Differences in femoral fracture localizations in men and women in Switzerland between 1998 and 2021-reversal of the secular trend?

Number and age-standardized incidences of femoral fractures by sex and localization were determined annually between 1998 and 2021 in subjects aged 45 years or older living in Switzerland. The number and incidences of femoral neck, pertrochanteric, subtrochanteric, and femoral shaft fractures followed distinct unexpected trend patterns. INTRODUCTION: Long-term incidence trends for femoral fractures by individual localizations are unknown. METHODS: Annual absolute number of hospitalizations and median age at hospital admission between 1998 and 2021 were extracted from the medical database of the Swiss Federal Office of Statistics by sex and 10-year age groups for the following 10th International Classification of Diseases (ICD-10) codes: femoral neck (ICD-10 S72.0), pertrochanteric (S72.1), subtrochanteric (S72.2), and femoral shaft fractures (S72.3). Age-standardized incidence rates (ASI) and corresponding trends were calculated. RESULTS: Over 24 years, the number of femoral neck fractures increased in men (+ 45%) but decreased in women (- 7%) with ASI significantly decreasing by 20% and 37% (p < 0.001 for trend for both), respectively. By contrast, the number of pertrochanteric fractures increased by 67% and 45% in men and women, respectively, corresponding to a horizontal ASI-trend in men (n.s.) and a modest significant decreasing ASI-trend in women (p < 0.001). The number of subtrochanteric fractures increased in both sexes with corresponding modest significant reductions in ASI-trends (p = 0.015 and 0.002, respectively). Femoral shaft fractures almost doubled in men (+ 71%) and doubled in women (+ 100%) with corresponding significant increases in ASI-trends (p = 0.001 and p < 0.001, respectively). Age at admission increased for all fracture localizations, more so in men than in women and more so for subtrochanteric and shaft fractures than for "typical" hip fractures. CONCLUSION: Incidence changes of pertrochanteric fractures and femoral shaft fractures deserve increased attention, especially in men. Pooling diagnostic codes for defining hip fractures may hide differing patterns by localization and sex.

A multi-stack registration technique to improve measurement accuracy and precision across longitudinal HR-pQCT scans.

BACKGROUND: Recent applications of high-resolution peripheral quantitative computed tomography (HR-pQCT) have demonstrated that changes in local bone remodelling can be quantified in vivo using longitudinal three-dimensional image registration. However, certain emerging applications, such as fracture healing and joint analysis, require larger multi-stack scan regions that can result in stack shift image artifacts. These artifacts can be detrimental to the accurate alignment of the bone structure across multiple timepoints. The purpose of this study was to establish a multi-stack registration protocol for evaluating longitudinal HR-pQCT images and to assess the accuracy and precision error in comparison with measures obtained using previously established three-dimensional longitudinal registration. METHODS: Three same day multi-stack HR-pQCT scans of the radius (2 stacks in length) and tibia (3 stacks in length) were obtained from 39 healthy individuals who participated in a previous reproducibility study. A fully automated multi-stack registration algorithm was developed to re-align stacks within a scan by leveraging slight offsets between longitudinal scans. Stack shift severity before and after registration was quantified using a newly proposed stack-shift severity score. The false discovery rate for bone remodelling events and precision error of bone morphology and micro-finite element analysis parameters were compared between longitudinally registered scans with and without the addition of multi-stack registration. RESULTS: Most scans (82 %) improved in stack alignment or maintained the lowest stack shift severity score when multi-stack registration was implemented. The false discovery rate of bone remodelling events significantly decreased after multi-stack registration, resulting in median false detection of bone formation and resorption fractions between 3.2 to 7.5 % at the radius and 3.4 to 5.3 % at the tibia. Further, precision error was significantly reduced or remained unchanged in all standard bone morphology and micro-finite element analysis parameters, except for total and trabecular cross-sectional areas. CONCLUSION: Multi-stack registration is an effective strategy for accurately aligning multi-stack HR-pQCT scans without modification of the image acquisition protocol. The algorithm presented here is a viable approach for performing accurate morphological analysis on multi-stack HR-pQCT scans, particularly for advanced application investigating local bone remodelling in vivo.

In major joint diseases the human synovium retains its potential to form repair cartilage.

The inner surface layer of human joints, the synovium, is a source of stem cells for the repair of articular cartilage defects. We investigated the potential of the normal human synovium to form novel cartilage and compared its chondrogenic capacity with that of two patient groups suffering from major joint diseases: young adults with femoro-acetabular impingement syndromes of the hip (FAI), and elderly individuals with osteoarthritic degeneration of the knee (OA). Synovial membrane explants of these three patient groups were induced in vitro to undergo chondrogenesis by growth factors: bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-ß1 (TGF-ß1) alone, or a combination of these two. Quantitative evaluations of the newly formed cartilages were performed respecting their gene activities, as well as the histochemical, immunhistochemical, morphological and histomorphometrical characteristics. Formation of adult articular-like cartilage was induced by the BMP-2/TGF-ß1 combination within all three groups, and was confirmed by adequate gene-expression levels of the anabolic chondrogenic markers; the levels of the catabolic markers remained low. Our data reveal that the chondrogenic potential of the normal human synovium remains uncompromised, both in FAI and OA. The potential of synovium-based clinical repair of joint cartilage may thus not be impaired by age-related joint pathologies.

Precision of bone mechanoregulation assessment in humans using longitudinal high-resolution peripheral quantitative computed tomography in vivo.

Local mechanical stimuli in the bone microenvironment are essential for the homeostasis and adaptation of the skeleton, with evidence suggesting that disruption of the mechanically-driven bone remodelling process may lead to bone loss. Longitudinal clinical studies have shown the combined use of high-resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis can be used to measure load-driven bone remodelling in vivo; however, quantitative markers of bone mechanoregulation and the precision of these analyses methods have not been validated in human subjects. Therefore, this study utilised participants from two cohorts. A same-day cohort (n = 33) was used to develop a filtering strategy to minimise false detections of bone remodelling sites caused by noise and motion artefacts present in HR-pQCT scans. A longitudinal cohort (n = 19) was used to develop bone imaging markers of trabecular bone mechanoregulation and characterise the precision for detecting longitudinal changes in subjects. Specifically, we described local load-driven formation and resorption sites independently using patient-specific odds ratios (OR) and 99 % confidence intervals. Conditional probability curves were computed to link the mechanical environment to the remodelling events detected on the bone surface. To quantify overall mechanoregulation, we calculated a correct classification rate measuring the fraction of remodelling events correctly identified by the mechanical signal. Precision was calculated as root-mean-squared averages of the coefficient of variation (RMS-SD) of repeated measurements using scan-rescan pairs at baseline combined with a one-year follow-up scan. We found no significant mean difference (p < 0.01) between scan-rescan conditional probabilities. RMS-SD was 10.5 % for resorption odds, 6.3 % for formation odds, and 1.3 % for correct classification rates. Bone was most likely to be formed in high-strain and resorbed in low-strain regions for all participants, indicating a consistent, regulated response to mechanical stimuli. For each percent increase in strain, the likelihood of bone resorption decreased by 2.0 ± 0.2 %, and the likelihood of bone formation increased by 1.9 ± 0.2 %, totalling 38.3 ± 1.1 % of strain-driven remodelling events across the entire trabecular compartment. This work provides novel robust bone mechanoregulation markers and their precision for designing future clinical studies.

2D-3D reconstruction of the proximal femur from DXA scans: Evaluation of the 3D-Shaper software.

Introduction: Osteoporosis is currently diagnosed based on areal bone mineral density (aBMD) computed from 2D DXA scans. However, aBMD is a limited surrogate for femoral strength since it does not account for 3D bone geometry and density distribution. QCT scans combined with finite element (FE) analysis can deliver improved femoral strength predictions. However, non-negligible radiation dose and high costs prevent a systematic usage of this technique for screening purposes. As an alternative, the 3D-Shaper software (3D-Shaper Medical, Spain) reconstructs the 3D shape and density distribution of the femur from 2D DXA scans. This approach could deliver a more accurate estimation of femoral strength than aBMD by using FE analysis on the reconstructed 3D DXA. Methods: Here we present the first independent evaluation of the software, using a dataset of 77 ex vivo femora. We extend a prior evaluation by including the density distribution differences, the spatial correlation of density values and an FE analysis. Yet, cortical thickness is left out of this evaluation, since the cortex is not resolved in our FE models. Results: We found an average surface distance of 1.16 mm between 3D DXA and QCT images, which shows a good reconstruction of the bone geometry. Although BMD values obtained from 3D DXA and QCT correlated well (r 2 = 0.92), the 3D DXA BMD were systematically lower. The average BMD difference amounted to 64 mg/cm3, more than one-third of the 3D DXA BMD. Furthermore, the low correlation (r 2 = 0.48) between density values of both images indicates a limited reconstruction of the 3D density distribution. FE results were in good agreement between QCT and 3D DXA images, with a high coefficient of determination (r 2 = 0.88). However, this correlation was not statistically different from a direct prediction by aBMD. Moreover, we found differences in the fracture patterns between the two image types. QCT-based FE analysis resulted mostly in femoral neck fractures and 3D DXA-based FE in subcapital or pertrochanteric fractures. Discussion: In conclusion, 3D-Shaper generates an altered BMD distribution compared to QCT but, after careful density calibration, shows an interesting potential for deriving a standardized femoral strength from a DXA scan.

The osteoporosis treatment gap in Switzerland between 1998 and 2018.

The annual number of patients treated for osteoporosis between 1998 and 2018 in Switzerland increased until 2008 and steadily decreased thereafter. With a continuously growing population at fracture risk exceeding an intervention threshold, the treatment gap has increased and the incidence of hip fractures has stopped declining in the past decade. INTRODUCTION: The existence of an osteoporosis treatment gap, defined as the percentage of patients at risk for osteoporotic fractures exceeding an intervention threshold but remaining untreated, is widely acknowledged. Between 1998 and 2018, new bone active substances (BAS) indicated for the treatment of osteoporosis became available. Whether and if so to what extent these new introductions have altered the treatment gap is unknown. METHODS: The annual number of patients treated with a BAS was calculated starting from single-drug unit sales. The number of patients theoretically eligible for treatment with a BAS was estimated based on four scenarios corresponding to different intervention thresholds (one based solely on a bone mineral density T score threshold and three FRAX-based thresholds) and the resulting annual treatment gaps were calculated. RESULTS: In Switzerland, the estimated number of patients on treatment with a BAS increased from 35,901 in year 1998 to 233,381 in year 2018. However, this number grew regularly since 1998, peaked in 2008, and steadily decreased thereafter, in timely coincidence with the launch of intravenous bisphosphonates and the RANKL inhibitor denosumab. When expressed in numbers of untreated persons at risk for osteoporotic fractures exceeding a given intervention threshold, the treatment gaps were of similar magnitude in 1998 (when the first BSAs just had become available) and 2018. There was a strong association, which does not imply causation, between the proportion of patients treated and hip fracture incidence. CONCLUSION: In Switzerland, the osteoporosis treatment gap has increased over the past decade. The availability of new BAS has not contributed to its decrease.

Human Bone Typing Using Quantitative Cone-Beam Computed Tomography.

INTRODUCTION: Bone typing is crucial to enable the choice of a suitable implant, the surgical technique, and the evaluation of the clinical outcome. Currently, bone typing is assessed subjectively by the surgeon. OBJECTIVE: The aim of this study is to establish an automatic quantification method to determine local bone types by the use of cone-beam computed tomography (CBCT) for an observer-independent approach. METHODS: Six adult human cadaver skulls were used. The 4 generally used bone types in dental implantology and orthodontics were identified, and specific Hounsfield unit (HU) ranges (grey-scale values) were assigned to each bone type for identification by quantitative CBCT (qCBCT). The selected scanned planes were labelled by nonradiolucent markers for reidentification in the backup/cross-check evaluation methods. The selected planes were then physically removed as thick bone tissue sections for in vitro correlation measurements by qCBCT, quantitative micro-computed tomography (micro-CT), and quantitative histomorphometry. RESULTS: Correlation analyses between the different bone tissue quantification methods to identify bone types based on numerical ranges of HU values revealed that the Pearson correlation coefficient of qCBCT with micro-CT and quantitative histomorphometry was R = 0.9 (P = .001) for all 4 bone types . CONCLUSIONS: We found that  qCBCT can reproducibly and objectively assess human bone types at implant sites.

Clinical observation of diminished bone quality and quantity through longitudinal HR-pQCT-derived remodeling and mechanoregulation.

High resolution peripheral quantitative computed tomography (HR-pQCT) provides methods for quantifying volumetric bone mineral density and microarchitecture necessary for early diagnosis of bone disease. When combined with a longitudinal imaging protocol and finite element analysis, HR-pQCT can be used to assess bone formation and resorption (i.e., remodeling) and the relationship between this remodeling and mechanical loading (i.e., mechanoregulation) at the tissue level. Herein, 25 patients with a contralateral distal radius fracture were imaged with HR-pQCT at baseline and 9-12 months follow-up: 16 patients were prescribed vitamin D3 with/without calcium supplement based on a blood biomarker measures of bone metabolism and dual-energy X-ray absorptiometry image-based measures of normative bone quantity which indicated diminishing (n = 9) or poor (n = 7) bone quantity and 9 were not. To evaluate the sensitivity of this imaging protocol to microstructural changes, HR-pQCT images were registered for quantification of bone remodeling and image-based micro-finite element analysis was then used to predict local bone strains and derive rules for mechanoregulation. Remodeling volume fractions were predicted by both average values of trabecular and cortical thickness and bone mineral density (R2 > 0.8), whereas mechanoregulation was affected by dominance of the arm and group classification (p < 0.05). Overall, longitudinal, extended HR-pQCT analysis enabled the identification of changes in bone quantity and quality too subtle for traditional measures.

Hospitalizations for major osteoporotic fractures in Switzerland: a long-term trend analysis between 1998 and 2018.

Between 1998 and 2018, the number of hospitalizations for major osteoporotic fractures increased. After standardization for age, these numerical increases translated into a reduced incidence of hospitalizations for hip fractures and an increased incidence of hospitalizations for spine, proximal humerus, and distal radius fractures in both sexes. INTRODUCTION: The longterm epidemiological trends of hospitalizations for major osteoporotic fractures (MOF) between 1998 and 2018 in Switzerland are unknown. METHODS: The absolute number of acute hospitalizations for MOF (hip fractures and fractures of the spine, proximal humerus, and distal radius) and related length of acute hospital stay were extracted from the medical database of the Swiss Federal Office of Statistics. Age-standardized incidence rates were calculated using 1998 as the reference year. RESULTS: Hospitalizations for MOF increased from 4483 to 7542 (+ 68.2%) in men and from 13,242 to 19,362 (+ 46.2%) in women. The age-standardized incidence of hospitalizations for MOF increased by 5.7% in men (p = 0.002) and by 5.1% in women (p = 0.018). The age-standardized incidence of hip fractures decreased by 15.3% in men (p < 0.001) and by 21.5% in women (p < 0.001). In parallel, the age-standardized incidence of MOF other than hip fractures increased by 31.8% in men (p < 0.001) and by 40.1% in women (p < 0.001). The mean length of acute hospital stays for MOF decreased from 16.3 to 8.5 days in men and from 16.9 to 8.1 days in women. CONCLUSION: Between 1998 and 2018, the number of hospitalizations for MOF increased significantly by a larger extent than expected based on the ageing of the Swiss population alone. This increase was solely driven by an increased incidence of MOF other than hip fractures as incident hip fractures decreased over time in both sexes, more so in women than in men.

Unified validation of a refined second-generation HR-pQCT based homogenized finite element method to predict strength of the distal segments in radius and tibia.

INTRODUCTION: HR-pQCT based micro finite element (µFE) analyses are considered as "gold standard" for virtual biomechanical analyses of peripheral bone sites such as the distal segment of radius and tibia. An attractive alternative for clinical use is a homogenized finite element method (hFE) based on constitutive models, because of its much shorter evaluation times and modest computational resource requirements. Such hFE models have been experimentally validated for the distal segment of the radius, but neither for the distal segments of the tibia nor for both measurement sites together. Accordingly, the aim of the present study was to refine and experimentally validate an hFE processing pipeline for in vivo prediction of bone strength and stiffness at the distal segments of the radius and the tibia, using only one unified set of material properties. MATERIAL AND METHODS: An existing hFE analysis procedure was refined in several aspects: 1) to include a faster evaluation of material orientation based on the mean surface length (MSL) method, 2) to distinguish cortical and trabecular bone compartments with distinct material properties and 3) to directly superimpose material properties in mixed phase elements instead of densities. Based on an existing dataset of the distal segment of fresh-frozen radii (double sections 20.4 mm, n = 21) and a newly established dataset of the distal segment of fresh-frozen tibiae (triple sections, 30.6 mm, n = 25), a single set of material properties was calibrated on the radius dataset and validated on the tibia dataset by comparing hFE stiffness and ultimate load with respective experimental results, obtained by compressing the samples on a servo-hydraulic testing machine at a monotonic and quasi-static displacement rate up to failure. RESULTS: Using the identified set of material properties, the hFE-predicted stiffness and failure load were in excellent agreement with respective experimental results at both measurement sites (radius stiffness R2 = 0.93, slope = 1.00, intercept = 479 N/mm2/radius ultimate load: R2 = 0.97, slope = 1.00, intercept = 679 N; tibia stiffness R2 = 0.96, slope = 1.01, intercept = -1027 N/mm2/tibia ultimate load: R2 = 0.97, slope = 1.04, intercept = 394 N; combined dataset stiffness R2 = 0.95, slope = 1.01, intercept = -230 N/mm2/combined dataset ultimate load: R2 = 0.97, slope = 1.03, intercept = 495 N). DISCUSSION AND CONCLUSION: In conjunction with unified BV/TV calibration, the established hFE pipeline accurately predicts experimental stiffness and ultimate load of distal multi-sections at the radius and tibia. Processing time for non-linear analysis was substantially reduced compared to previous µFE and hFE methods but could be further minimized by estimating bone strength based on a fast and linear analysis like as is currently done with µ FE.

Bone Microarchitecture and Strength in Long-Standing Type 1 Diabetes.

Type 1 diabetes (T1DM) is associated with an increased fracture risk, specifically at nonvertebral sites. The influence of glycemic control and microvascular disease on skeletal health in long-standing T1DM remains largely unknown. We aimed to assess areal (aBMD) and volumetric bone mineral density (vBMD), bone microarchitecture, bone turnover, and estimated bone strength in patients with long-standing T1DM, defined as disease duration ≥25 years. We recruited 59 patients with T1DM (disease duration 37.7 ± 9.0 years; age 59.9 ± 9.9 years.; body mass index [BMI] 25.5 ± 3.7 kg/m2 ; 5-year median glycated hemoglobin [HbA1c] 7.1% [IQR 6.82-7.40]) and 77 nondiabetic controls. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT) at the ultradistal radius and tibia, and biochemical markers of bone turnover were assessed. Group comparisons were performed after adjustment for age, gender, and BMI. Patients with T1DM had lower aBMD at the hip (p < 0.001), distal radius (p = 0.01), lumbar spine (p = 0.04), and femoral neck (p = 0.05) as compared to controls. Cross-linked C-telopeptide (CTX), a marker of bone resorption, was significantly lower in T1DM (p = 0.005). At the distal radius there were no significant differences in vBMD and bone microarchitecture between both groups. In contrast, patients with T1DM had lower cortical thickness (estimate [95% confidence interval]: -0.14 [-0.24, -0.05], p < 0.01) and lower cortical vBMD (-28.66 [-54.38, -2.93], p = 0.03) at the ultradistal tibia. Bone strength and bone stiffness at the tibia, determined by homogenized finite element modeling, were significantly reduced in T1DM compared to controls. Both the altered cortical microarchitecture and decreased bone strength and stiffness were dependent on the presence of diabetic peripheral neuropathy. In addition to a reduced aBMD and decreased bone resorption, long-standing, well-controlled T1DM is associated with a cortical bone deficit at the ultradistal tibia with reduced bone strength and stiffness. Diabetic neuropathy was found to be a determinant of cortical bone structure and bone strength at the tibia, potentially contributing to the increased nonvertebral fracture risk. © 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).

The Synovium of Human Osteoarthritic Joints Retains Its Chondrogenic Potential Irrespective of Age.

The autologous synovium is a potential tissue source for local induction of chondrogenesis by tissue engineering approaches to repair articular cartilage defects that occur in osteoarthritis. It was the aim of the present study to ascertain whether the aging of human osteoarthritic patients compromises the chondrogenic potential of their knee-joint synovium and the structural and metabolic stability of the transformed tissue. The patients were allocated to one of the following two age categories: 54-65 years and 66-86 years (n = 7-11 donors per time point and experimental group; total number of donors: 64). Synovial biopsies were induced in vitro to undergo chondrogenesis by exposure to bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-ß1 (TGF-ß1) alone, or a combination of the two growth factors, for up to 6 weeks. The differentiated explants were evaluated morphologically and morphometrically for the volume fraction of metachromasia (sulfated proteoglycans), immunohistochemically for type-II collagen, and for the gene expression levels of anabolic chondrogenic markers as well as catabolic factors by a real-time polymerase chain reaction analysis. Quantitative metachromasia revealed that chondrogenic differentiation of human synovial explants was induced to the greatest degree by either BMP-2 alone or the BMP-2/TGF-ß1 combination, that is, to a comparable level with each of the two stimulation protocols and within both age categories. The BMP-2/TGF-ß1combination protocol resulted in chondrocytes of a physiological size for normal human articular cartilage, unlike the BMP-2-alone stimulation that resulted in cell sizes of terminal hypertrophy. The stable gene expression levels of the anabolic chondrogenic markers confirmed the superiority of these two stimulation protocols and demonstrated the hyaline-like qualities of the generated cartilage matrix. The gene expression levels of the catabolic markers remained extremely low. The data also confirmed the usefulness of experimental in vitro studies with bovine synovial tissue as a paradigm for human synovial investigations. Our data reveal the chondrogenic potential of the human knee-joint synovium of osteoarthritic patients to be uncompromised by aging and catabolic processes. The potential of synovium-based clinical engineering (repair) of cartilage tissue using autologous synovium may thus not be reduced by the age of the human patient. Impact statement Our data reveal that in younger and older age groups alike, synovial explants from osteoarthritic joints can be equally well induced to undergo chondrogenesis in vitro; that is, the chondrogenic potential of the human synovium is not compromised by aging. These findings imply that the autologous synovium represents an adequate tissue source for the repair of articular cartilage in clinical practice by tissue engineering approaches in human patients suffering from osteoarthritis, independent of the patient's age.

A Bibliometric Analysis of Fragility Fractures: Top 50.

Background and Objectives: The population is aging and fragility fractures are a research topic of steadily growing importance. Therefore, a systematic bibliometric review was performed to identify the 50 most cited articles in the field of fragility fractures analyzing their qualities and characteristics. Materials and Methods: From the Core Collection database in the Thomson Reuters Web of Knowledge, the most influential original articles with reference to fragility fractures were identified in February 2021 using a multistep approach. Year of publication, total number of citations, average number of citations per year since year of publication, affiliation of first and senior author, geographic origin of study population, keywords, and level of evidence were of interest. Results: Articles were published in 26 different journals between 1997 and 2020. The number of total citations per article ranged from 12 to 129 citations. In the majority of publications, orthopedic surgeons and traumatologists (66%) accounted for the first authorship, articles mostly originated from Europe (58%) and the keyword mostly used was "hip fracture". In total, 38% of the articles were therapeutic studies level III followed by prognostic studies level I. Only two therapeutic studies with level I could be identified. Conclusions: This bibliometric review shows the growing interest in fragility fractures and raises awareness that more high quality and interdisciplinary studies are needed.

Formation Dominates Resorption With Increasing Mineralized Density and Time Postfracture in Cortical but Not Trabecular Bone: A Longitudinal HRpQCT Imaging Study in the Distal Radius.

Clinical evaluation of fracture healing is often limited to an assessment of fracture bridging from radiographic images, without consideration for other aspects of bone quality. However, recent advances in HRpQCT offer methods to accurately monitor microstructural bone remodeling throughout the healing process. In this study, local bone formation and resorption were investigated during the first year post fracture in both the fractured (n = 22) and contralateral (n = 19) radii of 34 conservatively treated patients (24 female, 10 male) who presented with a unilateral radius fracture at the Innsbruck University Hospital, Austria. HRpQCT images and clinical metrics were acquired at six time points for each patient. The standard HRpQCT image acquisition was captured for all radii, with additional distal and proximal image acquisitions for the fractured radii. Measured radial bone densities were isolated with a voxel-based mask and images were rigidly registered to images from the previous imaging session using a pyramid-based approach. From the registered images, bone formation and resorption volume fractions were quantified for multiple density-based thresholds and compared between the fractured and contralateral radius and relative to demographics, bone morphometrics, and fracture metrics using regression. Compared with the contralateral radius, both bone formation and resorption were significantly increased in the fractured radius throughout the study for nearly all evaluated thresholds. Higher density cortical bone formation continually increased throughout the duration of the study and was significantly greater than resorption during late-stage healing in both the fractured and intact regions of the radius. With the small and diverse study population, only weak relationships between fracture remodeling and patient-specific parameters were unveiled. However this study provides methods for the analysis of local bone remodeling during fracture healing and highlights relevant considerations for future studies, specifically that remodeling postfracture is likely to continue beyond 12-months postfracture. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Anticytokine Activity Enhances Osteogenesis of Bioactive Implants.

In dental clinical practice, systemic steroids are often applied at the end of implant surgeries to reduce postsurgical inflammation (tissue swelling, etc.) and to reduce patient discomfort. However, the use of systemic steroids is associated with generalized catabolic effects and with a temporarily reduced immunological competence. We hypothesize that by applying locally anticytokine antibodies (antitumor necrosis factor alpha and anti-interleukin-1 beta) together with a bioactive osteogenic implant at the time of the surgical intervention for the placement of a construct, we will be able to achieve the same beneficial effects as those using systemic steroids but are able to avoid the generalized antianabolic effects and the reduced immunocompetence effects, associated with the systemic use of steroids. In an adult rat model, a collagen sponge, soaked with the osteogenic agent bone morphogenetic protein-2, was used as an example for a bioactive implant material and was surgically placed subcutaneously. In the acute inflammatory phase after implantation (2 days after surgery) we investigated the local inflammatory tissue response, and 18 days postsurgically the efficiency of local osteogenesis (to assess possible antianabolic effects). We found that the negative control groups, treated postsurgically with systemic steroids, showed a significant suppression of both the inflammatory response and the osteogenetic activity, that is, they were associated with significant general antianabolic effects, even when steroids were used only at a low dose level. The local anticytokine treatment, however, was able to significantly enhance new bone formation activity, that is, the anabolic activity, over positive control values with BMP-2 only. However, the anticytokine treatment was unable to reduce the local inflammatory and swelling responses.

Induced Experimental Peri-Implantitis and Periodontitis: What Are the Differences in the Inflammatory Response?

This preliminary study investigates the differences between experimental periodontitis and peri-implantitis in a dog model, with a focus on the histopathology, inflammatory responses, and specific immunoregulatory activities driven by Th1/Th2-positive cells. Twelve dental implants were inserted into the edentulated posterior mandibles of 6 beagle dogs and were given 12 weeks for osseointegration. Experimental peri-implantitis and periodontitis (first mandible molar) were then induced using cotton-floss ligatures. Twelve weeks later, alveolar bones were quantitated by cone beam-computer tomography. Histopathologic analysis of the inflamed gingiva and periodontal tissues was performed by light microscopy, and the Th1/Th2 cell populations were investigated by flow cytometry. Peri-implantitis and periodontitis were both found to be associated with pronounced bone resorption effects, both to a similar degree vertically, but with a differential bone resorption pattern mesio-distally, and with a significantly higher and consistent bone resorption result in peri-implantitis, although with a higher variance of bone resorption in periodontitis. The histologic appearances of the inflammatory tissues were identical. The percentages of Th1/Th2 cells in the inflamed gingival tissues of both experimental peri-implantitis and periodontitis were also found to be similar. Experimental periodontitis and peri-implantitis in the dog model show essentially the same cellular pathology of inflammation. However, bone resorption was found to be significantly higher in peri-implantitis; the histopathologic changes in the periodontal tissues were similar in both groups but showed a higher interindividual variation in periodontitis and appeared more uniform in peri-implantitis. This preliminary study indicates that more focused experimental in vivo inflammation models need to be developed to better simulate the human pathology in the 2 different diseases and to have a valuable tool to investigate more specifically how novel treatments/prevention approaches may heal the differential adverse effects on bone tissue and on periodontium in periodontitis and in periimplantitis.

2020 recommendations for osteoporosis treatment according to fracture risk from the Swiss Association against Osteoporosis (SVGO).

Current guidelines from the Swiss Association against Osteoporosis (SVGO) dating from 2015 recommend therapy for men and women at increased fracture risk, specifically those with a vertebral or hip fracture; those with bone mineral density T-score <−2.5 at spine or hip; and those with a high 10-year probability of a major osteoporotic fracture as calculated by using FRAX. However no specific treatment recommendations have been made so far in our country to guide therapy according to the baseline level of risk. We now define four risk subgroup categories (imminent and very high, high, moderate, low) and propose an algorithm for osteoporosis therapy according to the level of fracture risk.

In vivo repeatability of homogenized finite element analysis based on multiple HR-pQCT sections for assessment of distal radius and tibia strength.

INTRODUCTION: Micro finite element analysis (µFE) is a widely applied tool in biomedical research for assessing in vivo mechanical properties of bone at measurement sites, including the ultra-distal radius and tibia. A finite element approach (hFE) based on homogenized constitutive models for trabecular bone offers an attractive alternative for clinical use, as it is computationally less expensive than traditional µFE. The respective patient-specific models for in vivo bone strength estimation are usually based on standard clinical high-resolution peripheral quantitative CT (HR-pQCT) measurements. They include a scan region of roughly 10 mm in height and are referred to as single-sections. It has been shown, that these small peripheral bone sections don't reliably cover the fracture line in Colles' fractures and therefore the weakest region at the radius. Recently introduced multiple section (multiple adjacent single-sections) measurements might improve the evaluation of bone strength, but little is known about the repeatability of hFE estimations in general, and especially for multiple section measurement protocols. Accordingly, the aim of the present work is to quantify repeatability of clinical in vivo bone strength measurement by hFE on multiple section HR-pQCT reconstructions at the distal radius and tibia. METHODS: Nineteen healthy Swiss women (43.6y ± 17.8y) and twenty men (48.2y ± 19.4y) were examined with HR-pQCT at 61 µm isotropic voxel resolution. Each subject was first scanned three times using a double-section (336 slices) at the distal radius and then three times using a triple-section (504 slices) at the distal tibia. The multiple section HR-pQCT reconstructions were graded for motion artefacts and non-linear hFE models (radius and tibia) and linear µFE models (only radius) were generated for estimation of stiffness and ultimate load. Then in vivo repeatability errors were computed in terms of root mean square coefficients of variation (CV). RESULTS: In vivo repeatability errors of non-linear hFE stiffness (S) and ultimate load (F) were significantly higher at the radius (S: 2.71% and F: 2.97%) compared to the tibia (S: 1.21%, F: 1.45%). Multiple section linear µFE at the radius resulted in substantially higher repeatability errors (S: 5.38% and F: 10.80%) compared to hFE. DISCUSSION/CONCLUSION: Repeatability errors of hFE outcomes based on multiple section measurements at the distal radius and tibia were generally lower compared to respective reported single-section µFE repeatability errors. Therefore, hFE is an attractive alternative to today's gold standard of µFE models and should especially be encouraged when analyzing multiple section measurements.

Osteoporosis in the lower extremities in chronic spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the effect of chronic motor complete spinal cord injury (SCI) and sex on bone densitometry parameters of the hip, femoral neck, tibial epiphysis, and diaphysis and on long bone fractures. SETTING: SCI rehabilitation center. METHODS: Women and men with long-term (≥7 years) motor complete SCI were compared with able-bodied women and men. Dual-energy X-ray absorptiometry was used to assess bone densitometry parameters at the hip and femoral neck, whereas peripheral quantitative computed tomography was used for the tibial epiphysis and diaphysis. RESULTS: The data of 18 women and 25 men with SCI with a mean age of 54.7 ± 12.4 and 53.5 ± 8.6 years, respectively, were analyzed. As reference groups, 74 able-bodied women and 46 men with a mean age of 51.0 ± 13.1 and 50.9 ± 11.2 years were evaluated. Most bone densitometry values were significantly (p ≤ 0.033) lower in the SCI compared with the reference groups, including total bone mineral density at the distal tibial epiphysis (-58.0% in SCI women and -53.6% in SCI men). Fracture rates per 100 patient-years were 3.17 and 2.66 in women and men with SCI compared with 0.85 and 0.21 in able-bodied women and men, respectively. CONCLUSIONS: Compared with able-bodied women and men, individuals with chronic motor complete SCI showed considerably lower bone densitometry values and a higher historical fracture rate. These findings support the need for preventative and therapeutic strategies against bone loss in individuals with SCI.

Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study.

BACKGROUND: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. METHODS: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). FINDINGS: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051). INTERPRETATION: Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.