A meta-analysis of previous falls and subsequent fracture risk in cohort studies

NC Harvey acknowledges funding from the UK Medical Research Council (MC_PC_21003; MC_PC_21001). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Funding for the MrOS USA study comes from the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. Funding for the SOF study comes from the National Institute on Aging (NIA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), supported by grants (AG05407, AR35582, AG05394, AR35584, and AR35583). Funding for the Health ABC study was from the Intramural research program at the National Institute on Aging under the following contract numbers: NO1-AG-6–2101, NO1-AG-6–2103, and NO1-AG-6–2106.Peer reviewedPostprin

Age-related changes in bone strength from HR-pQCT derived microarchitectural parameters with an emphasis on the role of cortical porosity

\u3cp\u3eThe high resolution peripheral computed tomography (HR-pQCT) technique has seen recent developments with regard to the assessment of cortical porosity. In this study, we investigated the role of cortical porosity on bone strength in a large cohort of women.The distal radius and distal tibia were scanned by HR-pQCT. We assessed bone strength by estimating the failure load by microfinite element analysis (μFEA), with isotropic and homogeneous material properties. We built a multivariate model to predict it, using a few microarchitecture variables including cortical porosity.Among 857 Caucasian women analyzed with μFEA, we found that cortical and trabecular properties, along with the failure load, impaired slightly with advancing age in premenopausal women, the correlations with age being modest, with |r\u3csub\u3eage\u3c/sub\u3e| ranging from 0.14 to 0.38. After the onset of the menopause, those relationships with age were stronger for most parameters at both sites, with |r\u3csub\u3eage\u3c/sub\u3e| ranging from 0.10 to 0.64, notably for cortical porosity and failure load, which were markedly deteriorated with increasing age. Our multivariate model using microarchitecture parameters revealed that cortical porosity played a significant role in bone strength prediction, with semipartial r\u3csup\u3e2\u3c/sup\u3e=0.22 only at the tibia in postmenopausal women.In conclusion, in our large cohort of women, we observed a small decline of bone strength at the tibia before the onset of menopause. We also found an age-related increase of cortical porosity at both scanned sites in premenopausal women. In postmenopausal women, the relatively high increase of cortical porosity accounted for the decline in bone strength only at the tibia.\u3c/p\u3

Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to conduct a systematic review and meta-analysis on the performance of the WHO\u27s Fracture Risk Assessment (FRAX) instrument in predicting 10-year risk of Major Osteoporotic Fractures (MOF) and Hip Fractures (HF), using the USA treatment thresholds, in populations other than their derivation cohorts. DESIGN: EMBASE and MEDLINE database were searched with search engine PubMed and OVID as well as Google Scholar for the English-language literature from July 2008 to July 2016. Limiting our search to articles that analyzed only MOF and/or HF as an outcome, 7 longitudinal cohorts from 5 countries (USA, Poland, France, Canada, New Zealand) were identified and included in the meta-analysis. SAS NLMIXED procedure (SAS v 9.3) was applied to fit the Hierarchical Summary Receiver Operating Characteristics (HSROC) model for meta-analysis. Forest plot and HSROC plot was generated by Review Manager (RevMan v 5.3). RESULTS: Seven studies (n=57,027) were analyzed to assess diagnostic accuracy of FRAX in predicting MOF, using 20% as the 10-year fracture risk threshold for intervention, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) were 10.25% (3.76%-25.06%), 97.02% (91.17%-99.03%) and 3.71 (2.73-5.05), respectively. For HF prediction, using 3% as the 10-year fracture risk threshold, six studies (n=50,944) were analyzed. The mean sensitivity, specificity, and DOR along with their 95% confidence intervals (CI) were 45.70% (24.88%-68.13%), 84.70% (76.41%-90.44%) and 4.66 (2.39-9.08), respectively. CONCLUSIONS: Overall, using the 10year intervention thresholds of 20% for MOF and 3% for HF, FRAX performed better in identifying patients who will not have a MOF or HF within 10years, than those who will. A substantial number of patients who developed fractures, especially MOF within 10years of follow up, were missed by the baseline FRAX assessment

Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: A systematic review and meta-analysis.

