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.

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.

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.

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.

Relationship of femoral neck areal bone mineral density to volumetric bone mineral density, bone size, and femoral strength in men and women.

UNLABELLED: Using combined dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography, we demonstrate that men matched with women for femoral neck (FN) areal bone mineral density (aBMD) have lower volumetric BMD (vBMD), higher bone cross-sectional area, and relatively similar values for finite element (FE)-derived bone strength. INTRODUCTION: aBMD by DXA is widely used to identify patients at risk for osteoporotic fractures. aBMD is influenced by bone size (i.e., matched for vBMD, larger bones have higher aBMD), and increasing evidence indicates that absolute aBMD predicts a similar risk of fracture in men and women. Thus, we sought to define the relationships between FN aBMD (assessed by DXA) and vBMD, bone size, and FE-derived femoral strength obtained from quantitative computed tomography scans in men versus women. METHODS: We studied men and women aged 40 to 90 years and not on osteoporosis medications. RESULTS: In 114 men and 114 women matched for FN aBMD, FN total cross-sectional area was 38% higher (P < 0.0001) and vBMD was 16% lower (P < 0.0001) in the men. FE models constructed in a subset of 28 women and 28 men matched for FN aBMD showed relatively similar values for bone strength and the load-to-strength ratio in the two groups. CONCLUSIONS: In this cohort of young and old men and women from Rochester, MN, USA who are matched by FN aBMD, because of the offsetting effects of bone size and vBMD, femoral strength and the load-to-strength ratio tended to be relatively similar across the sexes.

Determinants of forearm strength in postmenopausal women.

UNLABELLED: Bone strength at the ultradistal radius, quantified by micro-finite element modeling, can be predicted by variables obtained from high-resolution peripheral quantitative computed tomography scans. The specific formula for this bone strength surrogate (-555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) should be validated and tested in fracture risk assessment. INTRODUCTION: The purpose of this study was to identify key determinants of ultradistal radius (UDR) strength and evaluate their relationships with age, sex steroid levels, and measures of habitual skeletal loading. METHODS: UDR failure load (~strength) was assessed by micro-finite element (µFE) modeling in 105 postmenopausal controls from an earlier forearm fracture case-control study. Predictors of bone strength obtained by high-resolution peripheral quantitative computed tomography (HRpQCT) in this group were then evaluated in a population-based cohort of 214 postmenopausal women. Sex steroids were measured by mass spectrometry. RESULTS: A surrogate variable (-555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) predicted UDR strength modeled by µFE (R(2) = 0.81), and all parameters except total cross-sectional area declined with age. Evaluated cross-sectionally, the 21% fall in predicted bone strength between ages 40-49 years and 80+ years more resembled the change in trabecular volumetric bone mineral density (vBMD) (-15%) than that in cortical area (-41%). In multivariable analyses, measures of body composition and physical activity were stronger predictors of UDR trabecular vBMD, cortical area, total cross-sectional area, and predicted bone strength than were sex steroid levels, but bio-available estradiol and testosterone were correlated with body mass. CONCLUSIONS: Bone strength at the UDR, as quantified by µFE, can be predicted from variables obtained by HRpQCT. Predicted bone strength declines with age with changes in UDR trabecular vBMD and cortical area, related in turn to reduced skeletal loading and sex steroid levels. The predicted bone strength formula should be validated and tested in fracture risk assessment.

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.

Assessing forearm fracture risk in postmenopausal women.

