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| 2. |
- Forgetta, V., et al.
(författare)
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Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study
- 2020
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:7
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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.
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| 3. |
- Harvey, N. C., et al.
(författare)
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FRAX predicts incident falls in elderly men : findings from MrOs Sweden
- 2016
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 27:1, s. 267-274
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Tidskriftsartikel (refereegranskat)abstract
- A Summary Falls and fractures share several common risk factors. Although past falls is not included as an input variable in the FRAX calculator, we demonstrate that FRAX probability predicts risk of incident falls in the MrOs Sweden cohort. Introduction Although not included in the FRAXA (R) algorithm, it is possible that increased falls risk is partly dependent on other risk factors that are incorporated into FRAX. The aim of the present study was to determine whether fracture probability generated by FRAX might also predict risk of incident falls and the extent that a falls history would add value to FRAX. Methods We studied the relationship between FRAX probabilities and risk of falls in 1836 elderly men recruited to the MrOS study, a population-based prospective cohort of men from Sweden. Baseline data included falls history, clinical risk factors, bone mineral density (BMD) at femoral neck, and calculated FRAX probabilities. Incident falls were captured during an average of 1.8 years of follow-up. An extension of Poisson regression was used to investigate the relationship between FRAX, other risk variables, and the time-to-event hazard function of falls. All associations were adjusted for age and time since baseline. Results At enrolment, 15.5 % of the men had fallen during the preceding 12 months (past falls) and 39 % experienced one or more falls during follow-up (incident falls). The risk of incident falls increased with increasing FRAX probabilities at baseline (hazard ratio (HR) per standard deviation (SD), 1.16; 95 % confidence interval (95%CI), 1.06 to 1.26). The association between incident falls and FRAX probability remained after adjustment for past falls (HR per SD, 1.12; 95%CI, 1.03 to 1.22). High compared with low baseline FRAX score (>15 vs <15 % probability of major osteoporotic fracture) was strongly predictive of increased falls risk (HR, 1.64; 95%CI, 1.36 to 1.97) and remained stable with time. Whereas past falls were a significant predictor of incident falls (HR, 2.75; 95%CI, 2.32 to 3.25), even after adjustment for FRAX, the hazard ratio decreased markedly with increasing follow-up time. Conclusions Although falls are not included as an input variable, FRAX captures a component of risk for future falls and outperforms falls history with an extended follow-up time.
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| 4. |
- Harvey, N. C., et al.
(författare)
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Greater pQCT Calf Muscle Density Is Associated with Lower Fracture Risk, Independent of FRAX, Falls and BMD: A Meta-Analysis in the Osteoporotic Fractures in Men (MrOS) Study
- 2022
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Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the predictive performance of peripheral quantitative computed tomography (pQCT) measures of both calf muscle density (an established surrogate for muscle adiposity, with higher values indicating lower muscle adiposity and higher muscle quality) and size (cross-sectional area [CSA]) for incident fracture. pQCT (Stratec XCT2000/3000) measurements at the tibia were undertaken in Osteoporotic Fractures in Men (MrOS) United States (US), Hong Kong (HK), and Swedish (SW) cohorts. Analyses were by cohort and synthesized by meta-analysis. The predictive value for incident fracture outcomes, illustrated here for hip fracture (HF), using an extension of Poisson regression adjusted for age and follow-up time, was expressed as hazard ratio (HR) per standard deviation (SD) increase in exposure (HR/SD). Further analyses adjusted for femoral neck (fn) bone mineral density (BMD) T-score, Fracture Risk Assessment Tool (FRAX) 10-year fracture probability (major osteoporotic fracture) and prior falls. We studied 991 (US), 1662 (HK), and 1521 (SW) men, mean +/- SD age 77.0 +/- 5.1, 73.9 +/- 4.9, 80 +/- 3.4 years, followed for a mean +/- SD 7.8 +/- 2.2, 8.1 +/- 2.3, 5.3 +/- 2.0 years, with 31, 47, and 78 incident HFs, respectively. Both greater muscle CSA and greater muscle density were associated with a lower risk of incident HF [HR/SD: 0.84; 95% confidence interval [CI], 0.72-1.0 and 0.78; 95% CI, 0.66-0.91, respectively]. The pattern of associations was not materially changed by adjustment for prior falls or FRAX probability. In contrast, after inclusion of fn BMD T-score, the association for muscle CSA was no longer apparent (1.04; 95% CI, 0.88-1.24), whereas that for muscle density was not materially changed (0.69; 95% CI, 0.59-0.82). Findings were similar for osteoporotic fractures. pQCT measures of greater calf muscle density and CSA were both associated with lower incidence of fractures in older men, but only muscle density remained an independent risk factor for fracture after accounting for fn BMD. These findings demonstrate a complex interplay between measures of bone, muscle size, and quality, in determining fracture risk. (C) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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| 5. |
- Harvey, N. C., et al.
