Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Proteomic associations with forced expiratory volume - a Mendelian randomisation study.

A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins with potential causality to lung function.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Diffuse idiopathic skeletal hyperostosis in elderly Icelanders and its association with the metabolic syndrome: the AGES-Reykjavik Study.

Objective: To describe the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in a large population-based study of elderly Icelanders, with particular reference to weight-related factors and the metabolic syndrome.Method: The study population comprised 5321 participants aged 68-96 years (2276 males, mean ± sd age 76 ± 5 , and 3045 females, age 77 ± 6) from the AGES-Reykjavik Study. DISH diagnosis was based on computed tomography (CT) scans, and interpreted strictly by the Resnick criteria and additional suggestions for CT interpretation by Oudkerk et al. Radiology readings were taken by a radiology resident and sample readings by two experienced radiologists.Results: A diagnosis of DISH was made in 13.7% of males and 2.8% of females. There was no association with age, but a strong association was seen with the metabolic syndrome [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.69-2.64, p = 3.9 × 10-11]. Among the components of the metabolic syndrome, the association with DISH was significant for the insulin resistance criterion (OR 1.66, 95% CI 1.32-2.01, p < 0.001) and the body mass index (BMI) criterion (OR 2.16, 95% CI 1.70-2.74, p < 0.001). Other weight-related variables (midlife BMI, weight, and abdominal circumference) showed similar associations.Conclusions: This study, which to our knowledge is the largest published study on the prevalence of DISH, shows an association with the metabolic syndrome, particularly with the insulin resistance and BMI criteria. This is analogous with previous reports linking DISH with metabolic causes. In this age category, we did not observe any increase in prevalence with age.

The effect on subsequent fracture risk of age, sex, and prior fracture site by recency of prior fracture.

The risk of a recurrent fragility fracture varies by age and sex, as by site and recency of sentinel fracture. INTRODUCTION: The recency of prior fractures affects subsequent fracture risk. Variable recency may obscure other factors that affect subsequent fracture risk. The aim of this study was to quantify the effect of a sentinel fracture by site, age, and sex where the recency was held constant. 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 incidence was compared to that of the general population determined at fixed times after a sentinel fracture (humeral, clinical vertebral, forearm, hip, and minor fractures). Outcome fractures comprised a major osteoporotic fracture and hip fracture. RESULTS: Sentinel osteoporotic fractures were identified in 9504 men and women. Of these, 3616 individuals sustained a major osteoporotic fracture as the first subsequent fracture, of whom 1799 sustained a hip fracture. Hazard ratios for prior fracture were consistently higher in men than in women and decreased progressively with age. Hazard ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus, forearm, or minor osteoporotic fracture. CONCLUSION: The risk of a recurrent fragility fracture varies by age, sex, and site of sentinel fracture when recency is held constant.

Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

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 cm2 (- 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 cm2 (- 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.

The use of 2-, 5-, and 10-year probabilities to characterize fracture risk after a recent sentinel fracture.

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.

Bone density and strength from thoracic and lumbar CT scans both predict incident vertebral fractures independently of fracture location.

In a population-based study, we found that computed tomography (CT)-based bone density and strength measures from the thoracic spine predicted new vertebral fracture as well as measures from the lumbar spine, suggesting that CT scans at either the thorax or abdominal regions are useful to assess vertebral fracture risk. INTRODUCTION: Prior studies have shown that computed tomography (CT)-based lumbar bone density and strength measurements predict incident vertebral fracture. This study investigated whether CT-based bone density and strength measurements from the thoracic spine predict incident vertebral fracture and compared the performance of thoracic and lumbar bone measurements to predict incident vertebral fracture. METHODS: This case-control study of community-based men and women (age 74.6 ± 6.6) included 135 cases with incident vertebral fracture at any level and 266 age- and sex-matched controls. We used baseline CT scans to measure integral and trabecular volumetric bone mineral density (vBMD) and vertebral strength (via finite element analysis, FEA) at the T8 and L2 levels. Association between these measurements and vertebral fracture was determined by using conditional logistic regression. Sensitivity and specificity for predicting incident vertebral fracture were determined for lumbar spine and thoracic bone measurements. RESULTS: Bone measurements from T8 and L2 predicted incident vertebral fracture equally well, regardless of fracture location. Specifically, for predicting vertebral fracture at any level, the odds ratio (per 1-SD decrease) for the vBMD and strength measurements at L2 and T8 ranged from 2.0 to 2.7 (p < 0.0001) and 1.8 to 2.8 (p < 0.0001), respectively. Results were similar when predicting fracture only in the thoracic versus the thoracolumbar spine. Lumbar and thoracic spine bone measurements had similar sensitivity and specificity for predicting incident vertebral fracture. CONCLUSION: These findings indicated that like those from the lumbar spine, CT-based bone density and strength measurements from the thoracic spine may be useful for identifying individuals at high risk for vertebral fracture.

