FokI polymorphism at translation initiation site of the vitamin D receptor gene predicts bone mineral density and vertebral fractures in postmenopausal Italian women.

A novel T/C polymorphism (ATG to ACG) at the translation initiation site of the vitamin D receptor (VDR) gene, defined by FokI restriction endonuclease, has been recently associated with variation in bone mineral density (BMD) and rates of bone loss in a group of postmenopausal Mexican-American women. The presence of the restriction site, designated as f, allows protein translation to initiate from the first ATG, while the allele lacking the site, indicated as F, initiates translation at a second ATG. In this study, we investigated the role of FokI polymorphism in a group of 400 postmenopausal women of Italian descent stratified for BMD into osteoporotic (n = 164), osteopenic (n = 117), and normal (n = 119) groups. There were 159 (41%) FF homozygotes, 55 (14%) ff homozygotes, and 186 (45%) Ff heterozygotes. In the whole population, we observed a weak association between FokI polymorphism and lumbar BMD (p = 0.06, analysis of covariance [ANCOVA]) but not with femoral neck BMD (p = 0.5, ANCOVA). Interestingly, the effect of FokI genotypes on lumbar BMD was influenced by the years since menopause such that differences in BMD related to different VDR allelic variants were greater among women in the first 5 years of menopause (p = 0.04, ANCOVA), progressively declining afterward. In addition, a significantly higher prevalence of ff genotype in osteoporotic than in osteopenic and normal women was observed (p = 0.04, Chi-square test). Finally, ff genotype resulted significantly over-represented in the group of women with a vertebral fracture as compared with controls (p = 0.003, Chi-square test), equivalent to a relative risk of 2.58 (95% confidence intervals 1.36-4.91). We conclude that in this population, FokI polymorphism at the VDR gene locus accounts for a part of the heritable component of BMD at the lumbar spine.     

Low dietary riboflavin but not folate predicts increased fracture risk in postmenopausal women homozygous for the MTHFR 677 T allele.

The MTHFR C677T polymorphism is associated with mildly elevated homocysteine levels when folate and/or riboflavin status is low. Furthermore, a mildly elevated homocysteine level is a risk factor for osteoporotic fractures. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T variant on fracture risk in 5,035 men and women from the Rotterdam Study. We found that the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women. INTRODUCTION: The MTHFR C677T polymorphism is associated with mildly elevated homocysteine (Hcy) levels in the presence of low folate and/or riboflavin status. A mildly elevated Hcy level was recently identified as a modifiable risk factor for osteoporotic fracture. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T polymorphism on BMD and fracture risk. MATERIALS AND METHODS: We studied 5,035 individuals from the Rotterdam Study, >or=55 yr of age, who had data available on MTHFR, nutrient intake, and fracture risk. We performed analysis on Hcy levels in a total of 666 individuals, whereas BMD data were present for 4,646 individuals (2,692 women). RESULTS: In the total population, neither the MTHFR C677T polymorphism nor low riboflavin intake was associated with fracture risk and BMD. However, in the lowest quartile of riboflavin intake, female 677-T homozygotes had a 1.8 (95% CI: 1.1-2.9, p = 0.01) times higher risk for incident osteoporotic fractures and a 2.6 (95% CI: 1.3-5.1, p = 0.01) times higher risk for fragility fractures compared with the 677-CC genotype (interaction, p = 0.0002). This effect was not seen for baseline BMD in both men and women. No significant influence was found for dietary folate intake on the association between the MTHFR C677T genotype and fracture risk or BMD. In the lowest quartile of dietary riboflavin intake, T-homozygous individuals (men and women combined) had higher (22.5%) Hcy levels compared with C-homozygotes (mean difference = 3.44 microM, p = 0. 01; trend, p = 0.02). CONCLUSIONS: In this cohort of elderly whites, the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women.     

Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.

Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.     

Prediction of clinical non-spine fractures in older black and white men and women with volumetric BMD of the spine and areal BMD of the hip: the Health, Aging, and Body Composition Study*.

