Summary
Poor physical function and body composition my partly predict the risk of falls leading to fracture regardless of bone mineral density.
Introduction
To examine the relationship between body ...composition, physical function, and other markers of health with hip fractures in older community-dwelling Icelandic adults.
Methods
A prospective cohort of 4782 older adults from the AGES-Reykjavik study. Baseline recruitment took place between 2002 and 2006, and information on hip fractures occurring through 2012 was extracted from clinical records. Using multivariate regression analyses, baseline measures of bone health, physical function, and body composition were compared between those who later experienced hip fractures and to those who did not. Associations with the risk of fractures were quantified using Cox regression.
Results
Mean age was 76.3 years at baseline. After adjustment for age, regression showed that male hip fracture cases compared with non-cases had (mean (95% confidence interval)) significantly lower thigh muscle cross-sectional area − 5.6 cm
2
(− 10.2, − 1.1), poorer leg strength – 28 N (− 49, − 7), and decreased physical function as measured by longer timed up and go test 1.1 s (0.5, 1.7). After adjustment for age, female cases had, compared with non-cases, lower body mass index − 1.5 kg/m2 (− 2.1, − 0.9), less lean mass − 1.6 kg (− 2.5, − 0.8), thigh muscle cross-sectional area − 4.4 cm
2
(− 6.5, − 2.3), and worse leg strength − 16 N (− 25, − 6). These differences largely persisted after further adjustment for bone mineral density (BMD), suggesting that body composition may contribute to the risk of fracture independent of bone health. When examining the association between these same factors and hip fractures using Cox regression, the same conclusions were reached.
Conclusions
After accounting for age and BMD, older adults who later experienced a hip fracture had poorer baseline measures of physical function and/or body composition, which may at least partly contribute to the risk of falls leading to fracture.
Summary
The increase in fracture risk associated with a recent fragility fracture is more appropriately captured using a 10-year fracture probability than 2- or 5-year probabilities.
Introduction
The ...recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 2-, 5-, and 10-year probability of fracture.
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. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) occurring within the previous 2 years and probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios were used to adjust fracture probabilities over a 2-, 5-, and 10-year time horizon.
Results
As expected, probabilities decreased with decreasing time horizon. Probability ratios varied according to age and the site of sentinel fracture. Probability ratios to adjust for a prior fracture within the previous 2 years were higher the shorter the time horizon, but the absolute increases in fracture probabilities were much reduced. Thus, fracture probabilities were substantially lower with time horizons less than 10 years.
Conclusion
The 10-year probability of fractures is the appropriate metric to capture the impact of the recency of sentinel fractures. The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures, adjustments which can readily inform clinical decision-making.
Summary
Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older ...adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk.
Introduction
We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study.
Methods
The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4–12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type.
Results
Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk.
Conclusion
This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.
Background
Elevated copeptin, a marker for vasopressin release, has been associated with impaired prognosis in acute myocardial infarction (MI). The aim was to investigate whether this association ...extends beyond the acute phase and whether it is related to markers of stress (cortisol) and heart failure (NTproBNP).
Methods
Copeptin, cortisol and NTproBNP were measured in 926 participants (age: 76.0; male: 48.5%) in the ICELAND MI study whereof 246 had a previous MI (91 recognizable (RMI) and 155 previously unrecognizable (UMI) detected by cardiac magnetic resonance imaging). The primary endpoint was cardiovascular events (CVEs), and secondary endpoints were total mortality, heart failure and MI (median follow‐up was 9.1 years). The relation between copeptin and prognosis was assessed with the Cox proportional hazard regression (unadjusted, adjusted for cortisol and NTproBNP, respectively, and a multiple model: copeptin, cortisol, NTproBNP, age, sex, serum creatinine, heart failure).
Results
Copeptin was higher in participants with MI (8.9 vs. 6.4 pmol/L; P < .01), with no difference between RMI vs. UMI. Increased copeptin correlated with evening cortisol (r = .11; P < .01) and NTproBNP (r = .07; P = .04). Copeptin was associated with CVE and total mortality after adjusting for cortisol and NTproBNP separately, and remained significantly associated with total mortality in the multiple model.
Conclusions
Copeptin was higher in subjects with previous MI regardless whether previously recognized or not. Copeptin correlated weakly with cortisol and NTproBNP, and was independently associated with total mortality. This indicates that the prognostic implications of copeptin are not only mediated by heart failure or stress, supporting the assumption that copeptin is a marker of general vulnerability.
