The National Cancer Institute Working Group (NCI-WG 96) guidelines classified individuals having a B-cell clone with CLL immunophenotype as CLL if the absolute lymphocyte count (ALC) was ≥5 × 109/L. 2008 International Workshop on CLL guidelines (IWCLL 2008) classified as CLL if the absolute B-cell count is ≥5 × 109/L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count is <5 × 109/L. This study of Olmsted County, Minnesota, assessed effects of these changes on incidence rates and presentation from 2000–2010.
Using diagnostic indices available through the Rochester Epidemiology Project and the Mayo CLL database, we identified all newly diagnosed CLL and high count MBL cases from 2000–2010. Age and sex specific incidence rates were determined.
With NCI-WG 96 criteria, there were 115 cases of CLL and 8 cases of MBL. Using IWCLL 2008 classification, there were 79 cases of CLL and 40 cases of MBL. Rai stage distribution (low, intermediate, high) using NCI-WG 96 was 60.9%, 33.9% and 5.2% compared to 43.0%, 49.4%, and 7.6% under IWCLL 2008 criteria. The age- and sex-adjusted incidence rate (per 100,000) for CLL and MBL were 10.0 and 0.66 using NCI-WG 96 versus 6.8 and 3.5 using IWCLL 2008. Median time to treatment (TTT) using NCI-WG 96 was 9.2 years versus 6.5 years with IWCLL 2008
Use of the IWCLL 2008 guidelines reduce the incidence of CLL, alter the distribution of initial Rai stage at diagnosis and shorten median TTT.
Chronic lymphocytic leukemia; monoclonal B-cell lymphocytosis; incidence; epidemiology; natural history
To determine the extent to which excess mortality following fractures due
to particular causes at specific skeletal sites can be predicted using data
about all medical diagnoses, we conducted an historical cohort study among 1991
Olmsted County, Minnesota residents ≥50 years of age who experienced any
fracture in 1989-1991 and who were followed passively for up to 22 years for
death from any cause. We used a machine learning approach, gradient boosting
machine (GBM) modeling, to determine whether the comorbid conditions present at
the time of fracture and those that arose subsequently could, in aggregate,
identify patients at the greatest increased risk of death. During 21,867
person-years of follow-up, 1245 deaths were observed when 1061 were expected
(standardized mortality ratio, 1.2; 95% CI 1.1 to 1.2). Patients presented with
a median history of 26 comorbid conditions each as assessed by the Clinical
Classification Software system, and 57 each over the total duration of
follow-up. Using all available information, the excess deaths could be predicted
with good accuracy (c-index ≥0.80) in 89% of the GBM models built for
patients with different types of fracture; in one-third of the models, the
c-index was ≥0.90. The conditions most prominent in the GBM prediction
models were also reflected in the specific causes of death that were elevated,
suggesting the influence of confounding on the relationship. However, the
predominant comorbid conditions were mainly those responsible for mortality in
the general population, rather than the specific diseases most closely
associated with secondary osteoporosis. To reduce long-term deaths in the
fracture population as a whole, a more general approach to the fracture patient
AGING; FRACTURES; GENERAL POPULATION STUDIES; MORTALITY; OSTEOPOROSIS; STATISTICAL METHODS
Children and adolescents who sustain a distal forearm fracture (DFF) owing to mild, but not moderate, trauma have reduced bone strength and cortical thinning at the distal radius and tibia. Whether these skeletal deficits track into adulthood is unknown. Therefore, we studied 75 women and 75 men (age range, 20 to 40 years) with a childhood (age <18 years) DFF and 150 sex-matched controls with no history of fracture using high-resolution peripheral quantitative computed tomography (HRpQCT) to examine bone strength (ie, failure load) by micro–finite element (µFE) analysis, as well as cortical and trabecular bone parameters at the distal radius and tibia. Level of trauma (mild versus moderate) was assigned using a validated classification scheme, blind to imaging results. When compared to sex-matched, nonfracture controls, women and men with a mild trauma childhood DFF (eg, fall from standing height) had significant reductions in failure load (p < 0.05) of the distal radius, whereas women and men with a moderate trauma childhood DFF (eg, fall while riding a bicycle) had values similar to controls. Consistent findings were observed at the distal tibia. Furthermore, women and men with a mild trauma childhood DFF had significant deficits in distal radius cortical area (p < 0.05), and significantly lower dual-energy X-ray absorptiometry (DXA)-derived bone density at the radius, hip, and total body regions compared to controls (all p < 0.05). By contrast, women and men with a moderate trauma childhood DFF had bone density, structure, and strength that did not differ significantly from controls. These findings in young adults are consistent with our observations in children/adolescents with DFF, and they suggest that a mild trauma childhood DFF may presage suboptimal peak bone density, structure, and strength in young adulthood. Children and adolescents who suffer mild trauma DFFs may need to be targeted for lifestyle interventions to help achieve improved skeletal health.