In a prospective study of 1446 black and white adults 70-79 yr of age (average follow-up, 6.4 yr), vertebral TrvBMD from QCT predicted non-spine fracture in black and white women and black men, but it was not a stronger predictor than total hip aBMD from DXA. Hip aBMD predicted non-spine fracture in black men. INTRODUCTION: Areal BMD (aBMD) at multiple skeletal sites predicts clinical non-spine fractures in white and black women and white men. The predictive ability of vertebral trabecular volumetric BMD (TrvBMD) for all types of clinical non-spine fractures has never been tested or compared with hip aBMD. Also, the predictive accuracy of hip aBMD has never been tested prospectively for black men. MATERIALS AND METHODS: We measured vertebral TrvBMD with QCT and hip aBMD with DXA in 1446 elderly black and white adults (70-79 yr) in the Health, Aging, and Body Composition Study. One hundred fifty-two clinical non-spine fractures were confirmed during an average of 6.4 yr of >95% complete follow-up. We used Cox proportional hazards regression to determine the hazard ratio (HR) and 95% CIs of non-spine fracture per SD reduction in hip aBMD and vertebral TrvBMD. RESULTS: Vertebral TrvBMD and hip aBMD were both associated with risk of non-spine fracture in black and white women and black men. The age-adjusted HR of fracture per SD decrease in BMD was highest in black men (hip aBMD: HR = 2.04, 95% CI = 1.03, 4.04; vertebral TrvBMD: HR = 3.00, 95% CI = 1.29, 7.00) and lowest in white men (hip aBMD: HR = 1.23, 95% CI = 0.85, 1.78; vertebral TrvBMD: HR = 1.06, 95% CI = 0.73, 1.54). Adjusted for age, sex, and race, each SD decrease in hip aBMD was associated with a 1.67-fold (95% CI = 1.36, 2.07) greater risk of fracture, and each SD decrease in vertebral TrvBMD was associated with a 1.47-fold (95% CI = 1.18, 1.82) greater risk. Combining measurements of hip aBMD and vertebral TrvBMD did not improve fracture prediction. CONCLUSIONS: Low BMD measured by either spine QCT or hip DXA predicts non-spine fracture in older black and white women and black men. Vertebral TrvBMD is not a stronger predictor than hip aBMD of non-spine fracture.     

Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women

Osteoporotic fractures are a leading cause of disability and, indirectly, of death in the elderly population. Previous studies have shown that homocysteine level and the C677T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) may be involved in the development of osteoporosis and its related fracture in European populations. The aim of this study was to verify the association of this polymorphism with bone mineral density (BMD) and fractures in our 1899 Chinese postmenopausal women. The C677T T allele frequency in this population was 39.2%. The distribution of the MTHFR genotypes followed the Hardy-Weinberg equilibrium. BMD at total body, total hip or femoral neck did not significantly vary with MTHFR C677T genotype. The T allele carrier tended to have higher risk of having osteoporosis or osteopenia, but the difference was statistically insignificant. However, Poisson regression analysis revealed that the T allele carriers had an increased risk of fractures (RR=1.7, 95% CI=1.1-2.7, p=0.01) which occurred before or after menopause. As far as fracture incidence after menopause was concerned, the CT or TT genotype had more than twice the risk of the CC genotype (RR=2.5, 95% CI=1.2-4.9, p=0.009). This association was independent of age, physical activity, occupation, passive smoking, height, weight, years since menopause, and total hip BMD. Our data show that the MTHFR C677T polymorphism is an independent predictor of fracture risk, although it only had a weak effect on BMD. Further study on the mechanistic role that this polymorphism plays in the development of fractures may lead to better understanding of the etiology of osteoporotic fracture.     

Quantitative ultrasound predicts hip and non-spine fracture in men: the MrOS study

