252 research outputs found
Osteoporosis: more than fractures alone : an epidemiological approach
The main purposes of this thesis are to study the incidence of and risk factors
for vertebral fractures and to evaluate the interrelations between bone mineral
density, atherosclerosis and breast cancer, all of which are considered to be
influenced by estrogen exposure. We will look into fracture prevention; are the
current methods for identifying subjects at risk for fractures adequate and
should men and women be treated equally. Finally, the results of these studies
are combined in a model on cost-effectiveness of fracture prevention In Chapter 2, vertebral fractures are investigated in both men and women. In
chapter 2.1, the incidence of vertebral fractures will be described. In addition, the
associations of incident vertebral fractures with both BMD and the presence of
baseline prevalent vertebral fractures are studied. In chapter 2.2, we extended the
analyses on risk factors for incident vertebral fractures for men and women. At
first, we evaluated potential risk factors univariately for an association \Vith
incident vertebral fractures. Then, we evaluated whether univariately sigoificant risk factors were independent from BMD, prevalent vertebral fractures and
from each other.
In Chapter 3, we study the value of a T -score of BMD in fracture prevention.
In Chapter 3.1 it is evaluated whether the current criterion for osteoporosis, as
defined by the 'WHO, of a T-score at or below -2.5, is useful in accurately
identifying women who will fracture within the coming years. Chapter 3.2
discusses whether the association between BMD and fractures is similar for
both men and women and if so, whether using a gender specific T -score of
BMD is useful in describing the problem of osteoporosis in men.
Chapter 4 describes the associations between BMD and diseases other than
osteoporosis that are also considered to be influenced by estrogen exposure.
First, in Chapter 4.1, the association between BMD and peripheral arterial
disease, which is a measure for generalised atherosclerosis, is described. Chapter
4.2 then shows the association between BMD and incident breast cancer in
women.
Following the associations between BMD and morbidity, the association
between femoral neck BMD and overall mortality is described for both men and
women in Chapter 5.
The results of a mathematical model on the cost-effectiveness of fracture
prevention are discussed in Chapter 6. This model is an example of how the
results as described in the previous chapters can be used to evaluate the costeffectiveness
of fracture prevention. In this model, different treatment strategies
ofHRT, SERMs and bisphosphonates are compared.
Finally, in Chapter 7 the overall results of this thesis are placed in perspective in
a general discussion. We further discuss pitfalls, as well as the clinical relevance
of the research that was presented in this thesis. The general discussion ends
with some suggestions for further research
Next-generation sequencing of immunoglobulin gene rearrangements for clonality assessment: a technical feasibility study by EuroClonality-NGS
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Etanercept for steroid-refractory acute graft-versus-host disease
Background: Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic stem cell transplantation (alloSCT). High dose glucocorticosteroids, are currently recommended as first-line treatment for grade II-IV aGVHD resulting in overall complete responses (CR) in 40%-50% of patients. No standard second-line regimen has been established. Different options have been reported, including anti-TNFα antibodies. Methods: We retrospectively reviewed the outcome of 15 patients with steroid-refractory (SR) aGVHD treated with etanercept at our institution. Patients were transplanted for a hematological malignancy and received either a myeloablative or a non-myeloablative conditioning regimen. Prophylaxis of GVHD consisted of cyclosporin A and mycophenolic acid. Results: Acute GVHD was diagnosed at a median of 61 days post-transplantation. All patients had grade III aGVHD of the gut. Second-line treatment with etanercept was started at a median of 13 days after initiation of first-line therapy. Overall response rate was 53%, with CR in 3 patients and PR in 5 patients. Median overall survival after initiation of treatment with etanercept was 66 days (range 5–267) for the entire group. Median overall survival was 99 days (range 47–267 days) for responders and 17 days (range 5–66 days) for non-responders (p<0.01). Nevertheless, all patients died. Causes of death were progressive GVHD in 7 patients (47%), infection in 6 patients (40%), cardiac death in 1 patient (6.7%) and relapse in 1 patient (6,7%). Conclusion: Second-line treatment with etanercept does induce responses in SR-aGVHD of the gut but appears to be associated with poor long-term survival even in responding patients
Thiazide diuretics and the risk for hip fracture
