Zoledronic acid reduces the rate of clinical fractures after surgical repair of a hip fracture regardless of the Pretreatment bone mineral density.

In patients with surgical repair of a low-trauma hip fracture, zoledronic acid (ZA) reduced the risk of subsequent fractures regardless of pretreatment femoral neck and total hip bone mineral density (BMD). INTRODUCTION: Zoledronic acid reduces the risk of subsequent fractures after repair of a hip fracture. It is still unclear whether the benefits in fracture reduction with ZA depend upon hip bone mineral density at the time of fracture. METHODS: We preformed additional post hoc analyses of data from the HORIZON Recurrent Fracture Trial to determine if ZA treatment reduced the risk of new clinical fractures regardless of pretreatment BMD. We modeled femoral neck and total hip BMD as both continuous and dichotomous variables (BMD T-score above and below -2.5). RESULTS: There are no evidence that baseline femoral neck and total hip BMD modified the anti-fracture efficacy of ZA when pretreatment BMD was analyzed as a continuous or a dichotomous variable (interaction p-values > 0.20). The clinical fracture efficacy of ZA was similar among patients with pretreatment femoral neck BMD values above and below -2.5 (relative hazards = 0.60 and 0.67, respectively, interaction p-value = 0.95). A similar result was obtained using pretreatment total hip BMD values (relative hazards = 0.72 and 0.57, respectively, interaction p-value = 0.41). CONCLUSION: There data should provide more comfort in prescribing ZA after surgical repair of a hip fracture, regardless of pretreatment BMD.

OncotypeDX Recurrence Score Does Not Predict Nodal Burden in Clinically Node Negative Breast Cancer Patients.

BACKGROUND: OncotypeDX recurrence score (RS)® has been found to predict recurrence and disease-free survival in patients with node negative breast cancer. Whether RS is useful in guiding locoregional therapy decisions is unclear. We sought to evaluate the relationship between RS and lymph node burden. METHODS: Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18-30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant. RESULTS: A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23 months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015). CONCLUSIONS: OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.

Bone turnover markers to explain changes in lumbar spine BMD with abaloparatide and teriparatide: results from ACTIVE.

Early PINP changes correlate with 18-month lumbar spine BMD changes and the correlation was greater with abaloparatide versus teriparatide. The uncoupling index was similar between the two agents. INTRODUCTION: We evaluated the relationship between early PINP changes and subsequent changes in spine BMD following abaloparatide and teriparatide treatments. We also explored the use of an "uncoupling index" (UI), the balance between bone formation and bone resorption, which we hypothesised would be similar in response to these treatment groups. METHODS: Blood samples were taken for measurement of bone turnover markers (BTMs) s-PINP and s-CTX at baseline, 1, 3, 6, 12, and 18 months from 189 abaloparatide patients and 227 teriparatide patients randomly selected from all participants who completed the study. BMD was measured by DXA at baseline, 6, 12, and 18 months. Correlations were calculated between log ratio of BTMs from baseline to 3 months and percent change from baseline in BMD at 18 months. A UI was calculated using log transformation and subtraction of the standard deviate for s-CTX from the standard deviate for s-PINP for each patient. RESULTS: Early BTM changes were associated with subsequent BMD changes for both treatments. Pearson correlations for the log ratio of PINP over baseline at 3 months and BMD percent change from baseline at 18 months were larger (P < 0.0001) with abaloparatide (r = 0.561) than teriparatide (r = 0.198). The mean UI at 1 month was greater for abaloparatide versus teriparatide (1.743 and 1.493, respectively; P = 0.03) but was similar at 3 months or later time points. CONCLUSIONS: Early s-PINP changes correlate with percentage change in lumbar spine BMD 18 months after treatment with both abaloparatide and teriparatide, though the correlation with abaloparatide was greater. The UI was similar between abaloparatide and teriparatide suggesting that the balance between formation and resorption markers was similar.

Radiological criteria for atypical features of femur fractures: what we can learn when applied in a clinical study setting.

The paper focuses on the identification of atypical fractures (AFFs). This paper examines the concordance between objective classification and expert subjective review. We believe the paper adds critical information about how to apply the American Society of Bone and Mineral Research (ASBMR) criteria to diagnose AFFs and is of high interest to the field. INTRODUCTION: Assess American Society of Bone and Mineral Research (ASBMR) criteria for identifying atypical femoral fractures (AFFs). METHODS: Two orthopedic surgeons independently evaluated radiographs of 372 fractures, applying ASBMR criteria. We assessed ease of applying ASBMR criteria and whether criteria-based assessment matched qualitative expert assessment. RESULTS: There was up to 27% uncertainty about how to classify specific features. 84% of films were classified similarly for the presence of AFF according to ASBMR criteria; agreement increased to 94% after consensus meeting. Of 37 fractures categorized as AFFs based on ASBMR criteria, 23 (62.2%) were considered AFFs according to expert assessment (not relying on criteria). Only one (0.5%) femoral shaft fracture that did not meet ASBMR criteria was considered an AFF per expert assessment. The number of major ASBMR features present (four vs five) and whether there was periosteal or endosteal thickening ("beaking" or "flaring") played major roles in the discrepancies between ASBMR criteria-based and expert-based determinations. CONCLUSIONS: ASBMR AFF criteria were useful for reviewers but several features were difficult to interpret. Expert assessments did not agree with the ASBMR classification in almost one-third of cases, but rarely identified an AFF when a femoral shaft fracture did not meet ASBMR AFF criteria. Experts identified lateral cortical transverse fracture line and associated new-bone formation along with no or minimal comminution as crucial features necessary for the definition of atypical femoral fractures.

Multidisciplinary Intraoperative Assessment of Breast Specimens Reduces Number of Positive Margins.

BACKGROUND: Successful breast-conserving surgery requires achieving negative margins. At our institution, the whole surgical specimen is imaged and then serially sectioned with repeat imaging. A multidisciplinary discussion then determines need for excision of additional margins. The goal of this study was to determine the benefit of each component of this approach in reducing the number of positive margin. METHODS: This single-institution, prospective study included ten breast surgical oncologists who were surveyed to ascertain whether they would have taken additional margins based their review of whole specimen images (WSI) and review of serially sectioned images (SSI). These results were compared with the multidisciplinary decisions (MDD) and pathology results. Margin status was defined using consensus guidelines. RESULTS: One hundred surveys were completed. Margins on the original specimen were positive or close in 21%. After WSI, surgeons reported that they would have taken additional margins in 26 cases, reducing the number of positive/close margins from 21 to 13% (p < 0.001). After SSI, 52 would have taken additional margins; however, the number of positive/close margins remained 13%. MDD resulted in additional margins taken in 56 cases, reducing the number of positive/close margins to 7% (p < 0.001 compared with SSI). CONCLUSIONS: While surgeon review of specimen radiographs can decrease the number of positive or close margins from 21 to 13%, more rigorous multidisciplinary, intraoperative margin assessment reduces the number of close or positive margins to 7%.

Association of incident hip fracture with the estimated femoral strength by finite element analysis of DXA scans in the Osteoporotic Fractures in Men (MrOS) study.

Finite element model can estimate bone strength better than BMD. This study used such a model to determine its association with hip fracture risk and found that the strength estimate provided limited improvement over the hip BMDs in predicting femoral neck (FN) fracture risk only. INTRODUCTION: Bone fractures occur only when it is loaded beyond its ultimate strength. The goal of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of DXA scans, with incident hip fracture as a single condition or with femoral neck (FN) and trochanter (TR) fractures separately in older men. METHODS: This prospective case-cohort study included 91 FN and 64 TR fracture cases and a random sample of 500 men (14 had a hip fracture) from the Osteoporotic Fractures in Men study during a mean ± SD follow-up of 7.7 ± 2.2 years. We analysed the baseline DXA scans of the hip using a validated plane-stress, linear-elastic FE model of the proximal femur and estimated the femoral strength during a sideways fall. RESULTS: The estimated strength was significantly (P < 0.05) associated with hip fracture independent of the TR and total hip (TH) BMDs but not FN BMD, and combining the strength with BMD did not improve the hip fracture prediction. The strength estimate was associated with FN fractures independent of the FN, TR and TH BMDs; the age-BMI-BMD adjusted hazard ratio (95% CI) per SD decrease of the strength was 1.68 (1.07-2.64), 2.38 (1.57, 3.61) and 2.04 (1.34, 3.11), respectively. This association with FN fracture was as strong as FN BMD (Harrell's C index for the strength 0.81 vs. FN BMD 0.81) and stronger than TR and TH BMDs (0.8 vs. 0.78 and 0.81 vs. 0.79). The strength's association with TR fracture was not independent of hip BMD. CONCLUSIONS: Although the strength estimate provided additional information over the hip BMDs, its improvement in predictive ability over the hip BMDs was confined to FN fracture only and limited.

Insights into the bisphosphonate holiday: a preliminary FTIRI study.

Bone composition evaluated by FTIRI analysis of iliac crest biopsies from post-menopausal women treated with alendronate for 10 years, continuously or alendronate for 5 years, followed by a 5-year alendronate-holiday, only differed with the discontinued biopsies having increased cortical crystallinity and heterogeneity of acid phosphate substitution and decreased trabecular crystallinity heterogeneity. INTRODUCTION: Bisphosphonates (BP) are the most commonly used and effective drugs to prevent fragility fractures; however, concerns exist that prolonged use may lead to adverse events. Recent recommendations suggest consideration of a BP "holiday" in individuals taking long-term BP therapy not at high risk of fracture. Data supporting or refuting this recommendation based on bone quality are limited. We hypothesized that a "holiday" of 5 years would cause no major bone compositional changes. METHODS: We analyzed the 31 available biopsies from the FLEX-Long-term Extension of FIT (Fracture Intervention Trial) using Fourier transform infrared imaging (FTIRI). Biopsies from two groups of post-menopausal women, a "Continuously treated group" (N = 16) receiving alendronate for ~ 10 years and a "Discontinued group" (N = 15), alendronate treated for 5 years taking no antiresorptive medication during the following 5 years. Iliac crest bone biopsies were provided at 10 years. RESULTS: Key FTIRI parameters, mineral-to-matrix ratio, carbonate-to-phosphate ratio, acid phosphate substitution, and collagen cross-link ratio as well as heterogeneity of these parameters were similar for Continuously treated and Discontinued groups in age-adjusted models. The Discontinued group had 2% greater cortical crystallinity (p = 0.01), 31% greater cortical acid phosphate heterogeneity (p = 0.02), and 24% lower trabecular crystallinity heterogeneity (p = 0.02). CONCLUSIONS: Discontinuation of alendronate for 5 years did not affect key FTIRI parameters, supporting the hypothesis that discontinuation would have little impact on bone composition. Modest differences were observed in three parameters that are not likely to affect bone mechanical properties. These preliminary data suggest that a 5-year BP holiday is not harmful to bone composition.

Operator variability in scan positioning is a major component of HR-pQCT precision error and is reduced by standardized training.

In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ).

Changing patterns of prescription in vitamin D supplementation in adults: analysis of a regional dataset.

UNLABELLED: Scientific interest in vitamin D has greatly risen during the last 10 years. The analysis of the changes in vitamin D prescriptions and related costs in a regional prescription dataset has revealed a profound increase in the period 2006-2013. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed. INTRODUCTION: The aim of this study was to analyze the changes in population-based prescription patterns of vitamin D supplements in the general population in an Italian regional setting during an 8-year period (2006-2013). METHODS: Data have been retrieved from the database of reimbursed prescriptions of the Region of Tuscany containing all of the medical reimbursements for the whole regional population (total of 3,619,872 and 3,692,828 inhabitants in 2006 and 2013, respectively). Data referring to adult population (age 20-90+ years) have been considered for this analysis (3,033,530 in 2006 and 3,066,741 in 2013). Two different flows (pharmaceutical distribution dataset and general data flow) were taken into account, using the ATC5 coding system for vitamin D supplements alone or in combination with calcium or alendronate. The number of boxes dispensed was retrieved, the number of patients receiving a specific treatment was calculated, and a cost analysis was performed. RESULTS: An upsurge in the prescriptions of vitamin D compounds was disclosed, mainly sustained by a 75.3-fold increase in cholecalciferol, in all age groups and both sexes. This occurred in parallel to a 4.3-fold rise in prescriptions of oral alendronate in combination with cholecalciferol, a slight decrease in dispensed alendronate alone, and a modest increase in the prescription of the combination of calcium salts and cholecalciferol, and calcium alone. The total cost for reimbursement by the Regional Health System for vitamin D-related compounds rose from €3,242,100 euros in 2006 to €8,155,778 in 2013. CONCLUSION: The huge increase in vitamin D prescriptions and related costs in the last decade, as revealed by the analysis of a regional pharmaceutical dataset, reflects the increased awareness of the possible consequences of a poor vitamin D status. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed.

Serum 25-hydroxyvitamin D concentration does not independently predict incident diabetes in older women.

AIMS: To investigate whether 25-hydroxyvitamin D concentration was associated with incident diabetes in a large cohort of older women. METHODS: Data were analysed from women included in the Study of Osteoporotic Fractures, a cohort of community-dwelling women aged ≥65 years at enrolment. Serum 25-hydroxyvitamin D concentration was assessed at the year 6 visit, as were BMI and other factors associated with vitamin D and/or diabetes. Diabetes status was determined at each subsequent visit by self-report and medication use. Only those without prevalent diabetes at the year 6 visit were included in the present analysis (N = 5463, mean age 76.5 years). RESULTS: During a mean ±sd follow-up of 8.6 ± 4.4 years, incident diabetes was reported in 320 participants. The mean BMI was higher in those with a 25-hydroxyvitamin D concentration <20 ng/ml (<50 nmol/l) than in those with concentrations 20-30 or ≥30 ng/ml [50-74 or ≥75 nmol/l (P < 0.0001)]. A higher 25-hydroxyvitamin D concentration was associated with a 13% lower risk of incident diabetes after adjustment for age and clinic site [hazard ratio 0.87, 95% CI 0.76-0.99, per sd increase in 25-hydroxyvitamin D]; however, the addition of BMI to the model attenuated the estimated effect (hazard ratio 0.97, 95% CI 0.86-1.11). Adjustment for additional potential confounders yielded similar results. CONCLUSIONS: Serum 25-hydroxyvitamin D does not independently predict incident diabetes in older women. Although those with higher 25-hydroxyvitamin D concentrations are less likely to develop diabetes, this is mainly explained by their lower BMI.

Site-specific differential effects of once-yearly zoledronic acid on the hip assessed with quantitative computed tomography: results from the HORIZON Pivotal Fracture Trial.

UNLABELLED: We used new approaches to the analysis of diagnostic scans to detect changes in bone density in different regions of the hip after 3 years of treatment with the zoledronic acid. We showed that the drug significantly increases hip bone density compared to placebo at regions where hip fractures usually occur. INTRODUCTION: This study aims to identify whether treatment with zoledronic acid exerts site-specific differential effects on volumetric bone mineral density (vBMD) at the hip. METHODS: We analysed quantitative computed tomography scans of the hip obtained at baseline and 36 months in 179 women participating in the HORIZON Pivotal Fracture Trial. Cortical, trabecular and integral BMDs were determined at three main regions of interest-the femoral neck (FN), trochanter (TR) and total hip (TH)-and several sub-regions of interest, namely the proximal, middle, distal, anterior, posterior, inferomedial and superolateral FN, and the middle and distal TR. RESULTS: Volumetric BMD increased significantly (p < 0.05) from baseline with zoledronic acid compared to placebo. Trabecular vBMD increased as follows: FN, 5.4 %; FN sub-regions, 6.0 % (proximal), 4.4 % (middle), 5.6 % (distal), 7.5 % (anterior), 7.0 % (superolateral) and 5.4 % (posterior); TR, 6.5 % and TH, 5.7 %. Cortical vBMD increased as follows: FN sub-regions, 5.0 % (proximal FN) and 2.3 % (anterior); TR, 4.6 %; middle TR, 2.7 % and TH, 3.8 %. CONCLUSIONS: The effects on vBMD of annual infusion of 5 mg of zoledronic acid are site-specific and dominated by trabecular changes.

Updated fracture incidence rates for the Italian version of FRAX®.

UNLABELLED: In order to update data underlying the Italian version of FRAX, we computed the national hip fracture incidence in Italy from hospitalization records for the year 2008. Mortality data and 10-year probabilities of major osteoporotic fractures were also updated. This revision will improve FRAX accuracy and reliability. INTRODUCTION: The original Italian version of FRAX® was based on five regional estimates of hip fracture risk undertaken up to 20 years previously. Our objective was to update hip fracture rates for the model with more recently derived data from the whole Italian population and more recent data on mortality. METHODS: We analyzed the Italian national hospitalization database for the year 2008 in order to compute age- and sex-specific hip fracture incidence rates. Re-hospitalisations of the same patients within 1 year were excluded from the analysis. Hip fracture incidence rates were computed for the age range of 40-100 years, whereas the original FRAX model lacked data on the youngest and oldest age groups. In addition, we used the national mortality data for the same year 2008 to update the model. Ten-year fracture probabilities were re-calculated on the basis of the new fracture incidence rates. RESULTS: The new hip fracture age- and sex-specific incidence rates were close to those used in the original FRAX tool, although some significant differences (not exceeding 25-30 %) were found for men aged 65-75 years and women under 55 years of age. In general, the revision resulted in decreased estimated 10-year probabilities in the younger age groups, whilst those in the older age groups were slightly increased. CONCLUSIONS: The Italian version of FRAX has been updated using the new fracture incidence rates. The impact of these revisions on FRAX is likely to increase the accuracy and reliability of FRAX in estimating 10-year fracture probabilities.

Postmenopausal women treated with combination parathyroid hormone (1-84) and ibandronate demonstrate different microstructural changes at the radius vs. tibia: the PTH and Ibandronate Combination Study (PICS).

SUMMARY: In postmenopausal women receiving combination parathyroid hormone (PTH) (1-84) therapy and ibandronate, we evaluated bone microarchitecture and biomechanics using high-resolution peripheral quantitative computed tomography (HR-pQCT). Cortical and trabecular changes were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. INTRODUCTION: PTH therapy and bisphosphonates decrease fracture risk in postmenopausal osteoporosis, but their effects on bone microstructure and strength have not been fully characterized, particularly during combination therapy. PTH increases trabecular bone mineral density (BMD) substantially but may decrease cortical BMD, possibly by stimulating intracortical remodeling. We evaluated bone microarchitecture and biomechanics with HR-pQCT at the radius (a nonweight-bearing site) and tibia (weight bearing) in women receiving combination PTH(1-84) and ibandronate. METHODS: Postmenopausal women with low bone mass (n = 43) were treated with 6 months of PTH(1-84) (100 µg/day), either as one 6- or two 3-month courses, in combination with ibandronate (150 mg/month) over 2 years. HR-pQCT was performed before and after therapy. RESULTS: Because changes in HR-pQCT parameters did not differ between treatment arms, groups were pooled into one cohort for analysis. Trabecular BMD increased at both radius and tibia (p < 0.01 for each). Cortical thickness and BMD decreased at the radius (p < 0.01), consistent with changes in dual-energy X-ray absorptiometry, while these parameters did not change at the tibia (p ≤ 0.02 for difference between radius and tibia). In contrast, cortical porosity increased at the tibia (p < 0.01) but not radius. Stiffness and failure load decreased at the radius (p < 0.0001) but did not change at the tibia. CONCLUSIONS: Cortical and trabecular changes in response to the PTH/ibandronate treatment combinations utilized in this study were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. Our findings support the possibility that weight bearing may optimize the effects of osteoporosis therapy.

Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis.

UNLABELLED: The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. INTRODUCTION: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. METHODS: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. RESULTS: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. CONCLUSIONS: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy.

Absence of ST7 mutations in tumor-derived cell lines and tumors.

The gene ST7 has been proposed as the multi-tissue tumor-suppressor gene (TSG) at chromosome 7q31.1. However, we have sought and failed to detect the truncating mutations reported to exist in this gene.

Predictors of new and severe vertebral fractures: results from the HORIZON Pivotal Fracture Trial.

UNLABELLED: We examined prevalent and recent vertebral fractures in 1 year as predictors of new vertebral fractures over subsequent 2 years using data from RCT placebo patients. We found that prevalent and recent vertebral fractures strongly and independently predicted subsequent vertebral fractures including those which were severe. INTRODUCTION: While several studies have shown that prevalent vertebral fractures (pVFx) increase the risk of new vertebral fractures (VFx), the impact of recent vertebral fractures on future fractures is less studied. METHODS: Data from the placebo arm of the HORIZON Pivotal Fracture Trial, an international trial of zoledronic acid in postmenopausal, osteoporotic women between 65 and 85 years, were used. We included the subset of 2677 women with annual spinal radiographs to study the impact of vertebral fractures in year 1 (Y1 VF) on those occurring in years 2 and 3 using morphometric and semiquantitative (SQ) criteria. In addition, a subset of severe VFx was defined using SQ criteria. Logistic regression examined the impact of pVFx and Y1 VF on all incident VFx and on severe incident VFx. RESULTS: Two hundred fourty-five (9.1%) women sustained a new VFx in years 2-3. VFx risk in years 2-3 was 3.9% in those without pVFx or VFy1 and 29.8% in those with both risk factors. Both pVF and VFy1 remained independent predictors for future VF when they were both entered into a logistic regression model (odds ratio (OR) = 3.3; 95% confidence interval (CI), 2.3-4.7; OR = 3.7, 95% CI, 2.3, 5.8, respectively). ORs were similar after adjustment. Of the total number of women, 4.1% had severe VFx. PVFx and Y1 VF were also significant predictors of severe VFx; however, Y1 VF appeared more strongly predictive of severe VFx. CONCLUSIONS: Prevalent and incident vertebral fractures are highly predictive of subsequent new and severe vertebral fractures. Women with both of these risk factors are likely to benefit from anti-osteoporosis treatment.

Zoledronic acid does not slow spinal radiographic progression of osteoarthritis in postmenopausal women with osteoporosis and radiographic osteoarthritis.

Introduction: Post hoc analyses of osteoporosis trials have suggested that alendronate and strontium ranelate may be associated with a reduction in the progression of spinal radiographic osteoarthritis (OA). We performed an analysis on a subgroup of participants in the horizon PFT trial (a 3-year randomized controlled trial (RCT) of yearly zoledronic acid (ZA) in postmenopausal women with osteoporosis), to evaluate the effect of ZA on the structural progression of spinal osteophytes (OPh) and disk space narrowing (DN). Methods: Paired lateral spinal X-rays (baseline and 36 months) were selected from the horizon PFT trial records restricted to those with radiographic OA at baseline. The X-rays were analyzed by two readers blinded to the treatment allocation. OPh and DN were scored separately using the Lane atlas (0-3 for increasing severity at each vertebral level) at all evaluable levels from T4-12 and L1-5. Results: A total of 504 sets of paired radiographs were included in the analysis, 245 in the ZA group and 259 in the placebo group. Overall, the rates of change of OPh and DN scores were low, and they were not statistically different between the groups (change in the whole spine OPh ZA 1.0 ± 1.6, placebo 0.8 ± 1.3, p = 0.1; DN ZA 0.3 ± 1.0, placebo 0.3 ± 0.8, p = 0.7). Conclusion: Yearly ZA for 3 years was not associated with a slowing of progression of OPh or DN in the thoracolumbar spine in patients with pre-existing radiographic OA.

Brain stem death induces pro-inflammatory cytokine production and cardiac dysfunction in sheep model.

INTRODUCTION: Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-h ovine model of BSD. METHODS: Twelve healthy female sheep (37-42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 h. Plasma and BAL endothelin-1 and cytokines (IL-1ß, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. RESULTS: Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 h post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1 × 109 cells/L [95% confidence interval (CI) 2.06-4.14] vs. 6 × 109 cells/L [95%CI 3.92-7.97]; p < 0.01) and BAL (4.5 × 109 cells/L [95%CI 0.41-9.41] vs. 26 [95%CI 12.29-39.80]; p = 0.03) after 6 h of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18-24.37] vs. 78.68 pM [95%CI 53.16-104.21]; p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69-5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 h. CONCLUSIONS: BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.

Diffuse idiopathic skeletal hyperostosis (DISH): relation to vertebral fractures and bone density.

UNLABELLED: Radiographs and spinal bone mineral density (BMD) were evaluated from 342 elderly men regarding possible effects of diffuse idiopathic skeletal hyperostosis (DISH) on vertebral fractures and densitometry measurements. Prevalent vertebral fractures were more frequent among men with DISH compared to men with no DISH even after fracture prevalence was adjusted for BMD. Paravertebral calcifications should be considered in patients with DISH when interpreting BMD measurements because both dual X-ray absorptiometry (DXA) and quantitative CT (QCT) densitometry may not be reliable. INTRODUCTION: The purpose of this study is to evaluate the prevalence of DISH in older men and its association with vertebral fractures and with BMD determined by DXA and QCT. METHODS: Lateral radiographs of the spine were analyzed in a sample of 342 men aged ≥ 65 years participating in the MrOS Study concerning the presence and grade of DISH and vertebral fractures. Lumbar BMD was measured by both DXA (areal, grams per square centimeter) and QCT (volumetric, grams per cubic centimeter). The association between DISH, BMD, and presence of fractures was studied using χ ( 2 ) and t tests. RESULTS: DISH was present in 52% (178/342) of the men. Men with DISH were older (mean, 75.1 vs 73.3, p < 0.05) and more likely to have prevalent fractures (28% vs 20%, p < p = 0.09). BMD assessed with DXA (1.08 vs 1.00 g/cm(2), p ≤ 0.0001), but not with QCT (0.11 vs 0.11 g/cm3, p = 0.65), was significantly higher in men with DISH compared to men without DISH. Significantly lower BMD of men with both DISH and fractures compared to men with DISH but without fractures was only detected by QCT (-25%, 0.09 vs 0.12, p < 0.05). Both DXA BMD and QCT BMD were significantly higher in severe lumbar DISH (+22% and +31%, p < 0.0001), respectively. CONCLUSION: DISH was associated with a higher prevalence of vertebral fractures in elderly men. Lumbar ossifications related to DISH should be considered when interpreting BMD measurements to predict their fracture risk.

Updated fracture incidence rates for the US version of FRAX.

UNLABELLED: On the basis of updated fracture and mortality data, we recommend that the base population values used in the US version of FRAX be revised. The impact of suggested changes is likely to be a lowering of 10-year fracture probabilities. INTRODUCTION: Evaluation of results produced by the US version of FRAX indicates that this tool overestimates the likelihood of major osteoporotic fracture. In an attempt to correct this, we updated underlying fracture and mortality rates for the model. METHODS: We used US hospital discharge data from 2006 to calculate annual age- and sex-specific hip fracture rates and age-specific ratios to estimate clinical vertebral fracture rates. To estimate the incidence of any one of four major osteoporotic fractures, we first summed these newly derived hip and vertebral fracture estimates with Olmsted County, MN, wrist and upper humerus fracture rates, and then applied 10-20% discounts for overlap. RESULTS: Compared with rates used in the current FRAX tool, 2006 hip fracture rates are about 16% lower, with greatest reductions observed among those below age 65 years; major osteoporotic fracture rates are about one quarter lower, with similar reductions across all ages. CONCLUSIONS: We recommend revising the US-FRAX by updating current base population values for hip fracture and major osteoporotic fracture. The impact of these revisions on FRAX is likely to be lowering of 10-year fracture probabilities, but more precise estimates of the impact of these changes will be available after these new rates are incorporated into the FRAX tool.