Plasma proteomic signature of human longevity.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

Milk intake and hip fracture incidence in community-dwelling old Icelandic adults.

Milk and milk products have been known as important for bone health. Can ingestion of milk and milk products lower hip fracture risk for older adults? In this study, older Icelandic adults who were ingesting higher milk had a lower risk of hip fractures. INTRODUCTION: This study describes associations between milk intake and hip fracture risk in older Icelanders. The data indicate that no/low milk consumption is related to greater hip fracture risk. Hip fracture can have a severe effect on the life of older adults. Health authorities recommend milk intake for better bone health. However, previous studies addressing this association have been divergent. METHODS: This prospective study included 4614 subjects (mean age 76 years) recruited between 2002 and 2006 into the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study. Information on hip fractures occurring between recruitment and end of follow-up in 2012 was extracted from hospital records. RESULTS: A total of 14% of participants reported milk intake < 0.5 times/day (the lowest category) and 22% of the participants consumed at least milk two times/day (highest category). Milk consumption was positively related to the volumetric bone mineral density at baseline with a sex- and age-adjusted difference of 8.95 ± 2.5 mg/cm3 between the highest compared to lowest milk intake categories (P < 0.001). During the follow-up, 7.4% of participants had a hip fracture, and we observed a decreased risk of incident hip fractures in the highest compared to the lowest milk intake category with a hazard ratio of 0.69 (95% CI: 0.47-0.99) in adjusted model. Further analysis indicated a linear relationship between milk intake and fracture risk (P-value for linear trend < 0.001). CONCLUSION: Milk intake is associated with a lower risk of incident hip fracture in a linear way in Icelandic community-dwelling older adults.

Adjusting conventional FRAX estimates of fracture probability according to the number of prior fractures.

The risk of a recurrent fragility fracture is high following a first fracture and higher still with more than one prior fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the number of prior fractures. INTRODUCTION: Prior fractures increase subsequent fracture risk. The aim of this study was to quantify the effect of the number of prior fractures on the 10-year probability of fracture determined with FRAX®. METHODS: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Ten-year probabilities of hip fracture and major osteoporotic fracture (MOF) were determined according to the number of prior osteoporotic fractures over a 20-year interval from the hazards of death and fracture. Fracture probabilities were also computed for a prior osteoporotic fracture irrespective of the number of previous fractures. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability according to the number of prior fractures. RESULTS: Probability ratios to adjust 10-year FRAX probabilities of a hip fracture and MOF increased with the number of prior fractures but decreased with age in both men and women. Probability ratios were similar in men and women and for hip fracture and MOF. Mean probability ratios according to the number of prior fractures for all scenarios were 0.95, 1.08, 1.21 and 1.35, for 1,2, 3 and 4 or more prior fractures, respectively. Thus, a simple rule of thumb is to downward adjust FRAX-based fracture probabilities by 5% in the presence of a single prior fracture and to uplift probabilities by 10, 20 and 30% with a history of 2, 3 and 4 or more prior fractures, respectively. CONCLUSION: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability according to the number of prior fractures.

Serum 25-Hydroxy-Vitamin D Status and Incident Hip Fractures in Elderly Adults: Looking Beyond Bone Mineral Density.