BONE STRENGTH; BONE STRUCTURE; HRPQCT; DISTAL FOREARM FRACTURE; YOUNG ADULTS; BONE ANALYSIS/QUANTITATION; GENERAL POPULATION STUDIES, EPIDEMIOLOGY; BONE DENSITOMETRY
Older women and men with rheumatoid arthritis (RA) are at increased risk for fractures, but limited information is available on fracture risk in younger individuals with RA, and whether such risk occurs early following disease onset or only when older. We determined the risk for fractures in both young and older women and men following RA diagnosis.
We studied a population-based inception cohort with RA from Olmsted County, Minnesota. We identified 822 women and 349 men diagnosed with RA between 1955 and 2007 (308 women and 110 men diagnosed before age 50) and an equal number of paired non-RA subjects, matched by sex and birth year. Incident fractures were collected through review of complete (inpatient and outpatient) medical records available through the linkage system of the Rochester Epidemiology Project.
The hazard ratio (HR) [95% CI] for a non-pathologic fracture occurring from no more than moderate trauma was 1.63 [1.36–1.96] for women and 1.40 [1.02–1.93] for men with RA. Findings were consistent for women and men diagnosed with RA at age ≥ 50 years (HR: 1.43 [1.16–1.77] and 1.34 [0.92–1.94], respectively), or at age < 50 years (HR: 2.34 [1.61–3.42] and 1.74 [0.91–3.30], respectively). However, young women, but not young men, with RA were at increased fracture risk even before age 50 years (HR: 1.95 [1.08–3.51] and 0.82 [0.28–2.45], respectively).
Young men with RA are at increased risk for fractures only when older, whereas young women with RA have an elevated fracture risk even while still young.
rheumatoid arthritis; bone fractures; osteoporosis; epidemiology
Distal forearm fractures are among the most common fractures during childhood, but it remains unclear whether they predict an increased fracture risk later in life. We studied a population-based cohort of 1776 children ≤18 years of age, from Olmsted County, MN, USA, who had a distal forearm fracture in 1935–1992. Incident fractures occurring at age ≥35 years were identified through review of complete medical records using the linkage system of the Rochester Epidemiology Project. Observed nonpathologic fractures resulting from no more than moderate trauma (fragility fractures) were compared with expected numbers estimated from fracture site–specific incidence rates, based on age, sex, and calendar year, for Olmsted County (standardized incidence ratios [SIR]). In 1086 boys (mean ± SD age; 11 ± 4 years) and 690 girls (10 ± 4 years) followed for 27,292 person-years after the age of 35 years, subsequent fragility fractures were observed in 144 (13%) men and 74 (11%) women. There was an increased risk for future fragility fractures in boys who had a distal forearm fracture (SIR, 1.9; 95% CI, 1.6–2.3) but not girls (SIR, 1.0; 95% CI, 0.8–1.2). Fragility fractures at both major osteoporotic (hip, spine, wrist, and shoulder) sites (SIR, 2.6; 95% CI, 2.1–3.3) and remaining sites (SIR, 1.7; 95% CI, 1.3–2.0) were increased in men, irrespective of age at distal forearm fracture as boys. A distal forearm fracture in boys, but not girls, is associated with an increased risk for fragility fractures as older adults. It is necessary to determine whether the increased fractures observed in men is due to persistent deficits of bone strength, continued high fracture risk activity, or both. Until then, men should be asked about a childhood distal forearm fracture and, if so, warrant further screening and counseling on measures to optimize bone health and prevent fractures.
DISTAL FOREARM FRACTURE; CHILDHOOD; FRACTURES; OSTEOPOROSIS; EPIDEMIOLOGY
Pulmonary disease represents an important extra-articular manifestation of rheumatoid arthritis (RA). While the association of RA and interstitial lung disease is widely acknowledged, obstructive lung disease (OLD) in RA is less well understood. We therefore aimed to assess incidence, risk factors and mortality of OLD in patients with RA.
We examined a population-based incident cohort of patients with RA and a comparison cohort of individuals without RA. OLD was defined using a strict composite criterion. Cox-proportional hazards models were used to compare OLD incidence between the RA and comparator cohort, to investigate risk factors and to explore the impact of OLD on patient survival.
594 patients with RA and 596 subjects without RA were followed for a mean of 16.3 and 19.4 years, respectively. The lifetime risk of developing OLD was 9.6% for RA patients and 6.2% for subjects without RA; hazard ratio (HR) 1.54 (95% CI 1.01 to 2.34). The risk of developing OLD was higher among male patients, current or former smokers and for individuals with more severe RA. Survival of RA patients diagnosed with OLD was worse compared to those without OLD (HR 2.09, 95% CI 1.47 to 2.97).
