Validation of a genome-wide polygenic score in improving fracture risk assessment beyond the FRAX tool in the Women's Health Initiative study.

BACKGROUND: Previous study has established two polygenic scores (PGSs) related to femoral neck bone mineral density (BMD) (PGS_FNBMDldpred) and total body BMD (PGS_TBBMDldpred) that are associated with fracture risk. However, these findings have not yet been externally validated in an independent cohort. OBJECTIVES: This study aimed to validate the predictive performance of the two established PGSs and to investigate whether adding PGSs to the Fracture Risk Assessment Tool (FRAX) improves the predictive ability of FRAX in identifying women at high risk of major osteoporotic fracture (MOF) and hip fractures (HF). METHODS: The study used the Women's Health Initiative (WHI) cohort of 9,000 postmenopausal women of European ancestry. Cox Proportional Hazard Models were used to assess the association between each PGS and MOF/HF risk. Four models were formulated to investigate the effect of adding PGSs to the FRAX risk factors: (1) Base model: FRAX risk factors; (2) Base model + PGS_FNBMDldpred; (3) Base model + PGS_TBBMDldpred; (4) Base model + metaPGS. The reclassification ability of models with PGS was further assessed using the Net Reclassification Improvement (NRI) and the Integrated discrimination improvement (IDI). RESULTS: The study found that the PGSs were not significantly associated with MOF or HF after adjusting for FRAX risk factors. The FRAX base model showed moderate discrimination of MOF and HF, with a C-index of 0.623 (95% CI, 0.609 to 0.641) and 0.702 (95% CI, 0.609 to 0.718), respectively. Adding PGSs to the base FRAX model did not improve the ability to discriminate MOF or HF. Reclassification analysis showed that compared to the model without PGS, the model with PGS_TBBMDldpred (1.2%, p = 0.04) and metaPGS (1.7%, p = 0.05) improve the reclassification of HF, but not MOF. CONCLUSIONS: The findings suggested that incorporating genetic information into the FRAX tool has minimal improvement in predicting HF risk for elderly Caucasian women. These results highlight the need for further research to identify other factors that may contribute to fracture risk in elderly Caucasian women.

Bone mineral density, vitamin D receptor (VDR) gene polymorphisms, fracture risk assessment (FRAX), and trabecular bone score (TBS) in rheumatoid arthritis patients: connecting pieces of the puzzle.

PURPOSE: To assess vitamin D receptor (VDR) gene polymorphisms and bone mineral density and to investigate the possible risk factors of osteoporosis and fracture in rheumatoid arthritis (RA). METHODS: A total of 97 RA patients and 45 matched controls were enrolled. Serum vitamin D level, VDR genotyping, dual-energy X-ray absorptiometry (DEXA) scan, trabecular bone score (TBS), and fracture risk assessment (FRAX) in 10 years were assessed. Disease activity score (DAS28) and modified health assessment questionnaire (MHAQ) were measured. RESULTS: The mean age of the patients was 47.9 ± 8.9 years; 85 females, 12 males (F:M 7.1:1) and mean disease duration 9.4 ± 6.2 years. DAS28 was 4.52 ± 1.04 and MHAQ 0.6 ± 0.4. There was a significant difference between cases and controls as regards DEXA and FRAX (p < 0.0001) but the TBS and VDR genotyping were comparable (p = 0.29 and p = 0.12, respectively). The vitamin D level was comparable with the control (9.3 ± 6.5 vs 10.4 ± 7.5 ng/mL, p = 0.4). None of the patients was receiving anti-osteoporotic therapy or biologic therapy. There was a significant association between the presence of osteoporosis and age, disease duration, menopause, and rheumatoid factor (RF) positivity. The TBS was significantly lower and FRAX higher in patients with positive RF and anti-CCP. FRAX was significantly related and the TBS inversely with the age, disease duration, serum uric acid, alkaline phosphatase, and MHAQ. CONCLUSIONS: Reduced BMD and increased tendency to fractures are remarkable in RA patients. Vitamin D level was decreased in patients and control, and VDR gene polymorphisms were not linked to RA. TBS and FRAX are effective tools to assess osteoporotic fractures in RA. Key Points • Reduced bone mineral density (BMD) and increased tendency to fractures are remarkable in rheumatoid arthritis (RA) patients. • Vitamin D level was decreased in patients and control, and VDR gene polymorphisms were not linked to RA. • Trabecular bone score (TBS) and fracture risk assessment (FRAX) in 10 years are effective tools to assess osteoporotic fractures in RA.

