Radial HR-pQCT and Finite Element Analysis in HPP Patients are Superior in Identifying Susceptibility to Fracture-Associated Skeletal Affections Compared to DXA and Laboratory Tests.

Hypophosphatasia (HPP) is an inborn disease that causes a rare form of osteomalacia, a mineralization disorder affecting mineralized tissues. Identification of patients at high risk for fractures or other skeletal manifestations (such as insufficiency fractures or excessive bone marrow edema) by bone densitometry and laboratory tests remains clinically challenging. Therefore, we examined two cohorts of patients with variants in the ALPL gene grouped by bone manifestations. These groups were compared by means of bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) and simulated mechanical performance utilizing finite element analysis (FEA). Whereas the incidence of skeletal manifestations among the patients could not be determined by dual energy X-ray absorptiometry (DXA) or laboratory assessment, HR-pQCT evaluation showed a distinct pattern of HPP patients with such manifestations. Specifically, these patients had a pronounced loss of trabecular bone mineral density, increased trabecular spacing, and decreased ultimate force at the distal radius. Interestingly, the derived results indicate that the non-weight-bearing radius is superior to the weight-bearing tibia in identifying deteriorated skeletal patterns. Overall, the assessment by HR-pQCT appears to be of high clinical relevance due to the improved identification of HPP patients with an increased risk for fractures or other skeletal manifestations, especially at the distal radius.

Comparison of Motion Grading in 1,000 Patients by First- and Second-Generation HR-pQCT: A Propensity Score Matched Cohort Study.

In-vivo bone microstructure measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) is gaining importance in research and clinical practice. Second-generation HR-pQCT (XCT2) shows improved image quality and shorter measurement duration compared to the first generation (XCT1). Predicting and understanding the occurrence of motion artifacts is crucial for clinical practice. We retrospectively analyzed data from HR-pQCT measurements at the distal radius and tibia of 1,000 patients (aged 20 to 89) evenly distributed between both generations of HR-pQCT. Motion artifacts were graded between 1 (no motion) and 5 (severe motion), with grades greater 3 considered unusable. Additionally, baseline characteristics and patients' muscle performance and balance were measured. Various group comparisons between the two generations of HR-pQCT and regression analyses between patient characteristics and motion grading were performed. The study groups of XCT1 and XCT2 did not differ by age (XCT1: 64.9 vs. XCT2: 63.8 years, p = 0.136), sex (both 74.5% females, p > 0.999), or BMI (both 24.2 kg/m2, p = 0.911) after propensity score matching. XCT2 scans exhibited significantly lower motion grading in both extremities compared to XCT1 (Radius: p < 0.001; Tibia: p = 0.002). In XCT2 motion-corrupted scans were more than halved at the radius (XCT1: 35.3% vs. XCT2: 15.5%, p < 0.001), and at the tibia the frequency of best image quality scans was increased (XCT1: 50.2% vs. XCT2: 63.7%, p < 0.001). The strongest independent predictor for motion-corrupted images is the occurrence of high motion grading at the other scanning site during the same consultation. The association between high motion grading in one scan and a corresponding high motion grading in another scan within the same session suggests a non-resting patient. Additionally, aged, female, and patients with smaller stature tend towards higher motion grading, requiring special attention to a correct extremity fixation.

Human engineered heart tissue transplantation in a guinea pig chronic injury model.

Myocardial injury leads to an irreversible loss of cardiomyocytes (CM). The implantation of human engineered heart tissue (EHT) has become a promising regenerative approach. Previous studies exhibited beneficial, dose-dependent effects of human induced pluripotent stem cell (hiPSC)-derived EHT patch transplantation in a guinea pig model in the subacute phase of myocardial injury. Yet, advanced heart failure often results from a chronic remodeling process. Therefore, from a clinical standpoint it is worthwhile to explore the ability to repair the chronically injured heart. In this study human EHT patches were generated from hiPSC-derived CMs (15 × 106 cells) and implanted epicardially four weeks after injury in a guinea pig cryo-injury model. Cardiac function was evaluated by echocardiography after a follow-up period of four weeks. Hearts revealed large transmural myocardial injuries amounting to 27% of the left ventricle. EHT recipient hearts demonstrated compact muscle islands of human origin in the scar region, as indicated by a positive staining for human Ku80 and dystrophin, remuscularizing 5% of the scar area. Echocardiographic analysis demonstrated no significant functional difference between animals that received EHT patches and animals in the cell-free control group (fractional area change 36% vs. 34%). Thus, EHT patches engrafted in the chronically injured heart but in contrast to the subacute model, grafts were smaller and EHT patch transplantation did not improve left ventricular function, highlighting the difficulties for a regenerative approach.