Observational studies have consistently reported a higher risk of fractures among those with low levels of serum 25-hydroxyvitamin D (25(OH)D). Emerging evidence suggests that low serum 25(OH)D levels may increase the rate of falls through impaired physical function. Examine to what extent baseline measures of volumetric bone mineral density (vBMD), absolute bone mineral content (BMC), and markers of physical function may explain incident hip fractures in older adults with different serum levels of 25(OH)D. A prospective study of 4309 subjects (≥66 years) recruited between 2002 and 2006 into the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study. Hip fractures occurring until the end of 2012 were extracted from hospital records. Prevalence of serum 25(OH)D deficiency (<30 nmol/L), inadequacy (30-<50 nmol/L), and sufficiency (≥50 nmol/L) was 6%, 23%, and 71% for males; and 11%, 28%, and 53% for females, respectively. Female participants had ~30% lower absolute BMC compared to males. Serum 25(OH)D concentrations were positively associated with vBMD and BMC of the femoral neck and markers of physical function, including leg strength and balance. Those who had deficient compared to sufficient status at baseline had a higher age-adjusted risk of incidence hipfractures with hazard ratios (HRs) of 3.1 (95% confidence interval [CI], 1.9-5.2) and 1.8 (95% CI, 1.3-2.5) among males and females, respectively. When adjusting for vBMD and measures of physical function, the association was attenuated and became nonsignificant for males (1.3; 95% CI, 0.6-2.5) but remained significant for females (1.7; 95% CI, 1.1-2.4). Deficient compared to sufficient serum 25(OH)D status was associated with a higher risk of incident hip fractures. This association was explained by poorer vBMD and physical function for males but to a lesser extent for females. Lower absolute BMC among females due to smaller bone volume may account for these sex-specific differences. © 2021 American Society for Bone and Mineral Research (ASBMR).

Computed tomography-based skeletal muscle and adipose tissue attenuation: Variations by age, sex, and muscle.

OBJECTIVE: This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age. DESIGN: Population-based cross-sectional study. SETTING: Community-dwelling old population in Reykjavik, Iceland. SUBJECTS: A total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied. METHODS: Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable. RESULTS: Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle. CONCLUSIONS: Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles.

Accelerated decline in quadriceps area and Timed Up and Go test performance are associated with hip fracture risk in older adults with impaired kidney function.

OBJECTIVE: This study aimed to examine whether an accelerated decline in quadriceps cross-sectional area (CSA), attenuation (a surrogate of quality), and strength, as well as lower limb muscular function, are associated with hip fractures in older adults with impaired kidney function. DESIGN: Prospective population-based study. SETTING: Community-dwelling old population in Reykjavik, Iceland. SUBJECTS: A total of 875 older adults (mean baseline age 76 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study with impaired kidney function. METHODS: Quadriceps CSA and density were determined using computed tomography (CT), knee extension strength was measured with an isometric dynamometer chair, and muscular function was assessed using the Timed Up and Go (TUG) test. All muscle-related measurements were assessed twice over a mean follow-up of 5.2 years. Data on hip fracture incidence was obtained from medical records during a maximum of 8.4 years of follow-up time. RESULTS: Fully adjusted cox-proportional hazard regression models showed that a faster decline in quadriceps CSA and TUG test performance were significantly associated with increased hip fracture risk (HR = 1.55, 95% CI = 1.02-2.36, and HR = 1.80, 95% CI = 1.19-2.72, respectively). A faster decrease in quadriceps density and isometric knee extension strength were not associated with fracture risk. CONCLUSIONS: Accelerated decline in CT-derived quadriceps CSA and muscular function, as measured by the TUG test's performance, are predictive of hip fracture risk in older adults with impaired kidney function. TUG test is a simple measure and easily included in routine medical examinations, compared to CT scans, which seems to be useful for identifying a subgroup of individuals with high risk of fracture.

Cigarette Smoking Is Associated With Lower Quadriceps Cross-sectional Area and Attenuation in Older Adults.