Summary Quantitative ultrasound (QUS) is associated with fracture risk in women, but there are few data in men. We studied 5,607 older men and found that QUS predicts hip and any non-spine fracture risk nearly as well as BMD. Combined measurements of QUS and BMD are not superior to either measurement alone. Introduction Quantitative ultrasound (QUS) predicts fracture risk among older women, but there are few prospective studies among older men. We studied the ability of QUS and BMD measurements to predict hip and other non-spine fractures in a population-based study of older men. Methods Calcaneal QUS and hip BMD were measured in 5,607 men aged ≥65 years recruited from six US centers. At baseline duplicate QUS measurements with repositioning were obtained, and subsequent hip and other non-spine fractures were documented by review of x-rays or x-ray reports. The relationships between QUS and fractures were examined with proportional hazard models adjusted for age and clinic. We used receiver operating characteristic curves and predicted fracture risk models to determine the utility of QUS alone, BMD alone or the combination of QUS+BMD. Results During a mean follow-up of 4.2 years with 99% complete follow-up, 239 men suffered a non-spine fracture, including 49 hip fractures. Each standard deviation reduction in broadband ultrasonic attenuation (BUA) was associated with an increased risk of hip (relative hazard=2.0, CI: 1.5, 2.8) and any non-spine fracture (relative hazard=1.6, CI: 1.4, 1.8). The area under the receiver operating characteristic curve and the predicted probability of fracture were similar for BUA alone, BMD alone and the combination of BUA+BMD, indicating that once BUA or BMD is known, the other measurement does not add useful information. Other QUS parameters gave similar results. Conclusions QUS measurements predict the risk of hip and any non-spine fracture in older men, and do so nearly as well as hip BMD measurements. Combined measurements of QUS and BMD are not superior to either measurement alone. Funding: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), and the National Cancer Institute (NCI), under the following grant numbers: UO1 AG18197-02, UO1 AR45580-02, UO1 AR45614, UO1 AR45632, UO1 AR45647, UO1 AR45654, UO1 AR45583 and M01 RR00334.     

Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial.

We used data from the Fracture Intervention Trial to assess the relationship change in bone turnover after 1 year of alendronate or placebo treatment and subsequent hip, non-spine, and spine fracture risk among 6186 postmenopausal women. In the alendronate group (n = 3105), greater reductions in one or more biochemical marker were associated with a lower risk of fracture. INTRODUCTION: There are few data on the relationship between short-term change in biochemical markers of bone turnover and non-spine fracture risk among bisphosphonate-treated women, and the clinical use of such measurements is unknown. MATERIALS AND METHODS: We measured biochemical markers of bone turnover (bone-specific alkaline phosphatase [bone ALP], intact N-terminal propeptide of type I collagen, and C-terminal crosslinked telopeptide of type 1 collagen) and BMD of the spine and hip at baseline and after 1 year of alendronate or placebo. During a mean follow-up of 3.6 years, 72 hip, 786 non-spine, and 336 vertebral fractures were documented. RESULTS AND CONCLUSIONS: Each 1 SD reduction in 1-year change in bone ALP was associated with fewer spine (odds ratio = 0.74; CI: 0.63, 0.87), non-spine (relative hazard [RH] = 0.89; CI: 0.78, 1.00; p < 0.050), and hip fractures (RH = 0.61; CI: 0.46, 0.78). Alendronate-treated women with at least a 30% reduction in bone ALP had a lower risk of non-spine (RH = 0.72; CI: 0.55, 0.92) and hip fractures (RH = 0.26; CI: 0.08, 0.83) relative to those with reductions <30%. We conclude that greater reductions in bone turnover with alendronate therapy are associated with fewer hip, non-spine, and vertebral fractures, and the effect is at least as strong as that observed with 1-year change in BMD.     

The association of Parkinson’s disease with bone mineral density and fracture in older women

Among community-dwelling older women, compared to those without Parkinson's disease (PD), women with PD have 7.3% lower BMD and an increased risk for hip fracture (HR = 2.6). INTRODUCTION: Studies reporting an association of Parkinson's disease (PD) with low bone mineral density (BMD) and increased fracture risk often have been prone to selection bias, and have not accounted for potentially important explanatory variables, including recent weight loss. Further, little is known about the association between PD and non-hip fractures. Consequently, we investigated the independent association of PD with hip BMD and long-term fracture risk. METHODS: Associations of self-reported PD with hip BMD and incident hip and non-spine, non-hip fracture were analyzed using linear regression and Cox proportional hazards, respectively. This prospective cohort study analyzed 8,105 older women with known PD status (n = 73 with PD) at four US clinical centers of the Study of Osteoporotic Fractures. RESULTS: Compared to women without PD, age-adjusted mean total hip BMD was 7.3% lower in women with PD. Women with PD had a 2.6-fold higher age-adjusted risk for incident hip fracture. Parkinson's disease was not significantly associated with non-spine, non-hip fractures. CONCLUSIONS: In age-adjusted models, women with PD had lower hip BMD and increased hip fracture risk, associations that were no longer significant after further weight and multivariate adjustment. Older women with PD should be considered for evaluation and treatment to reduce their fracture risk.     