(författare)
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Sarcopenia Definitions as Predictors of Fracture Risk Independent of FRAX(R), Falls, and BMD in the Osteoporotic Fractures in Men (MrOS) Study: A Meta-Analysis
- 2021
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 36:7, s. 1235-1244
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Tidskriftsartikel (refereegranskat)abstract
- Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass/height(2) (ALM/ht(2)) is the most commonly used estimate of muscle mass in the assessment of sarcopenia, but its predictive value for fracture is substantially attenuated by femoral neck (fn) bone mineral density (BMD). We investigated predictive value of 11 sarcopenia definitions for incident fracture, independent of fnBMD, fracture risk assessment tool (FRAX(R)) probability, and prior falls, using an extension of Poisson regression in US, Sweden, and Hong Kong Osteoporois Fractures in Men Study (MrOS) cohorts. Definitions tested were those of Baumgartner and Delmonico (ALM/ht(2) only), Morley, the International Working Group on Sarcopenia, European Working Group on Sarcopenia in Older People (EWGSOP1 and 2), Asian Working Group on Sarcopenia, Foundation for the National Institutes of Health (FNIH) 1 and 2 (using ALM/body mass index [BMI], incorporating muscle strength and/or physical performance measures plus ALM/ht(2)), and Sarcopenia Definitions and Outcomes Consortium (gait speed and grip strength). Associations were adjusted for age and time since baseline and reported as hazard ratio (HR) for first incident fracture, here major osteoporotic fracture (MOF; clinical vertebral, hip, distal forearm, proximal humerus). Further analyses adjusted additionally for FRAX-MOF probability (n = 7531; calculated +/- fnBMD), prior falls (y/n), or fnBMD T-score. Results were synthesized by meta-analysis. In 5660 men in USA, 2764 Sweden and 1987 Hong Kong (mean ages 73.5, 75.4, and 72.4 years, respectively), sarcopenia prevalence ranged from 0.5% to 35%. Sarcopenia status, by all definitions except those of FNIH, was associated with incident MOF (HR = 1.39 to 2.07). Associations were robust to adjustment for prior falls or FRAX probability (without fnBMD); adjustment for fnBMD T-score attenuated associations. EWGSOP2 severe sarcopenia (incorporating chair stand time, gait speed, and grip strength plus ALM) was most predictive, albeit at low prevalence, and appeared only modestly influenced by inclusion of fnBMD. In conclusion, the predictive value for fracture of sarcopenia definitions based on ALM is reduced by adjustment for fnBMD but strengthened by additional inclusion of physical performance measures. (c) 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
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| 6. |
- Johansson, Helena, 1981, et al.
(författare)
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Is the Swedish FRAX model appropriate for Swedish immigrants?