Keratinocyte-derived S100A9 modulates neutrophil infiltration and affects psoriasis-like skin and joint disease.

OBJECTIVES: S100A9, an alarmin that can form calprotectin (CP) heterodimers with S100A8, is mainly produced by keratinocytes and innate immune cells. The contribution of keratinocyte-derived S100A9 to psoriasis (Ps) and psoriatic arthritis (PsA) was evaluated using mouse models, and the potential usefulness of S100A9 as a Ps/PsA biomarker was assessed in patient samples. METHODS: Conditional S100A9 mice were crossed with DKO* mice, an established psoriasis-like mouse model based on inducible epidermal deletion of c-Jun and JunB to achieve additional epidermal deletion of S100A9 (TKO* mice). Psoriatic skin and joint disease were evaluated in DKO* and TKO* by histology, microCT, RNA and proteomic analyses. Furthermore, S100A9 expression was analysed in skin, serum and synovial fluid samples of patients with Ps and PsA. RESULTS: Compared with DKO* littermates, TKO* mice displayed enhanced skin disease severity, PsA incidence and neutrophil infiltration. Altered epidermal expression of selective pro-inflammatory genes and pathways, increased epidermal phosphorylation of STAT3 and higher circulating TNFα were observed in TKO* mice. In humans, synovial S100A9 levels were higher than the respective serum levels. Importantly, patients with PsA had significantly higher serum concentrations of S100A9, CP, VEGF, IL-6 and TNFα compared with patients with only Ps, but only S100A9 and CP could efficiently discriminate healthy individuals, patients with Ps and patients with PsA. CONCLUSIONS: Keratinocyte-derived S100A9 plays a regulatory role in psoriatic skin and joint disease. In humans, S100A9/CP is a promising marker that could help in identifying patients with Ps at risk of developing PsA.

Silk Fiber-Reinforced Hyaluronic Acid-Based Hydrogel for Cartilage Tissue Engineering.

A continuing challenge in cartilage tissue engineering for cartilage regeneration is the creation of a suitable synthetic microenvironment for chondrocytes and tissue regeneration. The aim of this study was to develop a highly tunable hybrid scaffold based on a silk fibroin matrix (SM) and a hyaluronic acid (HA) hydrogel. Human articular chondrocytes were embedded in a porous 3-dimensional SM, before infiltration with tyramine modified HA hydrogel. Scaffolds were cultured in chondropermissive medium with and without TGF-ß1. Cell viability and cell distribution were assessed using CellTiter-Blue assay and Live/Dead staining. Chondrogenic marker expression was detected using qPCR. Biosynthesis of matrix compounds was analyzed by dimethylmethylene blue assay and immuno-histology. Differences in biomaterial stiffness and stress relaxation were characterized using a one-step unconfined compression test. Cell morphology was investigated by scanning electron microscopy. Hybrid scaffold revealed superior chondro-inductive and biomechanical properties compared to sole SM. The presence of HA and TGF-ß1 increased chondrogenic marker gene expression and matrix deposition. Hybrid scaffolds offer cytocompatible and highly tunable properties as cell-carrier systems, as well as favorable biomechanical properties.

Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice.

