| 1. |
- 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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| 2. |
- Johansson, Lena, 1972, et al.
(författare)
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Improved fracture risk prediction by adding VFA-identified vertebral fracture data to BMD by DXA and clinical risk factors used in FRAX
- 2022
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 33:8, s. 1725-1738
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Tidskriftsartikel (refereegranskat)abstract
- Vertebral fracture (VF) is a strong predictor of subsequent fracture. In this study of older women, VF, identified by dual-energy X-ray absorptiometry (DXA) vertebral fracture assessment (VFA), were associated with an increased risk of incident fractures and had a substantial impact on fracture probability, supporting the utility of VFA in clinical practice. Purpose Clinical and occult VF can be identified using VFA with dual-energy X-ray absorptiometry (DXA). The aim of this study was to investigate to what extent VFA-identified VF improve fracture risk prediction, independently of bone mineral density (BMD) and clinical risk factors used in FRAX. Methods A total of 2852 women, 75-80 years old, from the prospective population-based study SUPERB cohort, were included in this study. At baseline, BMD was measured by DXA, VF diagnosed by VFA, and questionnaires used to collect data on risk factors for fractures. Incident fractures were captured by X-ray records or by diagnosis codes. An extension of Poisson regression was used to estimate the association between VFA-identified VF and the risk of fracture and the 5- and 10-year probability of major osteoporotic fracture (MOF) was calculated from the hazard functions for fracture and death. Results During a median follow-up of 5.15 years (IQR 4.3-5.9 years), the number of women who died or suffered a MOF, clinical VF, or hip fracture was 229, 422, 160, and 124, respectively. A VFA-identified VF was associated with an increased risk of incident MOF (hazard ratio [HR] = 1.78; 95% confidence interval [CI] 1.46-2.18), clinical VF (HR = 2.88; 95% [CI] 2.11-3.93), and hip fracture (HR = 1.67; 95% [CI] 1.15-2.42), adjusted for age, height, and weight. For women at age 75 years, a VFA-identified VF was associated with 1.2-1.4-fold greater 10-year MOF probability compared with not taking VFA into account, depending on BMD. Conclusion Identifying an occult VF using VFA has a substantial impact on fracture probability, indicating that VFA is an efficient method to improve fracture prediction in older women.
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| 3. |
- Kanis, J. A., et al.
(författare)
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A decade of FRAX: how has it changed the management of osteoporosis?
- 2020
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Ingår i: Aging Clinical and Experimental Research. - : Springer Science and Business Media LLC. - 1594-0667 .- 1720-8319. ; 32:2, s. 187-196
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Tidskriftsartikel (refereegranskat)abstract
- The fracture risk assessment tool, FRAX(R), was released in 2008 and provides country-specific algorithms for estimating individualized 10-year probability of hip and major osteoporotic fracture (hip, clinical spine, distal forearm, and proximal humerus). Since its release, 71 models have been made available for 66 countries covering more than 80% of the world population. The website receives approximately 3 million visits annually. Following independent validation, FRAX has been incorporated into more than 80 guidelines worldwide. The application of FRAX in assessment guidelines has been heterogeneous with the adoption of several different approaches in setting intervention thresholds. Whereas most guidelines adopt a case-finding strategy, the case for FRAX-based community screening in the elderly is increasing. The relationship between FRAX and efficacy of intervention has been explored and is expected to influence treatment guidelines in the future.
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| 4. |
- Kanis, J. A., et al.
(författare)
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Adjusting conventional FRAX estimates of fracture probability according to the number of prior falls in the preceding year
- 2023
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 34:3, s. 479-487
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Tidskriftsartikel (refereegranskat)abstract
- A Summary A greater propensity to falling is associated with higher fracture risk. This study provides adjustments to FRAX-based fracture probabilities accounting for the number of prior falls. Introduction Prior falls increase subsequent fracture risk but are not currently directly included in the FRAX tool. The aim of this study was to quantify the effect of the number of prior falls on the 10-year probability of fracture determined with FRAX (R). Methods We studied 21,116 women and men age 40 years or older (mean age 65.7 +/- 10.1 years) with fracture probability assessment (FRAX (R)), self-reported falls for the previous year, and subsequent fracture outcomes in a registry-based cohort. The risks of death, hip fracture, and non-hip major osteoporotic fracture (MOF-NH) were determined by Cox proportional hazards regression for fall number category versus the whole population (i.e., an average number of falls). Ten-year probabilities of hip fracture and major osteoporotic fracture (MOF) were determined according to the number of falls from the hazards of death and fracture incorporated into the FRAX model for the UK. The probability ratios (number of falls vs. average number of falls) provided adjustments to conventional FRAX estimates of fracture probability according to the number of falls. Results Compared with the average number of falls, the hazard ratios for hip fracture, MOF-NH and death were lower than unity in the absence of a fall history. Hazard ratios increased progressively with an increasing number of reported falls. The probability ratio rose progressively as the number of reported falls increased. Probability ratios decreased with age, an effect that was more marked the greater the number of prior falls. Conclusion The probability ratios provide adjustments to conventional FRAX estimates of fracture probability according to the number of prior falls.