- 2015
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 26:11, s. 2617-2622
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of hip fracture in Sweden is substantially lower in immigrants than in the population born in Sweden. Thus, the use of a FRAXA (R) model in immigrants overestimates the risk of fracture, and the use of country of origin-specific models may be more appropriate. Introduction Age-specific fracture and mortality rates vary between countries so that FRAX tools are country-specific. In the case of immigrants, it is not known whether the model for the original or the new country is most appropriate. The aim of this study was to compare the incidence of hip fractures in foreign-born and Swedish-born individuals residing in Sweden. Methods We studied the incidence of hip fracture in all men and women aged 50 years or more in Sweden between 1987 and 2002. The population comprised 2.8 million Swedish-born and 270,000 foreign-born individuals. Results Incident hip fractures occurred in 239,842 Swedish-born and 12,563 foreign-born individuals. The hip fracture incidence rose with age for both groups and was higher for women than men amongst both Swedish-born and foreign-born individuals. The hip fracture incidence for the Swedish-born cohort was approximately twice that of immigrants. For example, at the age of 70 years, the annual hip fracture incidence (per 100,000) was 450 (95 % CI 446-454) for a Swedish-born woman and 239 (95 % CI 223-257) for a foreign-born woman at the time of immigration. The hip fracture incidence rose slowly with time from immigration (0.6 % per annum, 95 % CI 0.5-0.8 %) but remained significantly lower than for Swedish-born individuals even after 40 years of residence. Conclusions The incidence of hip fracture in Sweden is substantially lower in immigrants than in the population native to Sweden. Although there was a small rise in age- and sex-specific incidence after immigration, the incidence remained markedly lower than that observed in Swedish-born individuals. Thus, the use of a FRAX model for Sweden will overestimate the risk of fracture for foreign-born individuals living in Sweden.
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| 7. |
- Johansson, Helena, 1981, et al.
(författare)
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Low bone mineral density is associated with increased mortality in elderly men : MrOS Sweden
- 2011
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 22:5, s. 1411-1418
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Tidskriftsartikel (refereegranskat)abstract
- We studied the nature of the relationship between bone mineral density (BMD) and the risk of death among elderly men. BMD was associated with mortality risk and was independent of adjustments for other co-morbidities. A piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD (p = 0.020). Low BMD was associated with a substantial excess risk of death, whilst a higher than average BMD had little impact on mortality. Previous studies have demonstrated an association between low BMD and an increased risk of death among men and women. The aim of the present study was to examine the pattern of the risk in men and its relation to co-morbidities. We studied the nature of the relationship between BMD and death among 3,014 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health questionnaires, life style questionnaires and BMD measured using DXA. Men were followed for up to 6.5 years (average 4.5 years). Poisson regression was used to investigate the relationship between BMD, co-morbidities and the hazard function of death. During follow-up, 382 men died (all-cause mortality). Low BMD at all measured skeletal sites was associated with increased mortality. In multivariate analyses, the relationship between BMD and mortality was non-linear, and a piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD (p = 0.020). Low BMD is associated with a substantial excess risk of death compared to an average BMD, whereas a higher than average BMD has a more modest effect on mortality. These findings, if confirmed elsewhere, have implications for the constructing of probability-based fracture risk assessment tools.
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| 8. |
- Johansson, Helena, 1981, et al.