Patients with RA are at higher risk of developing OLD, which is significantly associated with premature mortality. Effective diagnostic and therapeutic strategies to detect and manage OLD in patients with RA may help to improve survivorship in these patients.
obstructive lung disease; rheumatoid arthritis; incidence; risk factors; mortality
Recent evidence suggests that adipose tissue may negatively impact bone health, challenging the traditional paradigm that increased fat mass, through mechanical loading or endogenous estrogen production, is beneficial to the skeleton. We hypothesized that it is primarily the visceral compartment of body fat that is detrimental to bone metabolism, resulting in impaired bone density and architecture. In an age-stratified population sample of 218 women and 291 men (age 20–97 years), we assessed visceral (VAT) and subcutaneous (SAT) adipose tissue areas at the L2–L3 interspace level by single slice quantitative computed tomography (QCT) and measured total body fat mass (TBF) by dual-energy X-ray absorptiometry. We then correlated these findings with volumetric bone mineral density (vBMD) at the femoral neck (FN) and lumbar spine (LS) assessed by central QCT, and with vBMD and microstructural parameters at the ultradistal radius (UDR) by high resolution peripheral QCT (HRpQCT). In unadjusted analyses in postmenopausal women, TBF and SAT were positively correlated with total, trabecular, and cortical vBMD at the FN, LS, and UDR and with trabecular microstructure at the UDR. By contrast, VAT was not correlated with vBMD at the FN or LS but was positively correlated with UDR total and trabecular vBMD but not cortical vBMD. Adjustment for age or for bioavailable estradiol and testosterone levels reduced these correlations, while adjustment for body weight eliminated most positive associations. Assessment of the VAT/SAT ratio, however, demonstrated a negative relationship with vBMD at the FN and LS in postmenopausal women, a relationship eliminated when adjusted for age. Correlations between skeletal parameters and adipose measurements in pre-menopausal women and older men were weaker and mostly non-significant. In younger men, VAT was negatively associated with vBMD, cortical thickness, and trabecular microstructure at the UDR, and with LS vBMD and FN cortical vBMD. These associations generally remained after adjustment, with some negative associations (e.g. UDR cortical area) being accentuated. Similar results were found when the VAT/SAT ratio was correlated with FN vBMD in younger men; in contrast, VAT/SAT was positively correlated with FN vBMD in older men and this relationship was strengthened by age-adjustment. Together, our data suggest that adiposity has associations with bone that are age-, gender-, menopausal status-, adipose depot-, and bone compartment-specific. These novel observations warrant further investigations to establish any causal relationships.
adipose tissue; visceral; subcutaneous; bone mineral density; bone microarchitecture
Multiple GWAS have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1178 cases and 1009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal OR=0.82, 95% CI=0.072-0.94, Ptrend=0.0037) and rs6983267 (ordinal OR=1.17, 95% CI=1.03-1.32, Ptrend=0.013). Survival analysis was performed using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (N=380) for structural abnormalities at or near the c-MYC locus using FISH analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by FISH, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several SNPs at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not appear to be associated with survival.
8q; SNP; association; survival; FISH; fragile site; c-MYC
Interstitial lung disease (ILD) has been recognized as an important co-morbidity in rheumatoid arthritis (RA). We aimed to assess incidence, risk factors and mortality of RA associated ILD.
We examined a population-based incidence cohort of patients with RA and a matched cohort of individuals without RA. All subjects were followed longitudinally until death, migration or January 1, 2006. The lifetime risk of ILD was estimated and Cox models were used to compare the incidence of ILD between cohorts, to investigate possible risk factors and to explore the impact of ILD on patient survival.
582 patients with RA and 603 subjects without RA were followed for a mean of 16.4 and 19.3 years, respectively. The lifetime risk of developing ILD was 7.7% for RA patients and 0.9% for subjects without RA. This difference translated into a hazard ratio of 8.96 (95% CI 4.02, 19.94). The risk of developing ILD was higher in patients with older age at RA onset, among male patients and for individuals with parameters that indicate more severe RA.
Survival of RA patients diagnosed with ILD was worse compared to RA patients without ILD (HR 2.86, 95% CI 1.98, 4.12). ILD contributed approximately 13% to the excess mortality of patients with RA patients when compared to the general population.
Our results emphasize the increased risk of ILD in patients with RA. The impact of ILD on patient survival provides evidence that development of better strategies for the treatment of ILD could significantly lower the excess mortality of individuals with RA.
Interstitial lung disease; rheumatoid arthritis; incidence; risk factors
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.
CLL; NHL; SNPs; IRF8; risk locus
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.
CLL; NHL; SNPs; BAK1; risk locus
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.
sarcopenia; osteoporosis; aging; sex steroids
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.
BONE DENSITY; BONE QUALITY; QCT; VERTEBRAL FRACTURE; DISTAL FOREARM FRACTURE; GRADIENT BOOSTING
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.
CANCER TREATMENTS; EPIDEMIOLOGY; FRACTURES; POPULATION-BASED; BREAST CANCER
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.
vitamin D; 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D; PTH; muscle; muscle strength; muscle mass
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.
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.
COHORT STUDY; EPIDEMIOLOGY; FRACTURES; POPULATION-BASED; PROSTATE CANCER
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.
finite element analysis; fractures; bone density; quantitative computed tomography; hip; proximal femur
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
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.
SCLEROSTIN; OSTEOPOROSIS; AGING
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.
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.
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
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.
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.
bone density; bone quality; finite-element analysis; QCT; vertebral fracture