First-trimester maternal renin-angiotensin-aldosterone system activation and the association with maternal telomere length after natural and IVF/ICSI conceived pregnancies: the Rotterdam periconception cohort.

OBJECTIVE: To study associations between the first-trimester maternal determinants of renin-angiotensin-aldosterone system (RAAS) activation and telomere length (TL) in pregnancies conceived natural and after IVF/ICSI. METHODS: In 145 pregnancies of the Rotterdam Periconception cohort renin, prorenin and aldosterone concentrations were measured in maternal blood at 9 weeks gestational age (GA). TL was measured by qPCR at 20 weeks GA. RESULTS: A significantly negative correlation was found between renin and TL, which was attenuated for prorenin but not observed for aldosterone. Maternal TL was significantly shorter in pregnancies conceived after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to natural pregnancies. CONCLUSION: The negative association between first-trimester maternal renin and maternal TL, and the shorter maternal TL in women after IVF/ICSI treatment compared to natural pregnancies, substantiates the role of excessive RAAS activation.

Metabolic syndrome and the progression of knee osteoarthritis on MRI.

OBJECTIVE: Metabolic osteoarthritis (OA) is one of the proposed clinical phenotypes defined by the existence of metabolic syndrome (MetS). This study aimed to (1) investigate whether MetS and its components are associated with progression of knee OA magnetic resonance imaging (MRI) features, and (2) to evaluate the interaction of MetS with menopause and progression of MRI features. METHOD: 682 women from the Rotterdam Study who participated in a sub-study with knee MRI data available and 5-year follow-up were included. Tibiofemoral (TF) and patellofemoral (PF) OA features were assessed with the MRI Osteoarthritis Knee Score. MetS was quantified by the MetS severity Z-score. Generalized estimating equations were used to evaluate associations between MetS and menopausal transition and progression of MRI features. RESULTS: MetS severity at baseline was associated with progression of osteophytes in all compartments, bone marrow lesions (BMLs) in the PF compartment, and cartilage defects in the medial TF compartment. Waist circumference was associated with progression of osteophytes in all compartments and cartilage defects in the medial TF compartment. High-density lipoprotein (HDL)-cholesterol levels were associated with progression of osteophytes in the medial and lateral TF compartment and glucose levels with osteophytes in the PF and medial TF compartment. No interactions were found between MetS with menopausal transition and MRI features. CONCLUSION: Women with higher MetS severity at baseline showed progression of osteophytes, BMLs, and cartilage defects, indicating more structural knee OA progression after 5 years. Further studies are required to understand whether targeting MetS components may prevent the progression of structural knee OA in women.

Skin autofluorescence, a non-invasive biomarker of advanced glycation end products, and its relation to radiographic and MRI based osteoarthritis.

OBJECTIVES: Accumulation of advanced glycation end products (AGEs) in articular cartilage during aging has been proposed as a mechanism involved in the development of osteoarthritis (OA). Therefore, we investigated a cross-sectional relationship between skin AGEs, a biomarker for systemic AGEs accumulation, and OA. METHODS: Skin AGEs were estimated with the AGE Reader™ as skin autofluorescence (SAF). Knee and hip X-rays were scored according to Kellgren and Lawrence (KL) system. KL-sum score of all four joints was calculated per participant to assess severity of overall radiographic OA (ROA) including or excluding those with prosthesis. Knee MRI of tibiofemoral joint (TFMRI) was assessed for cartilage loss. Sex-stratified regression models were performed after testing interaction with SAF. RESULTS: 2,153 participants were included for this cross-sectional analysis. In women (n = 1,206) for one unit increase in SAF, the KL-sum score increased by 1.15 (95% confidence interval = 1.00-1.33) but excluding women with prosthesis, there was no KL-sum score increase [0.96 (0.83-1.11)]. SAF was associated with higher prevalence of prosthesis [Odds ratio, OR = 1.67 (1.10-2.54)] but not with ROA [OR = 0.83 (0.61-1.14)] when compared to women with no ROA. In men (n = 947), there was inconclusive association between SAF and KL sum score or prosthesis. For TFMRI (n = 103 women), SAF was associated with higher prevalence of cartilage loss, full-thickness [OR = 5.44 (1.27-23.38)] and partial-thickness [OR = 1.45 (0.38-5.54)], when compared to participants with no cartilage loss. CONCLUSION: Higher SAF in women was associated with higher prosthesis prevalence and a trend towards higher cartilage loss on MRI. Our data presents inconclusive results between SAF and ROA in both sexes.

The prevalence, incidence, and progression of radiographic thumb base osteoarthritis in a population-based cohort: the Rotterdam Study.