Changes in bone matrix composition are frequently found with bone diseases and may be associated with increased fracture risk. Bone is rich in the trace element zinc. Zinc was established to play a significant role in the growth, development, and maintenance of healthy bones; however, the mechanisms underlying zinc effects on the integrity of the skeleton are poorly understood. Here, we show that the zinc receptor (ZnR)/Gpr39 is required for normal bone matrix deposition by osteoblasts. Initial analysis showed that Gpr39-deficient ( Gpr39-/-) mice had weaker bones as a result of altered bone composition. Fourier transform infrared spectroscopy analysis showed high mineral-to-matrix ratios in the bones of Gpr39-/- mice. Histologic analysis showed abnormally high numbers of active osteoblasts but normal osteoclast numbers on the surfaces of bones from Gpr39-/- mice. Furthermore, Gpr39-/- osteoblasts had disorganized matrix deposition in vitro with cultures exhibiting abnormally low collagen and high mineral contents, findings that demonstrate a cell-intrinsic role for ZnR/Gpr39 in these cells. We show that both collagen synthesis and deposition by Gpr39-/- osteoblasts are perturbed. Finally, the expression of the zinc transporter Zip13 and a disintegrin and metalloproteinase with thrombospondin motifs family of zinc-dependent metalloproteases that regulate collagen processing was downregulated in Gpr39-/- osteoblasts. Altogether, our results suggest that zinc sensing by ZnR/Gpr39 affects the expression levels of zinc-dependent enzymes in osteoblasts and regulates collagen processing and deposition.-Jovanovic, M., Schmidt, F. N., Guterman-Ram, G., Khayyeri, H., Hiram-Bab, S., Orenbuch, A., Katchkovsky, S., Aflalo, A., Isaksson, H., Busse, B., Jähn, K., Levaot, N. Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice.

Ultra-high matrix mineralization of sperm whale auditory ossicles facilitates high sound pressure and high-frequency underwater hearing.

The auditory ossicles-malleus, incus and stapes-are the smallest bones in mammalian bodies and enable stable sound transmission to the inner ear. Sperm whales are one of the deepest diving aquatic mammals that produce and perceive sounds with extreme loudness greater than 180 dB and frequencies higher than 30 kHz. Therefore, it is of major interest to decipher the microstructural basis for these unparalleled hearing abilities. Using a suite of high-resolution imaging techniques, we reveal that auditory ossicles of sperm whales are highly functional, featuring an ultra-high matrix mineralization that is higher than their teeth. On a micro-morphological and cellular level, this was associated with osteonal structures and osteocyte lacunar occlusions through calcified nanospherites (i.e. micropetrosis), while the bones were characterized by a higher hardness compared to a vertebral bone of the same animals as well as to human auditory ossicles. We propose that the ultra-high mineralization facilitates the unique hearing ability of sperm whales. High matrix mineralization represents an evolutionary conserved or convergent adaptation to middle ear sound transmission.

Clinical Significance of DXA and HR-pQCT in Autosomal Dominant Osteopetrosis (ADO II).

The main hallmark of high bone mass (HBM) disorders is increased bone mineral density, potentially visible in conventional radiographs and quantifiable by other radiographic methods. While one of the most common forms of HBM is CLCN7-related autosomal dominant osteopetrosis type II (ADO II), there is no consensus on diagnostic thresholds. We therefore wanted to assess whether CLCN7-osteopetrosis patients differ from benign HBM cases in terms of (1) bone mineral density, (2) bone structure, and (3) microarchitectural abnormalities. 16 patients meeting the criteria of HBM (DXA T/Z-score ≥ 2.5 at all sites) were included in this retrospective study. Osteologic assessment using dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses was performed. The presence of CLCN7 and/or other HBM gene mutations affecting bone mass were tested using a custom designed bone panel. While a DXA threshold for ADO II could be implemented (DXA Z-score ≥ + 6.0), the differences in bone microarchitecture were of lesser extent compared to the benign HBM group. All adult patients with ADO II suffered from elevated fracture rates independent from Z-score. In HR-pQCT, structural alterations, such as bone islets were found only inconsistently. In cases of HBM, a DXA Z-score ≥ 6 may be indicative for an inheritable HBM disorder, such as ADO II. Microarchitectural bone alterations might represent local microfracture repair or accumulation of cartilage remnants due to impaired osteoclast function, but seem not to be correlated with fracture risk.

Comparison of Bone Microarchitecture Between Adult Osteogenesis Imperfecta and Early-Onset Osteoporosis.