Femoral neck bone loss predicts fracture risk independent of baseline BMD.

Whereas low BMD is known to be a risk factor for fracture, it is not clear whether loss of BMD is also a risk factor. In elderly women, greater loss of BMD at the femoral neck was associated with increased risk of fracture, independent of baseline BMD and age. INTRODUCTION: Baseline measurement of BMD predicts fracture risk. However, it is not clear whether short-term bone loss is an independent risk factor for fractures. This study was designed to investigate the relationship between changes in BMD and fracture risk in elderly women in the general population. MATERIALS AND METHODS: A total of 966 women > or = 60 years of age (mean, 70 +/- 6.7 [SD] years), who had been followed for an average of 10.7 years, were studied. Atraumatic fracture of the proximal femur (hip), symptomatic vertebral fracture, and other major fractures, excluding pathological fractures or those resulting from severe trauma, were recorded and confirmed by radiographs. Femoral neck and lumbar spine BMD was measured by DXA. RESULTS: During the follow-up period, 224 had sustained a fracture (including 43 hip, 71 symptomatic vertebrae, 37 proximal humerus, 46 forearm and wrist, and 27 rib and pelvis fractures). The annual rate of change in BMD in fracture women (-2.1 +/- 4.2%) was significantly higher than that in nonfracture women (-0.8 +/- 2.8%; p = 0.005). In the multivariable Cox's proportional hazards analysis, the following factors were significant predictors of fracture risk: femoral neck bone loss (relative hazard [RH], 1.4; 95% CI, 1.1-1.8 per 5% loss), baseline femoral neck BMD (RH, 2.0; 95% CI, 1.7-2.7 per SD), and advancing age (RH, 1.2; 95% CI, 1.1-1.4). The proportion of fractures attributable to the three factors was 45%. For hip fracture, the attributable risk fraction was approximately 90%. CONCLUSION: Bone loss at the femoral neck is a predictor of fracture risk in elderly women, independent of baseline BMD and age.     

Association between prior non-spine non-hip fractures or prevalent radiographic vertebral deformities known to be at least 10 years old and incident hip fracture.

In this large cohort of elderly women, prior non-spine non-hip fractures and radiographic vertebral deformities >10 years old were modestly associated with incident hip fracture, but the excess risks of hip fracture attributable to those prior fractures and deformities seem to wane over time. INTRODUCTION: Whereas prior clinical fractures and prevalent radiographic vertebral deformities are well-documented predictors of incident hip fracture, the excess risks of incident fractures attributable to those prior fractures and deformities may decrease over time. Current guidelines regarding the assessment of fracture risk do not consider elapsed time since prior fracture or ascertainment of radiographic vertebral deformity. MATERIALS AND METHODS: We ascertained self-reported history of prior clinical fractures and calcaneal and total hip bone BMD and performed lateral spine radiographs in a cohort of 9516 community-dwelling elderly women who had not had a prior hip fracture. We prospectively followed them to assess incident hip fracture. Prevalent radiographic vertebral deformities were identified at baseline using morphometry, and incident hip fractures were confirmed by review of radiographic reports during three follow-up periods (0-5, >5-10, and >10 years after baseline exam). RESULTS: Among women who survived for 10 or more years after the baseline exam without having had a hip fracture, a history of non-spine non-hip fracture since age 50 reported at the baseline study examination was associated with a 21% age- and calcaneal BMD-adjusted excess risk (hazard ratio [HR], 1.21; 95% CI, 1.01-1.45) for subsequent incident hip fracture. Baseline radiographic vertebral deformity was associated with a 41% age- and BMD-adjusted excess risk (HR, 1.41; 95% CI, 1.15-1.73) of hip fracture after 10 years of follow-up. In comparison, the age- and BMD-adjusted HRs of incident hip fracture during the first 5 years of follow-up associated with prior non-spine non-hip fractures reported at the baseline study exam and prevalent radiographic vertebral deformities were 1.70 (95% CI, 1.30-2.22) and 2.10 (95% CI, 1.58-2.78), respectively. CONCLUSIONS: Self-reported prior non-spine non-hip fractures and prevalent radiographic vertebral deformities known to be at least 10 years old are modestly associated with incident hip fracture. The association between these predictor fractures and subsequent hip fractures seems to wane with increased time after ascertainment of the predictor fracture. Hip fracture risk assessment strategies incorporating prior fracture history should also consider elapsed time since those prior fractures.     