(författare)
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Low risk for hip fracture and high risk for hip arthroplasty due to osteoarthritis among Swedish farmers
- 2018
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 29:3, s. 741-749
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to study the risk of hip fracture and risk of hip arthroplasty among farmers in Sweden. Our results indicate that farming, representing an occupation with high physical activity, in men is associated with a lower risk of hip fracture but an increased risk of hip arthroplasty. Introduction The risks of hip fracture and hip arthroplasty are influenced by factors including socioeconomic status, education, urbanization, latitude of residence, and physical activity. Farming is an occupation encompassing rural living and high level of physical activity. Therefore, we aimed to study the risk of hip fracture and risk of hip arthroplasty among farmers in Sweden. Methods We studied the risk of hip fracture, and hip arthroplasty due to primary osteoarthritis, in all men and women aged 35 years or more in Sweden between 1987 and 2002. Documented occupations were available in 3.5 million individuals, of whom 97,136 were farmers. The effects of age, sex, income, education, location of residence, and occupation on risk of hip fracture or hip arthroplasty were examined using a modification of Poisson regression. Results A total of 4027 farmers and 93,109 individuals with other occupations sustained a hip fracture, while 5349 farmers and 63,473 others underwent a hip arthroplasty. Risk of hip fracture was higher with greater age, lower income, lower education, higher latitude, and urban area for all men and women. Compared to all other occupations, male farmers had a 20% lower age-adjusted risk of hip fracture (hazard ratio (HR) 0.80, 95% CI 0.77-0.84), an effect that was not seen in female farmers (HR 0.96, 95% CI 0.91-1.01). Both male and female farmers had a higher age-adjusted risk for hip arthroplasty. Conclusions Our results indicate that farming, representing an occupation with high physical activity, in men is associated with a lower risk of hip fracture but an increased risk of hip arthroplasty.
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| 9. |
- Johansson, Helena, 1981, et al.
(författare)
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Low serum vitamin D is associated with increased mortality in elderly men: MrOS Sweden
- 2012
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 23:3, s. 991-999
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Tidskriftsartikel (refereegranskat)abstract
- In elderly man, low serum 25-hydroxyvitamin D (25(OH)D) was associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l, but the association attenuated with time. The aim of the present study was to determine whether poor vitamin D status was associated with an increase in the risk of death in elderly men. We studied the relationship between serum 25(OH)D and the risk of death in 2,878 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health and lifestyle measures and serum 25(OH)D measured by competitive RIA. Men were followed for up to 8.2 years (average 6.0 years). Mortality adjusted for comorbidities decreased by 5% for each SD increase in 25(OH)D overall (gradient of risk 1.05; 95% confidence interval 0.96-1.14). The predictive value of 25(OH)D for death was greatest below a threshold value of 50-70 nmol/l, was greatest at approximately 3 years after baseline and thereafter decreased with time. Low serum 25(OH)D is associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l, but the association attenuates with time. These findings, if causally related, have important implications for intervention in elderly men.
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| 10. |
- Johansson, Helena, 1981, et al.
(författare)
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Waning predictive value of serum adiponectin for fracture risk in elderly men: MrOS Sweden
- 2014
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 25:7, s. 1831-1836
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Tidskriftsartikel (refereegranskat)abstract
- Serum adiponectin is a risk factor for fracture. The predictive value attenuates with time in elderly men so that its use for the risk assessment in the long term is questionable. The study underlines the importance of testing the long-term stability of potential risk factors. High serum adiponectin is associated with an increased risk of fracture in elderly men. The aim of the present study was to determine the impact of adiponectin on the probability of fracture as a function of time. The probability of osteoporotic fracture was computed in 989 elderly men from the MrOS study in Sweden. Baseline data included clinical risk factors for fracture, femoral neck BMD and serum adiponectin. Men were followed for up to 7.4 years with a mean follow up of 5.3 years (range 0.0-7.4 years). Poisson regression was used to model the hazard function for osteoporotic fracture and death to determine the 10 year probability of fracture. During follow up, 124 men sustained one or more osteoporotic fracture. There was a significant interaction between adiponectin and time since baseline (p = 0.026) such that the longer time since baseline, the lower the gradient of fracture risk. When using this interaction in the calculation of 10-year probability of fracture, the probabilities of osteoporotic fracture varied little over the range of adiponectin values. Serum adiponectin is a risk factor for fracture. Nevertheless, the predictive value attenuates with time so that its use for the risk assessment in the long term is questionable. This study underlines the importance of testing the long-term stability of potential risk factors that might be used in fracture risk assessment.
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