| 1. |
- 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. - : Springer Science and Business Media LLC. - 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.
|
|
| 2. |
- Keyak, J. H., et al.
(författare)
-
Effect of finite element model loading condition on fracture risk assessment in men and women: The AGES-Reykjavik study
- 2013
-
Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 57:1, s. 18-29
-
Tidskriftsartikel (refereegranskat)abstract
- Proximal femoral (hip) strength computed by subject-specific CT scan-based finite element (FE) models has been explored as an improved measure for identifying subjects at risk of hip fracture. However, to our knowledge, no published study has reported the effect of loading condition on the association between incident hip fracture and hip strength. In the present study, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort Baseline (pre-fracture) quantitative CT (QCT) scans of 5500 older male and female subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as controls from a pool of age- and sex-matched subjects. From the QCT data, FE models employing nonlinear material properties computed FE-strength of the left hip of each subject in loading from a fall onto the posterolateral (F-PL), posterior (F-P) and lateral (F-L) aspects of the greater trochanter (patent pending). For comparison, FE strength in stance loading (F-Stance) and total femur areal bone mineral density (aBMD) were also computed. For all loading conditions, the reductions in strength associated with fracture in men were more than twice those in women (p <= 0.01). For fall loading specifically, posterolateral loading in men and posterior loading in women were most strongly associated with incident hip fracture. After adjusting for aBMD, the association between F-P and fracture in women fell short of statistical significance (p = 0.08), indicating that FE strength provides little advantage over aBMD for identifying female hip fracture subjects. However, in men, after controlling for aBMD, F-PL was 424 N (11%) less in subjects with fractures than in controls (p = 0.003). Thus, in men, FE models of posterolateral loading include information about incident hip fracture beyond that in aBMD. (c) 2013 Elsevier Inc. All rights reserved.
|
|
| 3. |
- Keyak, J. H., et al.
(författare)
-
Male-female differences in the association between incident hip fracture and proximal femoral strength: A finite element analysis study
- 2011
-
Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 48:6, s. 1239-1245
-
Tidskriftsartikel (refereegranskat)abstract
- Hip fracture risk is usually evaluated using dual energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) which provide surrogate measures for proximal femoral strength. However, proximal femoral strength can best be estimated explicitly by combining QCT with finite element (FE) analysis. To evaluate this technique for predicting hip fracture in older men and women, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) QCT scans of 5500 subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as age- and sex-matched controls. FE-strength of the left hip of each subject for stance (F-Stance) and posterolateral fall (F-Fall) loading, and total femur areal bone mineral density (aBMD) were computed from the QCT data. F-Stance and F-Fall in incident hip fracture subjects were 13%-25% less than in control subjects (p <= 0.006) after controlling for demographic parameters. The difference between FE strengths of fracture and control subjects was disproportionately greater ill men (stance, 22%; fall, 25%) than in women (stance, 13%; fall, 18%) (p <= 0.033), considering that Fstar,ce and FFall in fracture subjects were greater in men than in women ( p < 0.001). For men, F-Stance was associated with hip fracture after accounting for aBMD (p = 0.013). These data indicate that F-Stance provides information about fracture risk that is beyond that provided by aBMD (p = 0.013). These findings support further exploration of possible sex differences in the predictors of hip fracture and of sex-specific strategies for using FE analysis to manage osteoporosis. (C) 2011 Elsevier Inc. All rights reserved.
|
|
| 4. |
- Lang, T. F., et al.
(författare)
-
Age-related loss of proximal femoral strength in elderly men and women: The Age Gene/Environment Susceptibility Study - Reykjavik
- 2012
-
Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 50:3, s. 743-748
-
Tidskriftsartikel (refereegranskat)abstract
- The risk of hip fracture rises rapidly with age, and is particularly high in women. This increase in fracture risk reflects both the age-related change in the risk of falling and decrements in the strength of the proximal femur. To better understand the extent to which proximal femoral density, structure and strength change with age as a function of gender, we have carried out a longitudinal analysis of proximal femoral volumetric quantitative computed tomographic (vQCT) images in men and women, analyzing changes in trabecular and cortical bone properties, and using subject-specific finite element modeling (FEM) to estimate changes in bone strength. In the AGES-Reykjavik Study vQCT scans of the hip were performed at a baseline visit in 2002-2006 and at a second visit 5.05 +/- 0.25 years later. From these, 223 subjects (111 men, 112 women, aged 68-87 years) were randomly selected. The subjects were evaluated for longitudinal changes in three bone variables assessed in a region similar to the total femur region quantified by DXA: areal bone mineral density (aBMD), trabecular volumetric bone mineral density (tBMD) and the ratio of cortical to total tissue volume (cvol/ivol). They were also evaluated for changes in bone strength using FEM models of the left proximal femur. Models were analyzed under single-limb stance loading (F-Stance), which approximates normal physiologic loading of the hip, as well as a load approximating a fall onto the