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1.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
2.  Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and potentially other non-Hodgkin lymphoma subtypes 
British journal of haematology  2012;159(5):572-576.
A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
PMCID: PMC3614403  PMID: 23025533
CLL; NHL; SNPs; BAK1; risk locus
3.  Skeletal Muscle Mass is Associated with Bone Geometry and Microstructure and Serum IGFBP-2 Levels in Adult Women and Men 
Skeletal muscle and bone form highly-integrated systems that undergo significant age-related changes, but the relationships between muscle mass and trabecular versus cortical bone or trabecular microarchitecture have not been systematically investigated. Thus, we examined the association between appendicular skeletal muscle mass relative to height2 (relative ASM) and bone parameters at several sites assessed by conventional as well as high-resolution peripheral QCT in a cohort of 272 women and 317 men aged 20 to 97 years. In women, relative ASM was associated with cortical thickness (CtTh) at the femoral neck, lumbar spine, radius and tibia (age-and physical activity adjusted r = 0.19 to 0.32; all p < 0.01). Relative ASM was also associated with trabecular volumetric bone mineral density (vBMD) at the femoral neck and spine (all p < 0.05), and trabecular bone volume to tissue volume (BV/TV), number (TbN), thickness (TbTh) and separation (TbSp) at the radius (all p ≤ 0.05). In all men, relative ASM was associated with CtTh at all sites (age- and physical activity adjusted r = 0.17 to 0.28; all p < 0.01). Associations between relative ASM and trabecular vBMD at the spine in men were lost after adjusting for age; however, relative ASM was associated with trabecular vBMD at the femoral neck and TbN and TbSp at the radius (all p < 0.01). We also investigated circulating factors associated with bone health that may be indicative of relative ASM and found that serum IGFBP-2 levels were the most robust negative predictors of relative ASM in both sexes. Collectively, these data add to the growing body of evidence supporting the highly-integrated nature of skeletal muscle and bone, and provide new insights into potential biomarkers that reflect the health of the musculoskeletal system.
PMCID: PMC3645866  PMID: 22623219
sarcopenia; osteoporosis; aging; sex steroids
4.  Assessing Fracture Risk using Gradient Boosting Machine (GBM) Models 
Advanced bone imaging with quantitative computed tomography (QCT) has had limited success in significantly improving fracture prediction beyond standard areal bone mineral density (aBMD) measurements. Thus, we examined whether a machine learning paradigm, gradient boosting machine (GBM) modeling, which can incorporate diverse measurements of bone density and geometry from central QCT imaging and of bone microstructure from high-resolution peripheral QCT imaging, can improve fracture prediction. We studied two cohorts of postmenopausal women: 105 with and 99 without distal forearm fractures (Distal Forearm Cohort) and 40 with at least one grade 2 or 3 vertebral deformity and 78 with no vertebral fracture (Vertebral Cohort). Within each cohort, individual bone density, structure, or strength variables had areas under receiver operating characteristic curves (AUCs) ranging from 0.50 to 0.84 (median 0.61) for discriminating women with and without fracture. Using all possible variables in the GBM model, the AUCs were close to 1.0. Fracture predictions in the Vertebral Cohort using the GBM models built with the Distal Forearm Cohort had AUCs of 0.82–0.95, while predictions in the Distal Forearm Cohort using models built with the Vertebral Cohort had AUCs of 0.80–0.83. Attempts at capturing a comparable parametric model using the top variables from the Distal Forearm Cohort resulted in resulted in an AUC of 0.81. Relatively high AUCs for differing fracture types suggest that an underlying fracture propensity is being captured by this modeling approach. More complex modeling, such as with GBM, creates stronger fracture predictions and may allow deeper insights into information provided by advanced bone imaging techniques.
PMCID: PMC3408850  PMID: 22367889
5.  Fracture Risk in Women With Breast Cancer: A Population-Based Study 
Journal of Bone and Mineral Research  2012;27(5):1196-1205.