OBJECTIVE: To describe the prevalence, incidence, and progression of radiographic thumb carpometacarpal (CMC-1) and trapezioscaphoid (TS) radiographic osteoarthritis (ROA) in the general Dutch population aged ≥55y. DESIGN: Data were from the first and second cohort of the Rotterdam Study (1990-2005, 4-12 years follow-up, age 55+). Participants underwent bilateral radiographs at baseline (N = 7792) and follow-up (N = 3804), read for Kellgren-Lawrence (K-L) grade. ROA was defined on the joint level as K-L grade ≥2. The prevalence was assessed at baseline, incidence at follow-up in those free of ROA at baseline, and progression in those with ROA. Differences based on sex and age were evaluated using logistic regression models. RESULTS: At baseline, 1977 (25.3%) had CMC-1 ROA and 1133 (14.5%) TS ROA. The prevalence was higher in females for CMC-1 (aOR = 1.98 95%CI [1.77-2.21]) and TS ROA (aOR = 2.00 [1.74-2.29]) and increased for every year of age (CMC-1 ROA 1.08 [1.07-1.08]) (TS ROA 1.06 [1.05-1.07]). Most (437/512; 85.4%) incident cases of CMC-1 ROA (2994 at risk) were mild (K-L = 2), whereas most (145/167; 86,8%) incident cases of TS ROA (3311 at risk) were moderate to severe (K-L = 3/4). CMC-1 ROA progression was mostly (88/100; 88.0%) seen in the K-L 2 group at baseline, whereas that was (4/17; 23.5%) for TS ROA. CONCLUSION: CMC-1 ROA and TS ROA are prevalent in the general Dutch population. While incident CMC-1 ROA was primarily mild, incident TS ROA was more often moderate to severe. CMC-1 ROA was a strong predictor for incident TS ROA.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Characterization of dynamic changes in Matrix Gla Protein (MGP) gene expression as function of genetic risk alleles, osteoarthritis relevant stimuli, and the vitamin K inhibitor warfarin.

OBJECTIVE: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. METHODS: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1ß; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. RESULTS: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. DISCUSSION & CONCLUSIONS: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Serum fatty acid chain length associates with prevalent symptomatic end-stage osteoarthritis, independent of BMI.

Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.

Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Development of a prediction model for future risk of radiographic hip osteoarthritis.

OBJECTIVE: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. DESIGN: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). RESULTS: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. CONCLUSIONS: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.

Osteoarthritis year in review 2016: genetics, genomics and epigenetics.

The purpose of this narrative review is to provide an overview of last year's publications in the field of genetics, genomics and epigenetics in the osteoarthritis (OA) field. Major themes arising from a Pubmed search on (epi)genetics in OA were identified. In addition, general developments in the fast evolving field of (epi)genetics are reviewed and relevance for the OA field is summarized. In the last 5 years, a number of genome-wide association studies have identified a modest number of genetic loci associated to OA. Continued functional research into these DNA variants is showing putative biological mechanisms underlying these associations. Over the last year, no additional large genome-wide association studies were published, but there clearly remains much to be discovered in the OA genetic field. A lot of research has been done into the epigenetics of OA over the last year. Several genome-wide screens examining the methylome of osteoarthritic cartilage were done. Pathway analysis confirmed deregulation of developmental and extracellular pathways in OA cartilage. Over the last year many microRNAs (miRNAs) have been identified that potentially play important roles in cartilage homeostasis and/or OA process. Continued research will learn whether these identified miRNAs are truly causal and can be used in clinical applications. Many of the epigenetic findings need further confirmation, but they highlight potential novel pathways involved in cartilage biology and OA.

Structural Brain Alterations in Community Dwelling Individuals with Chronic Joint Pain.

BACKGROUND AND PURPOSE: Central sensitization in chronic pain involves structural brain changes that influence vulnerability to pain. Identifying brain regions involved in pain processing and sensitization can provide more insight into chronic pain. This study examines structural brain changes in chronic pain and experimental pain in a large population-based study. MATERIALS AND METHODS: For 3892 participants in the Rotterdam study, global and regional MR imaging brain volumes were automatically segmented and quantified. Chronic joint pain was defined as pain for more than half of all days during the past 6 weeks. Heat pain thresholds were measured in a subset of 1538 individuals. The association between the presence of chronic joint pain and global and lobar brain volumes was studied. Subsequently, literature was reviewed and the association of chronic pain and heat pain thresholds with 11 brain regions associated with musculoskeletal pain in previous publications was studied. RESULTS: Total gray matter volume was smaller in women with chronic pain (ß = -0.066, P = .016). This effect was primarily driven by lower gray matter volume in the temporal lobe (ß = 0.086, P = .005), the frontal lobe (ß = -0.060, P = .039), and the hippocampus (ß = -0.099, P = .002). In addition, we observed that a lower heat pain threshold was associated with smaller volumes of the hippocampus (ß = 0.017, P = .048), the thalamus (ß = 0.018, P = .009), and the anterior cingulate cortex (ß = -0.016, P = .037). In men, no significant associations were observed. CONCLUSIONS: The primary identified brain areas, the temporal and frontal lobes and the hippocampus, indicated involvement of emotional processing. The volumetric differences found indicated a sex-specific neuroplasticity in chronic pain. These results emphasized sex-specific and multidisciplinary pain treatment.

Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.

The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons.

INTRODUCTION: High plasma homocysteine levels have been associated with incident osteoporotic fractures, but the mechanisms underlying this association are still unknown. It has been hypothesized that homocysteine might interfere with collagen cross-linking in bone, thereby weakening bone structure. Therefore, we wanted to investigate whether plasma homocysteine levels are associated with bone quality parameters, rather than with bone mineral density. METHODS: Cross-sectional data of the B-PROOF study (n=1227) and of two cohorts of the Rotterdam Study (RS-I (n=2850) and RS-II (n=2023)) were used. Data on bone mineral density of the femoral neck and lumbar spine were obtained in these participants using dual-energy X-ray assessment (DXA). In addition, participants of B-PROOF and RS-I underwent quantitative ultrasound measurement of the calcaneus, as a marker for bone quality. Multiple linear regression analysis was used to investigate the associations between natural-log transformed plasma levels of homocysteine and bone mineral density or ultrasound parameters. RESULTS: Natural-log transformed homocysteine levels were inversely associated with femoral neck bone mineral density in the two cohorts of the Rotterdam Study (B=-0.025, p=0.004 and B=-0.024, p=0.024). In B-PROOF, no association was found. Pooled data analysis showed significant associations between homocysteine and bone mineral density at both femoral neck (B=-0.032, p=0.010) and lumbar spine (B=-0.098, p=0.021). Higher natural-log transformed homocysteine levels associated significantly with lower bone ultrasound attenuation in B-PROOF (B=-3.7, p=0.009) and speed of sound in both B-PROOF (B=-8.9, p=0.001) and RS-I (B=-14.5, p=0.003), indicating lower bone quality. Pooled analysis confirmed the association between homocysteine and SOS (B=-13.1, p=0.016). Results from ANCOVA-analysis indicate that differences in SOS and BUA between participants having a plasma homocysteine level above or below median correspond to 0.14 and 0.09 SD, respectively. DISCUSSION: In this study, plasma levels of homocysteine were significantly inversely associated with both bone ultrasound parameters and with bone mineral density. However, the size of the associations seems to be of limited clinical relevance and may therefore not explain the previously observed association between plasma homocysteine and osteoporotic fracture incidence.

Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors.

OBJECTIVE: To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction. METHODS: The prognostic model was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other population-based cohorts: Rotterdam Study-II and Chingford Study. RESULTS: In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65 years (AUC 0.65), while it was only 0.55 for subjects aged ≥65 years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study. CONCLUSIONS: Easy obtainable 'Questionnaire' variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee.

Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study.

UNLABELLED: Serum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. INTRODUCTION: Inflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high-sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort. METHODS: At baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6 years). RESULTS: CRP was associated with a risk for any type of fracture [hazard ratio (HR) = 1.06; 95 % confidence interval (CI), 1.02-1.11], hip fractures (HR = 1.09; 1.02-1.17) and vertebral fractures [odds ratio (OR) = 1.34; 1.14-1.58]. An inverse relationship between CRP levels and section modulus (-0.011 cm(3); -0.020 to -0.003 cm(3)) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (p = 9 × 10(-56)), but not with fracture risk (HR = 1.00; 0.99-1.00; p = 0.23). CONCLUSIONS: Serum high-sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk.

Association of lumbar disc degeneration with osteoporotic fractures; the Rotterdam study and meta-analysis from systematic review.

OBJECTIVE: To investigate the relation between lumbar disc degeneration (LDD) and all type of osteoporotic (OP) fractures including vertebral. METHODS: This study is part of the Rotterdam study, a large prospective population-based cohort study among men and women aged 55years and over. In 2819 participants spine radiographs were scored for LDD (osteophytes and disc space narrowing (DSN)) from L1 till S1, using the Lane atlas. Osteoporotic (OP) fracture data were collected and verified by specialists during 12.8years. We considered two types of vertebral fractures (VFx): Clinical VFx (symptomatic fractures recorded by medical practitioners) and Radiographic VFx (using the McCloskey-Kanis method). Meta-analysis of published studies reporting an association of LDD features and VFx was performed. Differences in Bone Mineral Density (BMD) between participants with and without LDD features were analyzed using ANOVA. Risk of OP-fractures was analyzed using Cox regression. RESULTS: In a total of 2385 participants, during 12.8years follow-up, 558 suffered an OP-fracture. Subjects with LDD had an increased OP fracture risk compared to subjects without LDD (HR: 1.29, CI: 1.04-1.60). LDD-cases have between 0.3 and 0.72 standard deviations more BMD than non-cases in all analyzed regions including total body BMD and skull BMD (P<0.001). Only males with LDD had increased risk for OP-fractures compared to males without LDD (adjusted-HR: 1.80, 95%CI: 1.20-2.70, P=0.005). The risk was also higher for VFx in males (HR: 1.64, CI: 1.03-2.60, P: 0.04). The association LDD-OP-fractures in females was lower and not significant (adjusted-HR: 1.08, 95%CI: 0.82-1.41). Meta-analyses showed that the risk of VFx in subjects with LDD has been studied only in women and there is not enough evidence to confidently analyze the relationship between LDD-features (DSN or/and OPH) and VFx due to low power and heterogeneity in phenotype definition in the collected studies. CONCLUSIONS: Male subjects with LDD have a higher osteoporotic fracture risk, in spite of systemically higher BMD.

