Atypical Femoral Fractures: Transverse Morphology at Lateral Cortex Is a Critical Feature

In 2010, the American Society for Bone and Mineral Research (ASBMR) task force defined major and minor features to assist in the case finding and reporting of atypical femoral fractures (AFFs). One major feature that was proposed was a “transverse or short oblique configuration.” Our primary aim was to compare the conventional overall fracture morphology (OFM) with its associated angle (OFMA) and our proposed lateral cortical fracture angle (LCFA) in the assessment of fracture configuration in suspected AFFs and non‐AFFs. The radiographs of 79 patients with AFFs and 39 patients with non‐AFFs were each analyzed by two blinded reviewers to obtain the OFM, OFMA, and LCFA. Using the overall fracture morphology to assess the suspected AFFs resulted in discordance between reviewers in 18 cases (22.8%), of which 5 (6.3%) were discordant between short oblique (>30° to 60°) and long oblique (>60° to 90°) configurations, therefore affecting their classifications as AFFs. By assessing only the critical component within the lateral cortex, all the suspected AFFs fell well within the classification as transverse fractures with a mean LCFA of 4.8° (range 0.3 to 18.0, SD = 4.23). The inter‐reader variability was also lower for LCFA versus OFMA (4.1° versus 6.9°, p = 0.001) when used to assess AFFs. Fracture angles were significantly different in AFFs versus non‐AFFs regardless of whether the OFMA or LCFA methodology was employed, but the greater difference associated with LCFA suggests its greater discriminating power. When LCFA was used in conjunction with 0° to 30° as the criteria for transverse morphology, all the AFFs and non‐AFFs were correctly classified. By using a standardized and precise method in measuring the fracture angle, specifically using only the component of the lateral cortex and limiting to truly transverse fractures, ie, between 0° and 30°, the LCFA is a robust and accurate method to assess the fracture morphology in suspected AFFs. © 2014 American Society for Bone and Mineral Research.     

Five Freely Circulating miRNAs and Bone Tissue miRNAs Are Associated With Osteoporotic Fractures

Osteoporosis as a systemic skeletal disorder is characterized by increased bone fragility and the risk of fractures. According to the World Health Organization, osteoporosis is one of the 10 most common diseases and affects approximately 75 million people in Europe, the United States, and Japan. In this context, the identification of specific microRNA (miRNA) signatures is an important step for new diagnostic and therapeutic approaches. The focus of interest on miRNAs as biomarkers came with new publications identifying free circulating extracellular miRNAs associated with various types of cancer. This study aimed to identify specific miRNAs in patients with osteoporotic fractures compared with nonosteoporotic fractures. For the array analysis, miRNAs were isolated from the serum of 20 patients with hip fractures, transcribed, and the samples were pooled into 10 osteoporotic and 10 nonosteoporotic specimens. With each pool of samples, human serum and plasma miRNA PCR arrays were performed, which are able to identify 83 different miRNAs. Subsequently, a separate validation analysis of each miRNA found to be regulated in the array followed with miRNA samples isolated from the serum of 30 osteoporotic and 30 nonosteoporotic patients and miRNA samples isolated from the bone tissue of 20 osteoporotic and 20 nonosteoporotic patients. With the validation analysis of the regulated miRNAs, we identified 9 miRNAs, namely miR‐21, miR‐23a, miR‐24, miR‐93, miR‐100, miR‐122a, miR‐124a, miR‐125b, and miR‐148a, that were significantly upregulated in the serum of patients with osteoporosis. In the bone tissue of osteoporotic patients, we identified that miR‐21, miR‐23a, miR‐24, miR‐25, miR‐100, and miR‐125b displayed a significantly higher expression. A total of 5 miRNAs display an upregulation both in serum and bone tissue. This study reveals an important role for several miRNAs in osteoporotic patients and suggested that they may be used as biomarkers for diagnostic purposes and may be a target for treating bone loss and optimizing fracture healing in osteoporotic patients. © 2014 American Society for Bone and Mineral Research.     

Trabecular Bone Score: A Noninvasive Analytical Method Based Upon the DXA Image

The trabecular bone score (TBS) is a gray‐level textural metric that can be extracted from the two‐dimensional lumbar spine dual‐energy X‐ray absorptiometry (DXA) image. TBS is related to bone microarchitecture and provides skeletal information that is not captured from the standard bone mineral density (BMD) measurement. Based on experimental variograms of the projected DXA image, TBS has the potential to discern differences between DXA scans that show similar BMD measurements. An elevated TBS value correlates with better skeletal microstructure; a low TBS value correlates with weaker skeletal microstructure. Lumbar spine TBS has been evaluated in cross‐sectional and longitudinal studies. The following conclusions are based upon publications reviewed in this article: 1) TBS gives lower values in postmenopausal women and in men with previous fragility fractures than their nonfractured counterparts; 2) TBS is complementary to data available by lumbar spine DXA measurements; 3) TBS results are lower in women who have sustained a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; 4) TBS predicts fracture risk as well as lumbar spine BMD measurements in postmenopausal women; 5) efficacious therapies for osteoporosis differ in the extent to which they influence the TBS; 6) TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality. Based on these data, lumbar spine TBS holds promise as an emerging technology that could well become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment. © 2014 American Society for Bone and Mineral Research.     

Assessment of Bone Microarchitecture in Postmenopausal Women on Long‐Term Bisphosphonate Therapy With Atypical Fractures of the Femur

Reports of atypical femoral fractures (AFFs) in patients receiving long‐ term bisphosphonate therapy have raised concerns regarding the genesis of this rare event. Using high‐resolution peripheral quantitative computed tomography (HR‐pQCT), we conducted a study to evaluate bone microarchitecture in patients who had suffered an AFF during long‐term bisphosphonate treatment. The aim of our study was to evaluate if bone microarchitecture assessment could help explain the pathophysiology of these fractures. We compared bone volumetric density and microarchitectural parameters measured by HR‐pQCT in the radius and tibia in 20 patients with AFFs with 35 postmenopausal women who had also received long‐term bisphosphonate treatment but had not experienced AFFs, and with 54 treatment‐naive postmenopausal women. Control groups were similar in age, body mass index (BMI), and bone mineral density (BMD). Mean age of the 20 patients with AFFs was 71 years, mean lumbar spine T‐score was ?2.2, and mean femoral neck T‐score was ?2. Mean time on bisphosphonate treatment was 10.9 years (range, 5–20 years). None of the patients had other conditions associated with AFFs such as rheumatoid arthritis, diabetes or glucocorticoid use. There were no statistically significant differences in any of the parameters measured by HR‐pQCT between postmenopausal women with or without treatment history and with or without history of atypical fractures. We could not find any distinctive microarchitecture features in the peripheral skeleton of women who had suffered an atypical fracture of the femur while receiving bisphosphonate treatment. This suggests that risk of developing an atypical fracture is not related to bone microarchitecture deterioration. Our results indicate that there may be other individual factors predisposing to atypical fractures in patients treated with bisphosphonates, and that those are independent of bone microarchitecture. In the future, identification of those factors could help prevent and understand the complex physiopathology of these rare events. © 2014 American Society for Bone and Mineral Research.     

Analysis of αSMA‐Labeled Progenitor Cell Commitment Identifies Notch Signaling as an Important Pathway in Fracture Healing

Fracture healing is a regenerative process that involves coordinated responses of many cell types, but characterization of the roles of specific cell populations in this process has been limited. We have identified alpha smooth muscle actin (αSMA) as a marker of a population of mesenchymal progenitor cells in the periosteum that contributes to osteochondral elements during fracture healing. Using a lineage tracing approach, we labeled αSMA‐expressing cells, and characterized changes in the periosteal population during the early stages of fracture healing by histology, flow cytometry, and gene expression profiling. In response to fracture, the αSMA‐labeled population expanded and began to differentiate toward the osteogenic and chondrogenic lineages. The frequency of mesenchymal progenitor cell markers such as Sca1 and PDGFRα increased after fracture. By 6 days after fracture, genes involved in matrix production and remodeling were elevated. In contrast, genes associated with muscle contraction and Notch signaling were downregulated after fracture. We confirmed that activating Notch signaling in αSMA‐labeled cells inhibited differentiation into osteogenic and adipogenic lineages in vitro and ectopic bone formation in vivo. By characterizing changes in a selected αSMA‐labeled progenitor cell population during fracture callus formation, we have shown that modulation of Notch signaling may determine osteogenic potential of αSMA‐expressing progenitor cells during bone healing. © 2014 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     

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.     

The Effect of Latitude on the Risk and Seasonal Variation in Hip Fracture in Sweden

Although the optimal requirement of vitamin D for skeletal health in the general community is controversial, vitamin D deficiency impairs bone mineralization and increases bone turnover via secondary hyperparathyroidism, thus accelerating bone loss and increasing fracture risk. Support for a role of vitamin D deficiency in the epidemiology of hip fracture is found in the seasonal variation of hip fracture incidence that is reported in several studies. If the association were causal, then the incidence and amplitude of the seasonal variation in hip fracture risk should vary by latitude. We addressed this hypothesis by examining the incidence of hip fracture in men and women aged 50 years or more from Sweden (latitudes 55 to 69°) between 1987 and 2009. In order to reduce double counting, only one fracture in a period of a year was counted per individual. Men contributed 104,888 fractures in 33,313,065 person years and women 264,362 fractures in 38,387,660 person years. The effects of season and latitude were examined by Poisson regression. As expected, hip fracture rates were higher in women than in men. After adjustment for age, season and population density, hip fracture incidence increased by 3.0% (95% CI: 2.7–3.2%) per degree increase in latitude for men and by 1.9% (95% CI: 1.8–2.1%) for women. There was a marked seasonal variation of hip fracture with the highest risk in February and lower by 37.5% in men and by 23.5% women during the summer. There were significant interactions of amplitude of the seasonal variation with latitude (p < 0.001 for both men and women), indicating that seasonal variation during the year was more pronounced in the north of Sweden than in the south. The associations found with latitude and season is consistent with a role of vitamin D in hip fracture causation. © 2014 American Society for Bone and Mineral Research.     

Subgroup Variations in Bone Mineral Density Response to Zoledronic Acid After Hip Fracture

Minimizing post‐fracture bone loss is an important aspect of recovery from hip fracture, and determination of factors that affect bone mineral density (BMD) response to treatment after hip fracture may assist in the development of targeted therapeutic interventions. A post hoc analysis of the HORIZON Recurrent Fracture Trial was done to determine the effect of zoledronic acid (ZOL) on total hip (TH) and femoral neck (FN) BMD in subgroups with low‐trauma hip fracture. A total of 2127 patients were randomized (1:1) to yearly infusions of ZOL 5 mg (n = 1065) or placebo (n = 1062) within 90 days of operation for low‐trauma hip fracture. The 1486 patients with a baseline and at least one post‐baseline BMD assessment at TH or FN (ZOL = 745, placebo = 741) were included in the analyses. Percentage change from baseline in TH and FN BMD was assessed at months 12 and 24 and compared across subgroups of hip fracture patients. Percentage change from baseline in TH and FN BMD at months 12 and 24 was greater (p < 0.05) in ZOL‐treated patients compared with placebo in most subgroups. Treatment‐by‐subgroup interactions (p < 0.05) indicated that a greater effect on BMD was observed for TH BMD at month 12 in females, in patients in the lower tertile body mass index at baseline (≤22.6 kg/m²), and in patients with baseline FN BMD T‐score of ≤ –2.5; for FN BMD in patients who received ZOL for >6 weeks post‐surgery; and for TH and FN BMD in patients with a history of one or more prior fractures. All interactions were limited to the first 12 months after treatment with none observed for the 24‐month comparisons. (Clinical trial registration number NCT00046254.) © 2014 American Society for Bone and Mineral Research.     

张氏接骨散对骨折愈合影响的X线和血尿生化学的临床研究

将５６例骨折患者随机分为三组，从症体征、Ｘ线摄片、血尿生化学检查等几个方面，对照观察了张氏接骨散对骨折愈合的影响，结果表明，在临床症状消失，骨痂生长和新生骨质形成，碱性磷酸酶浓度与活性，体内胶原总转换率，骨折临床愈合时间等方面，试验组均优于对照组（Ｐ＜０．０５、Ｐ＜０．０１），提示该方能明显促进骨折愈合。