A positive association has been reported between greater bone density and higher breast cancer risk, suggesting that these women could be at reduced risk of fracture. To estimate fracture risk among unselected community women with breast cancer, and to systematically assess associations with various risk factors including breast cancer treatments, we conducted a population-based historical cohort study of 608 Olmsted County, MN women with invasive breast cancer first diagnosed in 1990-99 (mean age, 61.6 ± 14.8 years), who were followed for 5776 person-years. Altogether, 568 fractures were observed in 270 women (98 per 1000 person-years). Overall fracture risk was elevated 1.8-fold; but the absolute increase in risk was only 9%, and 56% of the women did not experience a fracture during follow-up. Excluding pathologic fractures (15%) and those found incidentally (24%), to allow for ascertainment bias, the standardized incidence ratio was 1.2 (95% CI, 0.99–1.3) for total fracture risk and 0.9 (95% CI, 0.7–1.2) for osteoporotic fracture risk alone. Various breast cancer treatments were associated with an increased risk of fracture, but those associations were strongest for pathologic fractures, which were relatively more common among the women who were premenopausal when their breast cancer was diagnosed. Moreover, underlying clinical characteristics prompting different treatments may have been partially responsible for the associated fracture outcomes (indication bias). These data thus demonstrate that breast cancer patients in general are not at greatly increased risk of fracture but neither are they protected from fractures despite any determinants that breast cancer and high bone density may have in common.
PMCID: PMC3361522  PMID: 22258822
6.  Is Vitamin D a Determinant of Muscle Mass and Strength? 
There remains little consensus on the link between vitamin D levels and muscle mass or strength. We therefore investigated the association of serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone (PTH) levels with skeletal muscle mass and strength.
We studied 311 men (mean age, 56 yrs; range, 23-91 yrs) and 356 women (mean age, 57 yrs; range, 21-97 yrs) representing an age-stratified, random sample of community adults. Multivariate linear regression models were used to examine the association of skeletal muscle mass (by total body dual-energy x-ray absorptiometry) and strength (handgrip force and isometric knee extension moment) with each of 25(OH)D, 1,25(OH)2D and PTH quartiles, adjusted for age, physical activity, fat mass and season.
We found no consistent association between 25(OH)D or PTH and any of our measurements of muscle mass or strength, in either men or women. However, in subjects younger than 65 years, there was a statistically significant association between low 1,25(OH)2D levels and low skeletal mass in both men and women and low isometric knee extension moment in women, after adjustment for potential confounders.
Modestly low 25(OH)D or high PTH levels may not contribute significantly to sarcopenia or muscle weakness in community adults. The link between low 25(OH)D and increased fall risk reported by others may be due to factors that affect neuromuscular function rather than muscle strength. The association between low 1,25(OH)2D and low skeletal mass and low knee extension moment, particularly in younger people, needs further exploration.
PMCID: PMC3248226  PMID: 21915904
vitamin D; 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D; PTH; muscle; muscle strength; muscle mass
7.  Potential Extensions of the US FRAX Algorithm 
Journal of Osteoporosis  2012;2012:528790.
To determine if the revised US FRAX can identify those at high risk for fractures at any skeletal site, we studied 250 women and 249 men ≥40 years old from an age-stratified random sample of Rochester, MN residents. At baseline, femoral neck (FN) bone density was assessed, as were the clinical risk factors included in FRAX, along with additional fracture risk factors such as bone turnover markers and fall history. Fracture ascertainment through periodic interviews and comprehensive medical record review was performed over 10 years of followup. In both women and men, a higher FRAX probability at baseline was associated with greater subsequent likelihood of a major osteoporotic fracture. However, a relative 10% increase in the FRAX 10-year fracture probability was also associated with a 1.4-fold increase (95% confidence interval (CI) 1.1–1.7) in other fractures in women and a 1.7-fold increase (95% CI 0.8–3.1) in men. Furthermore, FRAX predicted asymptomatic vertebral fractures and fractures generally in both sexes. The addition of risk factors not currently included in FRAX did not appear to improve the accuracy of fracture risk prediction. FRAX may provide a conservative estimate of risk for major osteoporotic fractures, but it also predicts fractures generally.
PMCID: PMC3426248  PMID: 22934235
8.  Fracture Risk in Men With Prostate Cancer: A Population-Based Study 
Journal of Bone and Mineral Research  2011;26(8):1808-1815.
