M Carola Zillikens

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands

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Publications (123)1390.46 Total impact

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    Human Molecular Genetics 08/2014; · 7.69 Impact Factor
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    ABSTRACT: several studies have been pointing towards a non-linear relationship between serum 25(OH)D and cardiovascular disease. Next to vitamin D deficiency, also higher levels of 25(OH)D have been reported to be associated with increased cardiovascular risk. We aimed to investigate the nature of the relationship between serum 25(OH)D and measures of arterial stiffness and arteriosclerosis in an elderly population.
    Age and Ageing 07/2014; · 3.82 Impact Factor
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    ABSTRACT: Elevated homocysteine levels are a risk indicator for cardiovascular disease, fractures and cognitive decline. Previous studies indicated associations between homocysteine levels and medication use, including antihypertensive, lipid-lowering and antidiabetic medication. However, results were often contradictory and inconclusive. Our objective was to study the associations established previously in more detail by sub-classifying medication groups, and investigate the potential mediating role of vitamin B12 and folate status.
    Drugs & Aging 07/2014; · 2.50 Impact Factor
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    ABSTRACT: To investigate the prevalence of frailty in a Dutch elderly population and to identify adverse health outcomes associated with the frailty phenotype independent of the comorbidities. Cross-sectional and longitudinal analyses within the Rotterdam Study (the Netherlands), a prospective population-based cohort study in persons aged ≥55 years. Frailty was defined as meeting three or more of five established criteria for frailty, evaluating nutritional status, physical activity, mobility, grip strength and exhaustion. Intermediate frailty was defined as meeting one or two frailty criteria. Comorbidities were objectively measured. Health outcomes were assessed by means of questionnaires, physical examinations and continuous follow-up through general practitioners and municipal health authorities for mortality. Of 2,833 participants (median age 74.0 years, inter quartile range 9) with sufficiently evaluated frailty criteria, 163 (5.8 %) participants were frail and 1,454 (51.3 %) intermediate frail. Frail elderly were more likely to be older and female, to have an impaired quality of life and to have fallen or to have been hospitalized. 108 (72.0 %) frail participants had ≥2 comorbidities, compared to 777 (54.4 %) intermediate frail and 522 (44.8 %) non-frail participants. Adjusted for age, sex and comorbidities, frail elderly had a significantly increased risk of dying within 3 years (HR 3.4; 95 % CI 1.9-6.4), compared to the non-frail elderly. This study in a general Dutch population of community-dwelling elderly able to perform the frailty tests, demonstrates that frailty is common and that frail elderly are at increased risk of death independent of comorbidities.
    European Journal of Epidemiology 06/2014; · 5.12 Impact Factor
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    ABSTRACT: Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n∼9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10-37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10-14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10-10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
    PLoS Genetics 06/2014; 10(6):e1004423. · 8.52 Impact Factor
  • Abstracts Conference European Society of Human Genetics (ESHG), Milan, Italy; 06/2014
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    ABSTRACT: Osteoporosis with its consequences, i.e., fractures, is major health problem in ageing societies. As osteoporosis is a prevalent disorder, understanding its etiological factors is very important. We recently identified novel pathogenic variants in PLS3 (encoding Plastin 3 (PLS3), a filamentous-actin bundling protein) as a cause of X-linked osteoporosis and osteoporotic fractures in five Dutch families (van Dijk et al. NEJM 2013:369(16):1529-36). These loss-of-function variants cause decreased bone mineral density and increased risk of fracture in hemizygous young men whereas the clinical picture in heterozygous women ranged from asymptomatic to early-onset osteoporosis. It was highly unexpected that mutations in this gene would cause osteoporosis and fractures as it had never been described as a candidate gene for osteoporosis nor was it known to play a role in bone formation. However, results of in vivo analyses in zebrafish strongly supported a role for PLS3 as a bone regulatory protein. Furthermore, a rare variant (rs140121121) in PLS3 was found to be associated with a twofold increased fracture risk in elderly female carriers in the normal population indicating genetic variation in PLS3 as a novel etiological factor involved in common, multifactorial osteoporosis. However, the exact mechanism by which PLS3 mutations cause osteoporosis and fractures is unknown and currently subject of further investigations. Unravelling this new bone regulatory pathway is of great importance for understanding the aetiology of osteoporosis, increasing also the possibilities for prevention, diagnosis and treatment aimed at bone formation.