The Role of the Trabecular Bone Score in the Assessment of Osteoarticular Disorders in Patients with HFE-Hemochromatosis: A Single-Center Study from Poland.

Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of HFE gene mutations, which are associated with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite a properly conducted treatment with phlebotomies. In this study, selected parameters of calcium and phosphate metabolism were analyzed in combination with the assessment of bone mineral density (BMD) disorders in patients from northern Poland with clinically overt HFE-HH. BMD was determined by a dual-energy X-ray absorptiometry (DXA) test with the use of the trabecular bone score (TBS) function. The study included 29 HH patients (mean age = 53.14 years) who were compared with 20 healthy volunteers. A significantly lower TBS parameter and serum 25-OH-D3 concentration, a higher concentration of intact parathormone and more a frequent occurrence of joint pain were found in HH patients compared with the control group. In HH patients, the diagnosis of liver cirrhosis was associated with lower serum 25-OH-D3 and osteocalcin concentrations. In HH, DXA with the TBS option is a valuable tool in the early assessment of the bone microarchitecture and fracture risk. A supplementation of vitamin D, monitoring its concentration, should be considered especially in HH patients with liver damage and liver cirrhosis.

Personalized fracture risk assessment: where are we at?

Introduction: Osteoporotic fracture imposes a significant health care burden globally. Personalized assessment of fracture risk can potentially guide treatment decisions. Over the past decade, a number of risk prediction models, including the Garvan Fracture Risk Calculator (Garvan) and FRAX®, have been developed and implemented in clinical practice. Areas covered: This article reviews recent development and validation results concerning the prognostic performance of the two tools. The main areas of review are the need for personalized fracture risk prediction, purposes of risk prediction, predictive performance in terms of discrimination and calibration, concordance between the Garvan and FRAX tools, genetic profiling for improving predictive performance, and treatment thresholds. In some validation studies, FRAX tended to underestimate fracture by as high as 50%. Studies have shown that the predicted risk from the Garvan tool is highly concordant with clinical decision. Expert opinion: Although there are some discrepancy in fracture risk prediction between Garvan and FRAX, both tools are valid and can aid patients and doctors communicate about risk and make informed decision. The ideal of personalized risk assessment for osteoporosis patients will be realized through the incorporation of genetic profiling into existing fracture risk assessment tools.

Assessment of Wnt pathway selected gene expression levels in peripheral blood mononuclear cells (PBMCs) of postmenopausal patients with low bone mass.

The purpose of the study was to assess the expression of selected genes of the Wnt pathway: APC, AXIN1, CTNNB1, DKK1, GSK3ß, KREMEN1, SFRP1, and WNT1 in peripheral blood mononuclear cells (PBMC) of patients, selected in consideration of their bone mineral density (BMD), and the occurrence of low-energy fractures. The study involved 45 postmenopausal women, divided into four groups, according to BMD and fracture history. Measurements of laboratory parameters and RNA expression in PBMC cells were carried out in material, collected once at the inclusion visit. The densitometric examination was performed on all participants. In the analysis of the relative expression levels (RELs) of the studied genes in the entire population, we observed an overexpression for SFRP1 in 100% of samples and WNT1. In addition, the REL of DKK1, APC, and GSK3ß genes were slightly elevated versus the calibrator. In contrast, CTNNB1 and AXIN1 presented with a slightly decreased RELs. Analysis did not show any significant differences among the groups in the relative gene expression levels (p < 0.05) of particular genes. However, we have observed quite numerous interesting correlations between the expression of the studied genes and BMD, the presence of fractures, and laboratory parameters, both in the whole studied population as well as in selected groups. In conclusion, the high level of CTNNB1 expression maintains normal BMD and/or protects against fractures. It also appears that the changes in expression levels of the Wnt pathway genes in PBMCs reflect the expected changes in bone tissue.

