WHO absolute fracture risk models (FRAX): Do clinical risk factors improve fracture prediction in older women without osteoporosis?

Bone mineral density (BMD) is a strong predictor of fracture, yet most fractures occur in women without osteoporosis by BMD criteria. To improve fracture risk prediction, the World Health Organization recently developed a country‐specific fracture risk index of clinical risk factors (FRAX) that estimates 10‐year probabilities of hip and major osteoporotic fracture. Within differing baseline BMD categories, we evaluated 6252 women aged 65 or older in the Study of Osteoporotic Fractures using FRAX 10‐year probabilities of hip and major osteoporotic fracture (ie, hip, clinical spine, wrist, and humerus) compared with incidence of fractures over 10 years of follow‐up. Overall ability of FRAX to predict fracture risk based on initial BMD T‐score categories (normal, low bone mass, and osteoporosis) was evaluated with receiver‐operating‐characteristic (ROC) analyses using area under the curve (AUC). Over 10 years of follow‐up, 368 women incurred a hip fracture, and 1011 a major osteoporotic fracture. Women with low bone mass represented the majority (n = 3791, 61%); they developed many hip (n = 176, 48%) and major osteoporotic fractures (n = 569, 56%). Among women with normal and low bone mass, FRAX (including BMD) was an overall better predictor of hip fracture risk (AUC = 0.78 and 0.70, respectively) than major osteoporotic fractures (AUC = 0.64 and 0.62). Simpler models (eg, age + prior fracture) had similar AUCs to FRAX, including among women for whom primary prevention is sought (no prior fracture or osteoporosis by BMD). The FRAX and simpler models predict 10‐year risk of incident hip and major osteoporotic fractures in older US women with normal or low bone mass. © 2011 American Society for Bone and Mineral Research     

Independent clinical validation of a Canadian FRAX tool: Fracture prediction and model calibration

A FRAX model for Canada was constructed for prediction of osteoporotic and hip fracture risk using national hip fracture data with and without the use of femoral neck bone mineral density (BMD). Performance of this system was assessed independently in a large clinical cohort of 36,730 women and 2873 men from the Manitoba Bone Density Program database that tracks all clinical dual‐energy X‐ray absorptiometry (DXA) test results for the Province of Manitoba, Canada. Linkage with other provincial health databases allowed for the direct comparison of fracture risk estimates from the Canadian FRAX model with observed fracture rates to 10 years (549 individuals with incident hip fractures and 2543 with incident osteoporotic fractures). The 10‐year Kaplan‐Meier estimate for hip fractures in women was 2.7% [95% confidence interval (CI) 2.1–3.4%] with a predicted value of 2.8% for FRAX with BMD, and in men the observed risk was 3.5% (95% CI 0.8–6.2%) with predicted value of 2.9%. The 10‐year estimate of osteoporotic fracture risk for all women was 12.0% (95% CI 10.8–13.4%) with a predicted value of 11.1% for FRAX with BMD, and in men, the observed risk was 10.7% (95% CI 6.6–14.9%) with a predicted value of 8.4%. Discrepancies were observed within some subgroups but generally were small. Fracture discrimination based on receiver operating characteristic curve analysis was comparable with published meta‐analyses with area under the curve for osteoporotic fracture prediction of 0.694 (95% CI 0.684–0.705) for FRAX with BMD and for hip fractures 0.830 (95% CI 0.815–0.846), both of which were better than FRAX without BMD or BMD alone. Individual risk factors considered by FRAX made significant independent contributions to fracture prediction in one or more of the models. In conclusion, a Canadian FRAX tool calibrated on national hip fracture data generates fracture risk predictions that generally are consistent with observed fracture rates across a wide range of risk categories. © 2010 American Society for Bone and Mineral Research.     

