Long-duration type 1 diabetes is associated with deficient cortical bone mechanical behavior and altered matrix composition in human femoral bone.

Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this study was to evaluate cortical bone material behavior in T1D by examining specimens from cadaveric femora from older adults with long-duration T1D (≥50 years; n = 20) and age- and sex-matched non-diabetic controls (n = 14). Cortical bone was assessed by mechanical testing (4-point bending, cyclic reference point indentation, impact microindentation), AGE quantification (total fluorescent AGEs, pentosidine, carboxymethyl-lysine (CML)), and matrix composition via Raman spectroscopy.

Germ-Free C57BL/6 Mice Have Increased Bone Mass and Altered Matrix Properties but Not Decreased Bone Fracture Resistance.

The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ-free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice.

A vitamin D deficient diet increases weight gain and compromises bone biomechanical properties without a reduction in BMD in adult female mice.

Vitamin D contributes to the development and maintenance of bone. Evidence suggests vitamin D status can also alter energy balance and gut health. In young animals, vitamin D deficiency (VDD) negatively affects bone mineral density (BMD) and bone microarchitecture, and these effects may also occur due to chronic ethanol intake.

Accumulation of fluorescent advanced glycation end products and carboxymethyl-lysine in human cortical and trabecular bone.

Chemical crosslinks known as advanced glycation end-products (AGEs) are associated with increased bone fracture risk and deteriorated bone mechanical properties. However, measurement of bone AGEs via ex vivo and in vitro methods has been limited to quantification of bulk fluorescent AGEs (fAGEs) and pentosidine only, which is a crosslinking fluorescent AGE. However, a non-crosslinking and non-fluorescent AGE such as carboxymethyl-lysine (CML) is found to be 40-100 times higher in quantity than pentosidine, but only one previous study has reported it in cortical bone, and one study reported it in trabecular bone.

Dose-dependent effects of pharmaceutical treatments on bone matrix properties in ovariectomized rats.

As both anabolic and anti-catabolic osteoporosis drugs affect bone formation and resorption processes, they may contribute to bone's overall mechanical behavior by altering the quality of the bone matrix. We used an ovariectomized rat model and a novel fracture mechanics approach to investigate whether treatment with an anabolic (parathyroid hormone) or anti-catabolic (alendronate) osteoporosis drugs will alter the organic and mineral matrix components and consequently cortical bone fracture toughness. Ovariectomized (at 5 months age) rats were treated with either parathyroid hormone or alendronate at low and high doses for 6 months (age 6-12 months).

Fracture behavior of human cortical bone: Role of advanced glycation end-products and microstructural features.

Diabetes is associated with increased fracture risk in human bone, especially in the elderly population. In the present study, we investigate how simulated advanced glycation end-products (AGEs) and materials heterogeneity affect crack growth trajectory in human cortical bone. We used a phase field fracture framework on 2D models of cortical microstructure created from human tibias to analyze crack propagation.

Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups.

Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid.

Increasing fluoride content deteriorates rat bone mechanical properties.

Elevation of bone fluoride levels due to drinking beverages with high fluoride content or other means such as inhalation can result in skeletal fluorosis and lead to increased joint pain, skeletal deformities, and fracture. Because skeletal fluorosis alters bone's mineral composition, it is likely to affect bone's tissue-level mechanical properties with consequent effects on whole bone mechanical behavior. To investigate this, we determined whether incubation with in vitro sodium fluoride (NaF) altered bone's mechanical behavior at both the tissue- and whole bone-levels using cyclic reference point indentation (cRPI) and traditional 3-point bending, respectively.

In Vitro-Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness.

Advanced glycation end-products (AGEs) have been suggested to contribute to bone fragility in type 2 diabetes (T2D). AGEs can be induced through in vitro sugar incubations but there is limited data on the effect of total fluorescent AGEs on mechanical properties of human cortical bone, which may have altered characteristics in T2D. Thus, to examine the effect of AGEs on bone directly in T2D patients with uncontrolled sugar levels, it is essential to first understand the fundamental mechanisms by studying the effects of controlled in vitro-induced AGEs on cortical bone mechanical behavior.

The Effect of Type 2 Diabetes on Bone Biomechanics.

Purpose Of Review: There is ample evidence that patients with type 2 diabetes (T2D) have increased risk of fracture even though they have normal or high bone mineral density. As a result, poor bone quality is suggested to contribute to skeletal fragility in this population. Thus, our goal was to conduct a comprehensive literature review to understand how bone quality components are altered in T2D and their effects on bone biomechanics and fracture risk.

Bone microarchitecture, biomechanical properties, and advanced glycation end-products in the proximal femur of adults with type 2 diabetes.

Skeletal fragility is a major complication of type 2 diabetes mellitus (T2D), but there is a poor understanding of mechanisms underlying T2D skeletal fragility. The increased fracture risk has been suggested to result from deteriorated bone microarchitecture or poor bone quality due to accumulation of advanced glycation end-products (AGEs). We conducted a clinical study to determine whether: 1) bone microarchitecture, AGEs, and bone biomechanical properties are altered in T2D bone, 2) bone AGEs are related to bone biomechanical properties, and 3) serum AGE levels reflect those in bone.