Clinical retrospective studies have only reported limited improvements in hip fracture classification accuracy using finite element (FE) models compared to conventional areal bone mineral density ...(aBMD) measurements. A possible explanation is that state-of-the-art quasi-static models do not estimate patient-specific loads. A novel FE modeling technique was developed to improve the biofidelity of simulated impact loading from sideways falling. This included surrogate models of the pelvis, lower extremities, and soft tissue that were morphed based on subject anthropometrics. Hip fracture prediction models based on aBMD and FE measurements were compared in a retrospective study of 254 elderly female subjects from the AGES-Reykjavik study. Subject fragility ratio (FR) was defined as the ratio between the ultimate forces of paired biofidelic models, one with linear elastic and the other with non-linear stress-strain relationships in the proximal femur. The expected end-point value (EEV) was defined as the FR weighted by the probability of one sideways fall over five years, based on self-reported fall frequency at baseline. The change in maximum volumetric strain (ΔMVS) on the surface of the femoral neck was calculated between time of ultimate femur force and 90% post-ultimate force in order to assess the extent of tensile tissue damage present in non-linear models. After age-adjusted logistic regression, the area under the receiver-operator curve (AUC) was highest for ΔMVS (0.72), followed by FR (0.71), aBMD (0.70), and EEV (0.67), however the differences between FEA and aBMD based prediction models were not deemed statistically significant. When subjects with no history of falling were excluded from the analysis, thus artificially assuming that falls were known a priori with no uncertainty, a statistically significant difference in AUC was detected between ΔMVS (0.85), and aBMD (0.74). Multivariable linear regression suggested that the variance in maximum elastic femur force was best explained by femoral head radius, pelvis width, and soft tissue thickness (R2 = 0.79; RMSE = 0.46 kN; p < 0.005). Weighting the hip fracture prediction models based on self-reported fall frequency did not improve the models' sensitivity, however excluding non-fallers lead to significant differences between aBMD and FE based models. These findings suggest that an accurate assessment of fall probability is necessary for accurately identifying individuals predisposed to hip fracture.
•254 subject-specific dynamic FE models of sideways fall were generated with pelvis, lower-extremities, and soft tissue.•Hip fracture risk models based on FEA had higher AUC than aBMD models, but not statistically significant.•Excluding non-fallers provided statistically significant AUC difference between strain-based predictor and total femur aBMD.•Simulated femur impact force was predicted as a function of pelvis width, femoral head radius, and soft tissue thickness.•Force reduction between the ultimate contact forces at the femoral head and the ground correlated with soft tissue thickness.
It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between ...biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.
Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.
After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 95% CI, 1.02-1.16;
=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.
A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.
Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably ...predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography-a fast, readily available clinical technique-that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies.
To determine whether microvascular damage, indicated by cerebral microbleeds (CMBs) and retinal microvascular signs, is associated with cognitive function and dementia in older persons.
This is a ...cross-sectional study of 3,906 participants (mean age 76 years; 58% women) in the AGES-Reykjavik Study (2002-2006). We assessed CMBs on MRI and retinal microvascular signs on digital retinal images. Composite Z scores of memory, processing speed, and executive function were derived from a battery of neurocognitive tests. Dementia and subtypes were diagnosed following international criteria. Regression models were used to relate cognitive Z scores and dementia to CMBs and retinal microvascular signs, adjusting for demographics, cardiovascular factors, and brain ischemic lesions.
People with multiple (≥ 2) CMBs had lower Z scores on tests of processing speed (β-coefficient -0.16; 95% confidence interval -0.26 to -0.05) and executive function (-0.14; -0.24 to -0.04); results were strongest for having multiple CMBs located in the deep hemispheric or infratentorial areas. The odds ratio of vascular dementia was 2.32 (95% confidence interval 1.02 to 5.25) for multiple CMBs and 1.95 (1.04 to 3.62) for retinopathy. Having both CMBs and retinopathy, compared to having neither, was significantly associated with markedly slower processing speed (-0.25; -0.37 to -0.12), poorer executive function (-0.19; -0.31 to -0.07), and an increased odds ratio of vascular dementia (3.10; 1.11 to 8.62).
Having multiple CMBs or concomitant CMBs and retinopathy is associated with a profile of vascular cognitive impairment. These findings suggest that microvascular damage, as indicated by CMBs and retinopathy lesions, has functional consequences in older men and women living in the community.
Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic stroke. There are ...few prevalence data on older populations. This paper reports on the prevalence and location of CMBs in a community based cohort of older men and women (born 1907-1935) who participated in the Age Gene/Environment Susceptibility (AGES)-Reykjavik Study, a population based cohort study that followed the Reykjavik Study
As part of the examination, all eligible and consenting cohort members underwent a full brain MRI, and blood was drawn for genotyping. Results are based on the first 1962 men (n = 820) and women (n = 1142), mean age 76 years, with complete MRI and demographic information available.
Evidence of CMBs was found in 218 participants (11.1% (95% CI 9.8% to 12.6%)); men had significantly more CMBs than women (14.4% vs 8.8%; p = 0.0002, age adjusted). The prevalence of CMBs increased with age (p = 0.0001) in both men (p = 0.006) and women (p = 0.007). CMBs were located in the cerebral lobes (70%), the basal ganglia region (10.5%) and infratentorium (18.6%). Having a CMB was significantly associated with a homozygote Apo E epsilon4epsilon4 genotype (p = 0.01).
Cerebral microbleeds are common in older persons. The association with homozygote Apo E epsilon4 genotype and finding a relative predominance in the parietal lobes might indicate an association with amyloid angiopathy.
Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by ...combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 × 10−324) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 × 10−13), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain ∼18.0 and ∼1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 × 10−13), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.
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