The FRAX tool in French women: How well does it describe the real incidence of fracture in the OFELY cohort

The FRAX tool estimates an individual's fracture probability over 10 years from clinical risk factors with or without bone mineral density (BMD) measurement. The aim of our study was to compare the predicted fracture probabilities and the observed incidence of fracture in French women during a 10‐year follow‐up. The probabilities of fracture at four major sites (hip, clinical spine, shoulder, or wrist) and at the hip were calculated with the FRAX tool in 867 women aged 40 years and over from the Os des Femmes de Lyon (OFELY) cohort.The incidence of fracture was observed over 10 years. Thus 82 women sustained 95 incident major osteoporotic (OP) fractures including 17 fractures at the hip. In women aged at least 65 years (n = 229), the 10‐year predicted probabilities of fracture with BMD were 13% for major OP fractures and 5% for hip fractures, contrasting with 3.6% and 0.5% in women younger than 65 years (p < .0001). The predicted probabilities of both major OP and hip fractures were significantly higher in women with osteoporosis (n = 77, 18% and 10%) and osteopenia (n= 390, 6% and 2%) compared with women with normal BMD (n = 208, 3% and <1%; p < .0001. The predicted probabilities of fracture were two and five times higher in women who sustained an incident major OP fracture and a hip fracture compared with women who did not (p < .0001). Nevertheless, among women aged at least 65 years with low BMD values (T‐score ≤ –1; n = 199), the 10‐year predicted probability of major OP fracture with BMD was 48% lower than the observed incidence of fractures (p < .01). A 10‐year probability of major OP fracture higher than 12% identified more women with incident fractures than did BMD in the osteoporotic range (p < .05). In French women from the OFELY cohort, the observed incidence of fragility fractures over 10 years increased with age following a pattern similar to the predicted probabilities given by the FRAX tool. However, in women aged at least 65 years with low BMD, the observed incidence of fractures was substantially higher than the predicted probability. © 2010 American Society for Bone and Mineral Research.     

Low Serum DHEAS Predicts Increased Fracture Risk in Older Men: The MrOS Sweden Study

The adrenal‐derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. DHEAS is considered an inactive precursor, which is converted into androgens and estrogens via local metabolism in peripheral target tissues. The predictive value of serum DHEAS for fracture risk is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEAS levels and incident fractures in a large cohort of older men. Serum DHEAS levels were analyzed with mass spectrometry in the population‐based Osteoporotic Fractures in Men study in Sweden (n = 2568, aged 69 to 81 years). Incident X‐ray validated fractures (all, n = 594; non‐vertebral major osteoporotic, n = 255; hip, n = 175; clinical vertebral, n = 206) were ascertained during a median follow‐up of 10.6 years. DHEAS levels were inversely associated with the risk of any fracture (hazard ratio [HR] per SD decrease = 1.14, 95% confidence interval [CI] 1.05–1.24), non‐vertebral major osteoporotic fractures (HR = 1.31, 95% CI 1.16–1.48), and hip fractures (HR = 1.18, 95% CI 1.02–1.37) but not clinical vertebral fractures (HR = 1.09, 95% CI 0.95–1.26) in Cox regression models adjusted for age, body mass index (BMI) and prevalent fractures. Further adjustment for traditional risk factors for fracture, bone mineral density (BMD), and/or physical performance variables as well as serum sex steroid levels only slightly attenuated the associations between serum DHEAS and fracture risk. Similarly, the point estimates were only marginally reduced after adjustment for FRAX estimates with BMD. The inverse association between serum DHEAS and all fractures or major osteoporotic fractures was nonlinear, with a substantial increase in fracture risk (all fractures 22%, major osteoporotic fractures 33%) for those participants with serum DHEAS levels below the median (0.60 μg/mL). In conclusion, low serum DHEAS levels are a risk marker of mainly non‐vertebral fractures in older men, of whom those with DHEAS levels below 0.60 μg/mL are at highest risk. © The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Risk Factors for Hip Fracture in Older Men: The Osteoporotic Fractures in Men Study (MrOS)

