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  • Borgström, Fredrik, et al. (författare)
  • Fragility fractures in Europe: burden, management and opportunities.
  • 2020
  • Ingår i: Archives of osteoporosis. - 1862-3514. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five countries of the European Union plus Sweden (EU6). In 2017, new fragility fractures in the EU6 are estimated at 2.7 million with an associated annual cost of €37.5 billion and a loss of 1.0 million quality-adjusted life years.Osteoporosis is characterized by reduced bone mass and strength, which increases the risk of fragility fractures, which in turn, represent the main consequence of the disease. This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five EU countries and Sweden (designated the EU6).A series of metrics describing the burden and management of fragility fractures were defined by a scientific steering committee. A working group performed the data collection and analysis. Data were collected from current literature, available retrospective data and public sources. Different methods were applied (e.g. standard statistics and health economic modelling), where appropriate, to perform the analysis for each metric.Total fragility fractures in the EU6 are estimated to increase from 2.7 million in 2017 to 3.3 million in 2030; a 23% increase. The resulting annual fracture-related costs (€37.5 billion in 2017) are expected to increase by 27%. An estimated 1.0 million quality-adjusted life years (QALYs) were lost in 2017 due to fragility fractures. The current disability-adjusted life years (DALYs) per 1000 individuals age 50 years or more were estimated at 21 years, which is higher than the estimates for stroke or chronic obstructive pulmonary disease. The treatment gap (percentage of eligible individuals not receiving treatment with osteoporosis drugs) in the EU6 is estimated to be 73% for women and 63% for men; an increase of 17% since 2010. If all patients who fracture in the EU6 were enrolled into fracture liaison services, at least 19,000 fractures every year might be avoided.Fracture-related burden is expected to increase over the coming decades. Given the substantial treatment gap and proven cost-effectiveness of fracture prevention schemes such as fracture liaison services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are appropriately assessed and treated.
  • Forgetta, V., et al. (författare)
  • Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study
  • 2020
  • Ingår i: PLoS medicine. - : Public Library of Science. - 1549-1277 .- 1549-1676. ; 17:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. Methods and findings A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N= 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r(2)= 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. Conclusions Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. Author summaryWhy was this study done? Osteoporosis screening identifies only a small proportion of the screened population to be eligible for intervention. The prediction of heritable risk factors using polygenic risk scores could decrease the number of screened individuals by reassuring those with low genetic risk. We investigated whether the genetic prediction of heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-could be incorporated into an established screening guideline to identify individuals at low risk for osteoporosis. What did the researchers do and find? Using UK Biobank, we developed a polygenic risk score (gSOS) consisting of 21,717 genetic variants that was strongly correlated with SOS ( = 23.2%). Using the National Osteoporosis Guideline Group clinical assessment guidelines in 5 validation cohorts, we estimate that reassuring individuals with a high gSOS, rather than doing further assessments, could reduce the number of clinical-risk-factor-based Fracture Risk Assessment Tool (FRAX) tests and bone-density-measurement-based FRAX tests by 37% and 41%, respectively, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. What do these findings mean? We show that genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk of osteoporotic fractures. Therefore, the potential exists to improve the efficiency of osteoporosis screening programs without large losses in sensitivity or specificity to identify individuals who should receive an intervention. Further translational studies are needed to test the clinical applications of this polygenic risk score; however, our work shows how such scores could be tested in the clinic.
  • Johansson, Helena, 1981, et al. (författare)
  • Optimization of BMD measurements to identify high risk groups for treatment--a test analysis.