    EUROPEAN HUMAN GENETICS CONFERENCE 2014, Milan, Italy; 05/2014
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    ABSTRACT: Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue, which results in bone fragility and fractures. It is a multifactorial disease which is often encountered in menopausal women. We recently identified novel pathogenic variants of the plastin 3 (PLS3) gene (Xq23) as causative factors for X-linked osteoporosis with fractures in five families (van Dijk et al. NEJM 2013:369(16):1529-36). These loss-of-function variants associated with decreased bone mineral density and increased risk of fracture in hemizygous young men whereas the clinical picture in heterozygous women ranged from asymptomatic to early-onset osteoporosis. The significance of plastin 3 in bone development was confirmed in a pls3 knock-down zebrafish demonstrating malformations of developing craniofacial bone structure, body axis and tail. These malformations could be rescued dose dependently by PLS3 mRNA co-injection. Moreover, analysis of femora by micro computed tomography (µCT) in 3 months old transgenic mice overexpressing human PLS3 showed significant differences between male and female cortical and trabecular bone structures depicting increased cortical thickness as well as increased trabecular thickness and altered shape when compared to control mice. Plastin 3 is a highly conserved filamentous actin (F-actin) - bundling protein found to be ubiquitously expressed in cells of solid tissues. It binds F-actin to produce bundles that are important for the dynamic regulation of the cell cytoskeleton. As such it would be expected that the plastin 3 lack of expression or loss of function would produce severe multisystemic effects. Surprisingly, the affected individuals only presented a specific bone phenotype. Analysis of dermal fibroblasts showed an upregulation of the expression of α-actinin-1, α-actinin-4 and fascin-1 in patients. This has lead us to hypothesize that other actin-bundling proteins with functional homology can compensate for the absence of plastin 3 in tissue types that present the normal phenotype. This was confirmed by the co-injection of zebrafish with pls3 morpholinos and ACTN1 or ACTN4 mRNA which rescued the muscular-skeletal phenotype induced by pls3 knock-down. Our findings reveal a novel molecular pathway for plastin 3 and other F-actin bundling proteins in bone development. This new pathway is investigated further and may prove to be an important target in the prevention and treatment of osteoporosis.
    IBMS Herbert Fleisch Workshop, Brugge, Belgium; 03/2014
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    ABSTRACT: Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue, which results in bone fragility and fractures. It is a multifactorial disease which is often encountered in menopausal women. We recently identified novel pathogenic variants of the plastin 3 (PLS3) gene (Xq23) as causative factors for X-linked osteoporosis with fractures in five families (van Dijk et al. NEJM 2013:369(16):1529-36). These loss-of-function variants associated with decreased bone mineral density and increased risk of fracture in hemizygous young men whereas the clinical picture in heterozygous women ranged from asymptomatic to early-onset osteoporosis. The significance of plastin 3 in bone development was confirmed in a pls3 knock-down zebrafish model demonstrating malformations of developing craniofacial bone structure, body axis and tail. These malformations could be rescued dose dependently by PLS3 mRNA co-injection. Moreover, analysis of femora by micro computed tomography (µCT) in 3 months old transgenic mice overexpressing human PLS3 showed significant differences between male and female cortical and trabecular bone structures depicting increased cortical thickness as well as increased trabecular thickness and altered shape when compared to control mice. Plastin 3 is a highly conserved filamentous actin (F-actin) - bundling protein found to be ubiquitously expressed in cells of solid tissues. It binds F-actin to produce bundles that are important for the dynamic regulation of the cell cytoskeleton. As such it would be expected that plastin 3 loss of function would produce severe multisystemic effects. Surprisingly, the affected individuals only presented a specific bone phenotype. Analysis of dermal fibroblasts showed an upregulation of the expression of α-actinin-1, α-actinin-4 and fascin-1 in patients. This has lead us to hypothesize that other actin-bundling proteins with functional homology can compensate for the absence of plastin 3 in tissue types that present the normal phenotype. This was confirmed by the co-injection of zebrafish with pls3 morpholinos and ACTN1 or ACTN4 mRNA which rescued the skeletal phenotype induced by pls3 knock-down. Our findings reveal a novel molecular pathway for plastin 3 and other F-actin bundling proteins in bone development. This new pathway is investigated further and may prove to be an important target in the prevention and treatment of osteoporosis.