Almost 30% of hip fractures occur in men; the mortality, morbidity, and loss of independence after hip fractures are greater in men than in women. To comprehensively evaluate risk factors for hip fracture in older men, we performed a prospective study of 5994 men, primarily white, age 65+ years recruited at six US clinical centers. During a mean of 8.6 years of 97% complete follow‐up, 178 men experienced incident hip fractures. Information on risk factors including femoral neck bone mineral density (FNBMD) was obtained at the baseline visit. Cox proportional hazards models were used to calculate the hazard ratio (HR) with 95% confidence intervals; Fine and Gray models adjusted for competing mortality risk. Older age (≥75 years), low FNBMD, currently smoking, greater height and height loss since age 25 years, history of fracture, use of tricyclic antidepressants, history of myocardial infarction or angina, hyperthyroidism or Parkinson's disease, lower protein intake, and lower executive function were all associated with an increased hip fracture risk. Further adjustment for competing mortality attenuated HR for smoking, hyperthyroidism, and Parkinson's disease. The incidence rate of hip fracture per 1000 person‐years (PY) was greatest in men with FNBMD T‐scores <–2.5 (white women reference database) who also had 4+ risk factors, 33.4. Men age ≥80 years with 3+ major comorbidities experienced hip fracture at rates of 14.52 versus 0.88 per 1000 PY in men age <70 years with zero comorbidities. Older men with low FNBMD, multiple risk factors, and multimorbidity have a high risk of hip fracture. Many of these assessments can easily be incorporated into routine clinical practice and may lead to improved risk stratification. © 2016 American Society for Bone and Mineral Research.     

High Serum SHBG Predicts Incident Vertebral Fractures in Elderly Men

Previous prospective cohort studies have shown that serum levels of sex steroids and sex hormone‐binding globulin (SHBG) associate with nonvertebral fracture risk in men. The predictive value of sex hormones and SHBG for vertebral fracture risk specifically is, however, less studied. Elderly men (aged ≥65 years) from Sweden and Hong Kong participating in the Osteoporotic Fractures in Men (MrOS) study had baseline estradiol and testosterone analyzed by gas chromatography–mass spectrometry (GC‐MS) and SHBG by immunoradiometric assay (IRMA). Incident clinical vertebral fractures (n = 242 cases) were evaluated in 4324 men during an average follow‐up of 9.1 years. In a subsample of these men (n = 2256), spine X‐rays were obtained at baseline and after an average follow‐up of 4.3 years to identify incident radiographic vertebral fractures (n = 157 cases). The likelihood of incident clinical and radiographic vertebral fractures was estimated by Cox proportional hazards models and logistic regression models, respectively. Neither serum estradiol (hazard ratio [HR] per SD increase = 0.93, 95% confidence interval [CI] 0.80–1.08) nor testosterone (1.05, 0.91–1.21) predicted incident clinical vertebral fractures in age‐adjusted models in the combined data set. High serum SHBG, however, associated with increased clinical vertebral fracture risk (1.24, 1.12–1.37). This association remained significant after further adjustment for FRAX with or without bone mineral density (BMD). SHBG also associated with increased incident radiographic vertebral fracture risk (combined data set; odds ratio [OR] per SD increase = 1.23, 95% CI 1.05–1.44). This association remained significant after adjustment for FRAX with or without BMD. In conclusion, high SHBG predicts incident clinical and radiographic vertebral fractures in elderly men and adds moderate information beyond FRAX with BMD for vertebral fracture risk prediction. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.     

A Meta‐Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX

Trabecular bone score (TBS) is a gray‐level textural index of bone microarchitecture derived from lumbar spine dual‐energy X‐ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)‐independent predictor of fracture risk. The objective of this meta‐analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual‐level data from 17,809 men and women in 14 prospective population‐based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow‐up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35–1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10‐year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24–1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65–1.87 versus 1.70, 95% CI 1.60–1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.     

Prediction of Incident Major Osteoporotic and Hip Fractures by Trabecular Bone Score (TBS) and Prevalent Radiographic Vertebral Fracture in Older Men

