Femoral neck width genetic risk score is a novel independent risk factor for hip fractures.

Femoral neck width (FNW) derived from DXA scans may provide a useful adjunct to hip fracture prediction. Therefore, we investigated whether FNW is related to hip fracture risk independently of femoral neck bone mineral density (FN-BMD), using a genetic approach. FNW was derived from points automatically placed on the proximal femur using hip DXA scans from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank (UKB). Genome-wide association study (GWAS) identified 71 independent genome-wide significant FNW SNPs, comprising genes involved in cartilage differentiation, hedgehog, skeletal development, in contrast to SNPs identified by FN-BMD GWAS which primarily comprised runx1/Wnt signaling genes (MAGMA gene set analyses). FNW and FN-BMD SNPs were used to generate genetic instruments for multivariable Mendelian randomization. Greater genetically determined FNW increased risk of all hip fractures (odds ratio [OR] 1.53; 95% CI, 1.29-1.82 per SD increase) and femoral neck fractures (OR 1.58;1.30-1.92), but not trochanteric or forearm fractures. In contrast, greater genetically determined FN-BMD decreased fracture risk at all 4 sites. FNW and FN-BMD SNPs were also used to generate genetic risk scores (GRSs), which were examined in relation to incident hip fracture in UKB (excluding the FNW GWAS population; n = 338 742, 3222 cases) using a Cox proportional hazards model. FNW GRS was associated with increased risk of all incident hip fractures (HR 1.08;1.05-1.12) and femoral neck fractures (hazard ratio [HR] 1.10;1.06-1.15), but not trochanteric fractures, whereas FN-BMD GRS was associated with reduced risk of all hip fracture types. We conclude that the underlying biology regulating FNW and FN-BMD differs, and that DXA-derived FNW is causally related to hip fractures independently of FN-BMD, adding information beyond FN-BMD for hip fracture prediction. Hence, FNW derived from DXA analyses or a FNW GRS may contribute clinically useful information beyond FN-BMD for hip fracture prediction.

Femoral neck width (FNW) derived from DXA scans may provide useful information about hip fracture prediction, over and above that provided by BMD measurements. Therefore, we investigated whether FNW is related to hip fracture risk independently of BMD, using a genetic approach. FNW was derived from points automatically placed on the hip in DXA scans obtained from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank. Seventy-one distinct genetic factors were found to be associated with FNW. Individuals who were predicted by their genes to have greater FNW had a higher risk of hip but not forearm fractures. In contrast, those with greater genetically determined BMD of the femoral neck had a lower risk of both hip and forearm fractures. We conclude that the underlying biology regulating FNW and BMD of the femoral neck differs, and that FNW derived from DXA analyses may contribute clinically useful information beyond BMD for hip fracture prediction.

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.

Association of LCT -13910C>T polymorphism and hip fracture in a cohort of older adult population from Northern Spain.

Hip fracture is a common health problem very frequent in the older adult population and is associated with significant morbidity, mortality, and societal costs. There are several factors that increase the risk of suffering a hip fracture, however, the effect of genetic lactase non-persistence is not clear-cut yet. For this reason, we investigated if the LCT -13910C>T polymorphism is a potential risk factor for osteoporotic hip fractures in older adult people from the Northern Spain population. A total of 740 individuals were included in this study. Of them, 364 belonged to the group of patients whit osteoporotic hip fracture while the control group consisted of 376 individuals without hip fracture. The genotypes for the LCT -13910C>T polymorphism were analyzed by using polymerase chain reaction and high resolution melting. The prevalence of the CC genotype, which is related to lactase non-persistence, did not differ significantly in both groups. Likewise, no differences were observed between groups when they were compared with regard to the C or the T allele, or when they were analyzed considering gender. Additionally, our results were compared with those obtained in a control group of 207 nonagenarian individuals originally from Northern Spain and no differences were observed. In conclusion, no significant association was observed between the LCT -13910C>T polymorphism and the risk for suffering hip fracture in the older adult population of Northern Spain.