Fractures are increased among men with prostate cancer, especially those on androgen deprivation therapy (ADT), but few data are available on men with localized prostate cancer. The purpose of this investigation was to estimate fracture risk among unselected community men with prostate cancer and systematically assess associations with ADT and other risk factors for fracture. In a population-based retrospective cohort study, 742 Olmsted County, MN men with prostate cancer first diagnosed in 1990–99 (mean age, 68.2 ± 8.9 years) were followed for 6821 person-years. We estimated cumulative fracture incidence; assessed relative risk by standardized incidence ratios; and evaluated risk factors in time-to-fracture regression models. Altogether, 482 fractures were observed in 258 men (71 per 1000 person-years). Overall fracture risk was elevated 1.9-fold, with an absolute increase in risk of 9%. Relative to rates among community men generally, fracture risk was increased even among men not on ADT but was elevated a further 1.7-fold among ADT-treated compared to untreated men with prostate cancer. The increased risk following various forms of ADT was mainly accounted for by associations with pathologic fractures (14% of all fractures). Among men not on ADT (62% of the cohort), more traditional osteoporosis risk factors were implicated. In both groups, underlying clinical characteristics prompting different treatments (indication bias) may have been partially responsible for the associations seen with specific therapies. To the extent that advanced stage disease and pathologic fractures account for the excess risk, the effectiveness of fracture prevention among men with prostate cancer may be limited.
PMCID: PMC3321611  PMID: 21520274
9.  Association of Hip Strength Estimates by Finite Element Analysis with Fractures in Women and Men 
Finite element (FE) analysis of quantitative computed tomography (QCT) scans can estimate site-specific whole bone strength. However, it is uncertain whether the site-specific detail included in FE-estimated proximal femur (hip) strength can determine fracture risk at sites with different biomechanical characteristics. To address this question, we used FE analysis of proximal femur QCT scans to estimate hip strength and load-to-strength ratio during a simulated sideways fall, and measured total hip areal and volumetric bone mineral density (aBMD and vBMD) from QCT images, in an age-stratified, random sample of community adults, age ≥ 35 years. Among 314 women (mean age ± SD: 61 ± 15 years; 235 postmenopausal) and 266 men (62 ± 16 years), 139 women and 104 men had any prevalent fracture, while 55 women and 28 men had a prevalent osteoporotic fracture that had occurred age ≥ 35 years. Odds ratios by age-adjusted logistic regression analysis for prevalent overall and osteoporotic fractures each were similar for FE hip strength and load-to-strength ratio, as well as total hip aBMD and vBMD. C-statistics (estimated areas under ROC curves) were also similar (e.g., 0.84–0.85 [women] and 0.75–0.78 [men] for osteoporotic fractures). In women and men, the association with prevalent osteoporotic fractures increased below an estimated hip strength of ~3000 N. Despite its site-specific nature, FE-estimated hip strength worked equally well at predicting prevalent overall, and osteoporotic, fractures. Furthermore, an estimated hip strength below 3000 N may represent a critical level of systemic skeletal fragility in both sexes that warrants further investigation.
PMCID: PMC3201782  PMID: 21305605
finite element analysis; fractures; bone density; quantitative computed tomography; hip; proximal femur
10.  Relation of Age, Gender, and Bone Mass to Circulating Sclerostin Levels in Women and Men 
Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population-based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean ± SEM) were significantly higher in men than women (33.3 ± 1.0 pmol/L versus 23.7 ± 0.6 pmol/L, p < .001). In pre- and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4- and 4.6-fold in the women and men, respectively. Moreover, for a given total-body bone mineral content, elderly subjects (age ≥ 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age-related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age-related impairment in bone formation. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179347  PMID: 20721932
11.  What Accounts for Rib Fractures in Older Adults? 
Journal of Osteoporosis  2011;2011:457591.