Correction to: Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

The original version of this article, published on 18 august 2020 contained a mistake. An author's name was misspelled.

Adjusting conventional FRAX estimates of fracture probability according to the recency of sentinel fractures.

The risk of a recurrent fragility fracture is particularly high immediately following the fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the site of a recent fracture. 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 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. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) from the hazards of death and fracture. Fracture probabilities were computed on the one hand for sentinel fractures occurring within the previous 2 years and on the other hand, probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures. RESULTS: Probability ratios to adjust 10-year FRAX probabilities of a major osteoporotic fracture for recent sentinel fractures were age dependent, decreasing with age in both men and women. Probability ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus or forearm fracture. Probability ratios to adjust 10-year FRAX probabilities of a hip fracture for recent sentinel fractures were also age dependent, decreasing with age in both men and women with the exception of forearm fractures. CONCLUSION: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures.

Lifestyle and 25-hydroxy-vitamin D among community-dwelling old adults with dementia, mild cognitive impairment, or normal cognitive function.

BACKGROUND: Several studies have indicated that older adults with cognitive impairment have a poorer lifestyle than their healthy peers including lower 25-hydroxy-vitamin D levels (25OHD). AIM: To investigate the associations between lifestyle and 25OHD depending on cognitive status among old adults. METHODS: Community-dwelling old adults (65-96 years) participated in this cross-sectional study based on the Age-Gene/Environment-Susceptibility-Reykjavik-Study. The analytical sample included 5162 subjects who were stratified by cognitive status, i.e., dementia (n = 307), mild cognitive impairment (MCI, n = 492), and normal cognitive status (NCS, n = 4363). Lifestyle variables were assessed and 25OHD was measured. The associations between lifestyle and 25OHD were calculated using linear models correcting for potential confounders. RESULTS: According to linear regression models, 25OHD was significantly lower in older people with dementia (53.8 ± 19.6 nmol/L) than in NCS participants (57.6 ± 17.7 nmol/L). Cod liver oil (7.1-9.2 nmol/L, P < 0.001) and dietary supplements (4.4-11.5 nmol/L, P < 0.001) were associated with higher 25OHD in all three groups. However, physical activity ≥ 3 h/week (2.82 nmol/L, P < 0.001), BMI < 30 kg/m2 (5.2 nmol/L, P < 0.001), non-smoking (4.8 nmol/L, P < 0.001), alcohol consumption (2.7 nmol/L, P < 0.001), and fatty fish consumption ≥ 3x/week (2.6 nmol/L, P < 0.001) were related to higher 25OHD in NCS only, but not in participants with dementia or MCI. DISCUSSION: Older people living in Iceland with dementia are at higher risk for 25OHD deficiency when compared to healthy individuals. Physical activity reported among participants with dementia, and MCI is low and is not significantly associated with 25OHD. CONCLUSIONS: Lifestyle factors among NCS participants are associated with 25OHD levels. Importantly, healthy lifestyle should be promoted among individuals with MCI and dementia.

Quantitative 3D imaging parameters improve prediction of hip osteoarthritis outcome.

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.

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Biofidelic finite element models for accurately classifying hip fracture in a retrospective clinical study of elderly women from the AGES Reykjavik cohort.

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.

Cardiovascular risk factors and incident giant cell arteritis: a population-based cohort study.

OBJECTIVE: To assess the strength of the effect of cardiovascular risk factors on the incidence of giant cell arteritis (GCA) in a general population context. METHOD: Data from the Reykjavik Study (RS), a population-based cohort study focusing on cardiovascular disease, were used. Everyone born in 1907-1935 living in Reykjavik, Iceland, or adjacent communities on 1 December 1967 were invited to participate. Subjects attended a study visit in 1967-1996 and information on cardiovascular risk factors [smoking habits, blood pressure, diabetes, body mass index (BMI), and serum cholesterol] was obtained. All temporal artery biopsies obtained from members of the RS cohort were re-examined by a single pathologist with expertise in vascular pathology. Effects of risk factors on GCA occurrence are expressed as incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: Altogether, 19 241 subjects contributed a median of 23.1 (interquartile range 17.6-29.4) years after the age of 50 to this analysis. During 444 126 person-years of follow-up, 194 subjects developed GCA, corresponding to an incidence rate of 43.6 (95% CI 37.8-50.2) per 100 000 person-years. Being overweight or obese  were inversely associated with GCA, especially in women [IRRs 0.70 (0.48-1.02) and 0.31 (0.14-0.71), respectively]. There was a weaker association between BMI and incident GCA in men. Smoking was inversely associated with GCA in men [IRR 0.47 (0.27-0.81)], but not in women. CONCLUSIONS: The incidence of GCA in Iceland is very high. High BMI protects against the occurrence of GCA, and smoking may protect against GCA in men.

Characteristics of recurrent fractures.

The present study, drawn from a sample of the Icelandic population, quantified high immediate risk and utility loss of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) that attenuated with time. INTRODUCTION: The risk of a subsequent osteoporotic fracture is particularly acute immediately after an index fracture and wanes progressively with time. The aim of this study was to quantify the risk and utility consequences of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) with an emphasis on the time course of recurrent fracture. METHODS: The Reykjavik Study fracture registration, drawn from a sample of the Icelandic population (n = 18,872), recorded all fractures of the participants from their entry into the study until December 31, 2012. Medical records for the participants were manually examined and verified. First sentinel fractures were identified. Subsequent fractures, deaths, 10-year probability of fracture and cumulative disutility using multipliers derived from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) were examined as a function of time after fracture, age and sex. RESULTS: Over 10 years, subsequent fractures were sustained in 28% of 1498 individuals with a sentinel hip fracture. For other sentinel fractures, the proportion ranged from 35 to 38%. After each sentinel fracture, the risk of subsequent fracture was highest in the immediate post fracture interval and decreased markedly with time. Thus, amongst individuals who sustained a recurrent fracture, 31-45% did so within 1 year of the sentinel fracture. Hazard ratios for fracture recurrence (population relative risks) were accordingly highest immediately after the sentinel fracture (2.6-5.3, depending on the site of fracture) and fell progressively over 10 years (1.5-2.2). Population relative risks also decreased progressively with age. The utility loss during the first 10 years after a sentinel fracture varied by age (less with age) and sex (greater in women). In women at the age of 70 years, the mean utility loss due to fractures in the whole cohort was 0.081 whereas this was 12-fold greater in women with a sentinel hip fracture, and was increased 15-fold for spine fracture, 4-fold for forearm fracture and 8-fold for humeral fracture. CONCLUSION: High fracture risks and utility loss immediately after fracture suggest that treatment given as soon as possible after fracture would avoid a higher number of new fractures compared with treatment given later. This provides the rationale for very early intervention immediately after a sentinel fracture.

Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

Imminent risk of fracture after fracture.

The risk of major osteoporotic fracture (MOF) after a first MOF is increased over the whole duration of follow-up, but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner. INTRODUCTION: A history of fracture is a strong risk factor for future fractures. The aim of the present study was to determine whether the predictive value of a past MOF for future MOF changed with time. METHODS: The study was based on a population-based cohort of 18,872 men and women born between 1907 and 1935. Fractures were documented over 510,265 person-years. An extension of Poisson regression was used to investigate the relationship between the first MOF and the second. All associations were adjusted for age and time since baseline. RESULTS: Five thousand thirty-nine individuals sustained one or more MOFs, of whom 1919 experienced a second MOF. The risk of a second MOF after a first increased by 4% for each year of age (95% CI 1.02-1.06) and was 41% higher for women than men (95% CI 1.25-1.59). The risk of a second MOF was highest immediately after the first fracture and thereafter decreased with time though remained higher than the population risk throughout follow-up. For example, 1 year after the first MOF, the risk of a second fracture was 2.7 (2.4-3.0) fold higher than the population risk. After 10 years, this risk ratio was 1.4 (1.2-1.6). The effect was more marked with increasing age. CONCLUSIONS: The risk of MOF after a first MOF is increased over the whole follow-up, but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner, particularly in the elderly.

Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study.

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.

Left-right differences in the proximal femur's strength of post-menopausal women: a multicentric finite element study.

UNLABELLED: The strength of both femurs was estimated in 198 post-menopausal women through subject-specific finite element models. Important random differences between contralateral femurs were found in a significant number of subjects, pointing to the usefulness of further studies to understand if strength-based classification of patients at risk of fracture can be affected by laterality issues. INTRODUCTION: Significant, although small, differences exist in mineral density and anatomy of contralateral proximal femurs. These differences, and their combined effect, may result in a side difference in femurs' strength. However, this has never been tested on a large sample of a homogenous population. METHODS: The strength of both femurs was estimated in 198 post-menopausal women through CT-derived finite element models, built using a validated procedure, in sideways fall conditions. The impact of the resulting asymmetry on the classification of subjects at risk of fracture was analysed. RESULTS: The small difference observed between sides (the right femur on average 4 % stronger than the left) was statistically significant but mechanically negligible. In contrast, higher random differences (absolute difference between sides with respect to mean value) were found: on average close to 15 % (compared to 9.2 % for areal bone mineral density (aBMD) alone), with high scatter among the subjects. When using a threshold-based classification, the right and left femurs were discordant up to over 20 % of cases (K always lower than 0.60) but the left femur was concordant (mean K = 0.84) with the minimum strength between right and left. CONCLUSION: Considering both femurs may be important when trying to classify subjects at risk of failure with strength estimates. Future studies including fracture assessment would be necessary to quantify the real impact.