| 1. |
- Johnell, Olof, et al.
(author)
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Predictive value of BMD for hip and other fractures.
- 2005
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In: Journal of bone and mineral research. - 0884-0431 .- 1523-4681. ; 20:7, s. 1185-94
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Journal article (peer-reviewed)abstract
- The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of approximately 39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score. INTRODUCTION: The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value. MATERIALS AND METHODS: We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients. RESULTS: BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value. CONCLUSIONS: We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.
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| 2. |
- Kanis, John A, et al.
(author)
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A meta-analysis of milk intake and fracture risk: low utility for case finding.
- 2005
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In: Osteoporosis international. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 16:7, s. 799-804
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Journal article (peer-reviewed)abstract
- A low intake of calcium is widely considered to be a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the effect of age, gender and bone mineral density (BMD) on this risk. We studied 39,563 men and women (69% female) from six prospectively studied cohorts comprising EVOS/EPOS, CaMos, DOES, the Rotterdam study, the Sheffield study and a cohort from Gothenburg. Cohorts were followed for 152,000 person-years. The effect of calcium intake as judged by the intake of milk on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age and BMD. The results of the different studies were merged by using the weighted beta-coefficients. A low intake of calcium (less than 1 glass of milk daily) was not associated with a significantly increased risk of any fracture, osteoporotic fracture or hip fracture. There was no difference in risk ratio between men and women. When both sexes were combined there was a small but non-significant increase in the risk of osteoporotic and of hip fracture. There was also a small increase in the risk of an osteoporotic fracture with age which was significant at the age of 80 years (RR = 1.15; 95% CI = 1.02-1.30) and above. The association was no longer significant after adjustment for BMD. No significant relationship was observed by age for low milk intake and hip fracture risk. We conclude that a self-reported low intake of milk is not associated with any marked increase in fracture risk and that the use of this risk indicator is of little or no value in case-finding strategies.
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| 3. |
- Uitterlinden, André G, et al.
(author)
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The association between common vitamin D receptor gene variations and osteoporosis : a participant-level meta-analysis
- 2006
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In: Annals of Internal Medicine. - 0003-4819. ; 145:4, s. 255-264
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Journal article (peer-reviewed)abstract
- BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear.OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures.DESIGN: Prospective multicenter large-scale association study.SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams.PARTICIPANTS: 26,242 participants (18,405 women).MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures.RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model).LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis.CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.
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| 4. |
- van Meurs, Joyce B, et al.
(author)
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Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
- 2008
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In: JAMA : the journal of the American Medical Association. - Chicago : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 299:11, s. 1277-90
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Journal article (peer-reviewed)abstract
- CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
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