INTRODUCTION: In addition to well-established links with cardiovascular and respiratory diseases, cigarette smoking may affect skeletal muscle; however, associations with quadriceps atrophy, density, and function are unknown. This study explored the associations of current and former smoking with quadriceps muscle area and attenuation as well as muscle force (assessed as knee extension peak torque) and rate of torque development-a measure of muscle power in older adults. METHODS: Data from 4469 older adults, aged 66-95 years at baseline in the Age, Gene/Environment Susceptibility-Reykjavik Study with measurements of thigh computed tomography, isometric knee extension testing, self-reported smoking history, and potential covariates were analyzed. RESULTS: Sex differences were observed in these data; therefore, our final analyses are stratified by sex. In men, both former smokers and current smokers had lower muscle area (with ß= -0.10, 95% confidence interval [CI] = -0.17 to -0.03 and ß = -0.19, 95% CI = -0.33 to -0.05, respectively) and lower muscle attenuation (ie, higher fat infiltration, ß = -0.08, 95% CI = -0.16 to -0.01 and ß = -0.17, 95% CI = -0.34 to -0.01, respectively) when compared with never smokers. Smoking status was not associated with male peak torque or rate of torque development. In women, current smoking was associated with lower muscle attenuation (ß = -0.24, 95% CI = -0.34 to -0.13) compared to never smoking. Among female smokers (current and former), muscle attenuation and peak torque were lower with increasing pack-years. CONCLUSIONS: Results suggest that cigarette smoking is related to multiple muscle properties at older age and that these relationships may be different among men and women. IMPLICATIONS: This article presents novel data, as it examined for the first time the relationship between smoking and computed tomography-derived quadriceps muscle size (cross-sectional area) and attenuation. This study suggests that current cigarette smoking is related to higher muscle fat infiltration, which may have significant health implications for the older population, because of its known association with poor physical function, falls, and hip fractures.

[Novel Innovation: Can Artificial Intelligence make Rehabilitation more Efficient?]

Demand for Vocational Rehabilitation in Iceland has been steadily rising in recent years where the presence of young patients has increased proportionally the most. It is essential that public spending is efficient without compromising the treatment quality. It is worth exploring if a solution for increasing the efficiency in this healthcare section is to use Artificial Intelligence (AI). An innovative project on developing, testing, and implementing specialised AI software in its services is being performed in Janus Rehabilitation. The software, named Völvan in Icelandic, can identify latent areas of possible interest in patient's circumstances which might affect the outcome of their treatment, and assist specialists in providing timely and appropriate interventions. The accuracy, precision, and recall of its predictions have been verified in two recent publications. Völvan seems to be a promising tool for individualised rehabilitation, where patients are dealing with difficult and complex problems. Janus Rehabilitation is in the process of launching Völvan as an unbiased member of the interdisciplinary teams of specialists. The aim of this report is to introduce Völvan and the associated research.

Interstitial lung abnormalities and physical function.

Reductions in objectively measured physical function are associated with interstitial lung abnormalities http://ow.ly/azAW30kMhqv.

Sex differences in the spatial distribution of bone in relation to incident hip fracture: Findings from the AGES-Reykjavik study.

In this case-cohort study, we used data-driven computational anatomy approaches to assess within and between sex spatial differences in proximal femoral bone characteristics in relation to incident hip fracture. One hundred male and 234 female incident hip fracture cases, and 1047 randomly selected noncase subcohort participants (562 female) were chosen from the population-based AGES-Reykjavik study (mean age of 77 years). The baseline -i.e. before hip fracture- hip quantitative computed tomography scans of these subjects were analyzed using voxel-based morphometry, tensor-based morphometry, and surface-based statistical parametric mapping to assess the spatial distribution of volumetric bone mineral density (vBMD), internal structure, and cortical bone properties (thickness, vBMD and trabecular vBMD adjacent to the endosteal surface) of the proximal femur, respectively, in relation to incident hip fracture. Results showed that in both men and women: 1) the superior aspect of the femoral neck and the trochanteric region (except for cortical bone thickness) were consistently identified as being associated with incident hip fracture, and 2) differences in bone properties between noncases and incident hip fracture cases followed similar trends, were located at compatible regions, and manifested heterogeneity in the spatial distribution of their magnitude with focal regions showing larger differences. With respect to sex differences, most of the regions with a significant interaction between fracture group and sex showed: 1) differences of greater magnitude in men between noncases and incident hip fracture cases with different spatial distributions for all bone properties with the exception of cortical bone thickness, and 2) that while most of these regions showed better bone quality in male cases than in female cases, female cases showed higher vBMD in the principal compressive group and higher endotrabecular vBMD at several regions including the anterior, posterior, and lateral aspects of the proximal femur. These findings indicate the value of these image analysis techniques by providing unique information about the specific patterns of bone deterioration associated with incident hip fracture and their sex differences, highlighting the importance of looking to men and women separately in the assessment of hip fracture risk.

