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.     

Trabecular Bone Score (TBS) Predicts Fracture in Ankylosing Spondylitis: The Manitoba BMD Registry

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine characterized among other features by spinal boney proliferation, back pain, loss of flexibility, and increased fracture risk. Overlying bone limits the utility of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) in the spine. Trabecular bone score (TBS) is a bone texture measurement derived from the spine DXA image that indicates bone quality and fracture risk independent of BMD. Methodology: Using the Manitoba Bone Density Program database, patients with diagnosis codes for ankylosing spondylitis, baseline DXA and lumbar spine TBS were identified. Incident nontraumatic fractures (major osteoporotic [MOF], clinical spine, hip, and all fracture) were identified from population based databases. Cox-proportional hazard models are presented. Results: We identified 188 patients with diagnosed AS. TBS was lower in those with incident MOF (1.278 ± 0.126, compared to 1.178 ± 0.136, p < 0.001). Unadjusted TBS and FRAX-MOF-BMD adjusted predicted major osteoporotic fracture (N = 19) (hazard ratio [HR] 2.04, 95% confidence interval [CI]: 1.28–2.26, p = 0.003; HR 1.81, 95% CI: 1.11–2.96, p = 0.018). TBS unadjusted and FRAX-MOF-BMD adjusted also predicted clinical spine fracture (N = 7) (HR 2.50, 95% CI: 1.17–5.37; p = 0.019; HR 2.40 95% CI: 1.1–5.25; p = 0.028). Higher HRs were observed for prediction of hip fracture (N = 6), but these did not achieve statistical significance (FRAX-adjusted HR 1.74, 95% 0.73–4.17; p = 0.211). Unadjusted models show TBS was predictive of all fracture (N = 27) (HR 1.60, 95% CI: 1.08–2.39; p = 0.020), which was borderline significant after adjustment for FRAX-MOF-BMD (HR 1.51, 95% CI: 1.00–2.29; p = 0.052). Conclusion: We report the first analysis of TBS for fracture prediction as an incident event in AS. TBS independently predicted major osteoporotic and clinical spine fracture in AS independent of FRAX.     

Clinical Utility of Using Lumbar Spine Trabecular Bone Score to Adjust Fracture Probability: The Manitoba BMD Cohort

Decreased lumbar spine trabecular bone score (TBS), a dual‐energy X‐ray absorptiometry (DXA)‐derived image texture measurement, is a risk factor for major osteoporotic fracture (MOF) and hip fracture (HF) independent of 10‐year fracture probability estimated using FRAX. We determined how often applying the TBS adjustment to fracture probability altered treatment qualification. Using a population‐based registry containing all clinical DXA results for Manitoba, Canada, we identified 34,316 women with baseline spine and hip DXA, FRAX‐based fracture probability measurements (computed with femoral neck bone mineral density), lumbar spine TBS, and minimum 5 years of observation (mean 8.7 years). Population‐based health services data were used to identify incident non‐traumatic MOF and HF in 3503 and 945 women, respectively. Baseline MOF and HF probabilities were estimated using FRAX before and after applying the TBS adjustment. Risk recategorization was assessed using net reclassification improvement (NRI) for individual FRAX‐based intervention criteria and three national clinical practice guidelines (CPGs) (US National Osteoporosis Foundation, Osteoporosis Canada, and UK National Osteoporosis Guideline Group). Overall, proportions of women reclassified with the TBS adjustment to FRAX were small (less than 5%) with more than 90% of the reclassification occurring close to the intervention threshold. For women close to an intervention cut‐off reclassification, rates ranged from 9.0% to 17.9% and were <1% otherwise. There was a small but significant improvement in overall NRI for all individual FRAX‐based intervention criteria (range 0.007 to 0.018) and all three national CPGs (range 0.008 to 0.011). NRI was larger in women below age 65 years (up to 0.056 for hip fracture). In summary, a small but significant improvement in MOF and HF risk assessment was found by using lumbar spine TBS to adjust FRAX probability. An improvement in risk reclassification was observed for CPGs from three different countries, with almost all of the benefit found in individuals close to an intervention threshold. © 2017 American Society for Bone and Mineral Research. © 2017 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.     