UNLABELLED: A diverse array of bone density, structure, and strength parameters were significantly associated with distal forearm fractures in postmenopausal women, but most of them were also correlated with femoral neck areal bone mineral density (aBMD), which provides an adequate measure of bone fragility at the wrist for routine clinical purposes. INTRODUCTION: This study seeks to test the clinical utility of approaches for assessing forearm fracture risk. METHODS: Among 100 postmenopausal women with a distal forearm fracture (cases) and 105 with no osteoporotic fracture (controls), we measured aBMD and assessed radius volumetric bone mineral density, geometry, and microstructure; ultradistal radius failure load was evaluated in microfinite element (microFE) models. RESULTS: Fracture cases had inferior bone density, geometry, microstructure, and strength. The most significant determinant of fracture in five categories were bone density (femoral neck aBMD; odds ratio (OR) per standard deviation (SD), 2.0; 95% confidence interval (CI), 1.4-2.8), geometry (cortical thickness; OR, 1.5; 95% CI, 1.1-2.1), microstructure (structure model index (SMI); OR, 0.5; 95% CI, 0.4-0.7), and strength (microFE failure load; OR, 1.8; 95% CI, 1.3-2.5); the factor-of-risk (applied load in a forward fall / microFE failure load) was 15% worse in cases (OR, 1.9; 95% CI, 1.4-2.6). Areas under receiver operating characteristic curves (AUC) ranged from 0.62 to 0.68. The predictors of forearm fracture risk that entered a multivariable model were femoral neck aBMD and SMI (combined AUC, 0.71). CONCLUSIONS: Detailed bone structure and strength measurements provide insight into forearm fracture pathogenesis, but femoral neck aBMD performs adequately for routine clinical risk assessment.

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.

Secular trends in hip fracture incidence and recurrence.

UNLABELLED: The decline in hip fracture incidence is now accompanied by a further reduction in the likelihood of a recurrent hip fracture among survivors of the first fracture. INTRODUCTION: Hip fracture incidence is declining in North America, but trends in hip fracture recurrence have not been described. METHODS: All hip fracture events among Olmsted County, Minnesota residents in 1980-2006 were identified. Secular trends were assessed using Poisson regression, and predictors of recurrence were evaluated with Andersen-Gill time-to-fracture regression models. RESULTS: Altogether, 2,752 hip fractures (median age, 83 years; 76% female) were observed, including 311 recurrences. Between 1980 and 2006, the incidence of a first-ever hip fracture declined by 1.37%/year for women (p < 0.001) and 0.06%/year for men (p = 0.917). Among 2,434 residents with a first-ever hip fracture, the cumulative incidence of a second hip fracture after 10 years was 11% in women and 6% in men with death treated as a competing risk. Age and calendar year of fracture were independently associated with hip fracture recurrence. Accounting for the reduction in first-ever hip fracture rates over time, hip fracture recurrence appeared to decline after 1997. CONCLUSION: A recent reduction in hip fracture recurrence is somewhat greater than expected from the declining incidence of hip fractures generally. Additional research is needed to determine the extent to which this can be attributed to improved patient management.

Comparison of sex steroid measurements in men by immunoassay versus mass spectroscopy and relationships with cortical and trabecular volumetric bone mineral density.

UNLABELLED: In men, measurement of serum testosterone and estradiol levels with immunoassays correlated with mass spectroscopic measurements, and correlations of sex steroids with volumetric bone mineral density were similar. INTRODUCTION: While immunoassays have been used extensively for measurement of serum testosterone (T) and estradiol (E(2)) levels, there is concern about their specificity, particularly at low E(2) levels as present in men. METHODS: We compared T and E(2) measured by mass spectroscopy to levels measured by immunoassay in men (n = 313, age 22 to 91 years) and related these to volumetric bone mineral density (vBMD) at various skeletal sites. RESULTS: Serum T and non-SHBG bound (or bioavailable) T levels by immunoassay correlated well with the corresponding mass spectroscopy measurements (R = 0.90 and 0.95, respectively, P < 0.001); the correlations for serum E(2) measured using the two techniques were less robust (R = 0.63 for total E(2) and 0.84 for bioavailable E(2), P < 0.001). Overall relationships between serum bioavailable T and E(2) levels with vBMD at various skeletal sites were similar for the immunoassay and mass spectroscopic measures. CONCLUSIONS: Although E(2) levels with immunoassay correlate less well with the mass spectroscopic measurements than do the T measurements in men, our findings indicate that the fundamental relationships observed previously between vBMD and the sex steroids by immunoassay are also present with the mass spectroscopic measurements.

