Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Morphology–elasticity relationships using decreasing fabric information of human trabecular bone from three major anatomical locations

With improving clinical CT scanning technology, the accuracy of CT-based finite element (FE) models of the human skeleton may be ameliorated by an enhanced description of apparent level bone mechanical properties. Micro-finite element (μFE) modeling can be used to study the apparent elastic behavior of human cancellous bone. In this study, samples from the femur, radius and vertebral body were investigated to evaluate the predictive power of morphology–elasticity relationships and to compare them across different anatomical regions. μFE models of 701 trabecular bone cubes with a side length of 5.3 mm were analyzed using kinematic boundary conditions. Based on the FE results, four morphology–elasticity models using bone volume fraction as well as full, limited or no fabric information were calibrated for each anatomical region. The 5 parameter Zysset–Curnier model using full fabric information showed excellent predictive power with coefficients of determination ( r2adj ) of 0.98, 0.95 and 0.94 of the femur, radius and vertebra data, respectively, with mean total norm errors between 14 and 20%. A constant orthotropy model and a constant transverse isotropy model, where the elastic anisotropy is defined by the model parameters, yielded coefficients of determination between 0.90 and 0.98 with total norm errors between 16 and 25%. Neglecting fabric information and using an isotropic model led to r2adj between 0.73 and 0.92 with total norm errors between 38 and 49%. A comparison of the model regressions revealed minor but significant (p<0.01) differences for the fabric–elasticity model parameters calibrated for the different anatomical regions. The proposed models and identified parameters can be used in future studies to compute the apparent elastic properties of human cancellous bone for homogenized FE models.

HGF Expressing Stem Cells in Usual Interstitial Pneumonia Originate from the Bone Marrow and Are Antifibrotic

BACKGROUND Pulmonary fibrosis may result from abnormal alveolar wound repair after injury. Hepatocyte growth factor (HGF) improves alveolar epithelial wound repair in the lung. Stem cells were shown to play a major role in lung injury, repair and fibrosis. We studied the presence, origin and antifibrotic properties of HGF-expressing stem cells in usual interstitial pneumonia. METHODS Immunohistochemistry was performed in lung tissue sections and primary alveolar epithelial cells obtained from patients with usual interstitial pneumonia (UIP, n = 7). Bone marrow derived stromal cells (BMSC) from adult male rats were transfected with HGF, instilled intratracheally into bleomycin injured rat lungs and analyzed 7 and 14 days later. RESULTS In UIP, HGF was expressed in specific cells mainly located in fibrotic areas close to the hyperplastic alveolar epithelium. HGF-positive cells showed strong co-staining for the mesenchymal stem cell markers CD44, CD29, CD105 and CD90, indicating stem cell origin. HGF-positive cells also co-stained for CXCR4 (HGF+/CXCR4+) indicating that they originate from the bone marrow. The stem cell characteristics were confirmed in HGF secreting cells isolated from UIP lung biopsies. In vivo experiments showed that HGF-expressing BMSC attenuated bleomycin induced pulmonary fibrosis in the rat, indicating a beneficial role of bone marrow derived, HGF secreting stem cells in lung fibrosis. CONCLUSIONS HGF-positive stem cells are present in human fibrotic lung tissue (UIP) and originate from the bone marrow. Since HGF-transfected BMSC reduce bleomycin induced lung fibrosis in the bleomycin lung injury and fibrosis model, we assume that HGF-expressing, bone-marrow derived stem cells in UIP have antifibrotic properties.

Development of an ex vivo protocol to model bone fracture in laying hens resulting from collisions.

Fractures of the keel bone, a bone extending ventrally from the sternum, are a serious health and welfare problem in free range laying hens. Recent findings suggest that a major cause of keel damage within extensive systems is collisions with internal housing structures, though investigative efforts have been hindered by difficulties in examining mechanisms and likely influencing factors at the moment of fracture. The objectives of this study were to develop an ex vivo impact protocol to model bone fracture in hens caused by collision, to assess impact and bird-related factors influencing fracture occurrence and severity, and to identify correlations of mechanical and structural properties between different skeletal sites. We induced keel bone fractures in euthanized hens using a drop-weight impact tester able to generate a range of impact energies, producing fractures that replicate those commonly found in commercial settings. The results demonstrated that impact energies of a similar order to those expected in normal housing were able to produce fractures, and that greater collision energies resulted in an increased likelihood of fractures and of greater severity. Relationships were also seen with keel's lateral surface bone mineral density, and the peak reactive force (strength) at the base of the manubrial spine. Correlations were also identified between the keel and long bones with respect to both strength and bone mineral density. This is the first study able to relate impact and bone characteristics with keel bone fracture at the moment of collision. Greater understanding of these relationships will provide means to reduce levels of breakage and severity in commercial systems.

Reduced bone breakage and increased bone strength in free range laying hens fed omega-3 polyunsaturated fatty acid supplemented diets

INTRODUCTION The omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are the immediate precursors to a number of important mediators of immunity, inflammation and bone function, with products of omega-6 generally thought to promote inflammation and favour bone resorption. Western diets generally provide a 10 to 20-fold deficit in omega-3 PUFAs compared with omega-6, and this is thought to have contributed to the marked rise in incidence of disorders of modern human societies, such as heart disease, colitis and perhaps osteoporosis. Many of our food production animals, fed on grains rich in omega-6, are also exposed to a dietary deficit in omega-3, with perhaps similar health consequences. Bone fragility due to osteoporotic changes in laying hens is a major economic and welfare problem, with our recent estimates of breakage rates indicating up to 95% of free range hens suffer breaks during lay. METHODS Free range hens housed in full scale commercial systems were provided diets supplemented with omega-3 alpha linolenic acid, and the skeletal benefits were investigated by comparison to standard diets rich in omega-6. RESULTS There was a significant 40-60% reduction in keel bone breakage rate, and a corresponding reduction in breakage severity in the omega-3 supplemented hens. There was significantly greater bone density and bone mineral content, alongside increases in total bone and trabecular volumes. The mechanical properties of the omega-3 supplemented hens were improved, with strength, energy to break and stiffness demonstrating significant increases. Alkaline phosphatase (an osteoblast marker) and tartrate-resistant acid phosphatase (an osteoclast marker) both showed significant increases with the omega-3 diets, indicating enhanced bone turnover. This was corroborated by the significantly lower levels of the mature collagen crosslinks, hydroxylysyl pyridinoline, lysyl pyridinoline and histidinohydroxy-lysinonorleucine, with a corresponding significant shift in the mature:immature crosslink ratio. CONCLUSIONS The improved skeletal health in laying hens corresponds to as many as 68million fewer hens suffering keel fractures in the EU each year. The biomechanical and biochemical evidence suggests that increased bone turnover has enhanced the bone mechanical properties, and that this may suggest potential benefits for human osteoporosis.

Measurement of structural anisotropy in femoral trabecular bone using clinical-resolution CT images

Discrepancies in finite-element model predictions of bone strength may be attributed to the simplified modeling of bone as an isotropic structure due to the resolution limitations of clinical-level Computed Tomography (CT) data. The aim of this study is to calculate the preferential orientations of bone (the principal directions) and the extent to which bone is deposited more in one direction compared to another (degree of anisotropy). Using 100 femoral trabecular samples, the principal directions and degree of anisotropy were calculated with a Gradient Structure Tensor (GST) and a Sobel Structure Tensor (SST) using clinical-level CT. The results were compared against those calculated with the gold standard Mean-Intercept-Length (MIL) fabric tensor using micro-CT. There was no significant difference between the GST and SST in the calculation of the main principal direction (median error=28°), and the error was inversely correlated to the degree of transverse isotropy (r=−0.34, p<0.01). The degree of anisotropy measured using the structure tensors was weakly correlated with the MIL-based measurements (r=0.2, p<0.001). Combining the principal directions with the degree of anisotropy resulted in a significant increase in the correlation of the tensor distributions (r=0.79, p<0.001). Both structure tensors were robust against simulated noise, kernel sizes, and bone volume fraction. We recommend the use of the GST because of its computational efficiency and ease of implementation. This methodology has the promise to predict the structural anisotropy of bone in areas with a high degree of anisotropy, and may improve the in vivo characterization of bone.

Topographic bone thickness maps for Bonebridge implantations.

Bonebridge™ (BB) implantation relies on optimal anchoring of the bone-conduction implant in the temporal bone. Preoperative position planning has to account for the available bone thickness minimizing unwanted interference with underlying anatomical structures. This study describes the first clinical experience with a planning method based on topographic bone thickness maps (TBTM) for presigmoid BB implantations. The temporal bone was segmented enabling three-dimensional surface generation. Distances between the external and internal surface were color encoded and mapped to a TBTM. Suitable implant positions were planned with reference to the TBTM. Surgery was performed according to the standard procedure (n = 7). Computation of the TBTM and consecutive implant position planning took 70 min on average for a trained technician. Surgical time for implantations under passive TBTM image guidance was 60 min, on average. The sigmoid sinus (n = 5) and dura mater (n = 1) were exposed, as predicted with the TBTM. Feasibility of the TBTM method was shown for standard presigmoid BB implantations. The projection of three-dimensional bone thickness information into a single topographic map provides the surgeon with an intuitive display of the anatomical situation prior to implantation. Nevertheless, TBTM generation time has to be significantly reduced to simplify integration in clinical routine.

Influence of Loudness Compression on Hearing with Bone Anchored Hearing Implants

Bone Anchored Hearing Implants (BAHI) are routinely used in patients with conductive or mixed hearing loss, e.g. if conventional air conduction hearing aids cannot be used. New sound processors and new fitting software now allow the adjustment of parameters such as loudness compression ratios or maximum power output separately. Today it is unclear, how the choice of these parameters influences aided speech understanding in BAHI users. In this prospective experimental study, the effect of varying the compression ratio and lowering the maximum power output in a BAHI were investigated. Twelve experienced adult subjects with a mixed hearing loss participated in this study. Four different compression ratios (1.0; 1.3; 1.6; 2.0) were tested along with two different maximum power output settings, resulting in a total of eight different programs. Each participant tested each program during two weeks. A blinded Latin square design was used to minimize bias. For each of the eight programs, speech understanding in quiet and in noise was assessed. For speech in quiet, the Freiburg number test and the Freiburg monosyllabic word test at 50, 65, and 80 dB SPL were used. For speech in noise, the Oldenburg sentence test was administered. Speech understanding in quiet and in noise was improved significantly in the aided condition in any program, when compared to the unaided condition. However, no significant differences were found between any of the eight programs. In contrast, on a subjective level there was a significant preference for medium compression ratios of 1.3 to 1.6 and higher maximum power output.

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: a three-year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m(2) ; TBS, 1.178 ± 0.1 but for LS T-score (ZOL-2.9 ± 1.5 versus PLB-2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus-0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once-yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years.