therefore be important. Thus, we conducted a family based case-control study of IBS cases and their relatives with the aims to (i) determine the frequency of childhood trauma among IBS cases and controls as well as their relatives, and (ii) assess childhood trauma among IBS cases with affected relatives (familial IBS). METHODS: Outpatients with IBS, matched controls, and their first-degree relatives completed a self-report version of Bremner' Early Trauma Inventory. Percent of cases and controls with a family history were compared and odds ratios were computed using chi-squared test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations. KEY RESULTS: Data were collected from 409 cases, 415 controls, 825 case relatives, and 921 control relatives. IBS cases had a median age of 50 and 83% were women. Of IBS cases, 74% had experienced any general trauma compared to 59% among controls, yielding an odds ratio of 1.56 (95% CI: 1.13-2.15, p < 0.008). There were no statistical differences between IBS relatives and control relatives with regards to lifetime trauma. CONCLUSIONS & INFERENCES: IBS is associated with childhood trauma, and these traumas often occur prior to onset of IBS symptoms. This provides further insight into how traumatic childhood events are associated with development of adult IBS.

A statistical model for removing inter-device differences in spectroscopy.

We are investigating spectroscopic devices designed to make in vivo cervical tissue measurements to detect pre-cancerous and cancerous lesions. All devices have the same design and ideally should record identical measurements. However, we observed consistent differences among them. An experiment was designed to study the sources of variation in the measurements recorded. Here we present a log additive statistical model that incorporates the sources of variability we identified. Based on this model, we estimated correction factors from the experimental data needed to eliminate the inter-device variability and other sources of variation. These correction factors are intended to improve the accuracy and repeatability of such devices when making future measurements on patient tissue.

Isolation and characterization of human osteoblasts from needle biopsies without in vitro culture.

SUMMARY: We isolate and characterize osteoblasts from humans without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders. INTRODUCTION: There is currently no data regarding the expression of specific genes or pathways in human osteoblasts that have not been subjected to extensive in vitro culture. Thus, we developed methods to rapidly isolate progressively enriched osteoblast populations from humans and characterized these cells. METHODS: Needle bone biopsies of the posterior iliac crest were subjected to sequential collagenase digests. The cells from the second digest were stained with an alkaline phosphatase (AP) antibody, and the AP+ cells were isolated using magnetic cell sorting. RESULTS: Relative to AP- cells, the AP+ cells contained virtually all of the mineralizing cells and were enriched for key osteoblast marker genes. The AP+ cells were further purified by depletion of cells expressing CD45, CD34, or CD31 (AP+/CD45/34/31- cells), which represented a highly enriched human osteoblast population devoid of hematopoietic/endothelial cells. These cells expressed osteoblast marker genes but very low to undetectable levels of SOST. We next used high-throughput RNA sequencing to compare the transcriptome of the AP+/CD45/34/31- cells to human fibroblasts and identified genes and pathways expressed only in human osteoblasts in vivo, but not in fibroblasts, including 448 genes unique to human osteoblasts. CONCLUSIONS: We provide a detailed characterization of highly enriched human osteoblast populations without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders.

Fracture risk following bariatric surgery: a population-based study.

UNLABELLED: The effects of bariatric surgery on skeletal health are poorly understood. We found that bariatric surgery patients are more prone to fracture when compared to the general population. While further studies of fracture risk in this population are needed, bone health should be discussed in bariatric surgery clinics. INTRODUCTION: Bariatric surgery is an increasingly common treatment for medically complicated obesity. Adverse skeletal changes after bariatric surgery have been reported, but their clinical importance remains unknown. We hypothesized that bariatric surgery patients are at increased risk of fracture. METHODS: We conducted a historical cohort study of fracture incidence among 258 Olmsted County, Minnesota, residents who underwent a first bariatric surgery in 1985-2004. Relative fracture risk was expressed as standardized incidence ratios (SIRs), while potential risk factors were evaluated by hazard ratios (HR) obtained from a time-to-fracture regression model. RESULTS: The mean (±SD) body mass index at bariatric surgery was 49.0 ± 8.4 kg/m(2), with an average age of 44 ± 10 years and 82% (212) females. Gastric bypass surgery was performed in 94% of cases. Median follow-up was 7.7 years (range, 6 days to 25 years), during which 79 subjects experienced 132 fractures. Relative risk for any fracture was increased 2.3-fold (95% confidence interval (CI), 1.8-2.8) and was elevated for a first fracture at the hip, spine, wrist, or humerus (SIR, 1.9; 95% CI, 1.1-2.9), as well as for a first fracture at any other site (SIR, 2.5; 95% CI, 2.0-3.2). Better preoperative activity status was associated with a lower age-adjusted risk (HR, 0.4; 95% CI, 0.2-0.8) while prior fracture history was not associated with postoperative fracture risk. CONCLUSIONS: Bariatric surgery, which is accompanied by substantial biochemical, hormonal, and mechanical changes, is associated with an increased risk of fracture.

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.

Long-term mortality following fractures at different skeletal sites: a population-based cohort study.