To address the epidemiology of rib fractures, an age- and sex-stratified random sample of 699 Rochester, Minnesota, adults age 21–93 years was followed in a long-term prospective study. Bone mineral density (BMD) was assessed at baseline, and fractures were ascertained by periodic interview and medical record review. During 8560 person-years of followup (median, 13.9 years), 56 subjects experienced 67 rib fracture episodes. Risk factors for falling predicted rib fractures as well as BMD, but both were strongly age-related. After age-adjustment, BMD was associated with rib fractures in women but not men. Importantly, rib fractures attributed to severe trauma were associated with BMD in older individuals of both sexes. Self-reported heavy alcohol use doubled fracture risk but did not achieve significance due to limited statistical power. Bone density, along with heavy alcohol use and other risk factors for falling, contributes to the risk of rib fractures, but no one factor predominates. Older women with rib fractures, regardless of cause, should be considered for an osteoporosis evaluation, and strategies to prevent falling should be considered in both sexes.
PMCID: PMC3199083  PMID: 22028986
12.  Common Occurrence of Monoclonal B-cell Lymphocytosis Among Members of High-Risk CLL Families 
British journal of haematology  2010;151(2):152-158.
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
PMCID: PMC2966536  PMID: 20738309
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
13.  Idiopathic Retroperitoneal Fibrosis: A Retrospective Review of Clinical Presentation, Treatment, and Outcomes 
Mayo Clinic Proceedings  2011;86(4):297-303.
OBJECTIVE: To describe the clinical manifestations, laboratory results, imaging findings, and treatments in patients with idiopathic retroperitoneal fibrosis (IRF) seen at Mayo Clinic in Rochester, MN.
PATIENTS AND METHODS: In this retrospective study, we used International Classification of Diseases, Ninth Revision codes to identify all patients evaluated for IRF between January 1, 1996, and December 31, 2006, at Mayo Clinic in Rochester, MN. Medical records were reviewed, and clinical information was abstracted. Idiopathic retroperitoneal fibrosis was diagnosed on the basis of compatible imaging findings. Patients were followed up until their last visit at Mayo Clinic, death, or December 31, 2008, whichever came first.
RESULTS: Of the 185 patients identified as having IRF, 113 (61%) were men and 72 (39%) were women. Mean ± SD age at diagnosis was 57.6±11.8 years. Biopsy specimens were obtained in 142 cases (77%). The most common presenting symptoms were back pain (38%) and abdominal pain (40%). Baseline erythrocyte sedimentation rate and/or C-reactive protein levels were elevated in 88 (58%) of the 151 patients tested. The median creatinine level at diagnosis was 1.3 mg/dL (interquartile range, 1.1-2.1 mg/dL). Fifteen patients (8%) were treated with ureteral procedures only, 58 patients (31%) with medications only, and 105 patients (57%) with a combination of medical and surgical therapies. Seven patients (4%) were not treated. Corticosteroids were initiated in 116 patients (63%), and tamoxifen was used in 120 patients (65%). Follow-up was available for 151 patients (82%). Creatinine levels were normal at last visit in 102 (68%) of the 151 patients with follow-up. No patient developed end-stage renal disease. Relapses occurred in 18 (12%) of the 151 patients. Eleven patients died.
CONCLUSION: In this cohort, outcomes such as end-stage renal disease or death from renal failure were not observed. Relapses may occur, and patients with IRF warrant long-term follow-up.
In this cohort of 185 patients, outcomes such as end-stage renal disease or death due to renal failure were not observed; relapses may occur, and patients with idiopathic retroperitoneal fibrosis warrant long-term follow-up.
PMCID: PMC3068889  PMID: 21454732
14.  Relation of Vertebral Deformities to Bone Density, Structure, and Strength 
Journal of Bone and Mineral Research  2010;25(9):1922-1930.