Individualized Assessment of Fracture Risk: Contribution of "Osteogenomic Profile".

Over the past decade, several genetic variants or genes for osteoporosis have been identified through genome-wide association studies and candidate gene association studies. These genetic variants are common in the general population but have modest effect sizes, with odds ratio ranging from 1.1 to 1.5. Thus, the utility of any single variant is limited. However, theoretical and empirical studies have suggested that a profiling of multiple variants that are associated with bone phenotypes (i.e., "osteogenomic profile") can improve the accuracy of fracture prediction and classification beyond that obtained by conventional clinical risk factors. These results support the view that an osteogenomic profile, when integrated into existing models, can help clinicians and patients alike to better assess the risk fracture for an individual, and raise the possibility of personalized osteoporosis care.

Implementation of personalized medicine for fracture risk assessment in osteoporosis.

The present review summarizes our efforts to identify genetic polymorphisms associated with osteoporotic fractures and to establish a genetic risk score (GRS) to predict fracture risk in consecutive Japanese autopsy cases carried out at Tokyo Metropolitan Geriatric Hospital between 1995 and 2011. Three single nucleotide polymorphisms in transforming growth factor ß-1, rs1800470; thrombospondin, type 1, domain-containing 7A, rs12673692; and formiminotransferase N-terminal subdomain-containing gene, rs7605378, showed a significant association with vertebral fracture prevalence, whereas five (α-l-iduronidase, rs3755955; C7orf58, rs190543052; homeobox C4, rs75256744; G patch domain-containing gene 1, rs2287679; and Werner syndrome, rs2230009) were significantly associated with femoral fracture. GRS values were calculated as the sum of risk allele counts (unweighted GRS) or of weighted scores estimated from logistic regression coefficients (weighted GRS). Both GRS values using the five single nucleotide polymorphisms adequately predicted femoral fracture prevalence for 924 male subjects; the areas under receiver-operating characteristic curves were 0.750 (95% confidence interval [CI] 0.660-0.840) and 0.770 (95% CI 0.681-0.859), respectively. Logistic regression analysis showed that the odds ratio for the association between fracture prevalence and unweighted GRS ≥3 (n = 124) was 8.39 (95% CI 4.22-16.69, P < 0.001) relative to GRS < 3 (n = 797). Likewise, the odds ratio for a weighted GRS of 6-15 (n = 135) was 7.73 (95% CI 3.89-15.36, P < 0.001) relative to GRS 0-5 (n = 786). Therefore, the GRS based on the risk allele profiles of these five single nucleotide polymorphisms could help identify at-risk individuals and enable implementation of preventive measures for femoral fracture.

[Investigate progress on risk factors and risk assessment of osteoporotic fractures].

Osteoporotic fracture is the most destructive ending of osteoporosis, many interacting risk factors play a role in its occurrence. With age, the bodies function decline gradually. Symptoms like soreness of the waist, back pain, cramp of the lower limb and weakness appears. These are related to TCM syndrome factors like kidney deficiency, liver deficiency, spleen deficiency and blood stagnation. Symptoms can act as a warning of the occurrence of osteoporotic fracture in the early stages. The risk assessment tool of osteoporotic fracture is mostly developed on the basis of modern risk factors and thus lacks syndrome differentiation, that may limit its utilization. If the relevant content of syndrome differentiation is integrated into the forecasting tool and a risk assessment tool of osteoporotic fracture which complies with the demographics of China is built up, population risk assessment for high of risk could be established and scientific evidence for the adoption of effective interventions could be applied.

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.

BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

An efficient paradigm for genetic epidemiology cohort creation.

Development of novel methodologies to efficiently create large genetic epidemiology cohorts is needed. Here we describe a rapid, precise and cost-efficient method for collection of DNA from cases previously experiencing an osteoporotic fracture by identifying cases using and administrative health-care databases. Over the course of 14 months we collected DNA from 1,130 women experiencing an osteoporotic fracture, at a cost of $54 per sample. This cohort is among the larger DNA osteoporotic fracture collections in the world. The novel method described addresses a major unmet health care research need and is widely applicable to any disease that can be identified accurately through administrative data.