The Effect of Abaloparatide‐SC on Fracture Risk Is Independent of Baseline FRAX Fracture Probability: A Post Hoc Analysis of the ACTIVE Study

Daily subcutaneous (SC) injections of the investigational drug abaloparatide‐SC (80 mcg) for 18 months significantly decrease the risk of vertebral and nonvertebral fracture compared with placebo in postmenopausal women. We examined the efficacy of abaloparatide‐SC as a function of baseline fracture risk, assessed using the FRAX tool. Baseline clinical risk factors (age, body mass index [BMI], prior fracture, glucocorticoid use, rheumatoid arthritis, and smoking) were entered into country‐specific FRAX models to calculate the 10‐year probability of major osteoporotic fractures, with or without femoral neck bone mineral density (BMD). The interaction between probability of a major osteoporotic fracture and treatment efficacy was examined by a Poisson regression. A total of 821 women randomized to placebo and 824 women to abaloparatide‐SC, mean age 69 years in both groups, were followed for up to 2 years. At baseline, the 10‐year probability of major osteoporotic fractures (with BMD) ranged from 2.3% to 57.5% (mean 13.2%). Treatment with abaloparatide‐SC was associated with a 69% (95% confidence interval [CI] 38–85%) decrease in major osteoporotic fracture (MOF) and a 43% (95% CI 9–64%) decrease in any clinical fracture compared with placebo. For all outcomes, hazard ratios tended to decrease (ie, greater efficacy) with increasing fracture probability. Whereas the interaction approached significance for the outcome of any fracture (p = 0.11), there was no statistically significant interaction for any of the fracture outcomes. Similar results were noted when FRAX probability was computed without BMD. Efficacy of abaloparatide‐SC to decrease the risk of major osteoporotic fracture or any clinical fracture in postmenopausal women with low BMD and/or prior fracture appears independent of baseline fracture probability. © 2017 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.     

Inflammatory bowel disease and the risk of fracture after controlling for FRAX

Subjects with inflammatory bowel disease (IBD) are at increased risk for hip and other major osteoporotic fractures. However, previous analyses have not fully accounted for differences in bone mineral density (BMD) and other clinical factors that affect the risk of fracture. The World Health Organization Fracture Risk Assessment tool (FRAX) can be used to predict the 10‐year fracture risk from BMD and clinical risk factors. A population‐based database containing clinical information on all IBD subjects in the province of Manitoba, Canada, was linked with the Manitoba Bone Mineral Density Database, which contains results of all dual X‐ray absorptiometry (DXA) scans in the province. FRAX probabilities were calculated for all subjects aged 50 years or more undergoing baseline DXA testing. Subjects were followed for occurrence of major osteoporotic fractures (MOF; hip, clinical spine, wrist, humerus). Cox proportional hazards models were used to determine whether IBD was independently predictive of MOF or hip fracture. After controlling for FRAX fracture probability computed with BMD, IBD was not associated with a significantly increased risk for MOF (hazard ratio [HR] = 1.12, 95% confidence interval [CI], 0.83–1.55) but was associated with an increased risk for hip fracture (HR = 2.14; 95% CI, 1.26–3.65). The addition of femoral neck T‐score to FRAX probability without knowledge of BMD had a negligible effect on the estimated HRs for IBD, suggesting that IBD mediates any effect on fracture risk independently of femoral neck BMD. After controlling for FRAX probability, subjects with IBD are not at an increased risk for overall MOF, but may be at increased risk of hip fracture. © 2013 American Society for Bone and Mineral Research.     

FRAX underestimates fracture risk in patients with diabetes

The study objective was to determine whether diabetes is a risk factor for incident hip or major osteoporotic fractures independent of the WHO fracture risk assessment tool (FRAX). Men and women with diabetes (n = 3518) and nondiabetics (n = 36,085) aged ≥50 years at the time of bone mineral density (BMD) testing (1990 to 2007) were identified in a large clinical database from Manitoba, Canada. FRAX probabilities were calculated, and fracture outcomes to 2008 were established via linkage with a population-based data repository. Multivariable Cox proportional hazards models were used to determine if diabetes was associated with incident hip fractures or major osteoporotic fractures after controlling for FRAX risk factors. Mean 10-year probabilities of fracture were similar between groups for major fractures (diabetic 11.1 ± 7.2 versus nondiabetic 10.9 ± 7.3, p = 0.116) and hip fractures (diabetic 2.9 ± 4.4 versus nondiabetic 2.8 ± 4.4, p = 0.400). Diabetes was a significant predictor of subsequent major osteoporotic fracture (hazard ratio [HR] = 1.61, 95% confidence interval [CI] 1.42-1.83) after controlling for age, sex, medication use, and FRAX risk factors including BMD. Similar results were seen after adjusting for FRAX probability directly (HR = 1.59, 95% CI 1.40-1.79). Diabetes was also associated with significantly higher risk for hip fractures (p < 0.001). Higher mortality from diabetes attenuated but did not eliminate the excess fracture risk. FRAX underestimated observed major osteoporotic and hip fracture risk in diabetics (adjusted for competing mortality) but demonstrated good concordance with observed fractures for nondiabetics. We conclude that diabetes confers an increased risk of fracture that is independent of FRAX derived with BMD. This suggests that diabetes might be considered for inclusion in future iterations of FRAX.     

Performance of FRAX in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study

FRAX was developed to predict 10-year probability of major osteoporotic fracture (MOF) and hip fracture in the general population. Aromatase inhibitors (AI) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk. AI exposure is not a direct input to FRAX but is captured under “secondary osteoporosis”. To inform use of FRAX in women treated with AI, we used a population-based registry for the Province of Manitoba, Canada, to identify women aged ≥40 years initiating AI for breast cancer with at least 12 months’ AI exposure (n = 1775), women with breast cancer not receiving AI (n = 1016), and women from the general population (n = 34,205). Among AI users, fracture probability estimated without BMD (AI use coded as secondary osteoporosis) significantly overestimated risk (10-year observed/predicted ratio 0.56, 95% confidence interval [CI] 0.45–0.68; 10-year hip fracture observed/predicted ratio 0.33, 95% CI 0.18–0.49). However, when BMD was included in the fracture probability, there was no significant difference between observed and predicted fracture risk. In Cox proportional hazards models, FRAX stratified risk of MOF, hip, and any fracture equally well in all subgroups (p-interaction >0.1). When adjusted for FRAX score without BMD, with AI use coded as secondary osteoporosis, AI users were at significantly lower risk for MOF (hazard ratio [HR] = 0.78, 95% CI 0.64–0.95), hip fracture (HR = 0.46, 95% CI 0.29–0.73) and any fracture (HR = 0.75, 95% CI 0.63–0.89). AI use was no longer significantly associated with fractures when AI use was not entered as secondary osteoporosis in FRAX without BMD or when BMD was included in the FRAX calculation. In conclusion, FRAX scores stratify fracture risk equally well in women receiving AI therapy as in non-users, but including secondary osteoporosis as a risk factor for AI users overestimates fracture risk. Our results call this practice into question. © 2019 American Society for Bone and Mineral Research.     

Lumbar spine texture enhances 10-year fracture probability assessment

Summary

We found that lumbar spine texture analysis using trabecular bone score (TBS) is a risk factor for MOF and a risk factor for death in a retrospective cohort study from a large clinical registry for the province of Manitoba, Canada.

Introduction

FRAX® estimates the 10-year probability of major osteoporotic fracture (MOF) using clinical risk factors and femoral neck bone mineral density (BMD). Trabecular bone score (TBS), derived from texture in the spine dual X-ray absorptiometry (DXA) image, is related to bone microarchitecture and fracture risk independently of BMD. Our objective was to determine whether TBS provides information on MOF probability beyond that provided by the FRAX variables.

Methods

We included 33,352 women aged 40–100 years (mean 63 years) with baseline DXA measurements of lumbar spine TBS and femoral neck BMD. The association between TBS, the FRAX variables, and the risk of MOF or death was examined using an extension of the Poisson regression model.

Results

During the mean of 4.7 years, 1,754 women died and 1,872 sustained one or more MOF. For each standard deviation reduction in TBS, there was a 36 % increase in MOF risk (HR 1.36, 95 % CI 1.30–1.42, p?p?T-scores.