Because they are not reliably discriminated by areal bone mineral density (aBMD) measurements, it is unclear whether minimal vertebral deformities represent early osteoporotic fractures. To address this, we compared 90 postmenopausal women with no deformity (controls) with 142 women with one or more semiquantitative grade 1 (mild) deformities and 51 women with any grade 2–3 (moderate/severe) deformities. aBMD was measured by dual-energy X-ray absorptiometry (DXA), lumbar spine volumetric bone mineral density (vBMD) and geometry by quantitative computed tomography (QCT), bone microstructure by high-resolution peripheral QCT at the radius (HRpQCT), and vertebral compressive strength and load-to-strength ratio by finite-element analysis (FEA) of lumbar spine QCT images. Compared with controls, women with grade 1 deformities had significantly worse values for many bone density, structure, and strength parameters, although deficits all were much worse for the women with grade 2–3 deformities. Likewise, these skeletal parameters were more strongly associated with moderate to severe than with mild deformities by age-adjusted logistic regression. Nonetheless, grade 1 vertebral deformities were significantly associated with four of the five main variable categories assessed: bone density (lumbar spine vBMD), bone geometry (vertebral apparent cortical thickness), bone strength (overall vertebral compressive strength by FEA), and load-to-strength ratio (45-degree forward bending ÷ vertebral compressive strength). Thus significantly impaired bone density, structure, and strength compared with controls indicate that many grade 1 deformities do represent early osteoporotic fractures, with corresponding implications for clinical decision making. © 2010 American Society for Bone and Mineral Research.
PMCID: PMC3153401  PMID: 20533526
bone density; bone quality; finite-element analysis; QCT; vertebral fracture
15.  Assessing forearm fracture risk in postmenopausal women 
To test the clinical utility of approaches for assessing forearm fracture risk.
Among 100 postmenopausal women with a distal forearm fracture (cases) and 105 with no osteoporotic fracture (controls), we measured areal bone mineral density (aBMD) and assessed radius volumetric BMD, geometry and microstructure using high-resolution peripheral QCT; ultradistal radius failure load was evaluated in micro-finite element (μFE) models.
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 SD, 2.0; 95% 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 (μFE failure load: OR, 1.8; 95% CI, 1.3–2.5); the factor-of-risk (applied load in a forward fall ÷ μFE failure load) was 15% worse in cases (OR, 1.9; 95% CI, 1.4–2.6). Areas under ROC 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).
Detailed bone structure and strength measurements provide insight into forearm fracture pathogenesis, but femoral neck aBMD performs adequately for routine clinical risk assessment.
PMCID: PMC2889027  PMID: 19714390
Bone density; Bone quality; Colles’ fracture; Epidemiology; Risk assessment
16.  Genetic susceptibility variants for chronic lymphocytic leukemia 
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
PMCID: PMC2852480  PMID: 20332261
IRF4; CLL; genetic association
17.  Relation of Serum Serotonin Levels to Bone Density and Structural Parameters in Women 
Recent studies have demonstrated an important role for circulating serotonin in regulating bone mass in rodents. In addition, patients treated with selective serotonin reuptake inhibitors (SSRIs) have reduced areal bone mineral density (aBMD). However, the potential physiologic role of serotonin in regulating bone mass in humans remains unclear. Thus we measured serum serotonin levels in a population-based sample of 275 women and related these to total-body and spine aBMD assessed by dual-energy X-ray absorptiometry, femur neck total and trabecular volumetric BMD (vBMD) and vertebral trabecular vBMD assessed by quantitative computed tomography (QCT), and bone microstructural parameters at the distal radius assessed by high-resolution peripheral QCT (HRpQCT). Serotonin levels were inversely associated with body and spine aBMD (age-adjusted R = −0.17 and −0.16, P < .01, respectively) and with femur neck total and trabecular vBMD (age-adjusted R = −0.17 and −0.25, P < .01 and < .001, respectively) but not lumbar spine vBMD. Bone volume/tissue volume, trabecular number, and trabecular thickness at the radius were inversely associated with serotonin levels (age-adjusted R = −0.16, −0.16, and −0.14, P < .05, respectively). Serotonin levels also were inversely associated with body mass index (BMI; age-adjusted R = −0.23, P < .001). Multivariable models showed that serotonin levels remained significant negative predictors of femur neck total and trabecular vBMD, as well as trabecular thickness at the radius, after adjusting for age and BMI. Collectively, our data provide support for a physiologic role for circulating serotonin in regulating bone mass in humans. © 2010 American Society for Bone and Mineral Research
PMCID: PMC3153390  PMID: 19594297
serotonin; bone density; bone structure; SSRI; osteoporosis
18.  Secular trends in hip fracture incidence and recurrence 
Hip fracture incidence is declining in North America, but trends in hip fracture recurrence have not been described.
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.
Altogether, 2752 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 2434 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.
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.
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.