Diagnosis and management of adult individuals with low bone mass and increased bone fragility before the age of 50 can be challenging. A number of these patients are diagnosed with mild osteogenesis imperfecta (OI) through detection of COL1A1 or COL1A2 mutations; however, a clinical differentiation from early-onset osteoporosis (EOOP) may be difficult. The purpose of this study was to determine the bone microstructural differences between mild OI and EOOP patients. 29 patients showed mutations in COL1A1 or COL1A2 and were classified as OI. Skeletal assessment included dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone turnover serum analyses. Bone microstructure of 21/29 OI patients was assessed and compared to 23 age- and sex-matched patients clinically classified EOOP but without mutations in the known disease genes as well as to 20 healthy controls. In the OI patients, we did not observe an age-dependent decrease in DXA Z-scores. HR-pQCT revealed a significant reduction in volumetric BMD and microstructural parameters in the distal radius and tibia in both the OI and EOOP cohorts compared to the healthy controls. When comparing the bone microstructure of OI patients with the EOOP cohort, significant differences were found in terms of bone geometry in the radius, while no significant changes were detected in all other HR-pQCT parameters at the radius and tibia. Taken together, adult mild OI patients demonstrate a predominantly high bone turnover trabecular bone loss syndrome that shows minor microstructural differences compared to EOOP without mutation detection.

How the European eel (Anguilla anguilla) loses its skeletal framework across lifetime.

European eels (Anguilla anguilla) undertake an impressive 5 000 km long migration from European fresh waters through the North Atlantic Ocean to the Sargasso Sea. Along with sexual maturation, the eel skeleton undergoes a remarkable morphological transformation during migration, where a hitherto completely obscure bone loss phenomenon occurs. To unravel mechanisms of the maturation-related decay of the skeleton, we performed a multiscale assessment of eels' bones at different life-cycle stages. Accordingly, the skeleton reflects extensive bone loss that is mediated via multinucleated bone-resorbing osteoclasts, while other resorption mechanisms such as osteocytic osteolysis or matrix demineralization were not observed. Preserving mechanical stability and releasing minerals for energy metabolism are two mutually exclusive functions of the skeleton that are orchestrated in eels through the presence of two spatially segregated hard tissues: cellular bone and acellular notochord. The cellular bone serves as a source of mineral release following osteoclastic resorption, whereas the mineralized notochord sheath, which is inaccessible for resorption processes due to an unmineralized cover layer, ensures sufficient mechanical stability as a part of the notochord sheath. Clearly, an eel's skeleton is structurally optimized to meet the metabolic challenge of fasting and simultaneous sexual development during an exhausting journey to spawning areas, while the function of the vertebral column is maintained to achieve this goal.

Approaching virtual osteoid volume estimation and in-depth tissue characterization in patients with tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) poses a significant diagnostic challenge, leading to increased disease duration and patient burden also by missing clinical suspicion. Today, diagnosis of osteomalacia relies on invasive iliac crest biopsy, if needed. Therefore, a noninvasive method would be beneficial for patients with severe osteomalacia, such as TIO, to inform their clinical management and address specific needs, like estimating the regeneration capacity at high osteoid volumes (OVs) or the potential of a hungry bone syndrome after tumor removal. Furthermore, given the lack of comprehensive histological characterization of TIO, there is a need for additional tissue characterization. Therefore, our assessment encompassed iliac crest biopsies that were examined using quantitative electron backscattered microscopy, Raman spectroscopy, micro-computed tomography, and histology to analyze the biopsy tissue. Our clinical assessment encompassed DXA and high-resolution peripheral quantitative computed tomography (HR-pQCT) alongside with biochemical analyses and clinical evaluations. Combining imaging and clinical data, we established a model to predict the OV. We compared 9 TIO patients with 10 osteoporosis (OPO) patients and 10 healthy controls. Histological analyses confirmed a pronounced OV in TIO patients (OPO: 1.20% ± 1.23% vs TIO: 23.55% ± 12.23%, P < .0005), and spectroscopy revealed lower phosphate levels in TIO biopsies. By combining HR-pQCT and laboratory diagnostics, we developed a linear regression model to noninvasively predict the OV revealing significantly higher modeled OV/BVmodel values of 24.46% ± 14.22% for TIO compared to the control group (5.952% ± 3.44%, P ≤ .001). By combining laboratory diagnostics, namely, ALP and Tt.BMDRadius measured by HR-pQCT, we achieved the calculation of the virtual osteoid volume to bone volume ratio (OV/BVmodel) with a significant correlation to histology as well as reliable identification of TIO patients compared to OPO and control. This novel approach is potentially helpful for predicting OV by noninvasive techniques in diagnostic procedures and improving the clinical management of TIO.