Conclusions

Lumbar spine TBS is able to predict incident MOF independent of FRAX clinical risk factors and femoral neck BMD even after accounting for the increased death hazard.     

Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial

The WHO Fracture Risk Assessment Tool (FRAX; http://www.shef.ac.uk/FRAX ) estimates the 10‐year probability of major osteoporotic fracture. Clodronate and bazedoxifene reduced nonvertebral and clinical fracture more effectively on a relative scale in women with higher FRAX scores. We used data from the Fracture Intervention Trial (FIT) to evaluate the interaction between FRAX score and treatment with alendronate. We combined the Clinical Fracture (CF) arm and Vertebral Fracture (VF) arm of FIT. The CF and VF arm of FIT randomized 4432 and 2027 women, respectively, to placebo or alendronate for 4 and 3 years, respectively. FRAX risk factors were assessed at baseline. FRAX scores were calculated by WHO. We used Poisson regression models to assess the interaction between alendronate and FRAX score on the risk of nonvertebral, clinical, major osteoporotic, and radiographic vertebral fractures. Overall, alendronate significantly reduced the risk of nonvertebral fracture (incidence rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.75–0.99), but the effect was greater for femoral neck (FN) bone mineral density (BMD) T‐score ≤ ?2.5 (IRR 0.76; 95% CI, 0.62–0.93) than for FN T‐score > ?2.5 (IRR 0.96; 95% CI, 0.80–1.16) (p = 0.02, interaction between alendronate and FN BMD). However, there was no evidence of an interaction between alendronate and FRAX score with FN BMD for risk of nonvertebral fracture (interaction p = 0.61). The absolute benefit of alendronate was greatest among women with highest FRAX scores. Results were similar for clinical fractures, major osteoporotic fractures, and radiographic vertebral fractures and whether or not FRAX scores included FN BMD. Among this cohort of women with low bone mass there was no significant interaction between FRAX score and alendronate for nonvertebral, clinical or major osteoporotic fractures, or radiographic vertebral fractures. These results suggest that the effect of alendronate on a relative scale does not vary by FRAX score. A randomized controlled trial testing the effect of antifracture agents among women with high FRAX score but without osteoporosis is warranted. © 2012 American Society for Bone and Mineral Research.     

Validation of the FRAX Predictive Model for Major Osteoporotic Fracture in a Historical Cohort of Spanish Women

FRAX is a fracture risk assessment tool to estimate the 10-yr probability of a major osteoporotic fracture or a hip fracture. The aim of the study was to assess the predictive ability of FRAX for major osteoporotic fracture in a cohort of Spanish women.The study was based on a retrospective cohort of women aged 40–90 yr. Patients were followed from their first bone densitometry to the first major osteoporotic fracture event (forearm, proximal humerus, clinical spine, or hip fracture) or for 10 yr whichever comes first. A total of 1231 women were included. Bone mineral density data and self-reported data on risk factors for fracture were obtained. The predictive ability of FRAX was assessed by analyzing calibration and discrimination, with the calculation of observed-to-expected (O/E) fracture ratios and the receiver operating characteristic (ROC) curve, respectively.A total of 222 women (18.1%) reported at least 1 fracture after the first assessment. The incidence of fracture was 14 (95% confidence interval [CI]: 10–17), 19 (95% CI: 15–23), 28 (95% CI: 21–36), and 67 (95% CI: 8–125) cases per 1000 woman-years in women aged <55, 55–64, 65–74, and ≥75 yr, respectively. The O/E ratio was 3.9 (95% CI: 3.4–4.5; p < 0.0001). The area under the ROC curve was 61% (95% CI: 57–65%).FRAX underestimated the risk of major osteoporotic fracture in this cohort of Spanish women, particularly in those with a low risk of fracture according to the clinical factors used in the FRAX tool. Our findings highlight the need for validation studies of FRAX in Spain.     