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.

Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men.

Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus, we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men (mean age 68 years), studying them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E, withdrawing only T, or only E, or continuing both. Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones. By two-factor ANOVA, E played the major role in preventing the increase in the bone resorption markers, whereas T had no significant effect. By contrast, serum osteocalcin, a bone formation marker, decreased in the absence of both hormones, and both E and T maintained osteocalcin levels. We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.

Nocturnal dyspnea and atrial fibrillation predict Cheyne-Stokes respirations in patients with congestive heart failure.

BACKGROUND: Cheyne-Stokes respirations have frequently been noted in highly selected groups of patients with congestive heart failure, but their prevalence in an unselected population with congestive heart failure is undefined. METHODS: One hundred consecutive unselected outpatients or stable inpatients with clinical congestive heart failure encountered by three clinical cardiologists during a 6-month period were screened for Cheyne-Stokes respirations with overnight oximetry. RESULTS: The mean age (+/- SD) of the patients was 70 +/- 8.6 years. Of the 100 patients, 33% had had previous coronary bypass surgery, 77% were men, 57% had hypertension, and 32% had atrial fibrillation. The mean ejection fraction (+/- SD) was 34% +/- 13%. Periodic breathing was assessed qualitatively as Cheyne-Stokes respirations in 27% of patients, nonspecific sleep-disordered breathing (apneas and/or hypopneas) in 43%, and normal in 30%. For patients with Cheyne-Stokes respirations, patients with nonspecific sleep-disordered breathing, and normal subjects, the mean numbers of oxyhemoglobin desaturation events per hour were 24, 10, and 2, and the total numbers of desaturations of 4% or more that lasted less than 3 minutes were 172, 74, and 13. Independent predictors of Cheyne-Stokes respirations vs non-Cheyne-Stokes respirations included a history of nocturnal dyspnea (odds ratio, 4.00; 95% confidence interval, 1.33 to 12.04; P = .01) and atrial fibrillation (odds ratio, 3.24; 95% confidence interval, 1.21 to 8.48; P = .02). CONCLUSIONS: Cheyne-Stokes respirations and nonspecific sleep-disordered breathing are common in unselected patients with congestive heart failure, and Cheyne-Stokes respirations are predicted by a history of nocturnal dyspnea and the presence of atrial fibrillation. Techniques designed to modify the nocturnal breathing pattern of patients with congestive heart failure may be applicable to a large portion of the congestive heart failure population.

Risk of age-related fractures in patients with primary hyperparathyroidism.

BACKGROUND: Bone mass is reduced, but the influence of primary hyperparathyroidism (HPT) on fracture risk is controversial. We addressed this issue in a population-based retrospective cohort study. METHODS: Ninety residents of Rochester, Minn, were first diagnosed with HPT in 1965 through 1976 and an equal number of age- and sex-matched control subjects from the community were identified. Fractures were assessed through review of each subject's complete (inpatient and outpatient) medical records in the community. RESULTS: Prior to the date of diagnosis, Rochester residents with HPT were more likely to have a history of fractures than were matched control subjects from the same population (30% vs 18%). Subsequently, 36% of cases and 31% of control subjects experienced one or more new fractures during 1072 person-years of follow-up; survival free of a new fracture was almost the same in the two groups. Women had more fractures than men, and fracture rates increased with age. Fractures appeared to be somewhat more frequent in those with baseline serum calcium levels of 2.74 mmol/L or more, in those with comorbid conditions possibly due to HPT and in those who did not undergo parathyroidectomy, but these differences were not statistically significant. In a multivariate analysis, only age at diagnosis was an independent predictor of fracture risk, with a 36% increase in risk per 10-year increase in age. CONCLUSIONS: Overall fracture risk was increased prior to diagnosis of HPT but not afterward. Because the numbers involved were small, however, we cannot exclude an increased likelihood of fractures in certain subgroups of HPT patients.