Osteomalacia, a bone mineralization disease, results in soft bones due to a lack of calcium or phosphate. Tumor-induced osteomalacia (TIO) is an acquired and challenging form of osteomalacia due to low serum phosphate levels that often lead to prolonged patient suffering. Current diagnosis of osteomalacia involves surgical bone biopsies, but a noninvasive approach would be beneficial, improving clinical management and addressing specific needs like estimating the bone's quality and ability to recover. We used advanced techniques like electron microscopy, spectroscopy, and high-resolution CT to study bone samples from 9 TIO patients. Additionally, we assessed their bone health through sophisticated imaging and blood analyses. Microscopy confirmed huge amounts of soft bone tissue due to a severe mineralization defect. By combining imaging and blood analysis, we developed a noninvasive method to predict the amount of soft tissue (osteoid) to understand soft bones without the need for surgical interventions. In conclusion, our innovative approach, combining blood diagnostics (alkaline phosphatase) with total BMD from high-resolution 3D clinical imaging of the lower arm, allows us to predict the osteoid amount virtually. This method can also compare TIO patients with controls or those with osteoporosis and might be helpful in the future.

Lower microhardness along with less heterogeneous mineralization in the femoral neck of individuals with type 2 diabetes mellitus indicates higher fracture risk.

There is still limited understanding of the microstructural reasons for the higher susceptibility to fractures in individuals with type 2 diabetes mellitus (T2DM). In this study, we examined bone mineralization, osteocyte lacunar parameters, and microhardness of the femoral neck trabeculae in 18 individuals with T2DM who sustained low-energy fracture (T2DMFx: 78 ± 7 years, 15 women and 3 men) and 20 controls (74 ± 7 years, 16 women and 4 men). Femoral necks of the T2DMFx subjects were obtained at a tertiary orthopedic hospital, while those of the controls were collected at autopsy. T2DMFx individuals had lower trabecular microhardness (P = .023) and mineralization heterogeneity (P = .001), and a tendency to a lower bone area with mineralization above 95th percentile (P = .058) than the controls. There were no significant intergroup differences in the numbers of osteocyte lacunae per bone area, mineralized lacunae per bone area, and total lacunae per bone area (each P > .05). After dividing the T2DMFx group based on the presence of vascular complications (VD) to T2DMFxVD (VD present) and T2DMFxNVD (VD absent), we observed that microhardness was particularly reduced in the T2DMFxVD group (vs. control group, P = .02), while mineralization heterogeneity was significantly reduced in both T2DMFx subgroups (T2DMFxNVD vs. control, P = .002; T2DMFxVD vs. control, P = .038). The observed changes in mineralization and microhardness may contribute to the increased hip fracture susceptibility in individuals with T2DM.

Zinc and vitamin D deficiency and supplementation in hypophosphatasia patients - A retrospective study.

Hypophosphatasia (HPP) is characterized by severe skeletal symptoms including mineralization defects, insufficiency fractures, and delayed facture healing or non-unions. HPP is caused by mutations of the tissue non-specific alkaline phosphatase (TNSALP). Zinc is a cofactor of TNSALP and vitamin D an important regulator of bone matrix mineralization. Data from this retrospective study indicates that deficiencies in zinc or vitamin D occur in HPP patients with a similar frequency as in the general population. While guidelines for repletion of these micronutrients have been established for the general population, the transferability of the efficacy and safety of these regiments to HPP patients still needed to be determined. We filtered for variant classification (ACMG 3-5, non-benign) and data completeness from a total cohort of 263 HPP patients. 73.5 % of this sub-cohort were vitamin D deficient while 27.2 % were zinc deficient. We retrospectively evaluated the effect of supplementation according to general guidelines in 10 patients with zinc-deficiency and 38 patients with vitamin d-deficiency. The treatments significantly raised serum zinc or vitamin D levels respectively. All other assessed disease markers (alkaline phosphatase, pyrodoxal-5-phosphate) or bone turnover markers (phosphate, calcium, parathyroid hormone, bone specific alkaline phosphatase, creatinine, desoxypyridinoline) remained unchanged. These results highlight that general guidelines for zinc and vitamin D repletion can be successfully applied to HPP patients in order to prevent deficiency symptoms without exacerbating the disease burden or causing adverse effects due to changes in bone and calcium homeostasis.

When Cortical Bone Matrix Properties Are Indiscernible between Elderly Men with and without Type 2 Diabetes, Fracture Resistance Follows Suit.

Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting bone tissue and leading to increased fracture risk in men and women, independent of bone mineral density (BMD). Thus, bone material quality (i.e., properties that contribute to bone toughness but are not attributed to bone mass or quantity) is suggested to contribute to higher fracture risk in diabetic patients and has been shown to be altered. Fracture toughness properties are assumed to decline with aging and age-related disease, while toughness of human T2DM bone is mostly determined from compression testing of trabecular bone. In this case-control study, we determined fracture resistance in T2DM cortical bone tissue from male individuals in combination with a multiscale approach to assess bone material quality indices. All cortical bone samples stem from male nonosteoporotic individuals and show no significant differences in microstructure in both groups, control and T2DM. Bone material quality analyses reveal that both control and T2DM groups exhibit no significant differences in bone matrix composition assessed with Raman spectroscopy, in BMD distribution determined with quantitative back-scattered electron imaging, and in nanoscale local biomechanical properties assessed via nanoindentation. Finally, notched three-point bending tests revealed that the fracture resistance (measured from the total, elastic, and plastic J-integral) does not significantly differ in T2DM and control group, when both groups exhibit no significant differences in bone microstructure and material quality. This supports recent studies suggesting that not all T2DM patients are affected by a higher fracture risk but that individual risk profiles contribute to fracture susceptibility, which should spur further research on improving bone material quality assessment in vivo and identifying risk factors that increase bone fragility in T2DM. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Compartment-specific effects of muscle strength on bone microarchitecture in women at high risk of osteoporosis.

BACKGROUND: It is well known that skeletal integrity is influenced by the musculature. Poor muscle strength (i.e. sarcopenia) is considered a major predictor of fragility fractures. While this observation appears particularly relevant for older women with increased risk of osteoporosis, there has been no comprehensive investigation to determine the influence of muscle performance on compartment-specific bone microarchitecture in multiple body regions. METHODS: We retrospectively analysed data from different muscle performance and bone microarchitecture assessments in 230 women (aged 21 to 87 years) at high risk of osteoporosis. Muscle performance tests included grip strength and chair rising test (CRT) combined with mechanography. Balance was determined by Romberg posturography. Areal bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Compartment-specific volumetric BMD, microarchitecture, and geometry were assessed by second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT) at multiple skeletal sites (distal radius, tibia, and fibula). Regression models were applied to test for interactions between muscle and bone parameters. Subgroups were defined to compare women with osteoporosis and osteosarcopenia regarding BMD and microarchitecture. RESULTS: While osteoporosis was diagnosed in 115/230 (50.0%) women, sarcopenia was detected in 38/230 (16.5%). Positive associations of both grip strength and CRT maximum force with cortical geometric and microarchitectural parameters were detected at all measured sites, with the strongest effect applying to CRT maximum force and tibial parameters (e.g. tibial cortical area R2  = 0.36, P < 0.0001, and tibial cortical thickness R2  = 0.26, P < 0.0001). Balance parameters showed much weaker or no associations with HR-pQCT parameters. Major associations between muscle strength and trabecular parameters could not be confirmed. Age and body mass index were confirmed as negative and positive predictors for several microarchitectural parameters, respectively. An independent predictive value of grip strength on radial, tibial, and fibular (all P < 0.01) cortical area and of CRT maximum relative force on cortical thickness (all P < 0.05) was revealed. Women with osteosarcopenia showed significantly reduced cortical HR-pQCT parameters but no differences in DXA values compared with women with osteoporosis but no sarcopenia. Stratification by fracture and treatment status revealed that vertebral fractures and denosumab treatment altered the muscle-bone interaction. CONCLUSIONS: A systemic interaction between muscle strength and bone microarchitecture was demonstrated, and this interaction appears to be primarily with the cortical bone compartment. The value of muscle assessments in fracture risk evaluation may be partly mediated by their effects on bone microarchitecture.

Superior Bone Microarchitecture in Anatomic Versus Nonanatomic Fibular Drill Tunnels for Reconstruction of the Posterolateral Corner of the Knee.

