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.     

Nitrate Medications,Fractures, and Change in Bone Mineral Density in Postmenopausal Women: Results from the Women's Health Initiative

Nitrate medications may increase bone mineral density (BMD), although information on fracture outcomes is sparse. We examined the association of nitrate medications with fractures (hip, wrist/arm, and total fractures) and changes in BMD (hip, spine, and whole body) in the Women's Health Initiative (WHI) Clinical Trials and Observational Study. A total of 139,211 postmenopausal women 50 to 79 years old without history of hip fracture were included in this prospective study. Medication use was ascertained directly from drug containers at baseline during in‐person interviews in 1993 to 1998. Exposure measures included any use (use/non‐use), type of nitrate (as‐needed, maintenance) and duration of use (≤5 years, >5 years). We used separate multivariable Cox proportional hazard models to analyze associations between each exposure and fracture outcome, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariable linear regression models were used to examine 3‐year and 6‐year changes in BMD. At baseline, 1.2% (n = 1647) women were using a nitrate. During the mean ± SD follow‐up of 7.7 ± 1.5 years through 2005, women experienced 1582 hip fractures, 5156 wrist or arm fractures, and 22, 589 total fractures. After adjustment for confounders, nitrate use was not statistically associated with risk for hip (HR, 0.81; 95% CI, 0.56 to 1.18), wrist/arm (HR, 0.95; 95% CI, 0.74 to 1.23), or total fractures (HR, 0.96; 95% CI, 0.85 to 1.08). As‐needed nitrate use, but not maintenance therapy, was associated with a lower risk of total fractures (HR, 0.77; 95% CI, 0.62 to 0.95) and wrist/arm fractures (HR, 0.57; 95% CI, 0.34 to 0.98). Nitrate use was not associated with 3‐year or 6‐year changes in BMD at any site. We conclude that any nitrate use was not significantly associated with lower risk of fractures or higher BMD; however, as‐needed nitrate use was associated with lower risks of total and wrist/arm fractures. © 2016 American Society for Bone and Mineral Research.     

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.     

Serum Levels of a Cathepsin‐K Generated Periostin Fragment Predict Incident Low‐Trauma Fractures in Postmenopausal Women Independently of BMD and FRAX

Periostin is a matricellular protein involved in bone formation and bone matrix organization, but it is also produced by other tissues. Its circulating levels have been weakly associated with bone microstructure and prevalent fractures, possibly because periostin measured by the current commercial assays does not specifically reflect bone metabolism. In this context, we developed a new ELISA for a periostin fragment resulting from cathepsin K digestion (K‐Postn). We hypothesized that circulating K‐Postn levels could be associated with bone fragility. A total of 695 women (age 65.0 ± 1.5 years), enrolled in the Geneva Retirees Cohort (GERICO), were prospectively evaluated over 4.7 ± 1.9 years for the occurrence of low‐trauma fractures. At baseline, we measured serum periostin, K‐Postn, and bone turnover markers (BTMs), distal radius and tibia microstructure by HR‐pQCT, hip and lumbar spine aBMD by DXA, and estimated fracture probability using the Fracture Risk Assessment Tool (FRAX). Sixty‐six women sustained a low‐trauma clinical fracture during the follow‐up. Total periostin was not associated with fractures (HR [95% CI] per SD: 1.19 [0.89 to 1.59], p = 0.24). In contrast, K‐Postn was significantly higher in the fracture versus nonfracture group (57.5 ± 36.6 ng/mL versus 42.5 ± 23.4 ng/mL, p < 0.001) and associated with fracture risk (HR [95%CI] per SD: 2.14 [1.54 to 2.97], p < 0.001). After adjustment for aBMD, FRAX, bone microstructure, or BTMs, K‐Postn remained significantly associated with fracture risk. The performance of the fracture prediction models was improved by adding K‐Postn to aBMD or FRAX (Harrell C index for fracture: 0.70 for aBMD + K‐Post versus 0.58 for aBMD alone, p = 0.001; 0.73 for FRAX + K‐Postn versus 0.65 for FRAX alone, p = 0.005). Circulating K‐Postn predicts incident fractures independently of BMD, BTMs, and FRAX in postmenopausal women. Hence measurement of a periostin fragment resulting from in vivo cathepsin K digestion may help to identify subjects at high risk of fracture. © 2017 American Society for Bone and Mineral Research     

Dietary Inflammatory Index,Bone Mineral Density,and Risk of Fracture in Postmenopausal Women: Results From the Women's Health Initiative

Previous studies suggest that bone loss and fracture risk are associated with higher inflammatory milieu, potentially modifiable by diet. The primary objective of this analysis was to evaluate the association of the dietary inflammatory index (DII), a measure of the inflammatory potential of diet, with risk of hip, lower‐arm, and total fracture using longitudinal data from the Women's Health Initiative Observational Study and Clinical Trials. Secondarily, we evaluated changes in bone mineral density (BMD) and DII scores. DII scores were calculated from baseline food frequency questionnaires (FFQs) completed by 160,191 participants (mean age 63 years) without history of hip fracture at enrollment. Year 3 FFQs were used to calculate a DII change score. Fractures were reported at least annually; hip fractures were confirmed by medical records. Hazard ratios for fractures were computed using multivariable‐adjusted Cox proportional hazard models, further stratified by age and race/ethnicity. Pairwise comparisons of changes in hip BMD, measured by dual‐energy X‐ray absorptiometry from baseline, year 3, and year 6 were analyzed by quartile (Q1 = least inflammatory diet) of baseline DII scores in a subgroup of women (n = 10,290). Mean DII score improved significantly over 3 years (p < 0.01), but change was not associated with fracture risk. Baseline DII score was only associated with hip fracture risk in younger white women (HR Q4,1.48; 95% CI, 1.09 to 2.01; p = 0.01). There were no significant associations among white women older than 63 years or other races/ethnicities. Women with the least inflammatory DII scores had less loss of hip BMD (p = 0.01) by year 6, despite lower baseline hip BMD, versus women with the most inflammatory DII scores. In conclusion, a less inflammatory dietary pattern was associated with less BMD loss in postmenopausal women. A more inflammatory diet was associated with increased hip fracture risk only in white women younger than 63 years. © 2016 American Society for Bone and Mineral Research.     

Association of Trabecular Bone Score (TBS) With Incident Clinical and Radiographic Vertebral Fractures Adjusted for Lumbar Spine BMD in Older Men: A Prospective Cohort Study

The association of trabecular bone score (TBS) with incident clinical and radiographic vertebral fractures in older men is uncertain. TBS was estimated from baseline spine dual‐energy X‐ray absorptiometry (DXA) scans for 5831 older men (mean age 73.7 years) enrolled in the Osteoporotic Fractures in Men (MrOS) study. Cox proportional hazard models were used to determine the association of TBS (per 1 SD decrease) with incident clinical vertebral fractures. Logistic regression was used to determine the association between TBS (per 1 SD decrease) and incident radiographic vertebral fracture among the subset of 4309 men with baseline and follow‐up lateral spine radiographs (mean 4.6 years later). We also examined whether any associations varied by body mass index (BMI) category. TBS was associated with a 1.41‐fold (95% confidence interval [CI] 1.23 to 1.63) higher aged‐adjusted odds of incident radiographic fracture, and this relationship did not vary by BMI (p value = 0.22 for interaction term). This association was no longer significant with further adjustment for lumbar spine bone mineral density (BMD; odds ratio [OR] = 1.11, 95% CI 0.94 to 1.30). In contrast, the age‐adjusted association of TBS with incident clinical vertebral fracture was stronger in men with lower BMI (≤ median value of 26.8 kg/m²; hazard ratio [HR] = 2.28, 95% CI 1.82 to 2.87) than in men with higher BMI (> median; HR = 1.60, 95% CI 1.31 to 1.94; p value = 0.0002 for interaction term). With further adjustment for lumbar spine BMD, the association of TBS with incident clinical vertebral fracture was substantially attenuated in both groups (HR = 1.30 [95% CI 0.99 to 1.72] among men with lower BMI and 1.11 [95% CI 0.87 to 1.41] among men with higher BMI). In conclusion, TBS is not associated with incident clinical or radiographic vertebral fracture after consideration of age and lumbar spine BMD, with the possible exception of incident clinical vertebral fracture among men with lower BMI. © 2017 American Society for Bone and Mineral Research.     