  • 2004
  • Ingår i: Journal of bone and mineral research. - : AMBMR. - 0884-0431 .- 1523-4681. ; 19:6, s. 906-13
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: The aim of this study was to develop a methodology to optimize the role of BMD measurements in a case finding strategy. We studied 2113 women > or = 75 years of age randomly selected from Sheffield, UK, and adjacent regions. Baseline assessment included hip BMD and clinical risk factors. Outcomes included death and fracture in women followed for 6723 person-years. MATERIALS AND METHODS: Poisson models were used to identify significant risk factors for all fractures and for death with and without BMD and the hazard functions were used to compute fracture probabilities. Women were categorized by fracture probability with and without a BMD assessment. A 10-year fracture probability threshold of 35% was taken as an intervention threshold. Discordance in categorization of risk (i.e., above or below the threshold probability) between assessment with and without BMD was examined by logistic regression as probabilities of re-classification. Age, prior fracture, use of corticosteroids, and low body mass index were identified as significant clinical risk factors. RESULTS: A total of 16.8% of women were classified as high risk based on these clinical risk factors. The average BMD in these patients was approximately 1 SD lower than in low-risk women; 21.5% of women were designated to be at high risk with the addition of BMD. Fifteen percent of all women were reclassified after adding BMD to clinical risk factors, most of whom lay near the intervention threshold. When a high probability of reclassification was accepted (without a BMD test) for high risk to low risk (p1< or = 0.8) and a low probability accepted for low to high risk (P2 < or = 0.2), BMD tests would be required in only 21% of the population. CONCLUSION: We conclude that the use of clinical risk factors can identify elderly women at high fracture risk and that such patients have a low average BMD. BMD testing is required, however, in a minority of women--a fraction that depends on the probabilities accepted for classification and the thresholds of risk chosen. These findings need to be validated in other cohorts at different ages and from different regions of the world.
  • Kanis, John A, et al. (författare)
  • A meta-analysis of prior corticosteroid use and fracture risk.
  • 2004
  • Ingår i: Journal of bone and mineral research. - : AMBMR. - 0884-0431 .- 1523-4681. ; 19:6, s. 893-9
  • Tidskriftsartikel (refereegranskat)abstract
    • The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of approximately 42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD. INTRODUCTION: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk. MATERIALS AND METHODS: We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. RESULTS: Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD. CONCLUSION: We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies.
  • Kanis, John A, et al. (författare)
  • FRAX and its applications to clinical practice
  • 2009
  • Ingår i: Bone. - 8756-3282 .- 1873-2763. ; 44:5, s. 734-43
  • Tidskriftsartikel (refereegranskat)abstract
    • The introduction of the WHO FRAX algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. FRAX integrates the influence of several well validated risk factors for fracture with or without the use of BMD. Its use in fracture risk prediction poses challenges for patient assessment, the development of practice guidelines, the evaluation of drug efficacy and reimbursement, as well as for health economics which are the topics outlined in this review.
  • Oei, L., et al. (författare)
  • Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
  • 2014
  • Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 59, s. 20-27
  • Tidskriftsartikel (refereegranskat)abstract
    • Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.
  • Estrada, Karol, et al. (författare)
  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
  • 2012
  • Ingår i: Nature genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
  • Giangregorio, Lora M, et al. (författare)
  • FRAX underestimates fracture risk in patients with diabetes
  • 2012
  • Ingår i: Journal of bone and mineral research. - 1523-4681. ; 27:2, s. 301-308
  • Tidskriftsartikel (refereegranskat)abstract
    • The study objective was to determine whether diabetes is a risk factor for incident hip or major osteoporotic fractures independent of FRAX. Men and women with diabetes (N = 3,518) and non-diabetics (N = 36,085) age ≥50 years at the time of BMD testing (1990-2007) were identified in a large clinical database from Manitoba, Canada. FRAX probabilities were calculated and fracture outcomes to 2008 were established via linkage with a population-based data repository. Multivariable Cox proportional hazards models were used to determine if diabetes was associated with incident hip fractures or major osteoporotic fractures after controlling for FRAX risk factors. Mean 10-year probabilities of fracture were similar between groups for major fractures (diabetic 11.1 ± 7.2 vs. non-diabetic 10.9 ± 7.3, p-value = 0.116) and hip fractures (diabetic 2.9 ± 4.4 vs. non-diabetic 2.8 ± 4.4, p-value = 0.400). Diabetes was a significant predictor of subsequent major osteoporotic fracture (HR 1.61 [95% CI; 1.42-1.83]) after controlling for age, sex, medication use, and FRAX risk factors including BMD. Similar results were seen after adjusting for FRAX probability directly (HR 1.59 [95% CI; 1.40-1.79]). Diabetes was also associated with significantly higher risk for hip fractures (p-value < 0.001). Higher mortality from diabetes attenuated but did not eliminate the excess fracture risk. FRAX underestimated observed major osteoporotic and hip fracture risk in diabetics (adjusted for competing mortality), but demonstrated good concordance with observed fractures for non-diabetics. We conclude that diabetes confers an increased risk of fracture that is independent of FRAX derived with BMD. This suggests that diabetes might be considered for inclusion in future iterations of FRAX. © 2011 American Society for Bone and Mineral Research.