Multiple bilateral hip fractures in a patient with dyskeratosis congenita caused by a novel mutation in the PARN gene.

We report a case of a young male patient with clinical signs of dyskeratosis congenita who presented with multiple bilateral low-traumatic hip fractures. Whole exome sequencing (WES) showed a previously unreported mutation in the poly(A)-specific ribonuclease (PARN) gene. Zoledronic acid 5 mg over 3 years was effective at preventing further fractures. A male patient was referred to our clinic at age 24 due to multiple bilateral hip fractures. At the time of admission, the patient's height was 160 cm and weight 40 kg; bone mineral density (BMD) at the lumbar spine was normal (L1-L4 0.0 Z-score). The patient was found to have abnormal skin pigmentation, hyperkeratosis of palms and soles, nail dystrophy, and signs of bone marrow failure (BMF). Bone fragility first presented at 5 years old with a wrist fracture, followed by multiple bilateral low-traumatic hip fractures without falls from 14 to 24 years. WES showed a previously unreported mutation (NM_002582.3: c.1652delA; p.His551fs) in the poly(A)-specific ribonuclease (PARN) gene. Flow fish telomere measurement result was 5.9 (reference range 8.0-12.6), which is consistent with the DC diagnosis. Permanent fixation with internal metal rods and zoledronic acid 5 mg over 3 years was effective at preventing further fractures over 4 years of follow-up. Additionally, BMF did not progress over 4 years of observation. DC associated with PARN gene mutations might predispose to low-traumatic multiple hip fractures in adolescents and young adults. Treatment with zoledronic acid in this case was effective and safe at preventing further fractures.

Effects of Xinkeshu combined with levosimendan on perioperative heart failure in oldest-old patients with hip fractures.

OBJECTIVE: To investigate the clinical effects of Xinkeshu combined with levosimendan on perioperative heart failure in oldest-old patients with hip fractures. METHODS: Oldest-old patients over 80 years old with perioperative heart failure and hip fractures were randomly divided into the control and observation groups, with 50 patients in each group. All patients in both groups were treated with conventional anti-heart failure therapy and levosimendan, whereas patients in the observation group additionally received Xinkeshu tablets. Clinical manifestations; left ventricular ejection fraction (LVEF); left ventricular end-diastolic dimension (LVEDD); left ventricular end-systolic dimension (LVESD); B-type natriuretic peptide (BNP), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and endothelin-1 (ET-1) levels; and self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores were compared between before and after treatment to evaluate the curative effects of Xinkeshu combined with levosimendan. RESULTS: After treatment, the efficacy rate was significantly higher in the observation group than in the control group. LVEF and the levels of SOD and NO were higher in the observation group than in the control group after treatment. However, LVEDD; LVESD; BNP, MDA, and ET-1 levels; and the SAS and SDS scores were lower after treatment in the observation group than in the control group. CONCLUSION: Levosimendan combined with Xinkeshu can improve cardiac function, alleviate oxidative stress, and relieve anxiety and depression in oldest-old patients with perioperative heart failure and hip fracture.

Single-nucleotide polymorphism rs10036727 in the SLIT3 gene is associated with osteoporosis at the femoral neck in older Mexican postmenopausal women.

AIMS: Osteoporosis (OP) remains a major public health problem worldwide. The most serious complications of this disease are fragility fractures, which increase morbidity and mortality. Management of OP represents an economic burden for health systems. Therefore, it is necessary to develop new screening strategies to identify the population at risk and implement preventive measures. We previously identified the SNPs rs3801387 in WNT16, rs7108738 in SOX6, rs10036727 in SLIT3 and rs7584262 in PKDCC as associated with bone mineral density in postmenopausal women through a genome-wide association study. The aim of this study was to validate those SNPs in two independent cohorts of non-related postmenopausal women. MATERIALS AND METHODS: We included 1160 women classifying them as normal, osteopenic or osteoporotic and a group with hip fragility fracture. Genotyping was performed using predesigned TaqMan assays. RESULTS: The variants rs10036727 and rs7108738 showed a significant association with BMD at the femoral neck. SLIT3 has been previously proposed as a potential biomarker and therapeutic resource. CONCLUSIONS: Our results provide new evidence regarding a possible involvement of SLIT3 in bone metabolisms and encourage the development of more studies in different populations to support these observations.