PMCID: PMC2664856  PMID: 18797813
Aging; Hip fracture; Incidence; Population-based study; Recurrence; Secular trends
19.  Diagnostic Ionizing Radiation Exposure in a Population-Based Cohort of Patients with Inflammatory Bowel Disease 
For diagnosis, assessing disease activity, complications and extraintestinal manifestations, and monitoring response to therapy, patients with inflammatory bowel disease undergo many radiological studies employing ionizing radiation. However, the extent of radiation exposure in these patients is unknown.
A population-based inception cohort of 215 patients with inflammatory bowel disease from Olmsted County, Minnesota, diagnosed between 1990 and 2001, was identified. The total effective dose of diagnostic ionizing radiation was estimated for each patient. Linear regression was used to assess the median total effective dose since symptom onset.
The number of patients with Crohn's disease and ulcerative colitis was 103 and 112, with a mean age at diagnosis of 38.6 and 39.4 yr, respectively. Mean follow-up was 8.9 yr for Crohn's disease and 9.0 yr for ulcerative colitis. Median total effective dose for Crohn's disease was 26.6 millisieverts (mSv) (range, 0–279) versus 10.5 mSv (range, 0–251) for ulcerative colitis (P < 0.001). Computed tomography accounted for 51% and 40% of total effective dose, respectively. Patients with Crohn's disease had 2.46 times higher total effective dose than ulcerative colitis patients (P = 0.001), adjusting for duration of disease.
Annualizing our data, the radiation exposure in the inflammatory bowel disease population was equivalent to the average annual background radiation dose from naturally occurring sources in the U.S. (3.0 mSv). However, a subset of patients had substantially higher doses. The development of imaging management guidelines to minimize radiation dose, dose-reduction techniques in computed tomography, and faster, more robust magnetic resonance techniques are warranted.
PMCID: PMC2831296  PMID: 18564113
20.  Fracture Risk in Type 2 Diabetes: Update of a Population-Based Study 
We found no significant excess of fractures among Rochester, MN, residents with diabetes mellitus initially recognized in 1950–1969, but more recent studies elsewhere have documented an apparent increase in hip fracture risk. To explore potential explanations for any increase in fractures, we performed an historical cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970–1994 (mean age, 61.7 ± 14.0 yr; 51% men). Fracture risk was estimated by standardized incidence ratios (SIRs), and risk factors were evaluated in Andersen-Gill time-to-fracture regression models. In 23,236 person-years of follow-up, 700 diabetic residents experienced 1369 fractures documented by medical record review. Overall fracture risk was elevated (SIR, 1.3; 95% CI, 1.2–1.4), but hip fractures were increased only in follow-up beyond 10 yr (SIR, 1.5; 95% CI, 1.1–1.9). As expected, fracture risk factors included age, prior fracture, secondary osteoporosis, and corticosteroid use, whereas higher physical activity and body mass index were protective. Additionally, fractures were increased among patients with neuropathy (hazard ratio [HR], 1.3; 95% CI, 1.1–1.6) and those on insulin (HR, 1.3; 95% CI, 1.1–1.5); risk was reduced among users of biquanides (HR, 0.7; 95% CI, 0.6–0.96), and no significant influence on fracture risk was seen with sulfonylurea or thiazolidinedione use. Thus, contrary to our earlier study, the risk of fractures overall (and hip fractures specifically) was increased among Rochester residents with diabetes, but there was no evidence that the rise was caused by greater levels of obesity or newer treatments for diabetes.