Lack of association between estrogen receptor genotypes and bone mineral density, fracture history, or muscle strength in elderly women.

The PvuII polymorphism of the estrogen receptor (ESR) gene and its relation to bone mineral density (BMD), fracture history, and muscle strength was studied in 313 postmenopausal (76 +/- 5 years) women of Caucasian origin, of whom 142 had suffered from a fragility fracture after the age of 50 years (14 with fracture of the hip, 38 of the spine, 45 of the wrist, and 85 of other bones). The ESR genotype distribution was similar in women with and without a history of fragility fracture (PP 21%, Pp 43%, pp 36% compared with PP 18%, Pp 47%, pp 35%). We did not find a correlation between the ESR genotypes and BMD at the lumbar spine, the femoral neck, or the proximal forearm. No association was found with grip or quadriceps strength. We further evaluated the relationship between the vitamin D receptor (VDR) and ESR haplotypes and BMD in a random subgroup of 270 elderly women. No differences were found in women with the BBpp versus the bbPP haplotype in the femoral neck (mean difference +/- SD, in Bbpp compared with bbPP groups: -0.05 +/- 0.15 g/cm2), the spine (0.01 +/- 0.13 g/cm2), or the forearm (0.04 +/- 0.08 g/cm2). The significant association of quadriceps strength with VDR genotypes (25% lower in BB compared with bb genotype, p < 0.05) was not influenced by ESR haplotypes. We conclude that in elderly Caucasian women the PvuII ESR polymorphism is not associated with osteoporosis, fracture history, nor muscle strength and does not influence the association of bone density and muscle strength with polymorphism of the VDR.     

COLIA1 polymorphism contributes to bone mineral density to assess prevalent wrist fractures

Wrist fractures associated with postmenopausal women are only partially explained by osteoporosis. Recent studies have shown that polymorphism of an Spl binding site in the first intron of the collagen I alpha 1 gene (COLIA1) may determine risk for vertebral and nonvertebral fractures in post-menopausal women independent of bone mass. We investigated the relationship between the COLIA1 polymorphism, lumbar spine and femoral neck bone mineral density (BMD), ultrasound stiffness of the heel, anthropometric variables, and risk for wrist fractures in 126 Czech postmenopausal women with low bone mass who suffered one or more wrist fracture in the last 5 years and in 126 postmenopausal women with low bone mass without any fracture. Genotypes for the Spl COLIA1 polymorphism were determined by polymerase chain reaction, digestion with Ball restriction enzyme, and agarose gel electrophoresis. The test discriminates two alleles, S and s, which correspond to the presence of guanine and thymidine, respectively, at the first bases in the Spl-binding site in the first intron of the gene for CO-LIA1. No significant differences were found between the fracture and control group with regard to age, weight, and years since menopause. However, BMD of the lumbar spine and femoral neck and ultrasound stiffness of the heel were significantly lower in patients with prevalent wrist fracture. Femoral neck BMD was the strongest determinant of prevalent fracture of the wrist. COLIA1 genotyping significantly strengthened prediction of prevalent fracture of the wrist. After multivariate adjustment, women in the Ss group had 2.0 times the risk of the women in the SS group (95% confidence interval [CI] = 1.1-3.8), and the women in the ss group had 2.8 times the risk of the women in the SS group (95% CI = 0.5-14.6). The overall gene-dose effect was an odds ratio of 2.1 per copy of the "s" allele (95% CI = 1.2-3.8). In the stepwise logistic regression, COLIA1 acted synergistically with femoral neck BMD and weight in increasing prediction of wrist fracture. The results demonstrate that COLIA1 Sp1 polymorphism is associated with an increased risk of wrist fracture in postmenopausal women independent of BMD and may be helpful in clinical practice by identifying patients with an increased fracture risk.     