Bisphosphonate Withdrawal: Effects on Bone Formation and Bone Resorption in Maturing Male Mice.

Bisphosphonates are being increasingly used to treat pediatric patients with skeletal disorders. However, the effects of long-term bisphosphonate therapy and cessation of therapy during growth are unclear. Thus, studies were undertaken to determine the effects of alendronate discontinuation after treatment of C57Bl/6 mice during the period of rapid skeletal growth.

Bone mechanical properties and changes with osteoporosis.

This review will define the role of collagen and within-bone heterogeneity and elaborate the importance of trabecular and cortical architecture with regard to their effect on the mechanical strength of bone. For each of these factors, the changes seen with osteoporosis and ageing will be described and how they can compromise strength and eventually lead to bone fragility.

Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties.

There is clear evidence that patients with type 2 diabetes mellitus (T2D) have increased fracture risk, despite having high bone mineral density (BMD) and body mass index (BMI). Thus, poor bone quality has been implicated as a mechanism contributing to diabetic skeletal fragility. Poor bone quality in T2D may result from the accumulation of advanced glycation end-products (AGEs), which are post-translational modifications of collagen resulting from a spontaneous reaction between extracellular sugars and amino acid residues on collagen fibers.

Comparison of cyclic and impact-based reference point indentation measurements in human cadaveric tibia.

Although low bone mineral density (BMD) is strongly associated with increased fracture risk, up to 50% of those who suffer fractures are not detected as high-risk patients by BMD testing. Thus, new approaches may improve identification of those at increased risk for fracture by in vivo assessment of altered bone tissue properties, which may contribute to skeletal fragility. Recently developed reference point indentation (RPI) allows for assessment of cortical bone indentation properties in vivo using devices that apply cyclic loading or impact loading, but there is little information available to assist with interpretation of RPI measurements.

Association between non-enzymatic glycation, resorption, and microdamage in human tibial cortices.

Unlabelled: To better understand the association between different components of bone quality, we investigated the relationship among in vivo generated non-enzymatic glycation, resorption, and microdamage. The results showed negative correlation between advanced glycation end-products (AGEs) and resorption independent of age highlighting the interaction between these parameters that may lead to bone fragility.

Introduction: Changes in the quality of bone material contribute significantly to bone fragility.

A review of rodent models of type 2 diabetic skeletal fragility.

Evidence indicating that adult type 2 diabetes (T2D) is associated with increased fracture risk continues to mount. Unlike osteoporosis, diabetic fractures are associated with obesity and normal to high bone mineral density, two factors that are typically associated with reduced fracture risk. Animal models will likely play a critical role in efforts to identify the underlying mechanisms of skeletal fragility in T2D and to develop preventative treatments.

Low level irradiation in mice can lead to enhanced trabecular bone morphology.

Charged particle radiation such as iron ions and their secondary fragmentation products are of particular concern to the skeleton due to their high charge and energy deposition. However, little is known about the long-term effects of these particles on trabecular and cortical bone morphology when applied at relatively low levels. We hypothesized that even a 4.

Adolescent girls with anorexia nervosa have impaired cortical and trabecular microarchitecture and lower estimated bone strength at the distal radius.

Context: Adolescents with anorexia nervosa (AN) have low areal bone mineral density (aBMD) at both cortical and trabecular sites, and recent data show impaired trabecular microarchitecture independent of aBMD. However, data are lacking regarding both cortical microarchitecture and bone strength assessment by finite element analysis (FEA) in adolescents with AN. Because microarchitectural abnormalities and FEA may predict fracture risk independent of aBMD, these data are important to obtain.

Heterogeneous glycation of cancellous bone and its association with bone quality and fragility.

Non-enzymatic glycation (NEG) and enzymatic biochemical processes create crosslinks that modify the extracellular matrix (ECM) and affect the turnover of bone tissue. Because NEG affects turnover and turnover at the local level affects microarchitecture and formation and removal of microdamage, we hypothesized that NEG in cancellous bone is heterogeneous and accounts partly for the contribution of microarchitecture and microdamage on bone fragility. Human trabecular bone cores from 23 donors were subjected to compression tests.

Biochemical characterization of major bone-matrix proteins using nanoscale-size bone samples and proteomics methodology.

There is growing evidence supporting the need for a broad scale investigation of the proteins and protein modifications in the organic matrix of bone and the use of these measures to predict fragility fractures. However, limitations in sample availability and high heterogeneity of bone tissue cause unique experimental and/or diagnostic problems. We addressed these by an innovative combination of laser capture microscopy with our newly developed liquid chromatography separation methods, followed by gel electrophoresis and mass spectrometry analysis.

Role of trabecular microarchitecture in the formation, accumulation, and morphology of microdamage in human cancellous bone.

Alterations in microdamage morphology and accumulation are typically attributed to impaired remodeling, but may also result from changes in microdamage initiation and propagation. Such alterations are relevant for cancellous bone with high metabolic activity and numerous bone quality changes. This study investigates the role of trabecular microarchitecture on morphology and accumulation of microdamage in human cancellous bone.