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  • 1
    Keywords: THERAPY ; PATIENT ; TRIALS ; AGE ; REPRODUCIBILITY ; POSTMENOPAUSAL WOMEN ; REQUIRING PROLONGED OBSERVATION ; RECALL ; COLLABORATIVE REANALYSIS ; SEX-HORMONES
    Abstract: BACKGROUND: Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. METHODS: Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. FINDINGS: Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p〈0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p〈0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p〈0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p〈0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p〈0.01 for both comparisons). INTERPRETATION: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. FUNDING: Cancer Research UK.
    Type of Publication: Journal article published
    PubMed ID: 23084519
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  • 2
    ISSN: 1433-2965
    Keywords: Key words:Broadband ultrasound attenuation – Quantitative ultrasound – Speed of sound
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip fractures and is currently an FDA-approved tool to identify women at risk of osteoporosis. However, few studies have investigated the lifestyle and genetic correlates of QUS in women. This study investigated the cross-sectional associates of several lifestyle, demographic and genetic factors with calcaneal QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS)) in 393 women aged 45–53 years. Leisure-time and historical physical activity, dietary calcium and protein, body composition, vitamin D receptor genotypes, menopause status, other health behaviors, calcaneal QUS parameters and bone mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent physical activity and African-American race were the strongest correlates of SOS whereas dietary protein, calcium and recent physical activity were the strongest correlates of BUA. These predictors explained 13% and 6% of the variance in SOS and BUA, respectively. Smoking, alcohol intake, education, hormone replacement therapy, calcium and vitamin D supplements, historical physical activity and vitamin D receptor genotypes were not significantly associated with BUA or SOS. Lean body mass and premenopausal status were the strongest correlates of lumbar BMD whereas lean body mass, physical activity, African-American race and body mass index were significantly related to femoral neck BMD. Physical activity remained predictive of SOS after controlling for lumbar BMD. The spectrum and magnitude of risk factors for SOS and BUA, including lean body mass, physical activity, race, protein and calcium intake, parallel previously observed predictors of BMD.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1433-2965
    Keywords: Key words:Fractures – Mortality – Osteoporosis – Public health impact
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: To examine the risk of mortality following all clinical fractures, we followed 6459 women age 55–81 years participating in the Fracture Intervention Trial for an average of 3.8 years. All fractures and deaths were confirmed by medical record or death certificate. Clinical fractures were fractures that came to medical attention. Fracture status was used as a time-dependent covariate in proportional hazards models. The 907 women who experienced a fracture were older, had lower bone mineral density and were more likely to report a positive fracture history. A total of 122 women died over the course of the study with 23 of these deaths occurring after a clinical fracture. The age-adjusted relative risk (95% confidence intervals) of dying following a clinical fracture was 2.15 (1.36, 3.42). This primarily reflected the higher mortality following a hip fracture, 6.68 (3.08, 14.52); and clinical vertebral fracture, 8.64 (4.45, 16.74). Results were similar after adjusting for treatment assignment, health status and specific common comorbidities. There was no increase in mortality following a forearm or other fracture (non-hip, non-wrist, non-vertebral fracture). In conclusion, clinical vertebral fractures and hip fractures are associated with a substantial increase in mortality among a group of relatively healthy older women.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1433-2965
    Keywords: Bone biomechanics ; Hip fracture: etiology, epidemiology, racial differences ; Proximal femur, anatomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Compared with white women, Asian women have about a 40%–50% and blacks a 50%–60% lower risk of hip fracture, but the reason for this racial difference is not known. Women with a shorter hip axis have a lower risk of hip fracture. To test the hypothesis that a shorter hip axis length could account for the lower risk of hip fracture among Asian and black women, we measured hip axis length in 135 Caucasian, 74 Asian and 50 black women. The mean hip axis lengths of Asian and black women were significantly shorter (1.2 and 0.7 standard deviations, respectively) than that of the whites (p〈0.0001). We estimate that, compared with white women, Asians would have a 47% lower risk (95% confidence interval: 32%–63%) and blacks would have a 32% (15%–45%) lower risk of hip fracture because of their shorter hip axis. We conclude that a shorter hip axis length might be a major factor accounting for Asian women's lower risk of hip fracture and might contribute to the lower risk in black women.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1433-2965