Trabecular bone score (TBS) has been shown to predict major osteoporotic (clinical vertebral, hip, humerus, and wrist) and hip fractures in postmenopausal women and older men, but the association of TBS with these incident fractures in men independent of prevalent radiographic vertebral fracture is unknown. TBS was estimated on anteroposterior (AP) spine dual‐energy X‐ray absorptiometry (DXA) scans obtained at the baseline visit for 5979 men aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) Study and its association with incident major osteoporotic and hip fractures estimated with proportional hazards models. Model discrimination was tested with Harrell's C‐statistic and with a categorical net reclassification improvement index, using 10‐year risk cutpoints of 20% for major osteoporotic and 3% for hip fractures. For each standard deviation decrease in TBS, there were hazard ratios of 1.27 (95% confidence interval [CI] 1.17 to 1.39) for major osteoporotic fracture, and 1.20 (95% CI 1.05 to 1.39) for hip fracture, adjusted for FRAX with bone mineral density (BMD) 10‐year fracture risks and prevalent radiographic vertebral fracture. In the same model, those with prevalent radiographic vertebral fracture compared with those without prevalent radiographic vertebral fracture had hazard ratios of 1.92 (95% CI 1.49 to 2.48) for major osteoporotic fracture and 1.86 (95% CI 1.26 to 2.74) for hip fracture. There were improvements of 3.3%, 5.2%, and 6.2%, respectively, of classification of major osteoporotic fracture cases when TBS, prevalent radiographic vertebral fracture status, or both were added to FRAX with BMD and age, with minimal loss of correct classification of non‐cases. Neither TBS nor prevalent radiographic vertebral fracture improved discrimination of hip fracture cases or non‐cases. In conclusion, TBS and prevalent radiographic vertebral fracture are associated with incident major osteoporotic fractures in older men independent of each other and FRAX 10‐year fracture risks, and these data support their use in conjunction with FRAX for fracture risk assessment in older men. © 2015 American Society for Bone and Mineral Research.     

Major Osteoporotic to Hip Fracture Ratios in Canadian Men and Women With Swedish Comparisons: A Population‐Based Analysis

Fracture Risk Assessment (FRAX) tools are calibrated from country‐specific fracture epidemiology. Although hip fracture data are usually available, data on non‐hip fractures for most countries are often lacking. In such cases, rates are often estimated by assuming similar non‐hip to hip fracture ratios from historical (1987 to 1996) Swedish data. Evidence that countries share similar fracture ratios is limited. Using data from Manitoba, Canada (2000 to 2007, population 1.2 million), we identified 21,850 incident major osteoporotic fractures (MOF) in men and women aged >50 years. Population‐based age‐ and sex‐specific ratios of clinical vertebral, forearm, and humerus fractures to hip fractures were calculated, along with odds ratios (ORs) and 95% confidence intervals (CIs). All ratios showed decreasing trends with increasing age for both men and women. Men and women showed similar vertebral/hip fracture ratios (all p > 0.1, with ORs 0.86 to 1.25). Forearm/hip and humerus/hip fracture ratios were significantly lower among men than women (forearm/hip ratio: p < 0.01 for all age groups, with ORs 0.29 to 0.53; humerus/hip ratio: p < 0.05 for all age groups [except 80 to 84 years] with ORs 0.46 to 0.86). Ratios for any MOF/hip fracture were also significantly lower among men than women in all but two subgroups (p < 0.05 for all age groups [except 80 to 84 and 90+ years] with ORs 0.48 to 0.87). Swedish vertebral/hip fracture ratios were similar to the Canadian fracture ratios (within 7%) but significantly lower for other sites (men and women: 46% and 35% lower for forearm/hip ratios, 19% and 15% lower for humerus/hip ratios, and 19% and 23% lower for any MOF/hip ratios). These differences have implications for updating and calibrating FRAX tools, fracture risk estimation, and intervention rates. Moreover, wherever possible, it is important that countries try to collect accurate non‐hip fracture data. © 2014 American Society for Bone and Mineral Research     

Falls Predict Fractures Independently of FRAX Probability: A Meta‐Analysis of the Osteoporotic Fractures in Men (MrOS) Study

Although prior falls are a well‐established predictor of future fracture, there is currently limited evidence regarding the specific value of falls history in fracture risk assessment relative to that of other clinical risk factors and bone mineral density (BMD) measurement. We therefore investigated, across the three Osteoporotic Fractures in Men (MrOS) Study cohorts, whether past falls predicted future fracture independently of FRAX and whether these associations varied with age and follow‐up time. Elderly men were recruited from MrOS Sweden, Hong Kong, and USA. Baseline data included falls history (over the preceding 12 months), clinical risk factors, BMD at femoral neck, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the associations between falls, FRAX probability, and incident fracture, adjusting for age, time since baseline, and cohort in base models; further models were used to investigate interactions with age and follow‐up time. Random‐effects meta‐analysis was used to synthesize the individual country associations. Information on falls and FRAX probability was available for 4365 men in USA (mean age 73.5 years; mean follow‐up 10.8 years), 1823 men in Sweden (mean age 75.4 years; mean follow‐up 8.7 years), and 1669 men in Hong Kong (mean age 72.4 years; mean follow‐up 9.8 years). Rates of past falls were similar at 20%, 16%, and 15%, respectively. Across all cohorts, past falls predicted incident fracture at any site (hazard ratio [HR] = 1.69; 95% confidence interval [CI] 1.49, 1.90), major osteoporotic fracture (MOF) (HR = 1.56; 95% CI 1.33, 1.83), and hip fracture (HR = 1.61; 95% CI 1.27, 2.05). Relationships between past falls and incident fracture remained robust after adjustment for FRAX probability: adjusted HR (95% CI) any fracture: 1.63 (1.45, 1.83); MOF: 1.51 (1.32, 1.73); and hip: 1.54 (1.21, 1.95). In conclusion, past falls predicted incident fracture independently of FRAX probability, confirming the potential value of falls history in fracture risk assessment. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Evaluation of the FRAX and Garvan fracture risk calculators in older women