Long-term use of oral anticoagulants and the risk of fracture.

BACKGROUND: Vitamin K participates in bone metabolism and, since oral anticoagulants antagonize vitamin K, their use may increase the risk of osteoporosis. OBJECTIVE: To evaluate fracture risk at all skeletal sites following exposure to oral anticoagulants. METHODS: In a population-based retrospective cohort study, 572 Olmsted County, Minnesota, women 35 years or older at their first lifetime venous thromboembolism event between 1966 and 1990 were followed up for fractures. Risk was assessed by comparing new fractures with the number expected from sex- and age-specific fracture incidence rates for the general population (standardized incidence ratio [SIR]). RESULTS: Altogether, 480 fractures occurred during 6314 person-years of follow-up. Increasing exposure to oral anticoagulation was associated with an increased SIR for vertebral fractures: at less than 3 months of exposure, 2.4 (95% confidence interval [CI], 1.6-3.4); 3 to less than 12 months, 3.6 (95% CI, 2.5-4.9); and 12 months or more, 5.3 (95% CI, 3.4-8.0); and for rib fractures: at less than 3 months, 1.6 (95% CI, 0.9-2.7); 3 to less than 12 months, 1.6 (95% CI, 0.9-2.6); and 12 months or more, 3.4 (95% CI, 1.8-5.7). The data revealed no increased risk for other types of fractures. Oral anticoagulation for 12 months or more was an independent predictor of vertebral fractures (P = .009) and rib fractures (P = .02), but not other fractures. CONCLUSIONS: Long-term exposure to oral anticoagulation is associated with an increased risk of vertebral and rib fractures. The mechanism by which this occurs is still unclear and needs further investigation.

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.

Relationship between body composition and bone mass in women.

Increasing body weight is associated both with higher bone mass and with lower rates of bone loss. Whether the effects of body weight are mediated by lean body mass (LBM) or fat body mass (FBM) is, however, uncertain because different studies have used different measures of bone mass and arrived at contradictory conclusions. The parameter actually measured is bone mineral content (BMC). Bone mineral density (BMD), bone mineral apparent density (BMAD), and the BMD/height attempt to "correct" BMC for differences in bone or body size, but these corrections may bias the analysis of the effects of body composition on the skeleton. To resolve this issue, we measured BMC at the total body, lumbar spine, proximal femur, and forearm using dual energy X-ray absorptiometry (DXA) in a population-based sample including 138 premenopausal women (age range 21-54 years, mean 35 years) and 213 postmenopausal women (age range 34-94 years, mean 68 years). BMD, BMAD, and BMD/ height were also calculated for each site. LBM and FBM were determined from the DXA whole body scan. In a multivariate analysis that included age and height, both LBM and FBM predicted total body BMC in pre- and postmenopausal women (p < 0.002 for LBM and FBM in both groups). LBM had a dominant effect on spine and forearm BMC in both groups (p < 0.004) and hip BMC in premenopausal women (p < 0.001), whereas both LBM and FBM predicted hip BMC in postmenopausal women (p < 0.001). However, as BMC was adjusted for bone or body size using BMD, BMAD, or BMD/height, FBM tended to become more important than LBM in the analysis. This was, in part, due to the fact that each of the correction factors in the BMD and BMAD calculations, as well as height, were highly correlated with LBM (r = 0.57 and 0.52 for height versus LBM in pre- and postmenopausal women, respectively [p < 0.001]), and weakly or not at all with FBM (r = 0.08 and 0.11, respectively). Therefore, dividing BMC by these correction factors tended to bias the analysis against potential effects of LBM on bone mass. Thus, the relationship between body composition and bone mass is critically dependent on which bone mass parameter is used in the analysis. Both LBM and FBM have important effects on bone mass, depending on the bone mass parameter used, the skeletal site measured, and menopausal status.