Trabecular Network Research Articles

Early-life perturbations in glucocorticoid activity impacts on the structure, function and molecular composition of the adult zebrafish (Danio rerio) heart

BackgroundTransient early-life perturbations in glucocorticoids (GC) are linked with cardiovascular disease risk in later life. Here the impact of early life manipulations of GC on adult heart structure, function and gene expression were assessed. Methods and resultsZebrafish embryos were incubated in dexamethasone (Dex) or injected with targeted glucocorticoid receptor (GR) morpholino knockdown (GR Mo) over the first 120 h post fertilisation (hpf); surviving embryos (>90%) were maintained until adulthood under normal conditions. Cardiac function, heart histology and cardiac genes were assessed in embryonic (120 hpf) and adult (120 days post fertilisation (dpf)) hearts.GR Mo embryos (120 hpf) had smaller hearts with fewer cardiomyocytes, less mature striation pattern, reduced cardiac function and reduced levels of vmhc and igf mRNA compared with controls. GR Mo adult hearts were smaller with diminished trabecular network pattern, reduced expression of vmhc and altered echocardiographic Doppler flow compared to controls. Dex embryos had larger hearts at 120 hpf (Dex 107.2 ± 3.1 vs. controls 90.2 ± 1.1 μm, p < 0.001) with a more mature trabecular network and larger cardiomyocytes (1.62 ± 0.13 cells/μm vs control 2.18 ± 0.13 cells/μm, p < 0.05) and enhanced cardiac performance compared to controls. Adult hearts were larger (1.02 ± 0.07 μg/mg vs controls 0.63 ± 0.06 μg/mg, p = 0.0007), had increased vmhc and gr mRNA levels. ConclusionPerturbations in GR activity during embryonic development results in short and long-term alterations in the heart.

Identification of couple-stress moduli of vertebral trabecular bone based on the 3D internal architectures

The purpose of this paper is to develop a homogeneous, orthotropic couple-stress continuum model as a substitute of the 3D periodic heterogeneous cellular solid model of vertebral trabecular bone. Vertebral trabecular bone is modeled as a porous material with an idealized periodic structure made of 3D open cubic cells, which is effectively orthotropic. The chosen architecture is based on studies of samples taken from the central part of vertebral bodies. The effective properties are obtained based on the response of the representative volume element under prescribed boundary conditions. Mixed boundary conditions comprising both traction and displacement boundary conditions are applied on the structure boundaries. In this contribution, the effective mechanical constants of the effective couple-stress continuum are deduced by an equivalent strain energy method. The characteristic lengths for bending and torsion are identified from the resulting homogenized orthotropic moduli. We conduct this study computationally using a finite element approach. Vertebral trabecular bone is modeled either as a cellular solid or as a two-phase material consisting of bone tissue (stiff phase) forming a trabecular network, and a surrounding soft tissue referring to the bone marrow present in the pores. Both the bone tissue forming the network and the pores are assumed to be homogeneous linear elastic, and isotropic media. The scale effects on the predicted couple stress moduli of these networks are investigated by varying the size of the bone specimens over which the boundary conditions are applied. The analysis using mixed boundary conditions gives results that are independent of unit cell size when computing the first couple stress tensor, while it is dependent on the cell size as to the second couple stress tensor moduli. This study provides overall guidance on how the size of the trabecular specimen influence couple stresses elastic moduli of cellular materials, with focus on bones. The developed approach is quite general and applicable to any heterogeneous cellular and composite materials.

Vertical Trabeculae are Thinned More Than Horizontal Trabeculae in Skeletal-Unloaded Rats.

Skeletal unloading results in a rapid thinning of the trabecular bone network, but it is unknown whether vertical and horizontal trabeculae are equally affected. Therefore, the purpose of the present study was to investigate whether horizontal and vertical trabeculae were thinned similarly during skeletal unloading in rats. Fifty-seven 16-week-old female Wistar rats were randomized into six groups: baseline; control 4 weeks; botulinum toxin A (BTX) 4 weeks; control 8 weeks; BTX 8 weeks; and two BTX injections 8 weeks (BTX + BTX8). The BTX animals were injected in the right hind limb with 4 IU BTX at the start of the study, while the BTX + BTX8 were also injected with 2 IU BTX after 4 weeks. The animals were killed after 0, 4, or 8 weeks. The distal femoral metaphyses were μCT scanned, and the strengths of the femoral necks, mid-diaphyses, and distal femoral metaphyses were ascertained. Disuse resulted in a significant loss of BV/TV, thinning of the trabeculae, and decrease in the degree of anisotropy, and in a significant reduced bone strength after both 4 and 8 weeks. The ratio of horizontal to vertical trabecular thickness (Tb.Th.horz/Tb.Th.vert) and the ratio of horizontal to vertical bone volume (BV.horz/BV.vert) were significantly higher in BTX animals than in control animals. In addition, the horizontal and vertical trabecular thickness probability density functions were more similar in BTX animals than in control animals. In conclusion, skeletal unloading decreased BV/TV, Tb.Th, the degree of anisotropy, and mechanical strength, while BV.horz/BV.vert and Tb.Th.horz/Tb.Th.vert were increased. This indicates that the more loaded vertical trabeculae are pronouncedly more thinned than the less loaded supporting horizontal trabeculae during unloading.

Bone Geometry, Volumetric Density, Microarchitecture, and Estimated Bone Strength Assessed by HR-pQCT in Adult Patients With Type 1 Diabetes Mellitus.

The primary goal of this cross-sectional in vivo study was to assess peripheral bone microarchitecture, bone strength, and bone remodeling in adult type 1 diabetes (T1D) patients with and without diabetic microvascular disease (MVD+ and MVD-, respectively) and to compare them with age-, gender-, and height-matched healthy control subjects (CoMVD+ and CoMVD-, respectively). The secondary goal was to assess differences in MVD- and MVD+ patients. Fifty-five patients with T1DM (MVD+ group: n = 29) were recruited from the Funen Diabetes Database. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultradistal radius and tibia, and biochemical markers of bone turnover were performed in all participants. There were no significant differences in HR-pQCT parameters between MVD- and CoMVD- subjects. In contrast, MVD+ patients had larger total and trabecular bone areas (p = 0.04 and p = 0.02, respectively), lower total, trabecular, and cortical volumetric bone mineral density (vBMD) (p < 0.01, p < 0.04, and p < 0.02, respectively), and thinner cortex (p = 0.03) at the radius, and lower total and trabecular vBMD (p = 0.01 and p = 0.02, respectively) at the tibia in comparison to CoMVD+. MVD+ patients also exhibited lower total and trabecular vBMD (radius p = 0.01, tibia p < 0.01), trabecular thickness (radius p = 0.01), estimated bone strength, and greater trabecular separation (radius p = 0.01, tibia p < 0.01) and network inhomogeneity (radius p = 0.01, tibia p < 0.01) in comparison to MVD- patients. These differences remained significant after adjustment for age, body mass index, gender, disease duration, and glycemic control (average glycated hemoglobin over the previous 3 years). Although biochemical markers of bone turnover were significantly lower in MVD+ and MVD- groups in comparison to controls, they were similar between the MVD+ and MVD- groups. The results of our study suggest that the presence of MVD was associated with deficits in cortical and trabecular bone vBMD and microarchitecture that could partly explain the excess skeletal fragility observed in these patients.

Temporal cohesion of the structural, functional and molecular characteristics of the developing zebrafish heart

Heart formation is a complex, dynamic and highly coordinated process of molecular, morphogenetic and functional factors with each interacting and contributing to formation of the mature organ. Cardiac abnormalities in early life can be lethal in mammals but not in the zebrafish embryo which has been widely used to study the developing heart. While early cardiac development in the zebrafish has been well characterized, functional changes during development and how these relate to architectural, cellular and molecular aspects of development have not been well described previously. To address this we have carefully characterised cardiac structure, function, cardiomyocyte proliferation and cardiac-specific gene expression between 48 and 120hpf in the zebrafish. We show that the zebrafish heart increases in volume and changes shape significantly between 48 and 72hpf accompanied by a 40% increase in cardiomyocyte number. Between 96 and 120hpf, while external heart expansion slows, there is rapid formation of a mature and extensive trabecular network within the ventricle chamber. While ejection fraction does not change during the course of development other determinants of contractile function increase significantly particularly between 72 and 96hpf leading to an increase in cardinal vein blood flow. This study has revealed a number of novel aspects of cardiac developmental dynamics with striking temporal orchestration of structure and function within the first few days of development. These changes are associated with changes in expression of developmental and maturational genes. This study provides important insights into the complex temporal relationship between structure and function of the developing zebrafish heart.

Numerical Analysis of Ultrasound Backscattered Waves in Cancellous Bone Using a Finite-Difference Time-Domain Method: Isolation of the Backscattered Waves From Various Ranges of Bone Depths.

Using a finite-difference time-domain method, ultrasound backscattered waves inside cancellous bone were numerically analyzed to investigate the backscatter mechanism. Two bone models with different thicknesses were modeled with artificial absorbing layers positioned at the back surfaces of the model, and an ultrasound pulse wave was transmitted toward the front surface. By calculating the difference between the simulated waveforms obtained using the two bone models, the backscattered waves from a limited range of depths in cancellous bone could be isolated. The results showed that the fast and slow longitudinal waves, which have previously been observed only in the ultrasound waveform transmitted through the bone, could be distinguished in the backscattered waveform from a deeper bone depth when transmitting the ultrasound wave parallel to the main orientation of the trabecular network. The amplitudes of the fast and slow backscattered waves were more closely correlated with the bone porosity [R2 = 0.84 and 0.66 (p < 0.001), respectively] than the amplitude of the whole (nonisolated) backscattered waves [R2 = 0.48 (p < 0.001)]. In conclusion, the nonisolated backscattered waves could be regarded as the superposition of the fast and slow waves reflected from various bone depths, returning at different times.

Bone structure assessed by HR-pQCT, TBS and DXL in adult patients with different types of osteogenesis imperfecta.

Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) was assessed in adult patients with mild, moderate, and severe osteogenesis imperfecta (OI). The trabecular bone score (TBS), bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), and dual X-ray and laser (DXL) at the calcaneus were likewise assessed in patients with OI. Trabecular microstructure and BMD in particular were severely altered in patients with OI. OI is characterized by high fracture risk but not necessarily by low BMD. The main purpose of this study was to assess bone microarchitecture and BMD at different skeletal sites in different types of OI. HR-pQCT was performed in 30 patients with OI (mild OI-I, n = 18 (41.8 [34.7, 55.7] years) and moderate to severe OI-III-IV, n = 12 (47.6 [35.3, 58.4] years)) and 30 healthy age-matched controls. TBS, BMD by DXA at the lumbar spine and hip, as well as BMD by DXL at the calcaneus were likewise assessed in patients with OI only. At the radius, significantly lower trabecular parameters including BV/TV (p = 0.01 and p < 0.0001, respectively) and trabecular number (p < 0.0001 and p < 0.0001, respectively) as well as an increased inhomogeneity of the trabecular network (p < 0.0001 and p < 0.0001, respectively) were observed in OI-I and OI-III-IV in comparison to the control group. Similar results for trabecular parameters were found at the tibia. Microstructural parameters were worse in OI-III-IV than in OI-I. No significant differences were found in cortical thickness and cortical porosity between the three subgroups at the radius. The cortical thickness of the tibia was thinner in OI-I (p < 0.001), but not OI-III-IV, when compared to controls. Trabecular BMD and trabecular bone microstructure in particular are severely altered in patients with clinical OI-I and OI-III-IV. Low TBS and DXL and their significant associations to HR-pQCT parameters of trabecular bone support this conclusion.

The metaphyseal bone defect in distal radius fractures and its implication on trabecular remodeling-a histomorphometric study (case series).

BackgroundThe invention of the locking plate technology leads to alterations of treatment strategies at metaphyseal fracture sites with the concept of spontaneous remodeling of trabecular bone voids. Whereas trabecular regeneration has been proven in experimental animal studies, no histologic data exist on human fracture healing with special emphasis on bone voids.MethodsIn order to qualify the trabecular bone remodeling capacity in vivo, bone specimens from the metaphyseal bone void were analyzed 14 months after trauma using quantitative histomorphometry. Twenty-five patients with an unstable dorsally displaced distal radius fracture were fixed with a palmar locking plate without additional bone graft or substitute. At implant removal, specimens from the previous compression void were harvested with a trephine in a volar-dorsal direction. In 16 patients, histomorphometric analysis could be performed, comparing the dorsal trabecular network with the volar, non-compressed ultrastructure.ResultsSignificant differences for bone volume/total volume (BV/TV), trabecular number (TbN) and trabecular separation (TbSp), but not for trabecular thickness (TbTh) and osteoid volume/total volume (OV/TV), were detected. Neither patient age, defect size nor gender had a significant influence on bone remodeling.ConclusionsThe results of this study indicate that trabecular bone remodeling does not lead to pre-trauma bone quality in metaphyseal bone compression voids following reduction and application of a locking plate.

Effectiveness of combined salmon calcitonin and aspirin therapy for osteoporosis in ovariectomized rats.

The objective of the present study was to assess the effectiveness of combined salmon calcitonin (sCT) and aspirin [acetylsalicylic acid (ASA)] treatment in an ovariectomized (OVX) rat model of postmenopausal osteoporosis. Following 12 weeks of treatment, therapeutic efficacy was assessed by evaluating changes in the biochemical and biophysical properties of bone (n=8 rats per group). Serological markers of bone metabolism were measured by ELISA; bone mineral densities (BMD) by dual energy X-ray absorptiometry; bone biomechanics of the femur and lumbar vertebrae by three-point stress test; trabecular bone morphology of lumbar vertebrae by hematoxylin and eosin staining; messenger RNA expression levels of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in bone marrow cells by reverse transcription-quantitative polymerase chain reaction and OPG and RANKL protein expression levels in the proximal tibia were analyzed by immunohistochemistry. Compared with treatment by sCT or ASA alone, combined treatment (sCT+ASA) increased BMD, improved femur bone strength, normalized trabecular network architecture and morphology, and increased mRNA and protein expression of OPG, while reducing the expression of RANKL. Collectively, these results demonstrated that combined treatment (sCT+ASA) of osteoporotic symptoms in OVX rats was more effective than treatment with sCT or ASA alone. Furthermore, these two drugs appeared to alter the expression of two distinct factors in the OPG/RANKL/RANK system, suggesting that their effects may be synergistic. Since sCT and ASA are currently approved for use in humans, the results of the present study suggest that the safety and efficacy of sCT+ASA combined therapy for postmenopausal osteoporosis should be assessed in clinical trials.

Numerical investigation of fast and slow longitudinal waves backscattered from various depths inside cancellous bone

Ultrasound backscattering in cancellous bone was numerically investigated using three-dimensional (3D) finite-difference time-domain (FDTD) simulations with microcomputed tomographic (μCT) models of the bone. The cancellous bone models with various thicknesses, in which artificial absorbing layers were set at the surfaces opposite to the ultrasound-transmitted surfaces, were prepared. The backscattered waveform inside cancellous bone was isolated by deriving the difference between two simulated waveforms obtained using the bone models with different thicknesses, and the backscatter properties from various depths of the bone were investigated. When an ultrasound pulse wave was transmitted in the direction parallel to the main orientation of the trabecular network, the backscattered waves from the deep bone depths could clearly separate into two waves, which could correspond to the backscattered waves of the fast and slow longitudinal waves propagating mainly in the trabecular elements and the pore spaces. For each of the fast and slow waves, the backscatter coefficient, which was the ratio of the backscattered fast/slow wave amplitude to the incident fast/slow wave amplitude, was obtained. The results showed that both backscatter coefficients were weakly correlated with the bone depth.

Insight into the 3D-trabecular architecture of the human patella

The subchondral bone plate (SBP), a dynamic component of the osteochondral unit, shows functional adaptation to long-term loading by distribution of the mineral content in a manner best serving the mechanical demands. Since the received joint-load is transmitted into the trabecular system, the spongy bone also exhibits differences in strain energy density which models it for optimal support. To evaluate the regional variations in trabecular architecture, in accordance with the density distribution of the SBP revealing its long-term load intake, CT- and μCT-datasets of ten physiologic patellae were analysed for defined parameters of bony structure. For the SBP, the density distributions as well as area measurements were used. The trabecular architecture was described using parameters of bone morphology comprising the first 5mm (examined in 1mm steps) below the SBP. The obtained measurements are: Bone volume fraction (BV/TV); Bone surface density (BS/TV); Trabecular number (Tb.N); Trabecular separation (Tb.Sp); Trabecular thickness (Tb.Th); structure model index (SMI); and the Degree of anisotropy (DA). The evaluated architectural parameters varied within the trabecular system and showed an inhomogeneous distribution pattern. It proved to be distinctive with maxima of material and stability situated below areas of the highest long-term load intake. With increasing depth, the pattern of distribution was persistent but lessened in intensity. The parameters significantly correlated with the density distribution of the SBP within the first and second millimetres. With increasing depth down to the fifth millimetre, the coefficients of correlation decreased for all values. The trabecular network adapts to its mechanical needs and is therefore not homogenously built. Dependent upon the long-term load intake, the trabecular model optimizes the support with significant correlation to the density distribution of the SBP.

Significant bone microarchitecture impairment in premenopausal women with active celiac disease

Patients with active celiac disease (CD) are more likely to have osteoporosis and increased risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) permits three-dimensional exploration of bone microarchitectural characteristics measuring separately cortical and trabecular compartments, and giving a more profound insight into bone disease pathophysiology and fracture. We aimed to determine the volumetric and microarchitectural characteristics of peripheral bones—distal radius and tibia—in an adult premenopausal cohort with active CD assessed at diagnosis. We prospectively enrolled 31 consecutive premenopausal women with newly diagnosed CD (median age 29years, range: 18–49) and 22 healthy women of similar age (median age 30years, range 21–41) and body mass index. Compared with controls, peripheral bones of CD patients were significantly lower in terms of total volumetric density mg/cm3 (mean±SD: 274.7±51.7 vs. 324.7±45.8, p 0.0006 at the radius; 264.4±48.7 vs. 307±40.7, p 0.002 at the tibia), trabecular density mg/cm3 (118.6±31.5 vs. 161.9±33.6, p<0.0001 at the radius; 127.9±28.7 vs. 157.6±15.6, p<0.0001 at the tibia); bone volume/trabecular volume ratio % (9.9±2.6 vs. 13.5±2.8, p<0.0001 at the radius; 10.6±2.4 vs. 13.1±1.3, p<0.0001 at the tibia); number of trabeculae 1/mm (1.69±0.27 vs. 1.89±0.26, p 0.009 at the radius; 1.53±0.32 vs. 1.80±0.26, p 0.002 at the tibia); and trabecular thickness mm (0.058±0.010 vs. 0.071±0.008, p<0.0001 at the radius with no significant difference at the tibia). Cortical density was significantly lower in both regions (D comp mg/cm3 860±57.2 vs. 893.9±43, p 0.02; 902.7±48.7 vs. 932.6±32.6, p 0.01 in radius and tibia respectively). Although cortical thickness was lower in CD patients, it failed to show any significant inter-group difference (a—8% decay with p 0.11 in both bones). Patients with symptomatic CD (n=22) had a greater bone microarchitectural deficit than those with subclinical CD. HR-pQCT was used to successfully identify significant deterioration in the microarchitecture of trabecular and cortical compartments of peripheral bones. Impairment was characterized by lower trabecular number and thickness—which increased trabecular network heterogeneity—and lower cortical density and thickness. In the prospective follow-up of this group of patients we expect to be able to assess whether bone microarchitecture recovers and to what extend after gluten-free diet.

G0200205 Micro Cantilever Bendingによる海綿骨骨梁単体の弾性率計測

Cancellous bone has a three-dimensional network of single trabecula. It has been reported that the apparent elastic modulus of cancellous bone is much smaller than that of cortical bone and that the elastic modulus depends on the trabecular network. However, the mechanical properties of single trabecula are still unclear, because mechanical tests of single trabecula are challenging. This study aimed to develop an experimental method to measure the elastic properties of single trabecula that was 1 mm in length by micro cantilever bending. In the experiments, 10 single-trabecula specimens taken from the proximal epiphysis of a 2-year-old bovine femur were used. The tests were conducted using a small testing device that consisted of an acrylic plate for applying load to the specimen, a linear stage, and a load cell. The specimen was in contact with the edge of a taper bore drilled in the acrylic plate and was deformed by applying the displacement with the stage. The deflection of the specimen was observed by optical microscopy. A finite element model of the specimen was constructed from a micro-CT observation. The elastic modulus of the specimen was calculated from the force-deflection relation by finite element analysis. As a result, elastic modulus of single trabecula was 8.2 ± 3.3 GPa. There was no correlation between the elastic modulus and trabecular orientation in the femur. The study showed that the elastic modulus of single trabecula was much smaller than that of the cortical bone in bovine femoral diaphyses by proposed method.

Association of QCT Bone Mineral Density and Bone Structure With Vertebral Fractures in Patients With Multiple Myeloma.

Computed tomography (CT) is used for staging osteolytic lesions and detecting fractures in patients with multiple myeloma (MM). In the OsteoLysis of Metastases and Plasmacell-infiltration Computed Tomography 2 study (OLyMP-CT) study we investigated whether patients with and without vertebral fractures show differences in bone mineral density (BMD) or microstructure that could be used to identify patients at risk for fracture. We evaluated whole-body CT scans in a group of 104 MM patients without visible osteolytic lesions using an underlying lightweight calibration phantom (Image Analysis Inc., Columbia, KY, USA). QCT software (StructuralInsight) was used for the assessment of BMD and bone structure of the T11 or T12 vertebral body. Age-adjusted standardized odds ratios (sORs) per SD change were derived from logistic regression analyses, and areas under the receiver operating characteristics (ROC) curve (AUCs) analyses were calculated. Forty-six of the 104 patients had prevalent vertebral fractures (24/60 men, 22/44 women). Patients with fractures were not significantly older than patients without fractures (mean ± SD, 64 ± 9.2 versus 62 ± 12.3 years; p = 0.4). Trabecular BMD in patients with fractures versus without fractures was 169 ± 41 versus 192 ± 51 mg/cc (AUC = 0.62 ± 0.06, sOR = 1.6 [1.1 to 2.5], p = 0.02). Microstructural variables achieved optimal discriminatory power at bone thresholds of 150 mg/cc. Best fracture discrimination for single microstructural variables was observed for trabecular separation (Tb.Sp) (AUC = 0.72 ± 0.05, sOR = 2.4 (1.5 to 3.9), p < 0.0001). In multivariate models AUCs improved to 0.77 ± 0.05 for BMD and Tb.Sp, and 0.79 ± 0.05 for Tb.Sp and trabecular thickness (Tb.Th). Compared to BMD values, these improvements of AUC values were statistically significant (p < 0.0001). In MM patients, QCT-based analyses of bone structure derived from routine CT scans permit discrimination of patients with and without vertebral fractures. Rarefaction of the trabecular network due to plasma cell infiltration and osteoporosis can be measured. Deterioration of microstructural measures appear to be of value for vertebral fracture risk assessment and may indicate early stages of osteolytic processes not yet visible.

Does mechanical stimulation really protect the architecture of trabecular bone? A simulation study.

Although it is beyond doubt that mechanical stimulation is crucial to maintain bone mass, its role in preserving bone architecture is much less clear. Commonly, it is assumed that mechanics helps to conserve the trabecular network since an "accidental" thinning of a trabecula due to a resorption event would result in a local increase of load, thereby activating bone deposition there. However, considering that the thin trabecula is part of a network, it is not evident that load concentration happens locally on the weakened trabecula. The aim of this work was to clarify whether mechanical load has a protective role for preserving the trabecular network during remodeling. Trabecular bone is made dynamic by a remodeling algorithm, which results in a thickening/thinning of trabeculae with high/low strain energy density. Our simulations show that larger deviations from a regular cubic lattice result in a greater loss of trabeculae. Around lost trabeculae, the remaining trabeculae are on average thinner. More generally, thin trabeculae are more likely to have thin trabeculae in their neighborhood. The plausible consideration that a thin trabecula concentrates a higher amount of strain energy within itself is therefore only true when considering a single isolated trabecula. Mechano-regulated remodeling within a network-like architecture leads to local concentrations of thin trabeculae.

Osseointegration of Ti-6Al-4V alloy implants with a titanium nitride coating produced by a PIRAC nitriding technique: a long-term time course study in the rat.

This study examined bone tissue responses to Ti-6Al-4V alloy implants with a hard TiN coating applied by an original powder immersion reaction-assisted coating (PIRAC) nitriding method. Progression of implant fixation in the distal epiphysis and within the medullary cavity of the rat femur was evaluated between 3 days and 6 months postimplantation by scanning electron microscopy, oxytetracycline incorporation, and histochemistry. After 6 months, successful osseointegration was achieved in both epiphyseal and diaphyseal sites. Throughout, implant portions located within the epiphysis remained in close contact with bone trabeculae that gradually engulfed the implant forming a bone collar continuous with the trabecular network of the epiphysis. In the diaphysis, woven bone was first formed within the marrow cavity around the implant and later was replaced by a shell of compact bone around the implant. In general, higher osseointegration rates were measured for TiN-coated versus the uncoated implants, both in the epiphysis and in the diaphysis. In conclusion, our findings indicate an excellent long-term biocompatibility of TiN coatings applied by the PIRAC nitriding technique and superior osteoinductive ability in comparison with uncoated Ti-6Al-4V alloy. Such coatings can, therefore, be considered for improving the corrosion and wear resistance of titanium-based orthopedic implants.

Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss.

Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population.

Bone geometry, volumetric bone mineral density, microarchitecture and estimated bone strength in Caucasian females with systemic lupus erythematosus. A cross-sectional study using HR-pQCT.

Patients with systemic lupus erythematosus (SLE) have an increased risk of fracture. We used high resolution peripheral quantitative computed tomography (HR-pQCT) to measure bone geometry, volumetric bone mineral density (vBMD), cortical and trabecular microarchitecture and estimated bone strength by finite element analysis (FEA) at the distal radius and tibia to assess bone characteristics beyond BMD that may contribute to the increased risk of fracture. Thirty-three Caucasian women with SLE (median age 48, range 21-64 years) and 99 controls (median age 45, range 21-64 years) were studied. Groups were comparable in radius regarding geometry and vBMD, but SLE patients had lower trabecular number (-7%, p < 0.05), higher trabecular separation (13%, p < 0.05) and lower FEA-estimated failure load compared to controls (-10%, p < 0.05). In tibia, SLE patients had lower total vBMD (-11%, p < 0.01), cortical area (-14%, p < 0.001) and cortical thickness (-16%, p < 0.001) and higher trabecular area (8%, p < 0.05). In subgroup analyses of the premenopausal participants (SLE n = 21, controls n = 63), SLE patients had significantly lower trabecular bone volume fraction [(BV/TV); -17%, p < 0.01], trabecular number (-9%, p < 0.01), trabecular thickness (-9%, p < 0.05) and higher trabecular separation (13%, p < 0.01) and trabecular network inhomogeneity (14%, p < 0.05) in radius along with lower BV/TV (-15%, p < 0.01) and higher trabecular separation (11%, p < 0.05) in tibia. FEA-estimated bone strength was lower in both radius (-11%, p < 0.01) and tibia (-10%, p < 0.05). In conclusion, Caucasian women with SLE compared to controls had fewer and more widely separated trabeculae and lower estimated bone strength in radius and lower total vBMD, cortical area and thickness in tibia.

High-resolution peripheral quantitative CT imaging: Cortical porosity, poor trabecular bone microarchitecture, and low bone strength in lung transplant recipients.

To characterize bone microarchitecture and quantify bone strength in lung transplant (LT) recipients by using high-resolution (HR) peripheral quantitative computed tomographic (CT) imaging of the ultradistal radius. After study approval by the local ethics committee, all participants provided written informed consent. Included were 118 participants (58 LT recipients [mean age, 46.8 years ± 1.9; 30 women, 28 men] and 60 control participants [mean age, 39.9 years ± 1.9; 41 women, 19 men]) between April 2010 and May 2012. HR peripheral quantitative CT of the ultradistal radius was performed and evaluated for bone mineral density and trabecular and cortical bone microarchitecture. Mechanical competence was quantified by microfinite element analysis. Differences between LT recipients and control participants were determined by using two-way factorial analysis of covariance with age adjustment. Total and trabecular bone mineral density were significantly lower (-13.4% and -16.4%, respectively; P = .001) in LT recipients than in healthy control participants. LT recipients had lower trabecular number (-9.7%; P = .004) and lower trabecular thickness (-8.1%; P = .025). Trabecular separation and trabecular network heterogeneity were higher (+24.3% and +63.9%, respectively; P = .007 and P = .012, respectively) in LT recipients. Moreover, there was pronounced cortical porosity (+31.3%; P = .035) and lower cortical thickness (-10.2%, P = .005) after LT. In addition, mechanical competence was impaired, which was reflected by low stiffness (-15.0%; P < .001), low failure force (-14.8%; P < .001), and low bone strength (-14.6%; P < .001). Men and women with recent LT showed severe deficits in cortical and trabecular bone microarchitecture. Poor bone microarchitecture and low bone strength are likely to contribute to high fracture susceptibility observed in LT recipients.

70-Year-Old Woman With Buttock Pain and Hypercalcemia

Resident in Internal Medicine (H.A.J.) and Fellow in Endocrinology (M.L.G.), Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN; Adviser to resident and fellow and Consultant in Pediatric Endocrinology and Metabolism, Mayo Clinic, Rochester, MN (P.J.T.) A generally healthy 70-year-old woman presented to her primary care physician for her yearly medical examination. Her medical/surgical history was notable for osteoarthritis and a total abdominal hysterectomy with bilateral salpingo-oophorectomy at age 47 for endometriosis. Her medications included a daily multivitamin, 500 mg of elemental calcium twice daily, 400 IU each of vitamins D and E daily, and naproxen and loratadine, both as needed. She was a nonsmoker and rarely drank alcohol. She weighed 65.3 kg and had a body mass index of 21.4. Physical examination findings were unremarkable. Laboratory evaluation (reference ranges provided parenthetically) revealed a mildly elevated total serum calcium level of 10.3 mg/dL (8.9-10.1 mg/dL), phosphorus value of 3.2 mg/dL (2.5-4.5 mg/dL), creatinine level of 1 mg/dL (0.6-1.1 mg/dL), and normal albumin value. Screening dual-energy x-ray absorptiometry (DXA) of the left hip yielded a total T score of þ3.2. During her general medical examination 3 years later, she complained of left buttock pain that had progressively worsened during the previous year. The pain was deep, aching, and worse after prolonged sitting or walking. Physical examination revealed no asymmetry or mass in the hips or buttocks, but tenderness was noted on palpation over her sacroiliac joints and left lower buttock. Findings on neurologic examination were normal. Plain radiography of the lumbar spine revealed degenerative arthritis in the spine and sacroiliac joints, as well as focal lytic lesions in the proximal left femur surrounded by a coarse trabecular network and thickened cortex (Supplemental Figure, available online at http://www.mayoclinic proceedings.org). Her creatinine value was stable at 1 mg/dL, and her hemoglobin level was 14.2 g/dL (12.0-15.5 g/dL).