Fracture risk calculators estimate the absolute risk of osteoporotic fractures. We investigated the performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal bone mineral density (BMD) for their age. Fractures were ascertained in women initially enrolled in a 5‐year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T‐score –1.3) were used to estimate fracture risk during follow‐up using the FRAX and Garvan calculators. The FRAX–New Zealand tool was used both with and without baseline BMD. The discrimination of the calculators was assessed using the area under the curve (AUC) of receiver operating characteristic curves. The calibration was assessed by comparing estimated risk of fracture with fracture incidence across a range of estimated fracture risks and clinical factors. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67–0.70; osteoporotic fracture 0.62–0.64; any fracture 0.60–0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. In summary, none of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility. The calibration varied, suggesting that the calculators should be validated in local cohorts before clinical use. © 2011 American Society for Bone and Mineral Research.     

Breastfeeding protects against hip fracture in postmenopausal women: The Tromsø study

Despite reported bone loss during pregnancy and lactation, no study has shown deleterious long‐term effects of parity or breastfeeding. Studies have shown higher bone mineral density and reduced risk for fracture in parous than in nulliparous women or no effect of parity and breastfeeding, so long‐term effects are uncertain. We studied the effect of parity and breastfeeding on risk for hip, wrist and non‐vertebral fragility fractures (hip, wrist, or proximal humerus) in 4681 postmenopausal women aged 50 to 94 years in the Tromsø Study from 1994–95 to 2010, using Cox's proportional hazard models. During 51 906 person‐years, and a median of 14.5 years follow‐up, 442, 621, and 1105 of 4681 women suffered incident hip, wrist, and fragility fractures, and the fracture rates were 7.8, 11.4, and 21.3 per 1000 person‐years, respectively. The risk for hip, wrist, and fragility fracture did not differ between parous (n = 4230, 90.4%) and nulliparous women (n = 451, 9.6%). Compared with women who did not breast‐feed after birth (n = 184, 4.9%), those who breastfed (n = 3564, 95.1%) had 50% lower risk for hip fracture (HR 0.50; 95% CI 0.32 to 0.78), and 27% lower risk for fragility fracture (HR 0.73; 95% CI 0.54 to 0.99), but similar risk for wrist fracture, after adjustment for age, BMI, height, physical activity, smoking, a history of diabetes, previous fracture of hip or wrist, use of hormone replacement therapy, and length of education. Each 10 months longer total duration of breastfeeding reduced the age‐adjusted risk for hip fracture by 12% (HR 0.88; 95% CI 0.78 to 0.99, p for trend = 0.03) before, and marginally after, adjustment for BMI and other covariates (HR 0.91; 95% CI 0.80 to 1.04). In conclusion, this data indicates that pregnancy and breastfeeding has no long‐term deleterious effect on bone fragility and fractures, and that breastfeeding may contribute to a reduced risk for hip fracture after menopause. © 2011 American Society for Bone and Mineral Research     