BACKGROUND: Since most hip fractures are related to osteoporosis, treating accelerated bone loss can be an important strategy to prevent hip fractures. Thiazides have been associated with reduced age-related bone loss by decreasing urinary calcium excretion. OBJECTIVE: To examine the association between dose and duration of thiazide diuretic use and the risk for hip fracture and to study the consequences of discontinuing use. DESIGN: Prospective population-based cohort study. SETTING: The Rotterdam Study. PARTICIPANTS: 7891 individuals 55 years of age and older. MEASUREMENTS: Hip fractures were reported by the general practitioners and verified by trained research assistants. Details of all dispensed drugs were available on a day-to-day basis. Exposure to thiazides was divided into 7 mutually exclusive categories: never use, current use for 1 to 42 days, current use for 43 to 365 days, current use for more than 365 days, discontinuation of use since 1 to 60 days, discontinuation of use since 6
Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk
In view of the interactions of vitamin D and the estrogen endocrine
system, we studied the combined influence of polymorphisms in the estrogen
receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the
susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr
and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI
restriction fragment length polymorphisms and three ERalpha haplotypes (1,
2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms
were identified. We captured 131 nonvertebral and 85 vertebral fracture
cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was
dose-dependently associated with increased vertebral fracture risk (P <
0.001) corresponding to an odds ratio of 1.9 [95% confidence interval
(CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was
overrepresented in vertebral fracture cases. There was a significant
interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in
determining vertebral fracture risk. The association of ERalpha haplotype
1 with vertebral fracture risk was only present in homozygous carriers of
VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for
heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha
haplotype 1. These associations were independent of bone mineral density.
In conclusion, interaction between ERalpha and VDR gene polymorphisms
leads to increased risk of osteoporotic vertebral fractures in women,
largely independent of bone mineral density
Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk
In view of the interactions of vitamin D and the estrogen endocrine
system, we studied the combined influence of polymorphisms in the estrogen
receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the
susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr
and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI
restriction fragment length polymorphisms and three ERalpha haplotypes (1,
2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms
were identified. We captured 131 nonvertebral and 85 vertebral fracture
cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was
dose-dependently associated with increased vertebral fracture risk (P <
0.001) corresponding to an odds ratio of 1.9 [95% confidence interval
(CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was
overrepresented in vertebral fracture cases. There was a significant
interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in
determining vertebral fracture risk. The association of ERalpha haplotype
1 with vertebral fracture risk was only present in homozygous carriers of
VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for
heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha
haplotype 1. These associations were independent of bone mineral density.
In conclusion, interaction between ERalpha and VDR gene polymorphisms
leads to increased risk of osteoporotic vertebral fractures in women,
largely independent of bone mineral density
Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk
This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied
Emergency department visits due to vertebral fractures in the Netherlands, 1986-2008: Steep increase in the oldest old, strong association with falls
Background: Vertebral fractures are a common consequence of osteoporosis in older persons. With the ageing of the population, number
Homocysteine levels and the risk of osteoporotic fracture
BACKGROUND: Very high plasma homocysteine levels are characteristic of
homocystinuria, a rare autosomal recessive disease accompanied by the
early onset of generalized osteoporosis. We therefore hypothesized that
mildly elevated homocysteine levels might be related to age-related
osteoporotic fractures. METHODS: We studied the association between
circulating homocysteine levels and the risk of incident osteoporotic
fracture in 2406 subjects, 55 years of age or older, who participated in
two separate prospective, population-based studies. In the Rotterdam
Study, there were two independent cohorts: 562 subjects in cohort 1, with
a mean follow-up period of 8.1 years; and 553 subjects in cohort 2, with a
mean follow-up period of 5.7 years. In the Longitudinal Aging Study
Amsterdam, there was a single cohort of 1291 subjects, with a mean
follow-up period of 2.7 years. Multivariate Cox proportional-hazards
regression mode
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