    Herbert Fleisch Workshop, Brugge, Belgium; 03/2014
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    ABSTRACT: Context: Low bone mineral density (BMD) has been associated with increased all-cause mortality. Cause-specific mortality studies have been controversial. Objective: To investigate associations between BMD and all-cause mortality and in-depth cause-specific mortality. Design and setting: Two cohorts from the prospective Rotterdam Study (RS), initiated in 1990 (RS-I) and 2000 (RS-II) with average follow-up of 17.1 (RS-I) and 10.2 (RS-II) years until January 2011. Baseline femoral neck BMD was analyzed in standard deviations. Deaths were classified according to International Classification of Diseases into 7 groups: cardiovascular diseases, cancer, infections, external, dementia, chronic lung diseases and other causes. Gender-stratified Cox and competing-risks models were adjusted for age, body mass index and smoking. Participants: 5779 (RS-I); 2055 (RS-II) subjects. Main outcome measurements: all-cause; cause-specific mortality. Results: A significant inverse association between BMD and all-cause mortality was found in males (HR(95%CI) RS-I: 1.07 (1.01-1.13), p=0.020; RS-II: 1.31 (1.12-1.55), p=0.001) but not in females (RS-I: 1.05 (0.99-1.11), p=0.098; RS-II: 0.91 (0.74-1.12), p=0.362). An inverse association with chronic lung disease mortality was found in males (RS-I: 1.75 (1.34-2.29), p <0.001; RS-II: 2.15 (1.05-4.42), p=0.037) and in RS-I in females (1.72 (1.16-2.57), p=0.008) persisting after multiple adjustments and excluding prevalent chronic obstructive pulmonary disease. A positive association between BMD and cancer mortality was detected in females in RS-I (0.89 (0.80-0.99), p=0.043). No association was found with cardiovascular mortality. Conclusions: BMD is inversely associated with mortality. The strong association of BMD with chronic lung disease mortality is a novel finding that needs further analysis to clarify underlying mechanisms.
    The Journal of clinical endocrinology and metabolism 02/2014; · 6.50 Impact Factor
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    ABSTRACT: Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.
    Bone 02/2014; 59:20-7. · 3.82 Impact Factor
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    ABSTRACT: Although the baby growing in its mother's womb needs calcium for skeletal development osteoporosis and fractures very rarely occur during pregnancy. A 27-year old woman in the seventh month of her first pregnancy contracted mid-thoracic back pain after lifting an object. The pain was attributed to her pregnancy, but remained post-partum. Her past medical history was uneventful, except for severely reduced vision of her left eye since birth. Family history revealed that her maternal grandmother had postmenopausal osteoporosis and her half-brother had three fractures during childhood after minor trauma. Her height was 1.58 m, she had no blue sclerae or joint hyperlaxity. Laboratory examination including serum calcium, phosphate, alkaline phosphatase, creatinine, bCTX, 25-hydroxyvitamin D and TSH was normal. Multiple thoracic vertebral fractures were diagnosed on X-ray examination and DXA-scanning showed severe osteoporosis (Z-scores L2-L4: -5.6 SD, femur neck: -3.9 SD). DNA analyses revealed two compound heterozygous missense mutations in LRP5. Her mother carried one of the LRP5 mutations and was diagnosed with osteoporosis. Her half-brother, treated with cabergoline for a microprolactinoma, also had osteoporosis of the lumbar spine on DXA and carried the same LRP5 mutation. The patient was treated with risedronate for 2.5 years. BMD and back pain improved. She stopped bisphosphonate use 6 months before planning a second pregnancy. Our patient was diagnosed with osteoporosis pseudoglioma syndrome/familial exudative vitreoretinopathy. Potentially underlying genetic causes should be considered in pregnancy-associated osteoporosis with implications for patients and relatives. More studies regarding osteoporosis treatment preceding conception are desirable.
    The Journal of clinical endocrinology and metabolism 01/2014; · 6.50 Impact Factor
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    ABSTRACT: 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.
    Bone 01/2014; · 3.82 Impact Factor
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    ABSTRACT: 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. 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. 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). 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). 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.
    Osteoporosis International 12/2013; · 4.04 Impact Factor
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    ABSTRACT: Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2,666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at P<5x10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6 x 10(-8). However, the association was not significant across 5,720 cases and 21,791 controls from 14 studies. Fixed-effects meta analyses summary estimate was 1.06 (95% CI: 0.98-1.14; P=0.17), displaying high degree of heterogeneity (I(2)=57%; Qhet p= 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (P=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions are needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.
    Bone 10/2013; · 3.82 Impact Factor
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    ABSTRACT: Denosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naïve or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55years received denosumab 60mg subcutaneously every 6months or risedronate 150mg orally every month for 12months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD) BMD T-scores of -1.6 (0.9), -1.9 (0.7), and -2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p<0.0001 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate at month 1 (median change from baseline of -78% vs -17%; p<0.0001) and month 6 (-61% vs -23%; p<0.0001). Overall and serious adverse events were similar between groups. In postmenopausal women who were suboptimally adherent to alendronate therapy, transitioning to denosumab was well tolerated and more effective than risedronate in increasing BMD and reducing bone turnover.
    Bone 10/2013; · 3.82 Impact Factor
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    ABSTRACT: Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multifactorial osteoporosis.