Objective: The aim of this study is to conduct a systematic review and meta-analysis on the performance of the WHO’s Fracture Risk Assessment (FRAX) instrument for predicting 10-year risk of Major Osteoporotic Fractures (MOF) and Hip Fractures (HF) in populations other than their derivation cohorts. Design: PubMed, Google Scholar, Embase, Cochrane Library, and MEDLINE were searched for the English-language literature from 2008 to 2015. Limiting our search to articles that analyzed only MOF and / or HF as an outcome, 7 longitudinal cohorts from 5 countries (USA, Poland, France, Canada, New Zeland) were identified and included in the meta-analysis. SAS NLMIXED procedure (SAS v 9.3) was applied to fit the Hierarchical Summary Receiver Operating Characteristics (HSROC) model for meta-analysis. Forest plot and HSROC plot was generated by Review Manager (RevMan v 5.3). Results: Seven studies (n=57,027) were analyzed to assess diagnostic accuracy of FRAX in predicting MOF. Using 20% as the 10-year fracture risk threshold, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) are 10.25% (3.76% - 25.06%), 97.02% (91.17% - 99.03%) and 3.71 (2.73 – 5.05), respectively. For HF prediction, using 3% as the 10-year fracture risk threshold, six studies (n=50,944) were analyzed. The mean sensitivity, specificity, and DOR along with their 95% confidence intervals (CI) are 45.70% (24.88% - 68.13%), 84.70% (76.41% - 90.44%) and 4.66 (2.39 – 9.08), respectively. Conclusion: Overall, FRAX performs better in identifying patients who will not have a MOF or HF within 10 years. However, a substantial number of patients who developed fractures, especially MOF within 10 years of follow up, were missed by the baseline FRAX assessment using the 10 year intervention thresholds of 20% for MOF and 3% for HF

Deterioration of cortical and trabecular microstructure identifies women with osteopenia or normal bone mineral density at imminent and long-term risk for fragility fracture : A prospective study

More than 70% of women sustaining fractures have osteopenia or “normal” bone mineral density (BMD). These women remain undetected using the BMD threshold of −2.5 SD for osteoporosis. As microstructural deterioration increases bone fragility disproportionate to the bone loss producing osteopenia/normal BMD, we hypothesized that the structural fragility score (SFS) of ≥70 units, a measure capturing severe cortical and trabecular deterioration, will identify these women. Distal radial images were acquired using high‐resolution peripheral quantitative tomography in postmenopausal French women, mean age 67 years (range 42–96 years); 1539 women were followed for 4 years (QUALYOR) and 561 women followed for 8 years (OFELY). Women with osteopenia or normal BMD accounted for ~80% of fractures. Women ≥70 years, 29.2% of the cohort, accounted for 39.2% to 61.5% of fractures depending on follow‐up duration. Women having fractures had a higher SFS, lower BMD, and a higher fracture risk assessment score (FRAX) than women remaining fracture‐free. In each BMD category (osteoporosis, osteopenia, normal BMD), fracture incidence was two to three times higher in women with SFS ≥70 than <70. In multivariable analyses, associations with fractures remained for BMD and SFS, not FRAX. BMD was no longer, or weakly, associated with fractures after accounting for SFS, whereas SFS remained associated with fracture after accounting for BMD. SFS detected two‐to threefold more women having fractures than BMD or FRAX. SFS in women with osteopenia/normal BMD conferred an odds ratio for fracture of 2.69 to 5.19 for women of any age and 4.98 to 12.2 for women ≥70 years. Receiver‐operator curve (ROC) analyses showed a significant area under the curve (AUC) for SFS, but not BMD or FRAX for the women ≥70 years of age. Targeting women aged ≥70 years with osteopenia indicated that treating 25% using SFS to allocate treatment conferred a cost‐effectiveness ratio < USD $21,000/QALY saved. Quantifying microstructural deterioration complements BMD by identifying women without osteoporosis at imminent and longer‐term fracture risk. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research