Can Change in FRAX Score Be Used to “Treat to Target”? A Population‐Based Cohort Study

It is unknown how responsive the Fracture Risk Assessment (FRAX) tool is to osteoporosis treatment (OTX) or whether it can serve as a target for “goal‐directed” treatment. We studied 11,049 untreated women aged ≥50 years undergoing baseline and follow‐up DXA examinations in Manitoba, Canada. We identified clinical risk factors, intervening OTX based on medication possession ratios (MPR), and incident fractures. FRAX scores for major osteoporotic and hip fractures were computed for each scan using the most current (updated) FRAX inputs. Over 4 years, median FRAX scores showed an increase of 1.1% for major fractures and 0.3% for hip fractures, including women highly adherent to OTX (0.6% and 0.1% increases). Few (2.2%) highly adherent women had a decrease in major fracture probability exceeding 4%, whereas 9.0% had a decrease in hip fracture probability exceeding 1%. Compared with untreated women, OTX was associated with a higher dose‐dependent likelihood of attenuating the expected increase in major fracture risk: adjusted odds ratios (aOR) 2.3 (95% confidence interval [CI] 1.8–2.9) for MPR <0.50; 7.3 (95% CI 5.6–9.6) for MPR 0.50–0.79; and 12.0 (95% CI 9.5–15.2) for MPR ≥0.80. In the 4 years after the second DXA scan, 620 (6%) women had major fractures (152 hip fractures). FRAX scores were strongly predictive of incident major fractures (adjusted hazard ratios [aHR] per SD increase in FRAX 1.8, 95% CI 1.7–1.9) and hip fractures (aHR per SD 4.5, 95% CI 3.7–5.7); however, change in FRAX score was not independently associated with major fracture (p = 0.8) or hip fracture (p = 0.3). In conclusion, FRAX scores slowly increased over time, and this increase was attenuated but not prevented by treatment. Few women had meaningful reductions in FRAX scores, and change in FRAX score did not independently predict incident fracture, suggesting that FRAX with BMD is not responsive enough to be used as a target for goal‐directed treatment. © 2014 American Society for Bone and Mineral Research.     

Fracture Risk Indices From DXA-Based Finite Element Analysis Predict Incident Fractures Independently From FRAX: The Manitoba BMD Registry

Objective: Finite element analysis (FEA) is a computational method to predict the behavior of materials under applied loading. We developed a software tool that automatically performs FEA on dual-energy X-ray absorptiometry hip scans to generate site-specific fracture risk indices (FRIs) that reflect the likelihood of hip fracture from a sideways fall. This longitudinal study examined associations between FRIs and incident fractures. Methods: Using the Manitoba Bone Mineral Density (BMD) Registry, femoral neck (FN), intertrochanter (IT), and subtrochanter (ST) FRIs were automatically derived from 13,978 anonymized dual-energy X-ray absorptiometry scans (Prodigy, GE Healthcare) in women and men aged 50 yr or older (mean age 65 yr). Baseline covariates and incident fractures were assessed from population-based data. We compared c-statistics for FRIs vs FN BMD alone and fracture risk assessment (FRAX) probability computed with BMD. Cox regression was used to estimate hazard ratios and 95% confidence intervals (95% CIs) for incident hip, major osteoporotic fracture (MOF) and non-hip MOF adjusted for relevant covariates including age, sex, FN BMD, FRAX probability, FRAX risk factors, and hip axis length (HAL). Results: During mean follow-up of 6 yr, there were 268 subjects with incident hip fractures, 1003 with incident MOF, and 787 with incident non-hip MOF. All FRIs gave significant stratification for hip fracture (c-statistics FN-FRI: 0.76, 95% CI 0.73–0.79, IT-FRI 0.74, 0.71–0.77; ST-FRI 0.72, 0.69–0.75). FRIs continued to predict hip fracture risk even after adjustment for age and sex (hazard ratio per standard deviation FN-FRI 1.89, 95% CI 1.66–2.16); age, sex, and BMD (1.26, 1.07–1.48); FRAX probability (1.30, 1.11–1.52); FRAX probability with HAL (1.26, 1.05–1.51); and individual FRAX risk factors (1.32, 1.09–1.59). FRIs also predicted MOF and non-hip MOF, but the prediction was not as strong as for hip fracture. Summary: Automatically-derived FN, IT, and ST FRIs are associated with incident hip fracture independent of multiple covariates, including FN BMD, FRAX probability and risk factors, and HAL.     