    New England Journal of Medicine 10/2013; · 51.66 Impact Factor
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    ABSTRACT: Osteoporotic vertebral fractures are an increasingly active area of research. Oftentimes assessments are performed by software-assisted quantitative morphometry. Here, we will discuss multi-functionality of these data for research purposes. A team of trained research assistants processed lateral spine radiographs from the population-based Rotterdam Study with SpineAnalyzer(®) software (Optasia Medical Ltd, Cheadle, UK). Next, the raw coordinate data of the two upper corners of Th5 and the two lower corners of Th12 were extracted to calculate the Cobb's kyphosis angle. In addition, two readers performed independent manual measurements of the Cobb's kyphosis angle between Th5 and Th12 for a sample (n=99). The mean kyphosis angle and its standard deviation were 53° and 10° for the SpineAnalyzer(®) software measurements and 54° and 12° by manual measurements, respectively. The Pearson's correlation coefficient was 0.65 [95% confidence interval (CI): 0.53-0.75; P=2×10(-13)]. There was a substantial intraclass correlation with a coefficient of 0.64 (95% CI: 0.51-0.74). The mean difference between methods was 1° (95% CI: -2°-4°), with 95% limits of agreement of -20°-17° and there were no systematic biases. In conclusion, vertebral fracture morphometry data can be used to derive the Cobb's kyphosis angle. Even more quantitative measures could be derived from the raw data, such as vertebral wedging, intervertebral disc space, spondylolisthesis and the lordosis angle. These measures may be of interest for research into musculoskeletal disorders such as osteoporosis, degenerative disease or Scheuermann's disease. Large-scale studies may benefit from efficient capture of multiple quantitative measures in the spine.
    Quantitative imaging in medicine and surgery. 10/2013; 3(5):249-255.
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    ABSTRACT: The aim of this study was to explore the possible mechanisms involved in an observed decline in serum calcium levels in patients with a neuroendocrine tumour (NET) treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). In 47 patients with NET who were normocalcaemic at baseline, serum calcium, albumin, creatinine, alkaline phosphatase, gamma glutamyl transpeptidase, magnesium, phosphate and 25-hydroxyvitamin D were prospectively analysed at baseline and up to 6 months after treatment. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3, type 1 aminoterminal propeptide of procollagen, bone-specific alkaline phosphatase, carboxyterminal crosslinking telopeptide of bone collagen, collagen type I crosslinked N-telopeptide, and creatinine and calcium in 24-h urine samples, were evaluated at baseline and at 3 and 6 months. Another 153 patients with NET were included in a retrospective study to estimate the occurrence of hypocalcaemia in a larger patient group. In the prospectively included patients, the mean serum calcium level decreased significantly after treatment (2.31 ± 0.01 to 2.26 ± 0.02 mmol/l, p = 0.02). Eight patients (17 %) showed a marked decrease in serum calcium levels with a nadir of ≤2.10 mmol/l. In five patients (11 %), calcium substitution therapy was prescribed. PTH increased significantly (5.9 ± 0.6 to 6.7 ± 0.8 pmol/l, p = 0.02), presumably in response to the decreasing serum calcium levels. 25-Hydroxyvitamin D remained stable after treatment. Creatinine levels increased significantly (73 ± 3 to 77 ± 3 μmol/l, p = 0.01), but not enough to explain the hypocalcaemia. Phosphate levels remained unaffected. In the retrospectively analysed patients, the mean serum calcium level decreased significantly from 2.33 ± 0.01 at baseline to a nadir of 2.24 ± 0.01 mmol/l at 18 months after treatment (p < 0.001). Of the 153 patients, 33 (22 %) showed a serum calcium nadir of ≤2.10 mmol/l, and 11 (7 %) received calcium substitution therapy. The mean serum calcium level decreased significantly after treatment with (177)Lu-octreotate, resulting in mild hypocalcaemia in about 20 % of patients. We excluded several potential causes of this hypocalcaemia, so the cause remains unknown. Serum calcium levels should be monitored after peptide receptor radionuclide therapy, and calcium substitution therapy should be initiated if appropriate.
    European Journal of Nuclear Medicine 07/2013; · 4.53 Impact Factor

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Institutions

  • 2006–2014
    • Erasmus Universiteit Rotterdam
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
  • 2004–2014
    • Erasmus MC
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
  • 2013
    • University of Gothenburg
      Goeteborg, Västra Götaland, Sweden
    • VU University Medical Center
      • Department of Clinical Genetics
      Amsterdamo, North Holland, Netherlands
  • 2012
    • Fudan University
      Shanghai, Shanghai Shi, China
  • 2010
    • University Hospital Regensburg
      Ratisbon, Bavaria, Germany
    • Leiden University Medical Centre
      • Department of Human Genetics
      Leiden, South Holland, Netherlands
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States