A Polygenic Risk Score as a Risk Factor for Medication-Associated Fractures.

Some commonly prescribed drugs are associated with increased risk of osteoporotic fractures. However, fracture risk stratification using skeletal measures is not often performed to identify those at risk before these medications are prescribed. We tested whether a genomically predicted skeletal measure, speed of sound (gSOS) from heel ultrasound, which was developed in 341,449 individuals from UK Biobank and tested in a separate subset consisting of 80,027 individuals, is an independent risk factor for fracture in users of fracture-related drugs (FRDs). To do this, we first assessed 80,014 UK Biobank participants (including 12,678 FRD users) for incident major osteoporotic fracture (MOF, n = 1189) and incident hip fracture (n = 209). Effects of gSOS on incident fracture were adjusted for baseline clinical fracture risk factors. We found that each standard deviation decrease in gSOS increased the adjusted odds of MOF by 42% (95% confidence interval [CI] 1.34-1.51, p < 2 × 10-16 ) and of hip fracture by 31% (95% CI 1.15-1.50, p = 9 × 10-5 ). gSOS below versus above the mean increased the adjusted odds of MOF by 79% (95% CI 1.58-2.01, p < 2 × 10-16 ) and of hip fracture by 42% (95% CI 1.08-1.88, p = 1.3 × 10-2 ). Among FRD users, each standard deviation decrease in gSOS increased the adjusted odds of MOF by 29% (nMOF = 256, 95% CI 1.14-1.46, p = 7 × 10-5 ) and of hip fracture by 30% (nhip fracture = 68, 95% CI 1.02-1.65, p = 0.0335). FRD users with gSOS below versus above the mean had a 54% increased adjusted odds of MOF (95% 1.19-1.99, p = 8.95 × 10-4 ) and a twofold increased adjusted odds of hip fracture (95% 1.19-3.31, p = 8.5 × 10-3 ). We therefore showed that genomically predicted heel SOS is independently associated with incident fracture among FRD users. © 2020 American Society for Bone and Mineral Research.

Association between rs12742784 polymorphism and hip fracture, bone mineral density, and EPHB2 mRNA expression levels in elderly Chinese women.

Objective: This study aimed to determine the association between rs12742784 polymorphism in the non-coding area and hip fracture, bone mineral density (BMD), and EPHB2 mRNA expression levels in elderly Chinese women.Methods: We investigated 250 Chinese women (mean age: 63.5 ± 8.3 years) including 123 hip fracture patients and 127 non-fracture controls. All participants underwent clinical examination to meet the inclusion criteria. Lumbar and hip BMD were detected by dual-energy X-ray absorptiometry. rs12742784 polymorphism was determined by restriction fragment length polymorphism and EPHB2 mRNA expression levels were measured by real-time polymerase chain reaction.Results: Distribution of rs12742784 genotypes agreed with Hardy-Weinberg equilibrium. The frequency of the CT + TT genotype was significantly associated with decreased risk of hip fracture (adjusted odds ratio = 0.57, p < 0.01) after adjusting for age and body mass index, and with increased BMD and EPHB2 mRNA expression levels. The T allele of the rs12742784 single nucleotide polymorphism (SNP) was a protective factor for hip fracture (adjusted odds ratio = 0.56, p < 0.01).Conclusion: rs12742784 polymorphism was associated with EPHB2 mRNA expression levels, BMD, and hip fracture in Chinese women. The T allele of the rs12742784 SNP was a protective factor for osteoporosis and hip fracture.

MicroRNA-205-5p Targets HMGB1 to Suppress Inflammatory Responses during Lung Injury after Hip Fracture.