UNLABELLED: Adjusting for age, sex, and precipitating cause, the relative risk of death was increased following fractures at most skeletal sites. INTRODUCTION: This study aims to determine long-term survival following fractures due to any cause at each skeletal site. METHODS: In a historical cohort study, 2,901 Olmsted County, MN, USA, residents ≥35 years old who experienced any fracture in 1989-1991 were followed passively for up to 22 years for death from any cause. Standardized mortality ratios (SMRs) compared observed to expected deaths. RESULTS: During 38,818 person-years of follow-up, 1,420 deaths were observed when 1,191 were expected (SMR, 1.2; 95 % CI, 1.1-1.3). The overall SMR was greatest soon after fracture, especially among the men, but remained elevated for over a decade thereafter. Adjusting for age and sex, relative death rates were greater for pathological fractures and less for severe trauma fractures compared to the fractures due to no more than moderate trauma. In the latter group, long-term mortality was increased following fractures at many skeletal sites. After further adjustment for precipitating cause, overall SMRs were elevated not only following fractures at the traditional major osteoporotic sites (i.e., distal forearm, proximal humerus, thoracic/lumbar vertebrae, and proximal femur) combined (SMR, 1.2; 95 % CI, 1.1-1.3) but also following all other fracture types combined (SMR 1.2; 95 % CI, 1.1-1.4), excluding the hand and foot fractures not associated with any increased mortality. CONCLUSIONS: The persistence of increased mortality long after the occurrence of a fracture has generally been attributed to underlying comorbidity, but this needs to be defined in much greater detail if specific opportunities are to be identified for reducing the excess deaths observed.

Accuracy of optical spectroscopy for the detection of cervical intraepithelial neoplasia without colposcopic tissue information; a step toward automation for low resource settings.

Optical spectroscopy has been proposed as an accurate and low-cost alternative for detection of cervical intraepithelial neoplasia. We previously published an algorithm using optical spectroscopy as an adjunct to colposcopy and found good accuracy (sensitivity=1.00 [95% confidence interval (CI)=0.92 to 1.00], specificity=0.71 [95% CI=0.62 to 0.79]). Those results used measurements taken by expert colposcopists as well as the colposcopy diagnosis. In this study, we trained and tested an algorithm for the detection of cervical intraepithelial neoplasia (i.e., identifying those patients who had histology reading CIN 2 or worse) that did not include the colposcopic diagnosis. Furthermore, we explored the interaction between spectroscopy and colposcopy, examining the importance of probe placement expertise. The colposcopic diagnosis-independent spectroscopy algorithm had a sensitivity of 0.98 (95% CI=0.89 to 1.00) and a specificity of 0.62 (95% CI=0.52 to 0.71). The difference in the partial area under the ROC curves between spectroscopy with and without the colposcopic diagnosis was statistically significant at the patient level (p=0.05) but not the site level (p=0.13). The results suggest that the device has high accuracy over a wide range of provider accuracy and hence could plausibly be implemented by providers with limited training.

Sclerostin levels during growth in children.

UNLABELLED: Serum sclerostin levels are associated with cortical porosity, suggesting that changes in sclerostin production during growth may play a role in defining cortical structure. INTRODUCTION: Sclerostin, produced by osteocytes, is a potent inhibitor of Wnt signaling and bone formation. While sclerostin levels increase with age in adults and are higher in men compared to women, there is currently no information on changes in circulating sclerostin levels during growth in humans. METHODS: We measured serum sclerostin levels in 6- to 21-year-old girls (n = 62) and boys (n = 56) and related these to trabecular and cortical bone microarchitectural parameters using high-resolution peripheral quantitative computed tomography and to markers of bone turnover. RESULTS: Serum sclerostin levels were higher in boys as compared to girls and declined in both sexes following the onset of puberty. There was no consistent relationship between sclerostin levels and trabecular bone parameters in either sex. However, serum sclerostin levels were inversely associated with cortical volumetric bone mineral density and cortical thickness in girls and positively associated with the cortical porosity index in both girls and boys. Bone turnover markers were positively correlated with serum sclerostin levels in both sexes. CONCLUSION: The gender difference in serum sclerostin levels appears to be established during puberty, and sclerostin levels tend to decline in late puberty in both girls and boys. Serum sclerostin levels are associated with cortical porosity, suggesting that changes in sclerostin production during growth may play a role in defining cortical structure.

Trends in subtrochanteric, diaphyseal, and distal femur fractures, 1984-2007.

UNLABELLED: The incidence of non-hip femur fractures increased between 1984 and 2007, with an increase in the rates for women after 1996. INTRODUCTION: Recent reports have suggested that non-hip femur fractures may be decreasing over time, similar to proximal femur fractures. METHODS: Incidence rates for non-hip femur fractures among Olmsted County, Minnesota, residents were assessed before and after 1995 when the oral bisphosphonate, alendronate, was approved in the USA. RESULTS: From 1984 to 2007, 727 non-hip femur fractures were observed in 690 Olmsted County residents (51% female [median age, 71.6 years] and 49% male [21.4 years]). Altogether, 20% of the fractures were subtrochanteric, 51% were diaphyseal, and 29% involved the distal femur. Causes included severe trauma in 51%, minimal to moderate trauma in 34%, and pathologic causes in 15%. The overall age- and sex-adjusted annual incidence of first non-hip femur fracture was 26.7 per 100,000 (25.0 per 100,000 for women and 26.6 per 100,000 for men). Incidence rates increased with age and were greater in women than men. Between 1984-1995 and 1996-2007, age-adjusted rates increased significantly for women (20.4 vs. 28.7 per 100,000; p = 0.002) but not for men (22.4 vs. 29.5 per 100,000; p = 0.202). CONCLUSION: The incidence of first non-hip femur fractures rose between 1984 and 2007, with an increase in the rates for women after 1995.