Hip fracture and risk of acute myocardial infarction: A nationwide study

Osteoporotic fractures are associated with increased mortality risk. However, little data are available on the risk of acute myocardial infarction (AMI) after hip fracture. Therefore, we investigated whether hip fracture increased the risk of AMI in a large, nationwide cohort study. We obtained data from 8758 patients diagnosed with hip fracture from 2000 to 2009 and from 4 matched controls for each patient from the Longitudinal Health Insurance Database (LHID 2000), Taiwan. Controls were matched for age, sex, comorbid disorders, and enrollment date. All subjects were followed up from the date of enrollment until AMI, death, or the end of data collection (2009). Cox's regression model adjusted for age, sex, comorbid disorders, and medication was used to assess independent factors determining the risk of development of AMI. As expected, despite the matching, the hip fracture patients had more risk factors for AMI at baseline. A total of 8758 subjects with hip fractures and 35,032 controls were identified. Among these patients, 1183 (257 hip fracture patients and 926 controls) developed AMI during the median 3.2‐year (interquartile range 1.4 to 5.8 years) follow‐up period. Patients with hip fractures had a higher incidence of AMI occurrence when compared with controls (8.7/1000 person‐years versus 6.82/1000 person‐years). Multivariate analysis adjusted for baseline covariates indicated that hip fracture was associated with a greater risk for AMI development (hazard ratio [HR] = 1.29; 95% confidence interval [CI] 1.12–1.48; p < 0.001). We conclude that hip fracture is independently associated with a higher risk of subsequent AMI. © 2013 American Society for Bone and Mineral Research     

Progressively increasing fracture risk with advancing age after initial incident fragility fracture: The Tromsø Study

The risk of subsequent fracture is increased after initial fractures; however, proper understanding of its magnitude is lacking. This population‐based study examines the subsequent fracture risk in women and men by age and type of initial incident fracture. All incident nonvertebral fractures between 1994 and 2009 were registered in 27,158 participants in the Tromsø Study, Norway. The analysis included 3108 subjects with an initial incident fracture after the age of 49 years. Subsequent fracture (n = 664) risk was expressed as rate ratios (RR) and absolute proportions irrespective of death. The rates of both initial and subsequent fractures increased with age, the latter with the steepest curve. Compared with initial incident fracture rate of 30.8 per 1000 in women and 12.9 per 1000 in men, the overall age‐adjusted RR of subsequent fracture was 1.3 (95% CI, 1.2–1.5) in women, and 2.0 (95% CI, 1.6–2.4) in men. Although the RRs decreased with age, the absolute proportions of those with initial fracture who suffered a subsequent fracture increased with age; from 9% to 30% in women and from 10% to 26% in men, between the age groups 50–59 to 80+ years. The type of subsequent fracture varied by age from mostly minor fractures in the youngest to hip or other major fractures in the oldest age groups, irrespective of type and severity of initial fracture. In women and men, 45% and 38% of the subsequent hip or other major fractures, respectively, were preceded by initial minor fractures. The risk of subsequent fracture is high in all age groups. At older age, severe subsequent fracture types follow both clinically severe and minor initial incident fractures. Any fragility fracture in the elderly reflects the need for specific osteoporosis management to reduce further fracture risk. © 2013 American Society for Bone and Mineral Research.     

Celiac Disease Autoimmunity and Hip Fracture Risk: Findings from a Prospective Cohort Study

The impact of celiac disease autoimmunity on bone health is unclear. We investigated the associations of seropositivity for tissue transglutaminase antibodies (tTGA) and endomysial antibodies (EMA) with incident hip fractures using data from a prospective cohort study, Mini‐Finland Health Survey. Baseline serum samples, taken in 1978–80, were tested for tTGA and EMA. Incident hip fractures up to the year 2011 were ascertained from a national hospitalization register. Associations between seropositivity and hip fractures were modeled using Cox proportional hazards regression adjusted for age, sex, body mass index, vitamin D, gamma‐glutamyl transferase, smoking, and self‐rated health. Our analyses were based on 6919 men and women who had no record of celiac disease or hip fracture before the study baseline. A total of 382 individuals had a hip fracture during a median follow‐up of 30 years. Compared with the tTGA‐negative individuals (n = 6350), tTGA‐positive participants (n = 569; with hip fracture, n = 51) had a higher risk of hip fractures (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.17, 2.14). The findings were similar for another tTGA test (n 200; with hip fracture, n = 26; HR = 2.23, 95% CI 1.49, 3.34). We found no evidence for an association between EMA positivity and hip fracture risk (HR = 0.92, 95% CI 0.34, 2.47; n = 74; with hip fracture, n = 4). In our prospective population‐based study of Finnish adults, seropositivity for tTGA was associated with an increased hip fracture risk. © 2014 American Society for Bone and Mineral Research.     