Hip fracture is the most common type of injury in elderly people and is associated with a high incidence of complications and risk of mortality. In these patients, subsequent pulmonary infection can contribute to the development of an acute lung injury, a consequence of the systemic inflammatory response induced by hip fracture. Although the crucial role of microRNAs (miRNAs) in inflammatory responses has been established, the functions of miRNAs in the inflammatory responses associated with lung injury after hip fracture remain poorly understood. In this study, we explored the potential role of miR-205-5p in lung injury after hip fracture in an in vivo hip fracture model and in vitro cultures of human pulmonary alveolar epithelial cells (HPAEpiC). An analysis of clinical serum samples revealed increased levels of miR-205-5p and high mobility group box 1 (HMGB1) after hip fracture. A bioinformatics analysis and dual-luciferase reporter assay identified HMGB1 as a potential target of miR-205-5p. The overexpression of miR-205-5p clearly reduced the expression of HMGB1 and inhibited NF-κB signaling, apoptosis, and proinflammatory cytokine production while enabling continued cell proliferation. Our results demonstrate that the upregulation of miR-205-5p suppresses inflammatory responses and promotes cell viability and proliferation by selectively targeting HMGB1 in the context of lung injury after hip fracture. Therefore, miR-205-5p may be an alternative target of therapeutic strategies for lung injury after hip fracture.

East-west gradient in hip fracture incidence in Spain: how much can we explain by following the pattern of risk factors?

Our objective was to analyze the incidence and trend of hip fracture in Spain and its distribution by Autonomous Community (AC). In Spain, the age-adjusted incidence rate of hip fracture is decreasing. There is great variability in the incidence and tendency of hip fracture among the different ACs. Genetic, demographic, and climatic factors and cohort effect factors of the civil war explain 96% of this variability. INTRODUCTION: In Spain, there is great variability between the different Autonomous Communities (ACs) in the incidence of hip fracture. The objectives of our study are (1) to estimate the incidence rate and trend of hospital admissions for hip fracture in Spain and by ACs and (2) to analyze risk factors/markers that could explain the variability in the incidence and trend between different ACs. METHOD: This work includes 2 studies (TREND-HIP and VAR-HIP). TREND-HIP: retrospective, national, observational study based on the administrative database of the National Health System that includes a Minimum Basic Data Set (MBDS) of hospital admissions. VAR-HIP: ecological study based on the analysis of the results obtained in TREND-HIP study, with different risk factors/markers obtained from different sources. RESULTS: In the 17 years included in the analysis, there were 744,848 patients diagnosed with hip fracture. The global age-adjusted rate of hip fracture at the national level was 315.38/100,000 person*year (95% CI 312.36-317.45); by AC, the rate varied from 213.97 in the Canary Islands to 363.13 in the Valencia and Cataluña communities. We observe an east-west gradient in Spain. The trend for both sexes was - 0.67% (95% CI 0.9990-0.9957) (p < 0.001). In the analysis of risk factors/markers that explain this distribution, we found significant correlations with genetic factors, demographics, climatic factors and the time a region was on the Republican side of the civil war. The linear regression model that includes the factors that show significant correlation explains 96% of the variability observed. CONCLUSION: In Spain, the age-adjusted incidence rate for hip fracture is decreasing. There is a great variability in the incidence and tendency of hip fracture among the different ACs. Genetic, demographic, climatic factors and the cohort effect of the civil war explain 96% of this variability.

Genotype, resilience and function and physical activity post hip fracture.