PMCID: PMC2574704  PMID: 18348689
cohort study; diabetes; epidemiology; fractures; hip fracture
21.  Serum Biomarker Profile Associated with High Bone Turnover and BMD in Postmenopausal Women 
Early diagnosis of the onset of osteoporosis is key to the delivery of effective therapy. Biochemical markers of bone turnover provide a means of evaluating skeletal dynamics that complements static measurements of bone mineral density by DEXA. Conventional clinical measurements of bone turnover, primarily the estimation of collagen and its breakdown products in the blood or urine, lack both sensitivity and specificity as a reliable diagnostic tool. As a result, improved tests are needed to augment the use of bone density measurements as the principle diagnostic modality. In this study, the serum proteome of 58 postmenopausal women with high or low/normal bone turnover (training set) was analyzed by surface enhanced laser-desorption/ionization time-of-flight mass spectrometry and a diagnostic fingerprint identified using a variety of statistical and machine learning tools. The diagnostic fingerprint was validated in a separate distinct test set, consisting of serum samples from an additional 59 postmenopausal women obtained from the same Mayo cohort, with a gap of two years. Specific protein peaks that discriminate between postmenopausal patients with high or low/normal bone turnover were identified and validated. Multiple supervised learning approaches were able to classify the level of bone turnover in the training set with 80% sensitivity and 100% specificity. In addition, the individual protein peaks were also significantly correlated with bone mineral density measurements in these patients. Four of the major discriminatory peaks in the diagnostic profile were identified as fragments of Inter-Alpha-Trypsin-Inhibitor Heavy chain H4 precursor (ITIH4), a plasma kallikrein-sensitive glycoprotein that is a component of the host response system. These data suggest that these serum protein fragments are the serum-borne reflection of the increased osteoclast activity leading to the increased bone turnover that is associated with decreasing BMD and presumably, an increased risk of fracture. In conjunction with the identification of the individual proteins, this protein fingerprint may provide a novel approach to evaluate high bone turnover states.
PMCID: PMC2652044  PMID: 18302502
Surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS); biomarkers; fracture risk; bone turnover
22.  Morbidity and Mortality Associated With Paget’s Disease of Bone: A Population-Based Study 
Limited information is available about the clinical features of Paget’s disease of bone among unselected patients in the community. We examined morbidity and mortality associated with this condition in a large inception cohort of Olmsted County, MN, residents with a new diagnosis of Paget’s disease from 1950 through 1994.
Materials and Methods
Survival was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to assess the impact of various covariates on death.
Paget’s disease of bone was diagnosed in 236 Olmsted County residents (mean age at diagnosis, 69.6 yr; 55% men). The majority were symptomatic at diagnosis (58%), and the proportion with symptoms did not change from the prescreening era (1950 to June 1974) to the postscreening era (July 1974–1994). Most patients had polyostotic disease (72%), and the pelvis (67%), vertebra (41%), and femur (31%) were the most common sites of involvement. Skeletal complications attributable to Paget’s disease included bowing deformities (7.6%), fracture of pagetic bone (9.7%), and osteosarcoma (0.4%). Osteoarthritis was observed in 73% of patients, and 11% had a hip or knee replacement. Nonskeletal complications related to Paget’s disease included cranial nerve (0.4%), peripheral nerve (1.7%), and nerve root (3.8%) compression, basilar invagination (2.1%), hypercalcemia (5.2%), and congestive heart failure (3.0%). Hearing loss, noted in 61%, was significantly higher than previously reported.
Compared with white Minnesota residents, overall survival was slightly better than expected (p = 0.010). No clinical risk factors were identified that were associated with an increased risk of death.
PMCID: PMC2515478  PMID: 18269308
epidemiology; morbidity; mortality; Paget’s disease; alkaline phosphatase
23.  Use of Renal Function Measurements for Assessing Fracture Risk in Postmenopausal Women 
Mayo Clinic proceedings. Mayo Clinic  2008;83(11):1231-1239.
To determine whether factors associated with moderate chronic kidney disease can be used to independently predict fracture risk in postmenopausal white women by analyzing the effect of adding renal function measurements to traditional risk factors (eg, age, body weight, bone mineral density) for fracture risk assessment.
In a prospective, population-based cohort study, postmenopausal women residing in Rochester, MN, with baseline measurements of bone mineral density and renal function were followed up for as long as 25 years for occurrence of fractures. Participants were enrolled in 1980-1984 or 1991-1993, and outcomes were analyzed in 2007. Standardized incidence ratios were used to compare the number of observed fractures with the number of predicted fractures, and potential risk factors were evaluated with Andersen-Gill time-to-fracture regression models.