Cigarette smoking and hip volumetric bone mineral density and cortical volume loss in older adults: The AGES-Reykjavik study.

This study aimed to explore the relationships of several indicators of cigarette smoking habits (smoking status, pack-years, age at smoking initiation and smoking cessation) with quantitative computed tomographic (QCT)-derived proximal femur bone measures (trabecular vBMD, integral vBMD and the ratio of cortical to total tissue volume (cvol/ivol)) and with subsequent change in these measures over the next five years. A total of 2673 older adults (55.9% women), aged 66-92 years at baseline from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, who had two QCT scans of the hip were studied. In multivariable linear regression models, compared to never-smokers, current smokers had lower cvol/ivol at baseline and former-smokers had poorer measures on all outcomes (lower trabecular vBMD, integral vBMD and cvol/ivol), even when adjusted for several potential confounders. Further, among former smokers, those with higher pack-years had worse bone outcomes and those with longer duration since smoking cessation had better bone health at baseline. Analyses of change in bone measures revealed that compared to never-smokers, current smokers had significantly greater loss of trabecular vBMD, integral vBMD, and cvol/ivol. The regression models included adjustment for sex, age, education, and baseline body mass index, creatinine, % weight change from age 50, 25OHD, physical activity level, high-sensitive C-Reactive protein levels, alcohol and coffee consumption, history of diabetes mellitus, arthritis, and respiratory diseases. In conclusion, both current and former smoking showed adverse associations with bone health assessed with QCT. Results suggest that current smoking in particular may aggravate the rate of bone loss at older age and highlight implications for targeting this risk factor in populations that present higher smoking prevalence and vulnerability to bone fragility.

Associations of Quadriceps Torque Properties with Muscle Size, Attenuation, and Intramuscular Adipose Tissue in Older Adults.

Background: Atrophy and fatty infiltration of muscle with aging are associated with fractures and falls, however, their direct associations with muscle function are not well described. It was hypothesized that participants with lower quadriceps muscle attenuation, area, and greater intramuscular adipose tissue (IMAT) will exhibit slower rates of torque development (RTD) and lower peak knee extension torques. Methods: Data from 4,842 participants (2,041 men, 2,801 women) from the Age Gene/Environment Susceptibility Reykjavik Study (mean age 76 ± 0.1 years) with complete thigh computed tomography and isometric knee testing. Regression models were adjusted for health, behavior, and comorbidities. Muscle attenuation was further adjusted for muscle area and IMAT; muscle area adjusted for IMAT and attenuation; and IMAT adjusted for muscle area and attenuation. Standardized betas (ß) indicate association effect sizes. Results: In the fully-adjusted models, attenuation (men ß = 0.06, 95% CI: 0.01, 0.11; women ß = 0.07, 95% CI: 0.03, 0.11) and muscle area (men ß = 0.13, 95% CI: 0.07, 0.19; women ß = 0.10, 95% CI: 0.06, 0.15) were associated with knee RTD. Attenuation (men ß = 0.12, 95% CI: 0.08, 0.16; women ß = 0.12, 95% CI: 0.09, 0.16) and muscle area (men ß = 0.38, 95% CI: 0.33, 0.43; women ß = 0.33, 95% CI: 0.29, 0.37) were associated with peak torque. Conclusions: These data suggest that muscle attenuation and area are independently associated with RTD and peak torque; and that area and attenuation demonstrate similar contributions to RTD.

[Five decades of coronary artery disease in Iceland. Data from the Icelandic Heart Association].

Coronary artery disease has been the leading cause of death and disability in Iceland during the past decades although in recent years, malignancy has taken over that position. A steady improvement in the level of major risk factors has been evident since 1980. This trend explains 72% of the decrease in premature mortality from coronary artery disease during the past three decades. However, an opposing trend in increasing obesity and type 2 diabetes has attenuated this decline in premature deaths. Unchanged risk factor trends will lead to increasing cardiovascular mortality in the years to come. This will result from the above mentioned changes in major risk factors as well as an increased ageing of the Icelandic population. At the same time case fatality after myocardial infarction has declined substantially. This will result in a steadily growing proportion of elderly in the population as well as a high burden of chronic non-communicable diseases among the elderly population. The resulting increase in long term disease and disability will put a major constraint on the health care system and economy alike. According to vital statistics and secular trends the rate of Icelanders in working age for each one reaching retirement age will decrease from the current 5.6 to 2.6 by year 2060. This paper addresses the driving factors of risk factor change in Iceland with previously unpublished data extending to 2013.