posterolateral aspect of the greater trochanter (F-Fall). We computed five-year absolute and percentage changes in aBmD, tBMD, cvol/ivol, F-Fall and F-Stance. The Mann-Whitney Test was employed to compare changes in bone variables between genders and the Wilcoxon Signed Rank Test was used to compare changes in bone strength between loading conditions. Multiple (linear) regression was employed to determine the association of changes in F-Fall and F-Stance with baseline age and five-year weight loss. Both men and women showed declines in indices of proximal femoral density and structure (aBMD: men -3.9 +/- 6.0%, women -6.1 +/- 6.2%; tBMD: men -14.8 +/- 20.3%, women -23.9 +/- 26.8%; cvol/ivol: men -2.6 +/- 4.6%, women -4.7 +/- 4.8%, gender difference: p<0.001). Both men and women lost bone strength in each loading condition (F-Stance: men -4.2 +/- 9.9%, women -8.3 +/- 8.5%; F-Fall: men -7.0 +/- 15.7%, women -12.8 +/- 13.2%; all changes from baseline p<0.0001). The gender difference in bone strength loss was statistically significant in both loading conditions (p<0.001 for F-Stance and P<0.01 for F-Fall) and F-Fall, was lost at a higher rate than F-Stance in men (p<0.01) and women (p<0.0001). The gender difference in strength loss was statistically significant after adjustment for baseline age and weight loss in both loading conditions (p<0.01). In these multi-linear models, men showed increasing rates of bone loss with increasing age (F-Fall: p=0.002; F-Stance; p=0.03), and women showed increasing bone strength loss with higher degrees of weight loss (F-Stance: p=0.003). The higher loss of F-Fall compared to F-Stance supports previous findings in animal and human studies that the sub-volumes of bone stressed under normal physiologic loading are relatively better protected in aging. The gender difference in hip bone strength loss is consistent with the higher incidence of hip fractureamong elderly women. (C) 2011 Elsevier Inc. All rights reserved.
|
|
| 5. |
- Moayyeri, Alireza, et al.
(författare)
-
Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
-
Tidskriftsartikel (refereegranskat)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
|
|
| 6. |
- Siggeirsdottir, K., et al.
(författare)
-
Epidemiology of fractures in Iceland and secular trends in major osteoporotic fractures 1989-2008
- 2014
-
Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 25:1, s. 211-219
-
Tidskriftsartikel (refereegranskat)abstract
- The incidence of the most common fracture types in Iceland is reported based on individual data from the Reykjavik Study 1967-2008. Time trend is reported for the major osteoporotic fractures (MOS) 1989-2008. This study aims to assess the incidence of all fractures in Iceland, with emphasis on the rate of hip fractures, and compare the incidence with other populations as well as examine the secular changes. Individuals from the prospective population-based cohort Reykjavik Study were examined between 1967 and 2008 (follow-up 26.5 years), which consisted of 9,116 men and 9,756 women born in 1907-1935, with age range 31-81 years. First fracture incidence was estimated using life table methods with age as the timescale. Fracture rate increased proportionally with age between the sexes for vertebral and proximal humerus but disproportionally for hip and distal forearm fractures. The ratio of first fracture incidence between the sexes varied considerably by site: 2.65 for hip fractures and the highest for distal forearm fractures at 4.83. By the age of 75, 36.7 % of women and 21 % of men had sustained a fracture, taking into account competing risk of death. The incidence of hip fractures was similar to results previously published from USA, Sweden, Norway, and Scotland. The incidence of MOS fractures in both sexes decreased over the last decade, except hip fractures in men, which remained unchanged, as reflected in the women/men ratio for the hip, which changed from 2.6 to 1.7. This study adds information to scarce knowledge on the relative fracture incidence of different fractures. The incidence of MOS fractures increased in the latter part of the last century in both sexes and declined during the last decade, less dramatically for men. This information is important for planning health resources.
|
|
| 7. |
- Siggeirsdottir, K., et al.
(författare)
-
The incidence of a first major osteoporotic fracture in Iceland and implications for FRAX
- 2014
-
Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 25:10, s. 2445-2451
-
Tidskriftsartikel (refereegranskat)abstract
- Based on an extensive cohort study over 25 years, the present study supports the assumption that major osteoporotic fractures can be reasonably predicted from hip fracture rates. The construct for FRAX models depends on algorithms to adjust for double counting of fracture outcomes in some models and in others, to estimate the incidence of a major fracture from hip fracture rates. The aim of the present study was to test the validity of these algorithms in a large prospective cohort. The incidence of hip, clinical spine, distal forearm, and humerus fracture was determined in the prospective and ongoing population-based Reykjavik Study with follow up of 257,001 person-years. The incidence of a first major fracture was compared with the correction factors used in FRAX to adjust the incidence of several fracture outcomes for double counting. In addition, the incidence of a major osteoporotic fracture estimated from the Icelandic hip fracture rates was compared with the Malmo ratios used in FRAX. The adjustments necessary to account for multiple fracture outcomes were similar to those previously derived from Sweden. Additionally, incidence of a first major osteoporotic fracture was similar to that derived for FRAX models. The findings of the present study support the algorithms used in FRAX to estimate the incidence of a first major fracture and the predictive value of hip fracture for other major fractures.
|
|