Polymorphism in the type I collagen (COLIA1) gene and risk of fractures in postmenopausal women.

Twin and family studies have demonstrated that a large part of a population's variance in bone mineral density (BMD) is attributable to genetic factors. A polymorphism in the collagen type I alpha1 (COLIA1) gene has recently been associated with low bone mass and fracture incidence. We analyzed the relationship between COLIA1 gene polymorphism, lumbar spine and hip BMD, and fracture prevalence in a population of 319 postmenopausal women classified by WHO standards, including 98 nonosteoporotic women (NOPW) and 221 osteoporotic postmenopausal women (OPW), divided into 139 osteoporotic women without fracture (OPWnF) and 82 osteoporotic women with fracture (OPWwF). The COLIA1 genotype was assessed by polymerase chain reaction and BalI endonuclease digestion. Genotype frequencies for the total group were 49.2% GG homozygotes, 39.5% GT heterozygotes, and 11.3% TT homozygotes. We found significant differences in the percentage of homozygous TT between NOPW and OPW (6.1% and 13.6%, respectively). Significantly, the occurrence of genotype TT in OPWnF was 6.2%, and 28% in OPWwF. We observed no associations between the COLIA1 genotype and lumbar spine and hip BMD. The prevalence of fractures varied significantly by genotype: GG, 26.1%; GT, 15.9%; and TT, 58.3%. Logistic regression analysis of fracture prevalence showed that, for prevalent fractures, the women with the TT genotype had a 5.9-fold increased risk when compared with the other genotypes (GG + GT). When prevalence was adjusted for age, body mass index, and BMD, the fracture risk was 4.8 for the TT group vs. the genotype GG, whereas it was 0.6 for the GT genotype. In conclusion, we found the COLIA1 Sp1 TT genotype to be associated with an increased fracture risk in postmenopausal women. Interestingly, this genotype-dependent risk could not be explained completely by BMD differences.     

BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures.

In a large cohort of U.S. women aged 65 and older, we report the relationships of BMD measured at several sites, and subsequent fracture risk at multiple sites over > 8 years of follow-up. Although we found almost all fracture types to be related to low BMD, the overall proportion of fractures attributable to low BMD is modest. INTRODUCTION: Although several studies have reported the relationship between bone mineral density (BMD) and subsequent fracture risk, most have been limited by short follow-up time, BMD measures at only one or two sites, or availability of data for only select fracture types. MATERIALS AND METHODS: In the multicenter Study of Osteoporotic Fractures (SOF), we studied the relationship of several different BMD measures to fracture risk of multiple types in 9704 non-black women aged 65 and older. We previously reported on the relationship of peripheral BMD measures to risk of several types of fracture during an average 2.2-year follow-up period. In this expanded analysis, we present results of the relationship of both peripheral and central BMD measures and fractures of multiple types during 10.4 and 8.5 years of follow-up, respectively. We also report population attributable risk (PAR) estimates for osteoporosis and risk of several types of fracture. RESULTS: Our results show that almost all types of fractures have an increased incidence in women with low BMD. However, hip BMD is somewhat more strongly related to most of the fracture types studied than spine or peripheral BMD measures. Nonetheless, the proportion of fractures attributable to osteoporosis (based on a standard definition of osteoporosis) is modest, ranging from < 10% to 44% based on the most commonly used definition of osteoporosis (BMD T-score < -2.5). CONCLUSION: Finding effective prevention strategies for fractures in older women will require additional interventions beside preventions for bone loss, such as prevention of falls and other fracture risk factors.     