[Review of epidemiology of fractures in the Icelandic Heart Association cohort].

IIn recent years, scientific papers have been published in Osteoporosis International on the epidemiology of fractures in Iceland based on the Icelandic Heart Association cohort. We report the main results with emphasis on the major osteoporotic fractures (MOF), distal forearm, upper arm, clinical vertebral and hip. Those four types of fractures have been reported to cause about 90% of the total burden of all osteoporotic fractures. The incidence of those four fractures in the Icelandic Heart Association cohort have been used as the basis for the international fracture risk calculator "FRAX "in Iceland. "FRAX" assesses the risk of those fractures for the next 10 years in both sexes in the age group 40-90 years. FRAX Iceland was opened on the internet in the year 2013. We emphasize the importance of previous fracture history as almost 40% of all major osteoporotic fractures occur after first MOF according to our cohort. The results demonstrate the importance of time from the first fracture as the risk of the second fracture is greater in the first two years although increased risk remains during the next 20 years. This indicates the importance of secondary prevention early after the first fracture especially amongst elderly people. These results give a good overall view about the epidemiology of fractures in Iceland in comparison with foreign studies and shows that age standardized incidence of the most important osteoporotic fracture, the hip fracture, reached a maximum around the millennium but has decreased among women until 2008 similar to what has been observed in Sweden and Denmark.

Associations of 24-hour sleep duration and CT-derived measurements of muscle and bone: The AGES-Reykjavik Study.

BACKGROUND: Although the importance of sleep on preservation of several physiological functions is well known, the relationship with the two interconnected tissues - muscle and bone is less understood. OBJECTIVES: This study aimed to examine the association of 24-hour sleep duration with mid-thigh muscle composition and proximal femur volumetric bone mineral density (vBMD). METHODS: 2438 men and 3326 women aged 66 to 96years, residents in the Reykjavik area, were included in this cross-sectional study. Proximal femur integral vBMD, mid-thigh muscle area and muscle attenuation were assessed with computed tomography. Sleep and nap habits were assessed using a questionnaire. RESULTS: We found that after adjustment for age and BMI long sleep duration (>8h/d) was negatively associated with thigh lean area in both men (B=-2.21, 95% confidence interval (CI): -4.01, -0.40) and women (B=-2.39, 95% CI: -3.75, -1.03) and with muscle attenuation (B=-0.95, 95% CI: -1.47, -0.43) only in women. After adjustments for age, health and lifestyle factors the association between long sleep duration and muscle lean area was attenuated and became nonsignificant while associations with muscle attenuation remained marginally significant (B=-0.51, 95% CI: -1.03, -0.002). Sleep duration was not associated with proximal femur integral vBMD in the multivariate models. CONCLUSION: Long sleep duration, particularly in old women, can affect thigh muscle attenuation (increase in intramuscular fat). Whether optimization of sleep can ameliorate age-associated intramuscular or intermuscular adipose tissue warrants further studies.

Proximal Femur Volumetric Bone Mineral Density and Mortality: 13 Years of Follow-Up of the AGES-Reykjavik Study.