During 5948 person-years of follow-up of 427 women, 254 women (59.5%) experienced a total of 563 fractures, 394 (70.0%) of which resulted from moderate trauma. Excluding incidentally diagnosed fractures, the 186 clinically diagnosed fractures were statistically undifferentiated from the 195 predicted fractures (standardized incidence ratio, 0.95; 95% confidence interval, 0.82-1.10). No significant trends were observed toward increasing fracture risk with inclusion of quintiles of declining renal function (P>.10). In univariate analyses, serum creatinine concentration, creatinine clearance rate, and estimated glomerular filtration rate were associated with greater risk of some fractures. In multivariate analyses, however, decreasing renal function was not found to be a significant risk factor, after adjusting for age, body weight, and bone mineral density.
The addition of serum creatinine concentration, creatinine clearance rate, or estimated glomerular filtration rate does not improve fracture risk prediction in postmenopausal white women who have moderate chronic kidney disease. This result can be partly explained by the fact that important risk factors for decreased renal function (eg, advanced age, lower body weight) are already accounted for in most fracture prediction models.
PMCID: PMC2593794  PMID: 18990322
24.  Influence of Hysterectomy on Long-Term Fracture Risk 
Fertility and sterility  2007;88(1):156-162.
To assess long-term fracture risk following hysterectomy, with or without oophorectomy.
Population-based cohort study.
Olmsted County, Minnesota.
9258 Olmsted County women who underwent hysterectomy in 1965-2002 compared to an equal number of age- and sex-matched community controls.
Observational study of the effect of hysterectomy for various indications on subsequent fractures.
Main outcome measures
Fractures of any type, and at osteoporotic sites (e.g., hip, spine, and wrist) alone, as assessed by electronic review of inpatient and outpatient diagnoses in the community.
Compared to controls, there was a significant increase (hazard ratio [HR], 1.21; 95% CI, 1.13-1.29) in overall fracture risk among the women with hysterectomy, but osteoporotic fracture risk was not elevated (HR, 1.09; 95% CI, 0.98-1.22). Most hysterectomy indications were associated with fractures generally, albeit often not statistically significantly, but only operations for uterine prolapse were associated with osteoporotic fractures (HR, 1.33; 95% CI, 1.01-1.74). Oophorectomy was not an independent predictor of fracture risk (HR, 1.0; 95% CI, 0.98-1.15).
Hysterectomy does not appear to pose much long-term risk for fractures, but the association of fractures with surgery for uterine prolapse deserves further attention.
PMCID: PMC2032011  PMID: 17270180
hysterectomy; fracture; cohort study; oophorectomy; pelvic prolapse
25.  Relationship of Volumetric Bone Density and Structural Parameters at Different Skeletal Sites to Sex Steroid Levels in Women 
Although estrogen clearly plays a central role in regulating bone mass in women, studies in men have suggested that there may be a threshold bioavailable (bio) estradiol (E2) level below which aging men begin to lose bone and that the threshold for estrogen deficiency in cortical bone may be considerably lower than that in trabecular bone. There are no data testing this in women.
Our objective was to assess volumetric bone mineral density (vBMD) and bone geometry by quantitative computed tomography and relate these to circulating bio E2 and bio testosterone levels.
We studied a cross-sectional, age-stratified population sample of 235 women (age, 21–97 yr).
vBMD/structural parameters were not related to sex steroid levels in young premenopausal women (age, 20–39 yr) with a median bio E2 level of 17 pg/ml (63 pmol/liter). By contrast, bio E2 and bio testosterone levels were both significantly associated with trabecular and cortical vBMD and cortical area at multiple sites in late postmenopausal women (age ≥ 60 yr) who had a median bio E2 level of 3 pg/ml (11 pmol/liter). Late premenopausal and early postmenopausal women (age, 40–59 yr) with an intermediate median bio E2 level of 11 pg/ml (42 pmol/liter) showed age-adjusted correlations of bio E2 levels with trabecular but not with cortical vBMD.
In women, bio E2 levels are associated with vBMD and some structural bone parameters at low but not high bio E2 levels. Similar to findings in men, the threshold for estrogen deficiency in cortical bone in women appears to be lower than that in trabecular bone.
PMCID: PMC1352154  PMID: 15998772
bio, Bioavailable; BMD, bone mineral density; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; E2, estradiol; ER, estrogen receptor; QCT, quantitative computed tomography; T, testosterone; vBMD, volumetric bone mineral density

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