维生素D受体基因TaqⅠ多态性与绝经后妇女骨密度的关系

目的 了解福州地区绝经后妇女维生素D受体基因TaqⅠ多态性的分布,探讨维生素D受体基因TaqⅠ多态性与绝经后妇女骨密度的关系.方法 用双能X线骨密度仪检测592例绝经后妇女的腰椎、股骨颈、大转子和Wards三角骨密度,应用PCR-RFLP技术检测维生素D受体基因TaqⅠ多态性.结果 ①维生素D受体基因型分布频率为TT型90.37%,tt型0.17%,Tt型9.46%.等位基因频率为T 95.1%,t 4.9%,基因型分布符合Hardy-Weinberg定律.②分析其基因型与骨密度的关系:TT、tt、Tt 3种基因型在腰椎、股骨颈、大转子、Ward's区4个部位骨密度差异均无显著性.结论 维生素D受体基因TaqⅠ多态性与骨密度间无关联,不能作为预测福州地区绝经后妇女发生骨质疏松危险性的遗传标志.     

Association between self-reported prior wrist fractures and risk of subsequent hip and radiographic vertebral fractures in older women: a prospective study.

In this large prospective cohort study of elderly women, the relationships between prior wrist fracture and incident hip and radiographic vertebral fractures were significantly attenuated when adjusted for BMD. This study suggests that BMD thresholds for drug therapy to prevent osteoporotic fracture should be only modestly adjusted in those with prior wrist fracture compared with those without prior wrist fracture. Validation of such an approach would require intervention trials in patients with prior wrist fracture. INTRODUCTION: Prior wrist fracture has been identified as a risk factor for incident hip and vertebral fractures and proposed as a criterion for determining who should be offered drug therapy to prevent osteoporotic fracture, even if their hip BMD T score is > -2.5. Previously published studies of the relationships between prior wrist fracture and incident hip and vertebral fractures did not adjust for BMD. MATERIALS AND METHODS: We ascertained prior history of wrist fracture since age 50, measured calcaneal and hip BMD, and performed lateral spine films in a cohort of 9704 elderly community-dwelling women, and then followed them prospectively for incident vertebral and hip fractures. Incident vertebral fractures were defined by morphometry using lateral spine radiography at the first examination and an average of 3.7 years later. Incident hip fractures were confirmed with radiographic reports over a mean follow-up period of 10.1 years. RESULTS: Prior wrist fracture was associated with an age-adjusted 72% increased odds of incident radiographic vertebral fracture (odds ratio [OR], 1.72; 95% CI, 1.31-2.25). After adjustment for calcaneal BMD, the association of prior wrist fracture with incident radiographic vertebral fracture was attenuated (OR, 1.39; 95% CI, 1.05-1.83). Prior wrist fracture was also associated with an age-adjusted 43% excess rate of incident hip fracture (hazards ratio [HR], 1.43; 95% CI, 1.17-1.74). After adjustment for hip BMD, the association of prior wrist fracture with rate of incident hip fracture was no longer statistically significant (HR, 1.12; 95% CI, 0.92-1.38). CONCLUSION: In elderly women, prior wrist fracture is a risk factor for radiographic vertebral fracture independent of BMD. The association between prior wrist fracture and incident hip fracture is largely explained by hip BMD. Modest adjustment of BMD drug treatment thresholds for prevention of osteoporotic fractures in those with prior wrist fracture compared with those without prior wrist fracture may be reasonable, but validation of such an approach would require intervention trials in patients with prior wrist fracture.     

The Collagen Ia1 SP1 Polymorphism is Associated With Differences in Ultrasound Transmission Velocity in the Calcaneus in Postmenopausal Women

Bone mineral density (BMD) and fracture risk are under genetic control. An association of a G to T polymorphism in the Sp1 binding site of the collagen Ia1 (COLIa1) gene with the risk for fractures has been previously reported. This association is only partly explained by differences in BMD. Thus, we analyzed the relationship between the COLIa1 Sp1 polymorphism and ultrasound (US) transmission velocity (speed of sound; SOS) in bone. In a population-based sample of 740 women (aged 55-80 years) we determined COLIa1 genotype and US parameters in the calcaneus. SOS in the "GG" genotype group was 1522 +/- 31 m/sec, in the "GT" group, 1519 +/- 30 m/sec, and in the "TT" group 1508 +/- 30 m/sec (P = 0.01). While the difference between the GG and TT genotype groups corresponds to 0.5 SD or 1%, we observed an allele-dose-effect of 4.3 m/sec decrease in SOS per each copy of the "T" allele (P = 0.01). The differences remained significant after adjustment for BMD measured at the femoral neck. When we analysed 45 incident nonvertebral fractures in this group of women, we found the risk for fracture by COLIA1 Sp1 genotype to be partly explained by SOS differences as well as by BMD differences. Linear regression analysis showed a progressive negative slope of the regression line of SOS over age from "GG" over "GT" to "TT" genotype. These data indicate that the collagen Ia1 Sp1 polymorphism is associated with the modulus of elasticity of bone as determined in vivo by acoustical measurement. The relationship is independent of BMD and increases with age, contributing to an explanation of the increased fracture risk observed for this polymorphism.     