Bone mineral density (BMD) has been linked to mortality, but little is known about the independent contribution of each endosteal bone compartment and also the rate of bone loss to risk of mortality. We examined the relationships between (1) baseline trabecular and cortical volumetric BMD (vBMD) at the proximal femur, and (2) the rate of trabecular and cortical bone loss and all-cause mortality in older adults from the AGES-Reykjavik study. The analysis of trabecular and cortical vBMD and mortality was based on the baseline cohort of 4654 participants (aged ≥66 years) with a median follow-up of 9.4 years; the association between rate of bone loss and mortality was based on 2653 participants with bone loss data (median follow-up of 5.6 years). Analyses employed multivariable Cox-proportional models to estimate hazard ratios (HRs) with time-varying fracture status; trabecular and cortical variables were included together in all models. Adjusted for important confounders, Cox models showed that participants in the lowest quartile of trabecular vBMD had an increased risk of mortality compared to participants in other quartiles (HR = 1.12; 95% confidence interval (CI), 1.01 to 1.25); baseline cortical vBMD was not related to mortality (HR = 1.08; 95% CI, 0.97 to 1.20). After adjustment for time-dependent fracture status, results were attenuated and not statistically significant. A faster loss (quartile 1 versus quartiles 2-4) in both trabecular and cortical bone was associated with higher mortality risk (HR = 1.37 and 1.33, respectively); these associations were independent of major potential confounders including time-dependent incident fractures (HR = 1.32 and 1.34, respectively). Overall, data suggest that faster bone losses over time in both the trabecular and cortical bone compartments are associated with mortality risk and that measurements of change in bone health may be more informative than single-point measurements in explaining mortality differences in older adults. © 2017 American Society for Bone and Mineral Research.

Bone disease in monoclonal gammopathy of undetermined significance: results from a screened population-based study.

Previous studies have shown that individuals with monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of fractures, although the underlying mechanisms remain unknown. Our aim was to analyze bone mineral density (BMD), bone volume, and risk of fractures among individuals with MGUS. We performed a screening using the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study cohort, consisting of 5764 elderly individuals, identifying 300 individuals with MGUS, and 275 with light-chain MGUS. Quantitative computerized tomography was performed in the lumbar spine and hip to evaluate BMD and bone geometry. Analysis of variance and the Tukey honest significance test were used to compare the groups. Hospital records were used to record fractures, with a mean follow-up of 6.9 years. Cox proportional hazard was used to compare fracture risk. No difference was found in BMD between subjects with MGUS and others in the spine (P = .34) or in total hip (P = .30). Individuals with MGUS had a significant increase in bone volume compared with others in the spine (P < .001) and total hip (P < .001). Overall, the risk of fractures was not significantly increased in individuals with MGUS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.94-1.50). Men with MGUS had a significantly increased fracture risk, compared with other men (HR, 1.46; 95% CI, 1.03-2.08). Our results show that although individuals with MGUS do not have decreased BMD, bone volume is increased, and MGUS men have a 50% increased fracture risk. These results indicate that bone disease and fractures in MGUS differ from processes known from osteoporosis.

Determinants of outcome of vocational rehabilitation.

BACKGROUND: Information regarding the determinants of successful vocational rehabilitation (VR) is scarce. OBJECTIVE: Investigate whether sex, duration, quality of life and financial circumstances influence the success of VR. METHODS: The study group consisted of 519 participants (293 women, 56%), who finished VR in the period 2000-2014. The group was divided into the following subgroups: dropouts, unsuccessful and successful VR. Data were collected by questionnaire. RESULTS: Income had the most impact on whether the outcome was successful. Having supplemental income when entering the VR program increased the likelihood of a successful conclusion, odds ratio (OR) 5.60 (95% CI; 2.43-13.59) (p < 0.001), being on sick leave OR 5.02 (95% CI 1.93-13.79) (p < 0.001) or rehabilitation pension OR 1.93 (95% CI 1.07-3.52) (p < 0.03). The participants in the successful sub-group were older (p < 0.06) and stayed in rehabilitation longer (p < 0.001), compared to those who were unsuccessful. However, the effect on OR was limited: 1.03 (95% CI 1.01-1.06) and 1.04 (95% CI 1.02-1.07), respectively. CONCLUSIONS: For this sample, supplemental income appears to be the most important factor for a successful rehabilitation outcome. Checking financial status at the beginning of the rehabilitation process could minimize financial strain and increase the likelihood of success.

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (ß = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (ß = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (ß = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (ß = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (ß = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-ß (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.