Background: Several fibula-based reconstruction techniques have been introduced to address ligamentous injuries of the posterolateral corner of the knee. These techniques involve a drill tunnel with auto- or allograft placement through the proximal fibula. Purpose: To determine the skeletal microarchitecture of the proximal fibula and its association with age and to compare the microarchitecture within the regions of different drill tunnel techniques for reconstruction of the posterolateral corner. Study Design: Descriptive laboratory study. Methods: A total of 30 human fibulae were analyzed in this cadaveric imaging study. High-resolution peripheral quantitative computed tomography measurements were performed in a 4.5 cm-long volume of interest at the proximal fibula. Three-dimensional microarchitectural data sets of cortical and trabecular compartments were evaluated using customized scripts. The quadrants representing the entry and exit drill tunnel positions corresponding to anatomic techniques (LaPrade/Arciero) and the Larson technique were analyzed. Linear regression models and group comparisons were applied. Results: Trabecular microarchitecture parameters declined significantly with age in women but not men. Analysis of subregions with respect to height revealed stable cortical and decreasing trabecular values from proximal to distal in both sexes. Along with a structural variability in axial slices, superior values were found for the densitometric and microarchitectural parameters corresponding to the fibular drill tunnels in the anatomic versus Larson technique (mean ± SD; bone volume to tissue volume at the entry position, 0.273 ± 0.079 vs 0.175 ± 0.063; P < .0001; cortical thickness at the entry position, 0.501 ± 0.138 vs 0.353 ± 0.081 mm; P < .0001). Conclusion: Age represented a relevant risk factor for impaired skeletal microarchitecture in the proximal fibula in women but not men. The region of drill tunnels according to anatomic techniques showed superior bone microarchitecture versus that according to the Larson technique.

Influence of X-rays and gamma-rays on the mechanical performance of human bone factoring out intraindividual bone structure and composition indices.

Doses of irradiation above 25 â€‹kGy are known to cause irreversible mechanical decay in bone tissue. However, the impact of irradiation doses absorbed in a clinical setting on the mechanical properties of bone remains unclear. In daily clinical practice and research, patients and specimens are exposed to irradiation due to diagnostic imaging tools, with doses ranging from milligray to Gray. The aim of this study was to investigate the influence of irradiation at these doses ranges on the mechanical performance of bone independent of inter-individual bone quality indices. Therefore, cortical bone specimens (n â€‹= â€‹10 per group) from a selected organ donor were irradiated at doses of milligray, Gray and kilogray (graft tissue sterilization) at five different irradiation doses. Three-point bending was performed to assess mechanical properties in the study groups. Our results show a severe reduction in mechanical performance (work to fracture: 50.29 â€‹± â€‹11.49 Nmm in control, 14.73 â€‹± â€‹1.84 Nmm at 31.2 â€‹kGy p â€‹≤ â€‹0.05) at high irradiation doses of 31.2 â€‹kGy, which correspond to graft tissue sterilization or synchrotron imaging. In contrast, no reduction in mechanical properties were detected for doses below 30 â€‹Gy. These findings are further supported by fracture surface texture imaging (i.e. more brittle fracture textures above 31.2 â€‹kGy). Our findings show that high radiation doses (≥31.2 â€‹kGy) severely alter the mechanical properties of bone. Thus, irradiation of this order of magnitude should be taken into account when mechanical analyses are planned after irradiation. However, doses of 30 â€‹Gy and below, which are common for clinical and experimental imaging (e.g., radiation therapy, DVT imaging, CT imaging, HR-pQCT imaging, DXA measurements, etc.), do not alter the mechanical bending-behavior of bone.

Dimorphic Mechanisms of Fragility in Diabetes Mellitus: the Role of Reduced Collagen Fibril Deformation.

Diabetes mellitus (DM) is an emerging metabolic disease, and the management of diabetic bone disease poses a serious challenge worldwide. Understanding the underlying mechanisms leading to high fracture risk in DM is hence of particular interest and urgently needed to allow for diagnosis and treatment optimization. In a case-control postmortem study, the whole 12th thoracic vertebra and cortical bone from the mid-diaphysis of the femur from male individuals with type 1 diabetes mellitus (T1DM) (n = 6; 61.3 ± 14.6 years), type 2 diabetes mellitus (T2DM) (n = 11; 74.3 ± 7.9 years), and nondiabetic controls (n = 18; 69.3 ± 11.5) were analyzed with clinical and ex situ imaging techniques to explore various bone quality indices. Cortical collagen fibril deformation was measured in a synchrotron setup to assess changes at the nanoscale during tensile testing until failure. In addition, matrix composition was analyzed including determination of cross-linking and non-crosslinking advanced glycation end-products like pentosidine and carboxymethyl-lysine. In T1DM, lower fibril deformation was accompanied by lower mineralization and more mature crystalline apatite. In T2DM, lower fibril deformation concurred with a lower elastic modulus and tendency to higher accumulation of non-crosslinking advanced glycation end-products. The observed lower collagen fibril deformation in diabetic bone may be linked to altered patterns mineral characteristics in T1DM and higher advanced glycation end-product accumulation in T2DM. © 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).