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be associated with increased plasma homocysteine levels in individuals with inadequate plasma folate levels. Recently, the TT genotype has been found to be associated with reduced bone mass. We therefore examined if the C677T polymorphism in the MTHFR gene is associated with changes in bone mass and risk of osteoporotic fractures in 388 osteoporotic patients and 336 normal individuals. The distributions of the genotypes CC, CT and TT in women with osteoporotic vertebral fractures and normal controls were 43.5%, 42.2% and 14.3% and 52.0%, 42.0% and 8.0%, respectively, ²=5.62, P=0.06. Since studies of the functionality of this polymorphism have revealed that only the TT genotype is associated with biochemical changes, we also compared the prevalence of the TT genotype versus the CT- and CC genotypes in patients and controls and found that the TT genotype is significantly more common in women with vertebral fractures (14.3%) compared with normal controls (8.0%), ²=4.31, P<0.05. Logistic regression analysis demonstrated that vertebral fractures were significantly associated with BMD (lumbar spine) and height but only marginally with the MTHFR genotype (P=0.06). Multiple linear regression analysis revealed that weight, age and the MTHFR polymorphism were predictors of lumbar spine BMD in women. However, age- and gender-corrected BMD of the lumbar spine and the hip was not significantly different between MTHFR genotypes. Furthermore, individuals with the TT genotype did not have BMD significantly lower than the combined group of individuals with the CT- or CC genotypes. In conclusion, we have demonstrated that the rare TT genotype of the C677T polymorphism in the MTHFR gene is associated with increased risk of osteoporotic fractures in women and a weak predictor of lumbar spine BMD.     

Wrist Fracture and Risk of Subsequent Fracture: Findings from the Women's Health Initiative Study

Wrist fractures are common in postmenopausal women and are associated with functional decline. Fracture patterns after wrist fracture are unclear. The goal of this study was to determine the frequency and types of fractures that occur after a wrist fracture among postmenopausal women. We carried out a post hoc analysis of data from the Women's Health Initiative Observational Study and Clinical Trials (1993–2010) carried out at 40 US clinical centers. Participants were postmenopausal women aged 50 to 79 years at baseline. Mean follow‐up duration was 11.8 years. Main measures included incident wrist, clinical spine, humerus, upper extremity, lower extremity, hip, and total non‐wrist fractures and bone mineral density (BMD) in a subset. Among women who experienced wrist fracture, 15.5% subsequently experienced non‐wrist fracture. The hazard for non‐wrist fractures was higher among women who had experienced previous wrist fracture than among women who had not experienced wrist fracture: non‐wrist fracture overall (hazard ratio [HR] = 1.40, 95% confidence interval [CI] 1.33–1.48), spine (HR = 1.48, 95% CI 1.32–1.66), humerus (HR = 1.78, 95% CI 1.57–2.02), upper extremity (non‐wrist) (HR = 1.88, 95% CI 1.70–2.07), lower extremity (non‐hip) (HR = 1.36, 95% CI 1.26–1.48), and hip (HR = 1.50, 95% CI 1.32–1.71) fracture. Associations persisted after adjustment for BMD, physical activity, and other risk factors. Risk of non‐wrist fracture was higher in women who were younger when they experienced wrist fracture (interaction p value 0.02). Associations between incident wrist fracture and subsequent non‐wrist fracture did not vary by baseline BMD category (normal, low bone density, osteoporosis). A wrist fracture is associated with increased risk of subsequent hip, vertebral, upper extremity, and lower extremity fractures. There may be substantial missed opportunity for intervention in the large number of women who present with wrist fractures. © 2015 American Society for Bone and Mineral Research.