Associations Between Late Pregnancy Dietary Inflammatory Index (DII) and Offspring Bone Mass: A Meta-Analysis of the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC)

Systemic inflammation is associated with reduced bone mineral density and may be influenced by pro-inflammatory diets. We undertook an observational analysis of associations between late pregnancy energy-adjusted dietary inflammatory index (E-DII) scores and offspring bone outcomes in childhood. E-DII scores (higher scores indicating pro-inflammatory diets) were derived from food frequency questionnaires in late pregnancy in two prospective mother-offspring cohorts: the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). The mean (SD) offspring age at dual-energy X-ray absorptiometry (DXA) scanning was 9.2 (0.2) years. Linear regression was used to assess associations between E-DII and bone outcomes, adjusting for offspring sex and age at DXA and maternal age at childbirth, educational level, pre-pregnancy body mass index (BMI), parity, physical activity level, and smoking in pregnancy. Associations were synthesized using fixed-effect meta-analysis. Beta coefficients represent the association per unit E-DII increment. In fully adjusted models (total n = 5910) late pregnancy E-DII was negatively associated with offspring whole body minus head bone area (BA: β = −3.68 [95% confidence interval −6.09, −1.27] cm²/unit), bone mineral content (BMC: β = −4.16 [95% CI −6.70, −1.62] g/unit), and areal bone mineral density (aBMD: β = −0.0012 [95% CI −0.0020, −0.0004] g.cm⁻²/unit), but there was only a weak association with BMC adjusted for BA (β = −0.48 [95% CI −1.11, 0.15] g/unit) at 9 years. Adjustment for child height partly or, for weight, fully attenuated the associations. Higher late pregnancy E-DII scores (representing a more pro-inflammatory diet) are negatively associated with offspring bone measures, supporting the importance of maternal and childhood diet on longitudinal offspring bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Optimism,Cynical Hostility,Falls, and Fractures: The Women's Health Initiative Observational Study (WHI‐OS)

Traits of optimism and cynical hostility are features of personality that could influence the risk of falls and fractures by influencing risk‐taking behaviors, health behaviors, or inflammation. To test the hypothesis that personality influences falls and fracture risk, we studied 87,342 women enrolled in WHI‐OS. Optimism was assessed by the Life Orientation Test–Revised and cynical hostility, the cynicism subscale of the Cook‐Medley questionnaire. Higher scores indicate greater optimism and hostility. Optimism and hostility were correlated at r = –0. 31, p < 0.001. Annual self‐report of falling ≥2 times in the past year was modeled using repeated measures logistic regression. Cox proportional hazards models were used for the fracture outcomes. We examined the risk of falls and fractures across the quartiles (Q) of optimism and hostility with tests for trends; Q1 formed the referent group. The average follow‐up for fractures was 11.4 years and for falls was 7.6 years. In multivariable (MV)‐adjusted models, women with the highest optimism scores (Q4) were 11% less likely to report ≥2 falls in the past year (odds ratio [OR] = 0.89; 95% confidence intervals [CI] 0.85–0.90). Women in Q4 for hostility had a 12% higher risk of ≥2 falls (OR = 1.12; 95% CI 1.07–1.17). Higher optimism scores were also associated with a 10% lower risk of fractures, but this association was attenuated in MV models. Women with the greatest hostility (Q4) had a modest increased risk of any fracture (MV‐adjusted hazard ratio = 1. 05; 95% CI 1.01–1.09), but there was no association with specific fracture sites. In conclusion, optimism was independently associated with a decreased risk of ≥2 falls, and hostility with an increased risk of ≥2 falls, independent of traditional risk factors. The magnitude of the association was similar to aging 5 years. Whether interventions aimed at attitudes could reduce fall risks remains to be determined. © 2016 American Society for Bone and Mineral Research.