FRAX and Risk of Vertebral Fractures: The Fracture Intervention Trial

The validity of the WHO 10‐yr probability of major osteoporotic fracture model (FRAX) for prediction of vertebral fracture has not been tested. We analyzed how well FRAX for major osteoporotic fractures, with and without femoral neck BMD (FN BMD), predicted the risk of vertebral fracture. We also compared the predictive validity of FRAX, FN BMD, and prevalent vertebral fracture detected by radiographs at baseline alone or in combination to predict future vertebral fracture. We analyzed data from the placebo groups of FIT (3.8‐yr follow‐up, n = 3221) with ORs and areas under receiver operating characteristics (ROC) curves (AUC). FRAX with and without FN BMD predicted incident radiographic vertebral fracture. The AUC was significantly greater for FRAX with FN BMD (AUC = 0.71) than FRAX without FN BMD (AUC = 0.68; p = 0.002). Prevalent vertebral fracture plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture as well as a combination of prevalent vertebral fracture and FRAX with FN BMD (AUC = 0.75; p = 0.76). However, baseline vertebral fracture status plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture significantly better than FRAX with FN BMD (AUC = 0.71; p = 0.0017). FRAX for major osteoporotic fractures (with and without FN BMD) predicts vertebral fracture. However, once FN BMD and age are known, the eight additional risk factors in FRAX do not significantly improve the prediction of vertebral fracture. A combination of baseline radiographic vertebral fracture, FN BMD, and age is the strongest predictor of future vertebral fracture.     

Declining Rates of Hip Fracture in End‐Stage Renal Disease: Analysis From the 2003–2011 Nationwide Inpatient Sample

The incidence of hip fracture in patients with end‐stage renal disease (ESRD) is considerably higher than that in the general age‐ and sex‐matched population. Although medical therapy for chronic kidney disease mineral bone disorder (CKD‐MBD) has changed considerably over the last decade, rates of hip fracture in the entire ESRD population have not been well‐characterized. Herein, we evaluated temporal trends in rates of hip fracture, in‐hospital mortality, and costs of associated hospital stay in ESRD. We identified hospitalizations for hip fracture from 2003 to 2011 using the Nationwide Inpatient Sample, a representative national database inclusive of all ages and payers. We incorporated data from the United States Renal Data System and the US Census to calculate population‐specific rates. Between 2003 and 2011, we identified 47,510 hip fractures in the ESRD population. The overall rate of hip fracture was 10.04/1000 person‐years. The rate was 3.73/1000 person‐years in patients aged less than 65 years, and 20.97/1000 person‐years in patients aged 65 or older. Age‐ and sex‐standardized rates decreased by 12.6% from 2003 (10.23/1000 person‐years; 95% confidence interval [CI], 7.99/1000 to 12.47/1000) to 2011 (8.94/1000 person‐years; 95% CI, 7.12/1000 to 10.75/1000). Hip fracture rates over time were virtually identical in patients aged less than 65 years; however, rates decreased by 15.3% among patients aged 65 years or older; rates declined more rapidly in older women compared with older men (p for interaction = 0.047). In‐hospital mortality rate after hip fracture operation declined by 26.7% from 2003 (8.6%; 95% CI, 6.8 to 10.4) to 2011 (6.3%; 95% CI, 4.9 to 7.7). In ESRD, age‐ and sex‐standardized hip fracture rates and associated in‐hospital mortality have declined substantially over the last decade. © 2017 American Society for Bone and Mineral Research.     

Prediction of Incident Hip Fracture with the Estimated Femoral Strength by Finite Element Analysis of DXA Scans in the Study of Osteoporotic Fractures