Selected serum microRNA, abdominal aortic calcification and risk of osteoporotic fracture

International audienceCONTEXT: MicroRNA (miRNA) regulate post-transcriptionally the expression of osteogenesis and angiogenesis associated genes and emerge as potential non-invasive biomarkers in vascular and bone diseases. Severe abdominal aortic calcification (AAC) is associated with higher risk of cardiovascular event and of fragility fracture.OBJECTIVE: To identify miRNA linked to the aggravation of AAC and to incident osteoporotic fracture.DESIGN: Postmenopausal women (>50 years) with available serum at inclusion and data for each outcome (Kauppila score and incident fracture) were selected from the OFELY prospective cohort. We conducted a case-control study in 434 age-matched women, 50% with incident osteoporotic fracture over 20 years of follow-up and a second study in 183 women to explore AAC over 17 years.METHODS: Serum expression of three miRNA involved in vascular calcification and bone turnover regulation (miRs-26a-5p,-34a-5p, and -223-5p) was quantified at baseline by TaqMan Advanced miRNA technology and expressed by relative quantification. Outcomes were the association of miRNA levels with (1) incident osteoporotic fractures during 20 years, (2) AAC aggravation during 17 years.RESULTS: MiRNA level was not associated with incident fractures (miR-26a-5p: 1.06 vs 0.99, p = 0.07; miR-34a-5p: 1.15 vs 1.26, p = 0.35; miR-223a-5p: 1.01 vs 1.05, p = 0.32). 93 women had an increase in Kauppila score over 17 years while 90 did not. None of the miRNAs was associated with an aggravation in AAC (miR-26a-5p: 1.09 vs 1.10, p = 0.95; miR-34a-5p: 0.78 vs 0.73, p = 0.90; miR-223-5p: 0.97 vs 0.78, p = 0.11).CONCLUSIONS: Circulating miR-26a-5p, -34a-5p and -223-5p are not significantly associated with incident fracture and AAC aggravation

Microarchitecture and Peripheral BMD are Impaired in Postmenopausal White Women With Fracture Independently of Total Hip T‐Score: An International Multicenter Study

Because single-center studies have reported conflicting associations between microarchitecture and fracture prevalence, we included high-resolution peripheral quantitative computed tomography (HR-pQCT) data from five centers worldwide into a large multicenter analysis of postmenopausal women with and without fracture. Volumetric BMD (vBMD) and microarchitecture were assessed at the distal radius and tibia in 1379 white postmenopausal women (age 67 ± 8 years); 470 (34%) had at least one fracture including 349 with a major fragility fracture. Age, height, weight, and total hip T-score differed across centers and were employed as covariates in analyses. Women with fracture had higher BMI, were older, and had lower total hip T-score, but lumbar spine T-score was similar between groups. At the radius, total and trabecular vBMD and cortical thickness were significantly lower in fractured women in three out of five centers, and trabecular number in two centers. Similar results were found at the tibia. When data from five centers were combined, however, women with fracture had significantly lower total, trabecular, and cortical vBMD (2% to 7%), lower trabecular number (4% to 5%), and thinner cortices (5% to 6%) than women without fracture after adjustment for covariates. Results were similar at the radius and tibia. Similar results were observed with analysis restricted to major fragility fracture, vertebral and hip fractures, and peripheral fracture (at the radius). When focusing on osteopenic women, each SD decrease of total and trabecular vBMD was associated with a significantly increased risk of major fragility fracture (OR = 1.55 to 1.88, p &lt; 0.01) after adjustment for covariates. Moreover, trabecular architecture modestly improved fracture discrimination beyond peripheral total vBMD. In conclusion, we observed differences by center in the magnitude of fracture/nonfracture differences at both the distal radius and tibia. However, when data were pooled across centers and the sample size increased, we observed significant and consistent deficits in vBMD and microarchitecture independent of total hip T-score in all postmenopausal white women with fracture and in the subgroup of osteopenic women, compared to women who never had a fracture. © 2016 American Society for Bone and Mineral Research

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a "one-size-fits-all" approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD