Hip and fragility fracture prediction by 4-item clinical risk score and mobile heel BMD: a women cohort study

<p>Abstract</p> <p>Background</p> <p>One in four Swedish women suffers a hip fracture yielding high morbidity and mortality. We wanted to revalidate a 4-item clinical risk score and evaluate a portable heel bone mineral density (BMD) technique regarding hip and fragility fracture risk among elderly women.</p> <p>Methods</p> <p>In a population-based prospective cohort study we used clinical risk factors from a baseline questionnaire and heel BMD to predict a two-year hip and fragility fracture outcome for women, in a fracture preventive program. Calcaneal heel BMD was measured by portable dual X-ray laser absorptiometry (DXL) and compared to hip BMD, measured with stationary dual X-ray absorptiometry (DXA) technique.</p> <p>Results</p> <p>Seven women suffered hip fracture and 14 women fragility fracture/s (at hip, radius, humerus and pelvis) among 285 women; 60% having heel BMD ≤ -2.5 SD. The 4-item FRAMO (Fracture and Mortality) Index combined the clinical risk factors age ≥80 years, weight <60 kg, prior fragility fracture, and impaired rise-up ability. Women having 2-4 risk factors showed odds ratio (OR) for hip fracture of 5.9 and fragility fracture of 4.4. High risk group hip fracture risk was 2.8% annually compared to 0.5% for the low risk majority (69%). Heel BMD showed hip fracture OR of 3.1 and fragility fracture OR of 2.6 per SD decrease. For 30 DXA assessed participants mean hip BMD at -2.5 SD level corresponded to a lower BMD at the heel. Five of seven hip fractures occurred within a small risk group of 32 women, identified by high FRAMO Index + prior fragility fracture + heel T-score ≤-3.5 SD.</p> <p>Conclusions</p> <p>In a follow-up study we identified high risk groups for hip and fragility fracture with our plain 4-item risk model. Increased fracture risk was also related to decreasing heel BMD in calcaneal bone, measured with a mobile DXL technique. A combination of high FRAMO Index, prior fragility fracture, and very low BMD restricted the high risk group to 11%, among whom most hip fractures occurred (71%). These practical screening methods could eventually reduce hip fracture incidence by concentrating preventive resources to high fracture risk women.</p

Young adult male patients with childhood-onset IBD have increased risks of compromised cortical and trabecular bone microstructures

Background Young adults with childhood-onset inflammatory bowel disease (IBD) have increased risks of low areal bone mineral density and low skeletal muscle mass. Volumetric BMD (vBMD), bone geometry and microstructures, in addition to possible associations with skeletal muscle index (SMI) and physical exercise have been scarcely studied in this patient group. Patients and methods In total, 49 young adult male patients with childhood-onset IBD and 245 age- and height-matched young adult male controls were scanned with high-resolution peripheral quantitative computed tomography. Bone geometry, vBMD, and bone microstructures were calculated as median values and compared between the patients and controls. Multivariable linear regression analyses were performed to determine the independent associations among IBD diagnosis, SMI (kg/m2), and physical exercise. Results The group of young adult patients had, in comparison with the controls, significantly smaller median cortical area (126.1 mm2 vs151.1 mm2, P < .001), lower median total vBMD (296.7 mg/cm3 vs 336.7 mg/cm3, P < .001), and lower median cortical vBMD (854.4 mg/cm3 vs 878.5 mg/cm3, P < .001). Furthermore, the patients compared with the controls had lower median trabecular volume fraction (16.8% vs 18.2%, P < .001) and thinner median trabeculae (0.084 mm vs 0.089 mm, P < .001). The differences between the patients with IBD and controls persisted in multivariable analyses that included adjustments for SMI and physical exercise. Conclusions Young adult men with childhood-onset IBD are at increased risk of having reduced bone quality in both the cortical and trabecular bone structures compared with normative matched controls

Extensive undertreatment of osteoporosis in older Swedish women

Summary In a population-based study of older Swedish women, we investigated the proportion of women treated with osteoporosis medication in relation to the proportion of women eligible for treatment according to national guidelines. We found that only a minority (22%) of those eligible for treatment were prescribed osteoporosis medication. Introduction Fracture rates increase markedly in old age and the incidence of hip fracture in Swedish women is among the highest in the world. Although effective pharmacological treatment is available, treatment rates remain low. Limited data are available regarding treatment rates in relation to fracture risk in a population-based setting in older women. Therefore, we aimed to investigate the proportion of older women eligible for treatment according to Swedish Osteoporosis Society (SvOS) guidelines. Methods A population-based study was performed in Gothenburg in 3028 older women (77.8 ± 1.6 years [mean ± SD]). Bone mineral density of the spine and hip was measured with dual-energy X-ray absorptiometry. Clinical risk factors for fracture and data regarding osteoporosis medication was collected with self-administered questionnaires. Logistic regression was used to evaluate whether the 10-year probability of sustaining a major osteoporotic fracture (FRAX-score) or its components predicted treatment with osteoporosis medication. Results For the 2983 women with complete data, 1107 (37%) women were eligible for treatment using SvOS criteria. The proportion of these women receiving treatment was 21.8%. For women eligible for treatment according to SvOS guidelines, strong predictors for receiving osteoporosis medication were glucocorticoid treatment (odds ratio (95% CI) 2.88 (1.80–4.59)) and prior fracture (2.58 (1.84–3.61)). Conclusion This study demonstrates that a substantial proportion of older Swedish women should be considered for osteoporosis medication given their high fracture risk, but that only a minority receives treatment

Low Serum Levels of Dehydroepiandrosterone Sulfate Predict All-Cause and Cardiovascular Mortality in Elderly Swedish Men.

Context: The age-related decline in dehydroepiandrosterone (DHEA) levels is thought to be of importance for general and vascular aging. However, data on the association between DHEA and mortality are conflicting. Objectives: We tested the hypothesis that low serum DHEA and DHEA sulfate (DHEA-S) levels predict all-cause and cardiovascular disease (CVD) death in elderly men. Design, Setting, and Participants: We used gas/liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based MrOS Sweden study (2644 men, aged 69-81 yr). Mortality data were obtained from central registers and analyzed using Cox proportional hazards regressions. Main Outcome Measures: All-cause and CVD mortality by serum DHEA(-S) levels. Results: During a mean 4.5-yr follow-up, 328 deaths occurred. Low levels of DHEA-S (quartile 1 vs. quartiles 2-4), predicted death from all causes [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.21-1.96; adjusted for traditional cardiovascular risk factors], from CVD (n = 123 deaths; HR 1.61, 95% CI 1.10-2.37) and ischemic heart disease (n = 73; HR 1.67, 95% CI 1.02-2.74) but not cancer. Analyses with DHEA gave similar results. The association between low DHEA-S and CVD death remained after adjustment for C-reactive protein and circulating estradiol and testosterone levels. When stratified by the median age of 75.4 yr, the mortality prediction by low DHEA-S was more pronounced among younger (age adjusted HR for CVD death 2.64, 95% CI 1.37-5.09) than older men (HR 1.30, 95% CI 0.83-2.04). Conclusions: Low serum levels of DHEA(-S) predict death from all causes, CVD, and ischemic heart disease in older men

Evidence for Geographical and Racial Variation in Serum Sex Steroid Levels in Older Men.

Background: Despite considerable racial and geographical differences in human phenotypes and in the incidence of diseases that may be associated with sex steroid action, there are few data concerning variation in sex steroid levels among populations. We designed an international study to determine the degree to which geography and race influence sex steroid levels in older men. Methods: Using mass spectrometry, concentrations of serum androgens, estrogens, and sex steroid precursors/metabolites were measured in 5003 older men from five countries. SHBG levels were assessed using radioimmunoassay. Results: There was substantial geographical variation in the levels of sex steroids, precursors, and metabolites, as well as SHBG. For instance, Asian men in Hong Kong and Japan, but not in the United States, had levels of total testosterone approximately 20% higher than in other groups. Even greater variation was present in levels of estradiol, SHBG, and dihydrotestosterone. Group differences in body mass index did not explain most geographical differences. In addition, body mass index-independent racial differences were present; Black men had higher levels of estrogens (estradiol, estrone), and Asian men had lower levels of glucuronidated androgen metabolites. Conclusions: On a global scale, there are important geographical and racial differences in the concentrations of serum sex steroids and SHBG in older men

Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the RANKL Locus and Potential Pleiotropic Effects on Bone

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMDC associations that had p<1×10−5 in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2×10−14, n = 5739). Each minor allele was associated with a decrease in BMDC of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males −6.77mg/cm3 per C allele, p = 2×10−6; females −2.79 mg/cm3 per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

CONTEXT: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. OBJECTIVE: To investigate the genetic regulation of serum E2 and E1 in men. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. MAIN OUTCOME MEASURES: Genetic determinants of serum E2 and E1 levels. RESULTS: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. CONCLUSIONS: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1

Tissue Effect on Genetic Control of Transcript Isoform Variation

Current genome-wide association studies (GWAS) are moving towards the use of large cohorts of primary cell lines to study a disease of interest and to assign biological relevance to the genetic signals identified. Here, we use a panel of human osteoblasts (HObs) to carry out a transcriptomic survey, similar to recent studies in lymphoblastoid cell lines (LCLs). The distinct nature of HObs and LCLs is reflected by the preferential grouping of cell type–specific genes within biologically and functionally relevant pathways unique to each tissue type. We performed cis-association analysis with SNP genotypes to identify genetic variations of transcript isoforms, and our analysis indicates that differential expression of transcript isoforms in HObs is also partly controlled by cis-regulatory genetic variants. These isoforms are regulated by genetic variants in both a tissue-specific and tissue-independent fashion, and these associations have been confirmed by RT–PCR validation. Our study suggests that multiple transcript isoforms are often present in both tissues and that genetic control may affect the relative expression of one isoform to another, rather than having an all-or-none effect. Examination of the top SNPs from a GWAS of bone mineral density show overlap with probeset associations observed in this study. The top hit corresponding to the FAM118A gene was tested for association studies in two additional clinical studies, revealing a novel transcript isoform variant. Our approach to examining transcriptome variation in multiple tissue types is useful for detecting the proportion of genetic variation common to different cell types and for the identification of cell-specific isoform variants that may be functionally relevant, an important follow-up step for GWAS

Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis

CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing