Summary
We compared microarchitecture and mechanical competence parameters measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite-element analysis of radius and ...tibia to those measured by histomorphometry, micro-CT, and finite-element analysis of transiliac bone biopsies. Correlations were weak to moderate between parameters measured on biopsies and scans.
Introduction
HR-pQCT is a new imaging technique that assesses trabecular and cortical bone microarchitecture of the radius and tibia in vivo. The purpose of this study was to determine the extent to which microarchitectural variables measured by HR-pQCT reflect those measured by the “gold standard,” transiliac bone biopsy.
Methods
HR-pQCT scans (Xtreme CT, Scanco Medical AG) and iliac crest bone biopsies were performed in 54 subjects (aged 39 ± 10 years). Biopsies were analyzed by 2D quantitative histomorphometry and 3D microcomputed tomography (µCT). Apparent Young’s modulus, an estimate of mechanical competence or strength, was determined by micro-finite-element analysis (µFE) of biopsy µCT and HR-pQCT images.
Results
The strongest correlations observed were between trabecular parameters (bone volume fraction, number, separation) measured by µCT of biopsies and HR-pQCT of the radius (
R
0.365–0.522;
P
< 0.01). Cortical width of biopsies correlated with cortical thickness by HR-pQCT, but only at the tibia (
R
= 0.360,
P
< 0.01). Apparent Young’s modulus calculated by µFE of biopsies correlated with that calculated for both radius (
R
= 0.442;
P
< 0.001) and tibia (
R
= 0.380;
P
< 0.001) HR-pQCT scans.
Conclusions
The associations between peripheral (HR-pQCT) and axial (transiliac biopsy) measures of microarchitecture and estimated mechanical competence are significant but modest.
Summary Objective To investigate changes in bone structure, turnover, and articular cartilage localized in subchondral bone cyst (SBC) regions associated with knee osteoarthritis (OA). Methods Tibial ...plateaus ( n = 97) were collected from knee OA patients during total knee arthroplasty (TKA). SBCs were identified using micro-computed tomography, and the specimens were divided into non-cyst ( n = 25) and bone cyst ( n = 72) groups. Microstructure of subchondral bone was assessed using bone volume fraction (BV/TV), trabecular number (Tb.N), structure model index (SMI) and bone mineral density (BMD). In bone cyst group, the cyst subregion, which contained at least one cyst, and the peri-cyst subregion, which contained no cysts, were further selected for microstructure analysis. Articular cartilage damage was estimated using the Osteoarthritis Research Society International (OARSI) score. The numbers of TRAP+ osteoclasts, Osterix+ osteoprogenitors, Osteocalcin+ osteoblasts and expression of SOX9 were evaluated by immunohistochemistry. Results Bone cyst group presented higher BV/TV, Tb.N and SMI at subchondral bone than non-cyst group. Furthermore, cyst subregion displayed increased BV/TV and Tb.N but lower BMD and SMI than peri-cyst subregion. Histology revealed a higher OARSI score in bone cyst group. SBC exhibited a weak relationship with BV/TV, etc . The numbers of TRAP+ osteoclasts, Osterix+ osteoprogenitors, Osteocalcin+ osteoblasts and expression of SOX9, were higher in bone cyst group. Conclusion SBCs within knee OA are characterized by focally increased bone turnover, altered bone structure and more severe articular cartilage damage. The increased bone turnover possibly contributes to altered bone structure localized in SBC areas, and thus aggravates articular cartilage degeneration.
Wear of articular cartilage is not well understood. We hypothesize that cartilage wears due to fatigue failure in repetitive compression instead of reciprocating friction.
This study compares ...reciprocating sliding of immature bovine articular cartilage against glass in two testing configurations: (1) a stationary contact area configuration (SCA), which results in static compression, interstitial fluid depressurization, and increasing friction coefficient during reciprocating sliding, and (2) a migrating contact area configuration (MCA), which maintains pressurization and low friction while producing repetitive compressive loading in addition to reciprocating sliding. Contact pressure, sliding duration, and sliding distance were controlled to be similar between test groups.
SCA tests exhibited an average friction coefficient of μ=0.084±0.032, while MCA tests exhibited a lower average friction coefficient of μ=0.020±0.008 (p<10
). Despite the lower friction, MCA cartilage samples exhibited clear surface damage with a significantly greater average surface deviation from a fitted plane after wear testing (R
=0.125±0.095 mm) than cartilage samples slid in a SCA configuration (R
=0.044±0.017 mm, p=0.002), which showed minimal signs of wear. Polarized light microscopy confirmed that delamination damage occurred between the superficial and middle zones of the articular cartilage in MCA samples.
The greatest wear was observed in the group with lowest friction coefficient, subjected to cyclical instead of static compression, implying that friction is not the primary driver of cartilage wear. Delamination between superficial and middle zones implies the main mode of wear is fatigue failure under cyclical compression, not fatigue or abrasion due to reciprocating frictional sliding.
Renal osteodystrophy (ROD) contributes substantially to morbidity in CKD, including increased fracture risk. Metabolic acidosis (MA) contributes to the development of ROD, but an up-to-date skeletal ...phenotype in CKD-associated acidosis has not been described. We comprehensively studied associations between acidosis and bone in patients with CKD using advanced methods to image the skeleton and analyze bone-tissue, along with biochemical testing. Cross-sectionally, acidosis was associated with higher markers of bone remodeling and female-specific impairments in cortical and trabecular bone quality. Prospectively, acidosis was associated with cortical expansion and trabecular microarchitectural deterioration. At the bone-tissue level, acidosis was associated with deficits in bone mineral content. Future work investigating acidosis correction on bone quality is warranted.
Renal osteodystrophy is a state of impaired bone quality and strength. Metabolic acidosis (MA) is associated with alterations in bone quality including remodeling, microarchitecture, and mineralization. No studies in patients with CKD have provided a comprehensive multimodal skeletal phenotype of MA. We aim to describe the structure and makeup of bone in patients with MA in the setting of CKD using biochemistry, noninvasive imaging, and histomorphometry.
The retrospective cross-sectional analyses included 180 patients with CKD. MA was defined as bicarbonate ≤22 mEq/L. We evaluated circulating bone turnover markers and skeletal imaging with dual energy x-ray absorptiometry and high-resolution peripheral computed tomography. A subset of 54 participants had follow-up. We assessed associations between baseline and change in bicarbonate with change in bone outcomes. Histomorphometry, microCT, and quantitative backscatter electron microscopy assessed bone biopsy outcomes in 22 participants.
The mean age was 68±10 years, 54% of participants were male, and 55% were White. At baseline, acidotic subjects had higher markers of bone turnover, lower areal bone mineral density at the radius by dual energy x-ray absorptiometry, and lower cortical and trabecular volumetric bone mineral density and impaired trabecular microarchitecture. Over time, acidosis was associated with opposing cortical and trabecular effects: cortical expansion but trabecular deterioration. Bone-tissue analyses showed reduced tissue mineral density with increased heterogeneity of calcium distribution in acidotic participants.
MA is associated with multiple impairments in bone quality. Future work should examine whether correction of acidosis improves bone quality and strength in patients with CKD.
Mandibular condylar cartilage functions as the load-bearing, shock-absorbing, lubricating material in temporomandibular joints. Little is known about the precise nature of the biomechanical ...characteristics of this fibro-cartilaginous tissue. We hypothesized that the fixed charge density associated with proteoglycans that introduces an osmotic pressure inside condylar cartilage will significantly increase the tissue’s apparent stiffness. Micro-indentation creep tests were performed on porcine TMJ condylar cartilage at 5 different regions—anterior, posterior, medial, lateral, and central—in physiologic and hypertonic solutions. The intrinsic and apparent mechanical properties, including aggregate modulus, shear modulus, and permeability, were calculated by indentation test data and the biphasic theory. The apparent properties (with osmotic effect) were statistically higher than those of the intrinsic solid matrix (without osmotic effect). Regional variations in fixed charge density, permeability, and mechanical modulus were also calculated for condylar surface. The present results provide important quantitative data on the biomechanical properties of TMJ condylar cartilage.
Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by ...Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.
Summary
Bone strength is dependent on bone density and microstructure. High-resolution peripheral quantitative computed tomography (HR-pQCT) can measure microstructure but is somewhat limited due to ...its resolution. We compared a new HR-pQCT scanner to existing technology and found very good agreement for most parameters. This study will be important when interpreting results from different devices.
Introduction
Recently, a second-generation HR-pQCT scanner (XCT2) has been developed with a higher nominal isotropic resolution (61 μm) compared to the first-generation device (XCT1, 82 μm). It is unclear how in vivo measurements from these two devices compare. In this study, we obtained and analyzed in vivo XCT1 and XCT2 measurements of bone microarchitecture and estimated strength.
Methods
We scanned 51 adults (16 men and 35 women, age 44.8 ± 16.0) on both XCT2 and XCT1 on the same day. We first compared XCT1 and XCT2 measurements obtained using their respective standard patient protocols. In XCT1, microarchitecture parameters were derived, while XCT2 measurements were directly measured. We also compared XCT2-D with XCT1 by finding the overlapping regions of interest and using the standard patient protocol for XCT1.
Results
We obtained excellent agreement between XCT1 and XCT2 for most of the volumetric bone mineral density (vBMD), trabecular and cortical measurements (All
R
2
> 0.820) except for cortical porosity at the radius (
R
2
= 0.638), trabecular number (
R
2
= 0.694, 0.787) and trabecular thickness (
R
2
= 0.569, 0.527) at both radius and tibia, respectively. XCT1 and XCT2-D measurements also had excellent agreement for most of the measurements (all
R
2
> 0.870) except trabecular number (
R
2
= 0.524, 0.706), trabecular thickness (
R
2
= 0.758, 0.734) at both radius and tibia, respectively, and trabecular separation (
R
2
= 0.656) at the radius.
Conclusion
While some caution should be exercised for parameters that are more dependent on image resolution, results from our study indicate that second-generation scans can be compared to more widely available first-generation data and may be beneficial for multicenter and longitudinal studies using both scanner generations.
Summary
Postmenopausal (PM) women using inhaled glucocorticoids (IGCs) had substantial abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness using high resolution peripheral ...computed tomography (HRpQCT) compared to age- and race-matched controls. Abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs.
Introduction
While oral glucocorticoids are well recognized to have destructive skeletal effects, less is known about the effects of IGCs. The detrimental skeletal effects of IGCs may be greatest in PM women, in whom they compound negative effects of estrogen loss and aging. The goal of this study was to evaluate microarchitecture and stiffness in PM women using chronic IGCs.
Methods
This case-control study compared PM women using IGCs for ≥ 6 months (
n
= 20) and controls matched for age and race/ethnicity (
n
= 60). Skeletal parameters assessed included areal BMD (aBMD) by DXA, trabecular and cortical vBMD and microarchitecture by HRpQCT of the radius and tibia, and whole bone stiffness by finite element analysis.
Results
By DXA, mean values in both groups were in the osteopenic range; hip aBMD was lower in IGC users (
P
< 0.04). By HRpQCT, IGC users had lower total, cortical, and trabecular vBMD at both radius and tibia (all
P
< 0.05). IGC users had lower cortical thickness, lower trabecular number, greater trabecular separation and heterogeneity at the radius (all
P
< 0.03), and greater heterogeneity at the tibia (
P
< 0.04). Whole bone stiffness was lower in IGC users at radius (
P
< 0.03) and tended to be lower at the tibia (
P
= 0.09).
Conclusions
PM women using IGCs had substantial abnormalities in vBMD, microarchitecture, and stiffness compared to controls. These abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs.
The mechanical properties of bone tissue are determined by composition as well as structural, microstructural and nanostructural organization. The aim of this study was to quantify the elastic ...properties of bone at the lamellar level and compare these properties among osteonal, interstitial and trabecular microstructures from the diaphysis and the neck of the human femur. A nanoindentation technique with a custom irrigation system was used for simultaneously measuring force and displacement of a diamond tip pressed 500
nm into the moist bone tissue. An isotropic elastic modulus was calculated from the unloading curve with an assumed Poisson ratio of 0.3, while hardness was defined as the maximal force divided by the corresponding contact area. The elastic moduli ranged from 6.9±4.3
GPa in trabecular tissue from the femoral neck of a 74
yr old female up to 25.0±4.3
GPa in interstitial tissue from the diaphyseal cortex of a 69
yr old female. The mean elastic modulus was found to be significantly influenced by the type of lamella (
p<10
−6) and by donor (
p<10
−6). The interaction between the type of lamella and the donor was also highly significant (
p<10
−6). Hardness followed a similar distribution as elastic modulus among types of lamellae and donor, but with lower statistical contrast. It is concluded that the nanostructure of bone tissue must differ substantially among lamellar types, anatomical sites and individuals and suggests that tissue heterogeneity is of potential importance in bone fragility and adaptation.
Background:
Pyrotinib is a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor. Evidence of the efficacy of pyrotinib-based treatments for HER2-positive metastatic breast cancer (MBC) in ...patients exposed to lapatinib is limited.
Methods:
Ninety-four patients who received pyrotinib as a third- or higher-line treatment for HER2-positive MBC were included in this retrospective study. The primary and secondary endpoints were overall survival (OS) and progression‐free survival (PFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were implemented to balance important patient characteristics between groups.
Results:
Thirty (31.9%) patients were pretreated with lapatinib and subsequently received pyrotinib as an anti-HER2 treatment, and 64 (68.1%) patients did not receive this treatment. The OS and PFS indicated a beneficial trend in lapatinib-naive group compared to lapatinib-treated group in either the original cohort (PFS: 9.02 vs 6.36 months,
p
= 0.05; OS: 20.73 vs 14.35 months,
p
= 0.08) or the PSM (PFS: 9.02 vs 6.08 months,
p
= 0.07; OS: 19.07 vs 18.00 months,
p
= 0.61) or IPTW (PFS: 9.90 vs 6.17 months,
p
= 0.05; OS: 19.53 vs 15.10 months,
p
= 0.08) cohorts. Subgroup analyses demonstrated lapatinib treatment-related differences in PFS in the premenopausal subgroup and the no prior trastuzumab treatment subgroup, but no significant differences were observed in OS.
Conclusion:
Pyrotinib-based therapy demonstrated promising effects in HER2-positive MBC patients in a real-world study, especially in lapatinib-naive patients, and also some activity in lapatinib-treated patients.
PDF