  • Harvey, Nicholas C., et al. (författare)
  • Falls Predict Fractures Independently of FRAX Probability : A Meta-Analysis of the Osteoporotic Fractures in Men (MrOS) Study
  • 2018
  • Ingår i: Journal of Bone and Mineral Research. - : WILEY. - 0884-0431 .- 1523-4681. ; 33:3, s. 510-516
  • Tidskriftsartikel (refereegranskat)abstract
    • Although prior falls are a well-established predictor of future fracture, there is currently limited evidence regarding the specific value of falls history in fracture risk assessment relative to that of other clinical risk factors and bone mineral density (BMD) measurement. We therefore investigated, across the three Osteoporotic Fractures in Men (MrOS) Study cohorts, whether past falls predicted future fracture independently of FRAX and whether these associations varied with age and follow-up time. Elderly men were recruited from MrOS Sweden, Hong Kong, and USA. Baseline data included falls history (over the preceding 12 months), clinical risk factors, BMD at femoral neck, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the associations between falls, FRAX probability, and incident fracture, adjusting for age, time since baseline, and cohort in base models; further models were used to investigate interactions with age and follow-up time. Random-effects meta-analysis was used to synthesize the individual country associations. Information on falls and FRAX probability was available for 4365 men in USA (mean age 73.5 years; mean follow-up 10.8 years), 1823 men in Sweden (mean age 75.4 years; mean follow-up 8.7 years), and 1669 men in Hong Kong (mean age 72.4 years; mean follow-up 9.8 years). Rates of past falls were similar at 20%, 16%, and 15%, respectively. Across all cohorts, past falls predicted incident fracture at any site (hazard ratio [HR]=1.69; 95% confidence interval [CI] 1.49, 1.90), major osteoporotic fracture (MOF) (HR=1.56; 95% CI 1.33, 1.83), and hip fracture (HR=1.61; 95% CI 1.27, 2.05). Relationships between past falls and incident fracture remained robust after adjustment for FRAX probability: adjusted HR (95% CI) any fracture: 1.63 (1.45, 1.83); MOF: 1.51 (1.32, 1.73); and hip: 1.54 (1.21, 1.95). In conclusion, past falls predicted incident fracture independently of FRAX probability, confirming the potential value of falls history in fracture risk assessment.
  • Harvey, Nicholas C, et al. (författare)
  • Incidence of myocardial infarction and associated mortality varies by latitude and season: findings from a Swedish Registry Study.
  • 2019
  • Ingår i: Journal of public health (Oxford, England). - 1741-3850. ; 42:4, s. e440-e448
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated whether the incidence of death following myocardial infarction (MI) varied by season and latitude in the Swedish population.We studied deaths following MI from January 1987 to December 2009, using the Swedish National Cause of Death Register. County of residence was used to determine latitude and population density. An extension of Poisson regression was used to study the relationship between risk of death following MI with age, latitude, time (from 1987), population density and calendar days.Over the study period, there was a secular decrease in the incidence of MI-related death. In men, MI-related death incidence increased by 1.3% [95% confidence interval (CI) = 1.1-1.5] per degree of latitude (northwards). In women, MI-related death incidence increased by 0.6% (95% CI = 0.4-0.9) per degree of latitude. There was seasonal variation in the risk of MI-related death with peak values in the late winter and a nadir in the summer months in both the north and the south of Sweden. Findings were similar with incident MI as the outcome.The incidence of MI-related death varied markedly by season and latitude in Sweden, with summer months and more southerly latitude associated with lower rates than winter months and more northerly latitude.
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