BACKGROUND: Individuals who are resilient are more likely to engage in functional tasks and exercise post hip fracture. There may be a genetic predisposition to being resilient. OBJECTIVES: This study tested the direct and indirect association of 10 candidate genes, age, cognition, gender, comorbidities, pain and social activity on resilience, function and exercise post hip fracture. METHOD: This was a descriptive study including 172 community dwelling older adults. Measures included: age, gender, cognition (Modified Mini Mental Status Exam), comorbidities, social activities (self-report), DNA (GRM1, NTRK1, NTRK2, GNB3, NPY, SLC6A15. SLC6A4, BDNF, CR1TR1, FKBP5), pain (areas of pain and Numeric Rating Scale), function (Physical and Instrumental Activities of Daily Living; Lower Extremity Gains Score; Short Physical Performance Battery; Grip Strength) and exercise (Yale Physical Activity Scale). RESULTS: The majority of participants were Caucasian (93%), 50% were women and the average age was 81.09 (SD = 7.42). There were significant associations between resilience and single nucleotide polymorphisms from GRM1, NTRK1, NTRK2, GNB3, NPY and SLC6A15. Resilience, age, cognition, social activity, pain and genetic variability were directly and/or indirectly associated with exercise and/or function. DISCUSSION: This study highlights the importance of resilience for engagement in exercise and function after hip fracture and provides preliminary evidence for a genetic role for resilience.

Alcohol intake, specific alcoholic beverages, and risk of hip fractures in postmenopausal women and men age 50 and older.

BACKGROUND: Although a number of studies have examined the association between alcohol intake and hip fractures, few have considered specific alcoholic beverages separately. OBJECTIVES: We prospectively assessed total alcohol and specific alcoholic beverage consumption and risk of hip fractures in US men and women. METHODS: Health, lifestyle information, and hip fractures were self-reported on biennial questionnaires between 1980 and 2014 in 75,180 postmenopausal women from the Nurses' Health Study, and between 1986 and 2014 in 38,398 men aged ≥50 y from the Health Professionals Follow-Up Study. Diet was assessed approximately every 4 y with a semiquantitative FFQ. RRs were computed for hip fracture using Cox proportional hazards models, adjusting for potential confounders. RESULTS: We ascertained 2360 incident low trauma hip fractures in women and 709 in men. Among women, RRs for low trauma hip fractures compared with nondrinkers were 0.89 (95% CI: 0.80, 0.99) for an average daily consumption of <5.0 g, 0.81 (95% CI: 0.70, 0.94) for 5.0 to <10.0 g, 0.83 (95% CI: 0.71, 0.96) for 10.0 to <20.0 g, and 0.93 (95% CI: 0.78, 1.10) for ≥20.0 g. Among men, risk declined linearly with higher alcohol consumption (P-trend = 0.002). Multivariable RR compared with nondrinkers was 0.77 (95% CI: 0.59, 1.01), 0.69 (0.49, 0.96), and 0.67 (0.48, 0.95) for an average intake of 10 g/d to <20 g/d, 20 g/d to <30 g/d, and 30.0 g/d or more, respectively. In women, the alcoholic beverage most significantly associated with hip fracture risk was red wine (RR per serving = 0.59; 95% CI: 0.45, 0.79). In men, there was no clear association with specific alcoholic beverages. CONCLUSION: In these 2 US cohorts, low to moderate alcohol consumption, when compared with no consumption, was associated with a lower risk of hip fractures, particularly with red wine consumption among women.

GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10-42, ß = -0.090) and confers risk of hip fracture (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.

Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry.

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.

Association of RMND1/CCDC170-ESR1 single nucleotide polymorphisms with hip fracture and osteoporosis in postmenopausal women.

OBJECTIVE: This study aimed to investigate the association of seven single nucleotide polymorphisms (SNPs) on the RMND1, CCDC170, and ESR1 genes with osteoporosis or hip fracture in a postmenopausal Mexican population. METHODS: We included a group of 400 postmenopausal women from the Health Workers Cohort Study from the Mexican Institute of Social Security. As a replication sample, we recruited 423 postmenopausal women from the National Institute of Rehabilitation. Demographic data were collected through a structured questionnaire. Bone mineral density was assessed using dual X-ray absorptiometry. Individuals were classified as normal, osteopenia, osteoporosis, and fracture, according to World Health Organization criteria. Genotyping was performed using predesigned TaqMan Probes. Linear regression analysis was used to investigate association. RESULTS: All of the analyzed SNPs showed association with at least one of the phenotypes of the study groups. In addition, we observed a region with linkage disequilibrium within the ESR1 gene in all groups. CONCLUSION: This study shows that an association of the SNPs can exist with osteopenia, osteoporosis, or fragility fracture. Our results agree with data published elsewhere, supporting the potential of these loci for the identification of the population at risk. However, additional studies are required to determine the extent of this association for other geographic regions of Mexico.

Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies.

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

The RANKL rs12585014 polymorphism is associated with age at menarche in postmenopausal women with hip fracture.

The RANK/RANKL/OPG signaling is important in the regulation of bone turnover. The aim of the present work was to analyze the rs3018362 and rs12585014 polymorphisms in the RANK and RANKL genes, as well as risk factors in postmenopausal women. Women with hip fracture, with femoral neck osteoporosis and controls (n = 646) were recruited. From these, 303 women who fulfill the inclusion criteria were genotyped using real-time PCR with TaqMan probes. There were no associations of the rs3018362 and rs12585014 with osteoporosis or fracture. When women were divided by age at menarche, the rs12585014 GG genotype was strongly associated with age at menarche >13 years [p = .00774, OR = 6.429 (1.907-21.103)] in women with hip fracture. Significant differences in risk factors such as body mass index, age at menopause, use of estrogens, the presence of hypertension, and diabetes mellitus were found. Carrying the GG genotype of rs12585014 entails a higher risk of having menarche later (>13 years), which could involves a greater risk of fractures. The rs3018362 and rs12585014 do not seem to be associated with hip osteoporosis or hip fracture in Mexican women.

A functional polymorphism at miR­491­5p binding site in the 3'UTR of MMP9 gene confers increased risk for pressure ulcers after hip fracture.

The roles of matrix metalloproteinase (MMP)9 in the control of pressure ulcers (PU) after hip fracture as well as how the rs1056629 in MMP9 3'UTR compromises the interaction between MMP9 and miR­491 were explored. Online miRNA database (http://www.bioguo.org) was utilized to explore gene polymorphism in MMP9 3'UTR that might break the interaction between MMP9 and miRNA. Luciferase assay was utilized to confirm the miRNA targeted MMP9. Real­time PCR, western blot analysis and immunohistochemistry were carried out to understand the roles of MMP9 in PU as well as how rs1056629 in MMP9 3'UTR compromises the interaction between MMP9 and miR­491. rs1056629 in MMP9 3'UTR that compromised the interaction between MMP9 and four miRNAs including miR­194­3p, miR­491, miR­1915­3p and miR­941, and only miR­491 among miR­194­3p, miR­491, miR­1915­3p and miR­941 decreased luciferase activity of wild­type MMP9 3'UTR, and luciferase activities of mutant­3 and mutant­4 MMP9 3'UTR in miR­491 overexpressing cells was comparable with scramble control. miR­194­3p, miR­491, miR­1915­3p and miR­941 levels in PU group was comparable with healthy control, and miR­194­3p, miR­491, miR­1915­3p and miR­941 in subjects carrying AA genotype was similar with those in AC and CC groups. MMP9 mRNA and protein, and histology score in subjects with PU were much higher, and were also much higher in AA group. Only miR­491 mimic among miR­194­3p, miR­491, miR­1915­3p and miR­941 mimics downregulated the MMP9 level, and only miR­491 inhibitor among miR­194­3p, miR­491, miR­1915­3p and miR­941 inhibitors upregulated the MMP9 level. Our study indicated that rs1056629 polymorphism could be a novel biomarker for predicting the occurrence of PU after a hip fracture.

Lactase persistence, milk intake, hip fracture and bone mineral density: a study of 97 811 Danish individuals and a meta-analysis.