A bone fractures only when loaded beyond its strength. The purpose of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of dual‐energy X‐ray absorptiometry (DXA) scans, with incident hip fracture in comparison to hip bone mineral density (BMD), Fracture Risk Assessment Tool (FRAX), and hip structure analysis (HSA) variables. This prospective case‐cohort study included a random sample of 1941 women and 668 incident hip fracture cases (295 in the random sample) during a mean ± SD follow‐up of 12.8 ± 5.7 years from the Study of Osteoporotic Fractures (n = 7860 community‐dwelling women ≥67 years of age). We analyzed the baseline DXA scans (Hologic 1000) of the hip using a validated plane‐stress, linear‐elastic finite element (FE) model of the proximal femur and estimated the femoral strength during a simulated sideways fall. Cox regression accounting for the case‐cohort design assessed the association of estimated femoral strength with hip fracture. The age–body mass index (BMI)‐adjusted hazard ratio (HR) per SD decrease for estimated strength (2.21; 95% CI, 1.95–2.50) was greater than that for total hip (TH) BMD (1.86; 95% CI, 1.67–2.08; p < 0.05), FN BMD (2.04; 95% CI, 1.79–2.32; p > 0.05), FRAX scores (range, 1.32–1.68; p < 0.0005), and many HSA variables (range, 1.13–2.43; p < 0.005), and the association was still significant (p < 0.05) after further adjustment for hip BMD or FRAX scores. The association of estimated strength with incident hip fracture was strong (Harrell's C index 0.770), significantly better than TH BMD (0.759; p < 0.05) and FRAX scores (0.711–0.743; p < 0.0001), but not FN BMD (0.762; p > 0.05). Similar findings were obtained for intracapsular and extracapsular fractures. In conclusion, the estimated femoral strength from FE analysis of DXA scans is an independent predictor and performs at least as well as FN BMD in predicting incident hip fracture in postmenopausal women. © 2014 American Society for Bone and Mineral Research.     

Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans

Finite element analysis of computed tomography (CT) scans provides noninvasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a 5‐year case‐control study of 1110 women and men over age 65 years from the AGES‐Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that for incident radiographically confirmed spine fractures (n = 167), the age‐adjusted odds ratio for vertebral strength was significant for women (2.8, 95% confidence interval [CI] 1.8 to 4.3) and men (2.2, 95% CI 1.5 to 3.2) and for men remained significant (p = 0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n = 171), the age‐adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI 2.6 to 6.9) and men (3.5, 95% CI 2.3 to 5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p = 0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD‐based interventional thresholds for osteoporosis and at corresponding preestablished thresholds for “fragile bone strength” (spine: women ≤ 4500 N, men ≤ 6500 N; hip: women ≤ 3000 N, men ≤ 3500 N). Because it is well established that individuals over age 65 years who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have fragile bone strength at the hip or spine should also be considered at high risk of fracture. © 2014 American Society for Bone and Mineral Research.     

Management of Patients With High Baseline Hip Fracture Risk by FRAX Reduces Hip Fractures—A Post Hoc Analysis of the SCOOP Study

The Screening for Osteoporosis in Older Women for the Prevention of Fracture (SCOOP) study was a community‐based screening intervention in women aged 70 to 85 years in the United Kingdom. In the screening arm, licensed osteoporosis treatments were recommended in women identified to be at high risk of hip fracture using the FRAX risk assessment tool (including bone mineral density measurement). In the control arm, standard care was provided. Screening led to a 28% reduction in hip fractures over 5 years. In this planned post hoc analysis, we wished to examine for interactions between screening effectiveness on fracture outcome (any, osteoporotic, and hip fractures) on the one hand and baseline FRAX 10‐year probability of hip fracture on the other. All analyses were conducted on an intention‐to‐treat basis, based on the group to which women were randomized, irrespective of whether screening was completed. Of 12,483 eligible participants, 6233 women were randomized to screening, with treatment recommended in 898 (14.4%). No evidence of an effect or interaction was observed for the outcomes of any fracture or osteoporotic fracture. In the screening arm, 54 fewer hip fractures were observed than in the control arm (164 versus 218, 2.6% versus 3.5%), and commensurate with treatment being targeted to those at highest hip fracture risk, the effect on hip fracture increased with baseline FRAX hip fracture probability (p = 0.021 for interaction); for example, at the 10th percentile of baseline FRAX hip probability (2.6%), there was no evidence that hip fractures were reduced (hazard ratio [HR] = 0.93; 95% confidence interval [CI] 0.71 to 1.23), but at the 90th percentile (16.6%), there was a 33% reduction (HR = 0.67; 95% CI 0.53 to 0.84). Prior fracture and parental history of hip fracture positively influenced screening effectiveness on hip fracture risk. We conclude that women at high risk of hip fracture based on FRAX probability are responsive to appropriate osteoporosis management. © 2018 American Society for Bone and Mineral Research.