    Keywords: Alendronate ; Clinical trial ; Osteoporosis ; Vertebral fracture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The Fracture Intervention Trial (FIT) is a randomized, double-masked, placebo-controlled trial designed to test the hypothesis that alendronate, an amino-bisphosphonate, will reduce the rate of fractures in women aged 55–80 years with low hip bone marrow density (〈0.68 gm/cm2 at the femoral neck). It is being conducted at 11 clinical centers around the United States with a coordinating center at UC San Francisco. The goal was to randomize 6000 women. When recruitment was completed (in May 1993), 6457 women had been randomized, amounting to 108% of goal. The women were assigned to one of two substudies. The first (Vertebral Deformity study) includes 2023 women who have at least one vertebral deformity, and will test the hypothesis that alendronate reduces the rate of new vertebral deformities during 3 years of follow-up. This substudy has a power of 0.90 to detect a 32% reduction in the incidence of new vertebral deformities, assuming a 6.5% annual incidence of new vertebral deformities in the placebo group. The second study (Clinical Fracture study) includes 4434 women without vertebral deformities at baseline and will test the hypothesis that alendronate reduces the rate of clinically recognized fractures of all types over an average of 4.25 years of follow-up. This substudy has a 0.90 power to detect a 25% reduction in the rate of all clinical fractures, assuming 4% annual incidence in the placebo group. To our knowledge, this is the largest prospective, randomized, controlled study undertaken to determine the effectiveness of a treatment in reducing the risk of fractures in postmenopausal women.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1433-2965
    Keywords: Bone mineral density ; Osteoporosis ; Premenopausal ; Vitamin D receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The genetic influence on bone mineral density (BMD) is thought to be mediated in part by alleles at the vitamin D receptor (VDR) locus. In order to assess the effect of VDR on BMD in premenopausal women, we studied 470 healthy white subjects, aged 44–50 years, participating in the Women's Healthy Lifestyle Project. Each participant was genotyped for theBsmI polymorphism at the VDR gene locus. BMD at the lumbar spine, hip and whole-body, and the whole-body soft tissue composition, were measured cross-sectionally using a Hologic QDR 2000 densitometer. The presence of a polymorphic restriction site at the VDR gene locus was specified asb, whereas absence of this site wasB. The frequency distribution of the VDR genotype was:bb, 20.6%;Bb, 39.1%; andBB, 40.2%. Spinal BMD (mean±SD) was significantly lower in women with VDR genotypeBB (1.038±0.11 g/cm2) as compared with those with genotypebb (1.069±0.12 g/cm2,p〈0.05). Trochanter BMD was 2.7% lower in those with genotypeBB versusbb (0.685±0.10 g/cm2 vs 0.708±0.09 g/cm2). A similar trend was shown at each subregion of the hip, but not at the whole-body. In premenopausal women, allelic status at the VDR locus contributed to variations in spinal and trochanteric BMDs, but the absolute difference in BMDs was small, amounting to 0.26 and 0.23 standard deviations, respectively. It is concluded that in this population of healthy premenopausal women there was a significant association between polymorphisms at the VDR gene locus and both spinal and trochanteric BMDs, yet no association was demonstrated for the whole-body BMD.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0827
    Keywords: Key words: Genetics — Osteoporosis — Quantitative ultrasound — Alpha-2-HS glycoprotein — Polymorphism.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract. Calcaneal broadband ultrasound attenuation (BUA) is an independent predictor of hip and vertebral fractures. BUA is under genetic control, but the specific genes contributing to BUA are not well defined. We examined the relationship between genetic variation in α2HS-glycoprotein (AHSG), an abundant noncollagenous protein of bone matrix, and calcaneal BUA. Genetic polymorphism in AHSG was determined in 222 Caucasian women (age 66–92) enrolled in the Pittsburgh Study of Osteoporotic Fractures clinical center by isoelectric focusing of serum samples. Calcaneal BUA and bone mineral density (BMD) were measured on the same foot with a Walker Sonix UBA 575+ and single X-ray absorptiometry. Hip and spine BMD were determined with a Hologic QDR-1000 densitometer using dual-energy X-ray absorptiometry. AHSG polymorphism was not significantly related to hip, lumbar spine, or calcaneal BMD. Compared with the homozygous AHSG*2 women, calcaneal BUA was 13% lower in heterozygous (P 〈 0.05) and 16% lower in homozygous AHSG*1 women (P 〈 0.05). This relationship persisted after controlling for age, weight, height, walks for exercise, and calcaneal BMD. Current and self-reported height were also lowest in homozygous AHSG*1 women, intermediate in heterozygous women, and highest among homozygous AHSG*2 subjects. These results suggest that the AHSG polymorphism may contribute to the genetic influence on calcaneal BUA and stature.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0827
    Keywords: Key words: Cytokines — Bone mineral density — Premenopausal — Interleukin-1 — Interleukin-6 — Tumor necrosis factor.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract. Cytokines such as interleukin-1 (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) can influence both bone resorption and bone formation. The objective of this cross-sectional study was to examine the relationship between cytokine production by peripheral blood mononuclear cells (PBMC) and bone mineral density (BMD); the annual rate of change in BMD was examined. Subjects participating in a randomized clinical trial entitled the Women's Healthy Lifestyle Project in Allegheny County, Pennsylvania were used. They included 50 healthy premenopausal women, aged 45–52 years, who had regular menses within the past 3 months and were not on replacement estrogens. Dual-energy X-ray absorptiometry measurements at the AP lumbar spine and femoral neck were made at baseline and at the first annual exam using a Hologic QDR 2000 densitometer. Cytokine production of IL-1β, IL-6, and TNF-α by PBMC was measured at the annual exam. The median values for stimulated cytokine production by PBMC were 3.92 ng/ml, 31.3 ng/ml, and 1.05 ng/ml, for IL-1β, IL-6, and TNF-α, respectively. There were modest correlations between cytokine production and cross-sectional BMD, ranging from r =−0.30 to r =−0.13. Trends of greater spinal bone loss were observed in women with ``high'' (≥75th percentile) cytokine production of stimulated IL-1β and IL-6 (IL-1β: ``high'' =−1.56% ± 0.70 versus ``low'' (〈75th percentile) =−0.56% ± 0.35, P= 0.21). In contrast, greater annual gains in femoral neck BMD were observed in those with high cytokine production of IL-1β and IL-6 (IL-1β: high = 3.39% ± 1.16 versus low =−0.85 ± 0.58, P= 0.002). There was no association between stimulated TNF production and annual change in BMD. In this population of healthy premenopausal women, the relationship between cytokine production by PBMC and the rate of change in BMD was significantly different for the lumbar spine and femoral neck, possibly reflecting differences in the proportion of trabecular and cortical bone at these sites.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1433-2965
    Keywords: Bone quality ; Broadband ultrasound attenuation ; Epidemiology ; Osteoporosis ; Quantitative ultrasound ; Speed of sound
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1433-2965
    Keywords: Bone ultrasound ; Osteoporosis fractures ; Race ; Ethnicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The lower fracture rates among African-American women relative to Caucasian women may reflect their higher bone mass. However, bone mass is not the only determinant of bone strength: the quality and microarchitecture of the bone are also important. Quantitative ultrasound is believed to measure properties of bone strength that are independent of bone mass. To test the hypothesis that there are racial differences in quantitative ultrasound measures of bone, we recruited 154 African-American women age ⩾65 years. A random sample of 300 Caucasian women participating in the Study of Osteoporotic Fractures in Pittsburgh, Pennsylvania, was chosen for comparison. The Walker Sonix UBA 575+ was used to measure calcaneal broadband ultrasonic attenuation (BUA). Duplicate BUA measurements were obtained with a reproducibility of 5%. We measured bone mineral density (BMD) of the hip and calcaneus using single (calcaneus) or dual (hip) energy X-ray absorptiometry. The correlation between BUA and calcaneal BMD was similar in Caucasians (r=0.66,p〈0.001) and African-Americans (r=0.58,p〈0.001). Age-adjusted BUA (dB/MHz) was higher among the African-American women than Caucasian women (69.1 and 66.2, respectively), but these differences were not statistically significant, (p=0.12). Adjustment for calcaneal BMD completely attenuated the racial differences in BUA. BMD at the femoral neck and calcaneus was higher among the African-American women, even after adjusting for age, height and weight. In conclusion, our results suggest that racial differences in rates of fracture cannot be explained by differences in bone quality as assessed by ultrasound attenuation.
    Type of Medium: Electronic Resource
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