BACKGROUND: Whether a causal relationship exists between milk intake and reduced risk of fractures is unclear. OBJECTIVES: We tested the hypothesis that genetically determined milk intake reduces the risk of fractures and increases bone mineral density (BMD). METHODS: We investigated the association between milk intake, LCT-13910 C/T (rs4988235), which is associated with lactase persistence (TT/TC) in Northern Europeans, and hip fractures in three Danish prospective studies (N = 97 811, age ≥20 years). We added meta-analyses of LCT-13910 and fractures and BMD from five published Northern European population studies. RESULTS: In the Danish studies, the adjusted hazard ratio (HR) for hip fracture per one glass per week higher milk intake was 1.00 (95% CI: 0.99-1.01). The per T-allele milk intake was 0.58 (0.49-0.68) glasses per week, but HR was 1.01 (0.94-1.09) for hip fracture. In meta-analyses of Danish studies with published Northern European population studies, the random effects odds ratio for any fracture was 0.86 (0.61-1.21; I2 = 73%) for TT vs. CC and 0.90 (0.68-1.21; I2 = 63%) for TC vs. CC. The standardized mean difference in femoral neck BMD was 0.10 (0.02-0.18; I2 = 0%) g cm-2 for TT vs. CC and 0.06 (-0.04 to 0.17; I2 = 17%) g cm-2 for TC vs. CC. There were no differences in lumbar spine or total hip BMD comparing TT or TC with CC. CONCLUSION: Genetically lifelong lactase persistence with high milk intake was not associated with hip fracture in Danish population-based cohorts. A meta-analysis combining Danish studies with published Northern European population studies also showed that lactase persistence was not associated with fracture risk. Genetic lactase persistence was associated with a higher femoral neck BMD, but not lumbar spine or total hip BMD.

Bone Turnover Status: Classification Model and Clinical Implications.

Aim: To develop a practical model for classification bone turnover status and evaluate its clinical usefulness. Methods: Our classification of bone turnover status is based on internationally recommended biomarkers of both bone formation (N-terminal propeptide of type1 procollagen, P1NP) and bone resorption (beta C-terminal cross-linked telopeptide of type I collagen, bCTX), using the cutoffs proposed as therapeutic targets. The relationships between turnover subtypes and clinical characteristic were assessed in1223 hospitalised orthogeriatric patients (846 women, 377 men; mean age 78.1±9.50 years): 451(36.9%) subjects with hip fracture (HF), 396(32.4%) with other non-vertebral (non-HF) fractures (HF) and 376 (30.7%) patients without fractures. Resalts: Six subtypes of bone turnover status were identified: 1 - normal turnover (P1NP>32 µg/L, bCTX≤0.250 µg/L and P1NP/bCTX>100.0[(median value]); 2- low bone formation (P1NP ≤32 µg/L), normal bone resorption (bCTX≤0.250 µg/L) and P1NP/bCTX>100.0 (subtype2A) or P1NP/bCTX<100.0 (subtype 2B); 3- low bone formation, high bone resorption (bCTX>0.250 µg/L) and P1NP/bCTX<100.0; 4- high bone turnover (both markers elevated ) and P1NP/bCTX>100.0 (subtype 4A) or P1NP/bCTX<100.0 (subtype 4B). Compared to subtypes 1 and 2A, subtype 2B was strongly associated with nonvertebral fractures (odds ratio [OR] 2.0), especially HF (OR 3.2), age>75 years and hyperparathyroidism. Hypoalbuminaemia and not using osteoporotic therapy were two independent indicators common for subtypes 3, 4A and 4B; these three subtypes were associated with in-hospital mortality. Subtype 3 was associated with fractures (OR 1.7, for HF OR 2.4), age>75 years, chronic heart failure (CHF), anaemia, and history of malignancy, and predicted post-operative myocardial injury, high inflammatory response and length of hospital stay (LOS) above10 days. Subtype 4A was associated with chronic kidney disease (CKD), anaemia, history of malignancy and walking aids use and predicted LOS>20 days, but was not discriminative for fractures. Subtype 4B was associated with fractures (OR 2.1, for HF OR 2.5), age>75 years, CKD and indicated risks of myocardial injury, high inflammatory response and LOS>10 days. Conclusions: We proposed a classification model of bone turnover status and demonstrated that in orthogeriatric patients altered subtypes are closely related to presence of nonvertebral fractures, comorbidities and poorer in-hospital outcomes. However, further research is needed to establish optimal cut points of various biomarkers and improve the classification model.