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| 5. |
- Kanis, J A, et al.
(författare)
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Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.
- 2023
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Ingår i: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. - : Springer Nature. - 1433-2965 .- 0937-941X. ; 34:12, s. 2027-2045
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Tidskriftsartikel (refereegranskat)abstract
- 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.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).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 β-coefficients.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.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.
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| 6. |
- Kanis, J. A., et al.
(författare)
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The use of 2-, 5-, and 10-year probabilities to characterize fracture risk after a recent sentinel fracture
- 2021
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 32, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Leslie, W. D., et al.
(författare)
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FRAX Adjustment by Trabecular Bone Score with or Without Bone Mineral Density: The Manitoba BMD Registry
- 2023
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Ingår i: Journal of Clinical Densitometry. - 1094-6950. ; 26:3
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Tidskriftsartikel (refereegranskat)abstract
- Trabecular bone score (TBS), a texture measure derived from spine dual-energy x-ray absorptiometry (DXA) images, is a FRAX & REG;-independent risk factor for fracture. The TBS adjustment to FRAX assumes the presence of femoral neck BMD in the calculation. However, there are many individuals in whom hip DXA cannot be acquired. Whether the TBS-adjustment would apply to FRAX probabilities calculated without BMD has not been studied. The current analysis was performed to evaluate major osteoporotic fracture (MOF) and hip fracture risk adjusted for FRAX with and without femoral neck BMD. The study cohort consisted of 71,209 individuals (89.8% female, mean age 64.0 years). During mean follow-up 8.7 years, 6743 (9.5%) individuals sustained one or more incident MOF, of which 2037 (2.9%) sustained a hip fracture. Lower TBS was significantly associated with increased fracture risk when adjusted for FRAX probabilities, with a slightly larger effect when BMD was not included. Inclusion of TBS in the risk calculation gave a small but significant increase in stratification for fracture probabilities estimated with and without BMD. Calibration plots showed very minor deviations from the line of identity, indicating overall good calibration. In conclusion, the existing equations for incorporating TBS in FRAX estimates of fracture probability work similarly when femoral neck BMD is not used in the calculation. This potentially extends the range of situations where TBS can be used clinically to those individuals in whom lumbar spine TBS is available but femoral neck BMD is not available.
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| 8. |
- Lu, T. Y., et al.
(författare)
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Improved prediction of fracture risk leveraging a genome-wide polygenic risk score
- 2021
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction. Methods We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors. Results A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072. Conclusions We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
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| 9. |
- McCloskey, E. V., et al.
(författare)
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Fracture risk assessment by the FRAX model
- 2022
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Ingår i: Climacteric. - : Informa UK Limited. - 1369-7137 .- 1473-0804. ; 25:1, s. 22-28
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Tidskriftsartikel (refereegranskat)abstract
- The introduction of the 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 bone mineral density. Since age-specific rates of fracture and death differ across the world, FRAX models are calibrated with regard to the epidemiology of hip fracture (preferably from national sources) and mortality (usually United Nations sources). Models are currently available for 73 nations or territories covering more than 80% of the world population. FRAX has been incorporated into more than 80 guidelines worldwide, although the nature of this application has been heterogeneous. The limitations of FRAX have been extensively reviewed. Arithmetic procedures have been proposed in order to address some of these limitations, which can be applied to conventional FRAX estimates to accommodate knowledge of dose exposure to glucocorticoids, concurrent data on lumbar spine bone mineral density, information on trabecular bone score, hip axis length, falls history, type 2 diabetes, immigration status and recency of prior fracture.
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| 10. |
- Vandenput, L., et al.
(författare)
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A meta-analysis of previous falls and subsequent fracture risk in cohort studies
- 2024
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Ingår i: Osteoporosis International. - : Springer Nature. - 0937-941X .- 1433-2965. ; 35:3, s. 469-494
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Tidskriftsartikel (refereegranskat)abstract
- Summary: The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Introduction: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). Methods: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. Results: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51) and men (HR 1.53, 95% CI 1.41–1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27–1.84) in men vs. HR 1.32 (95% CI 1.20–1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. Conclusions: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.
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