Prediction of Fractures and Major Cardiovascular Events in Men Using Serum Osteoprotegerin Levels: The Prospective STRAMBO Study

Fragility fractures and cardiovascular diseases often coincide. However, data on shared risk factors and markers are scarce. Our aim was to assess the independent associations of serum osteoprotegerin (OPG) levels with the risk of fracture and cardiovascular outcomes (acute coronary syndrome, cardiac death) in older men. A cohort of 819 home‐dwelling men aged 60 to 87 years was followed prospectively for 8 years. Serum OPG was measured at baseline by ELISA. Bone mineral density (BMD) at femoral neck and Trabecular Bone Score (TBS) were assessed by DXA. Clinical risk factors and Fracture Risk Assessment Tool (FRAX) were assessed. The incident events (self‐reported peripheral fractures and acute coronary syndrome, cardiac death reported by a proxy) confirmed by a health professional were retained for the statistical analysis. Incident vertebral fractures were assessed on lateral DXA scans after 4 and 8 years. Hazard risk (HR) was assessed using the Cox model. After adjustment for FRAX corrected for femoral neck BMD and TBS, diabetes mellitus, ischemic heart disease, and prior falls, the risk of fracture was twofold higher in the highest versus the lowest OPG quartile (HR 2.35; 95% CI, 1.35 to 4.10). The risk of vertebral and nonvertebral fracture was higher in the highest versus the lowest OPG quartile (OR 2.76 [95% CI, 1.08 to 7.05] and HR 2.46 [95% CI, 1.23 to 4.92]). The risk of major osteoporotic fracture was higher in the fourth versus the first OPG quartile (HR 2.43; 95% CI, 1.16 to 5.10). The risk of cardiovascular outcome (adjusted for confounders) was higher in the highest versus the lowest OPG quartile (HR 3.93; 95% CI, 1.54 to 10.04). The risk of fracture and cardiovascular outcome was higher in the highest OPG quartile versus the lower quartiles combined (HR 2.06 [95% CI, 1.35 to 3.14] and HR 2.98 [95% CI, 1.60 to 5.54], respectively). In conclusion, in older men, higher serum OPG levels represent an independent risk factor for cardiovascular and fracture risk. © 2017 American Society for Bone and Mineral Research.     

Predictive Value of DXA Appendicular Lean Mass for Incident Fractures,Falls, and Mortality,Independent of Prior Falls,FRAX, and BMD: Findings from the Women's Health Initiative (WHI)

In the Women's Health Initiative (WHI), we investigated associations between baseline dual-energy X-ray absorptiometry (DXA) appendicular lean mass (ALM) and risk of incident fractures, falls, and mortality (separately for each outcome) among older postmenopausal women, accounting for bone mineral density (BMD), prior falls, and Fracture Risk Assessment Tool (FRAX^®) probability. The WHI is a prospective study of postmenopausal women undertaken at 40 US sites. We used an extension of Poisson regression to investigate the relationship between baseline ALM (corrected for height²) and incident fracture outcomes, presented here for major osteoporotic fracture (MOF: hip, clinical vertebral, forearm, or proximal humerus), falls, and death. Associations were adjusted for age, time since baseline and randomization group, or additionally for femoral neck (FN) BMD, prior falls, or FRAX probability (MOF without BMD) and are reported as gradient of risk (GR: hazard ratio for first incident fracture per SD increment) in ALM/height² (GR). Data were available for 11,187 women (mean [SD] age 63.3 [7.4] years). In the base models (adjusted for age, follow-up time, and randomization group), greater ALM/height² was associated with lower risk of incident MOF (GR = 0.88; 95% confidence interval [CI] 0.83–0.94). The association was independent of prior falls but was attenuated by FRAX probability. Adjustment for FN BMD T-score led to attenuation and inversion of the risk relationship (GR = 1.06; 95% CI 0.98–1.14). There were no associations between ALM/height² and incident falls. However, there was a 7% to 15% increase in risk of death during follow-up for each SD greater ALM/height², depending on specific adjustment. In WHI, and consistent with our findings in older men (Osteoporotic Fractures in Men [MrOS] study cohorts), the predictive value of DXA-ALM for future clinical fracture is attenuated (and potentially inverted) after adjustment for femoral neck BMD T-score. However, intriguing positive, but modest, associations between ALM/height² and mortality remain robust. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Usefulness of Trabecular Bone Score (TBS) to Identify Bone Fragility in Patients with Primary Hyperparathyroidism

Background: Patients with primary hyperparathyroidism usually show decreased bone strength that are often not well diagnosed by conventional Dual-energy X-ray absorptiometry (DXA). Trabecular Bone Score (TBS) is a new technique for assessing bone microarchitecture indirectly. This cross-sectional study evaluates the usefulness of TBS in patients with primary hyperparathyroidism in clinical practice. Methodology: Bone mineral density (BMD) by DXA and TBS values by TBS InSight® software were determined in 72 patients with primary hyperparathyroidism to analyze its relationship with fragility fractures. A receiver operating curve was performed to evaluate the usefulness of TBS as predictor of fragility fractures. FRAX index with and without adjustment by TBS was calculated. Additionally, longitudinal data of a subgroup of patients according to the therapeutic management were also evaluated. Results: A total of 51.4% of the patients showed degraded microarchitecture while only 37.5% of them were diagnosed of osteoporosis by DXA. No significant correlation was found between TBS values and BMD parameters. However, TBS values were lower in osteoporotic patients compared to those classified as normal by BMD (1.16 ± 0.12vs 1.26 ± 0.17; p?=?0.043) and in patients with fragility fractures compared to nonfractured patients (1.19 ± 0.03vs 1.24 ± 0.02, p < 0.001). The area under the curve for TBS performed better than the combination of femoral, hip and spine-BMD for prevalent fractures (0.714vs 0.679). TBS-adjusted FRAX was higher than nonadjusted model for both major osteoporotic and hip fracture (4.5% vs 3%; 0.9% vs 0.7%; p < 0.001). At follow-up, an improvement in TBS values was observed in treated patients (medical or surgical) vs nontreated close to significance (1.27 ± 0.10vs 1.24 ± 0.11, p?=?0.074). Conclusions: TBS could be a useful tool to identify increased fracture risk in patients with primary hyperparathyroidism underdiagnosed by BMD. Moreover, FRAX adjusted by TBS could be a more robust tool for predicting the risk of osteoporotic fracture to help in therapeutic decisions in this population.     

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.     

Association Between Muscle Mass Determined by D3-Creatine Dilution and Incident Fractures in a Prospective Cohort Study of Older Men

The relation between a novel measure of total skeletal muscle mass (assessed by D₃-creatine dilution [D₃Cr]) and incident fracture is unknown. In 1363 men (mean age 84.2 years), we determined D₃Cr muscle mass; Fracture Risk Assessment Tool (FRAX) 10-year probability of hip and major osteoporotic (hip, humerus, vertebral, forearm) fracture; and femoral neck bone mineral density (BMD) (by dual-energy X-ray absorptiometry [DXA]). Incident fractures were centrally adjudicated by review of radiology reports over 4.6 years. Correlations adjusted for weight and height were calculated between femoral neck BMD and D₃Cr muscle mass. Across quartiles of D₃Cr muscle mass/weight, proportional hazards models calculated hazard ratios (HRs) for any (n = 180); nonspine (n = 153); major osteoporotic fracture (n = 85); and hip fracture (n = 40) after adjustment for age, femoral neck BMD, recurrent fall history, and FRAX probability. Models were then adjusted to evaluate the mediating influence of physical performance (walking speed, chair stands, and grip strength). D₃Cr muscle mass was weakly correlated with femoral BMD (r = 0.10, p < 0.001). Compared to men in the highest quartile, those in the lowest quartile of D₃Cr muscle mass/weight had an increased risk of any clinical fracture (HR 1.8; 95% confidence interval [CI], 1.1–2.8); nonspine fracture (HR 1.8; 95% CI, 1.1–3.0), major osteoporotic fracture (HR 2.3; 95% CI, 1.2–4.6), and hip fracture (HR 5.9; 95% CI, 1.6–21.1). Results were attenuated after adjustment for physical performance, but associations remained borderline significant for hip and major osteoporotic fractures (p ≥ 0.05 to 0.10). Low D₃Cr muscle mass/weight is associated with a markedly high risk of hip and potentially other fractures in older men; this association is partially mediated by physical performance. © 2022 American Society for Bone and Mineral Research (ASBMR).     

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