Bone microarchitecture of the distal fibula assessed by HR-pQCT.

The distal fibula represents one of the most common fracture sites, and its epidemiology is characterized by a high incidence in both adolescence and the elderly. While fracture occurrence is influenced by trauma mechanism, a possible underlying skeletal microarchitectural deterioration in certain patient groups remains elusive. The purpose of this study was to determine the influence of age, sex, and overall skeletal status on fibular microarchitecture. We analyzed the microarchitecture of the distal fibula in 300 people by high-resolution peripheral quantitative computed tomography (HR-pQCT). Three areal bone mineral density (aBMD) groups (normal, osteopenia, osteoporosis; n = 100 per group) based on the concurrent assessment of aBMD by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and total hip were established. Next to group comparisons, linear and non-linear regression analyses were carried out to assess the association between age, sex, BMI, tibial and fibular microarchitecture. While women had lower values for both trabecular bone volume fraction (BV/TVd, p < 0.001) and cortical thickness (Ct.Thd, p < 0.001) than men, osteoporosis by DXA negatively affected these parameters in both sexes. Remarkably, cortical but not trabecular microarchitecture declined with age, with a stronger decrease in females compared to males (Ct.Thd female -10.0 µm/year (95% CI: -12.2 to -7.7 µm/year), male -4.0 µm/year (95% CI: -6.3 to -1.7 µm/year)). Moderate positive associations between distal tibial and fibular microarchitecture were noted (e.g., BV/TVd R2 = 0.54, Ct.Thd R2 = 0.58). In summary, we here demonstrate the severe negative effects of age, female sex and osteoporosis on distal fibula bone mineralization and microarchitecture. The presented findings are likely to explain the higher susceptibility to distal fibula fractures in elderly women (independent of trauma mechanism). These alterations in fibular bone quality must be taken into account in the context of fracture prevention and treatment (e.g., osteosynthesis planning).

Bone healing and reactivation of remodeling under asfotase alfa therapy in adult patients with pediatric-onset hypophosphatasia.

Hypophosphatasia (HPP) is a hereditary musculoskeletal disorder caused by inactivating variants in the ALPL gene and subsequently reduced serum tissue-nonspecific alkaline phosphatase (TNSALP) activity. This inborn error of metabolism results in decreased bone quality, accumulations of osteoid, and reduced bone mineralization. Increased incidence of fractures and prolonged bone healing are characteristic features for HPP. Available enzyme replacement therapy (asfotase alfa), was reported to recover bone mineralization and bone quality in adult HPP patients. Moreover, it was shown that asfotase alfa improved fracture healing of former nonunions in two adult HPP patients. We hypothesized that the nonunions are filled partially with osteoid, offering great potential to benefit from the treatment with asfotase alfa to promote bone healing. In the present study, we report three adult patients with pediatric-onset HPP and detected ALPL-mutations with prolonged bone healing after arthrodesis, tibial stress fracture, and osteotomy. After the initiation of asfotase alfa, immediately increased levels of alkaline phosphatase (ALP) and bone-specific ALP, as well as decreased levels of pyridoxal-5-phosphate (PLP), were detected in biochemical analysis. Importantly, even after up to 5 years of non-healing, a progredient consolidation was shown, assessed by a custom three-dimensional evaluation of repeated cone-beam computed tomography (CBCT) images, characterized by rapidly increasing levels of bone volume per tissue volume (BV/TV) within the volume of interest (i.e., the region of the non-healing bone). These radiographical findings were in line with the reported restoration of functional ability and pain-free full weight-bearing, as well as increased neuromuscular parameters (e.g., improved muscle strength). Taken together, our findings indicate that asfotase alfa improves the osseous consolidation of nonunions likely due to re-mineralization of osteoid tissue filling the former gap and improving the functional ability in adult HPP patients, characterized by increasing levels of BV/TV assessed via an innovative three-dimensional evaluation of CBCT images.