The contribution of hip geometry to the prediction of hip osteoarthritis.

OBJECTIVE: To determine how well measures of hip geometry can predict radiological incident hip osteoarthritis (HOA) compared to well known clinical risk factors. DESIGN: The study population is part of the Rotterdam Study, a prospective population-based cohort. Baseline pelvic radiographs were used to measure hip geometry by two methods: Statistical Shape Models (SSM) and predefined geometry parameters (PGPs). Incident HOA (Kellgren and Lawrence (KL) ≥ 2) was assessed in 688 participants after 6.5 years without radiographic HOA at baseline. The ability to predict HOA was quantified using the area under the Receiver Operating Characteristics (ROC) curve (AUC). RESULTS: Comparison of the two methods showed that both contain information that is not captured by the other method. At 6.5 years follow-up 132 hips had incident HOA. Five PGPs (Wiberg angle, Neck Width (NW), Pelvic Width (PW), Hip Axis Length (HAL) and Triangular Index (TI)) and two SSM (modes 5 and 9) were significant predictors of HOA (P = 0.007). Hip geometry added 7% to the prediction obtained by clinical risk factors (AUC = 0.67 (geometry), 0.66 (gender, age, Body Mass Index (BMI)) and combining both: AUC = 0.73, respectively). Mode 12 (associated with position of the femoral head in acetabulum) and Wiberg angle were predictors of HOA in participants without radiological signs at baseline (KL = 0). Although the strength of the prediction decreased for all variables at a longer follow-up, the contribution of hip geometry was still significant (P = 0.01). CONCLUSIONS: Hip geometry has a moderate ability to predict HOA in participants with and without initial signs of osteoarthritis (OA), similar to and largely independent of the predictive value of clinical risk factors.

Homocysteine and the methylenetetrahydrofolate reductase 677C-->T polymorphism in relation to muscle mass and strength, physical performance and postural sway.

BACKGROUND/OBJECTIVES: Elevated plasma homocysteine has been linked to reduced mobility and muscle functioning in the elderly. The relation of methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism with these associations has not yet been studied. This study aimed to investigate (1) the association of plasma homocysteine and the MTHFR 677C-->T polymorphism with muscle mass, handgrip strength, physical performance and postural sway; (2) the interaction between plasma homocysteine and the MTHFR 677C-->T polymorphism. SUBJECTS/METHODS: Baseline data from the B-PROOF study (n=2919, mean age=74.1±6.5) were used. Muscle mass was measured using dual X-ray absorptiometry, handgrip strength with a handheld dynamometer, and physical performance with walking-, chair stand- and balance tests. Postural sway was assessed on a force platform. The data were analyzed using regression analyses with plasma homocysteine levels in quartiles. RESULTS: There was a significant inverse association between plasma homocysteine and handgrip strength (quartile 4: regression coefficient B=-1.14, 95% confidence interval (CI)=-1.96; -0.32) and physical performance score (quartile 3: B=-0.53, 95% CI=-0.95; -0.10 and quartile 4: -0.94; 95% CI=-1.40; -0.48) in women only, independent of serum vitamin B12 and folic acid. No association was observed between the MTHFR 677C-->T polymorphism and the outcomes. High plasma homocysteine in the 677CC and 677CT genotypes, but not in the 677TT genotype, was associated with lower physical performance. CONCLUSIONS: Elevated plasma homocysteine concentrations are associated with reduced physical performance and muscle strength in older women. There is an urgent need for randomized controlled trials to examine whether lowering homocysteine levels might delay physical decline.

Osteoarthritis year 2012 in review: genetics and genomics.

The field of genetics and genomics is a highly technological driven field that is advancing fast. The purpose of this year in review of genetics and genomics was to highlight the publications that apply these new technologies tools to improve understanding of the pathophysiology of osteoarthritis (OA). In addition, most recent developments in genetics and genomics research and their relevance to OA are discussed in this review.