Differential risk of fracture attributable to type 2 diabetes mellitus according to skeletal site.

BACKGROUND: Impaired bone quality, especially related to accumulation of advanced glycation end-products (AGEs) and higher incidence of falls contribute substantially to a higher risk of fracture associated with type 2 diabetes mellitus (T2DM). These factors may predispose to fractures more at skeletal sites where impaired bone toughness and falls play a larger pathogenic role (such as hip fractures) compared to skeletal sites where they are less important (such as vertebral fractures). OBJECTIVE: To determine if the associations of T2DM with prevalent and incident vertebral fractures are as strong as they are for hip and other non-vertebral fractures. METHODS: Amongst 80,238 individuals in the Manitoba Bone Density Program database (mean [SD] age 64.4 [11.1] years, 89.8% female, 8676 with diagnosed T2DM) with a baseline BMD test (1996-2016), we estimated hazard ratios (HRs) for incident clinical fracture at different skeletal sites in those with compared to those without T2DM using Cox proportional hazards models over a mean (SD) 9.0 (5.0) year follow-up period. We also estimated odds ratios for prevalent vertebral fracture on VFA images amongst 9594 individuals (mean [SD] 76 [6.8] years, 1185 with T2DM diagnosis at time of DXA-VFA) and for prior clinical fractures at different skeletal sites using logistic regression models. RESULTS: After multivariable adjustment, T2DM was associated with incident hip (HR 1.63, 95% CI 1.44 to 1.85) and proximal humerus fractures (HR 1.59, 95% CI 1.39 to 1.83), but was not associated with incident forearm fracture (HR 1.00, 95% CI 0.86 to 1.17) and only weakly with incident clinical vertebral fracture (HR 1.16, 95% CI 1.01 to 1.33). Similarly, T2DM was associated with prior hip (OR 1.78, 95% CI 1.21 to 2.61) and prior proximal humerus fracture (OR 1.31, 95% CI 1.02 to 1.68) but not with prior forearm (OR 0.89, 95% CI 0.74 to 1.06) or prevalent vertebral fracture on VFA images (OR 0.91, 95% CI 0.77 to 1.08). CONCLUSION: T2DM is a stronger risk factor for hip and proximal humerus fractures than for vertebral and wrist fractures. Further research is warranted to determine if the known differences in falls and/or bone quality between T2DM and age-related osteoporosis account for these differential associations.

Small leucine-rich proteoglycans in physiological and biomechanical function of bone.

Proteoglycans (PGs) contain long unbranched glycosaminoglycan (GAG) chains attached to core proteins. In the bone extracellular matrix, PGs represent a class of non-collagenous proteins, and have high affinity to minerals and collagen. Considering the highly negatively charged character of GAGs and their interfibrillar positioning interconnecting with collagen fibrils, PGs and GAGs play pivotal roles in maintaining hydrostatic and osmotic pressure in the matrix. In this review, we will discuss the role of PGs, especially the small leucine-rich proteoglycans, in regulating the bioactivity of multiple cytokines and growth factors, and the bone turnover process. In addition, we focus on the coupling effects of PGs and GAGs in the hydration status of bone extracellular matrix, thus modulating bone biomechanical properties under physiological and pathological conditions.

Bone biomechanical properties and tissue-scale bone quality in a genetic mouse model of familial dysautonomia.

PURPOSE: Familial dysautonomia (FD) is associated with a high prevalence of bone fractures, but the impacts of the disease on bone mass and quality are unclear. The purpose of this study was to evaluate tissue through whole-bone scale bone quality in a mouse model of FD. METHODS: Femurs from mature adult Tuba1a-Cre; Elp1LoxP/LoxP conditional knockouts (CKO) (F = 7, M = 4) and controls (F = 5, M = 6) were evaluated for whole-bone flexural material properties, trabecular microarchitecture and cortical geometry, and areal bone mineral density (BMD). Adjacent maps spanning the thickness of femur midshaft cortical bone assessed tissue-scale modulus (nanoindentation), bone mineralization, mineral maturity, and collagen secondary structure (Raman spectroscopy). RESULTS: Consistent with prior studies on this mouse model, the Elp1 CKO mouse model recapitulated several key hallmarks of human FD, with one difference being the male mice tended to have a more severe phenotype than females. Deletion of Elp1 in neurons (using the neuronal-specific Tuba1a-cre) led to a significantly reduced whole-bone toughness but not strength or modulus. Elp1 CKO female mice had reduced trabecular microarchitecture (BV/TV, Tb.Th, Conn.D.) but not cortical geometry. The mutant mice also had a small but significant reduction in cortical bone nanoindentation modulus. While bone tissue mineralization and mineral maturity were not impaired, FD mice may have altered collagen secondary structure. Changes in collagen secondary structure were inversely correlated with bone toughness. BMD from dual-energy x-ray absorptiometry (DXA) was unchanged with FD. CONCLUSION: The deletion of Elp1 in neurons is sufficient to generate a mouse line which demonstrates loss of whole-bone toughness, consistent with the poor bone quality suspected in the clinical setting. The Elp1 CKO model, as with human FD, impacts the nervous system, gut, kidney function, mobility, gait, and posture. The bone quality phenotype of Elp1 CKO mice, which includes altered microarchitecture and tissue-scale material properties, is complex and likely influenced by these multisystemic changes. This mouse model may provide a useful platform to not only investigate the mechanisms responsible for bone fragility in FD, but also a powerful model system with which to evaluate potential therapeutic interventions for bone fragility in FD patients.

Investigation of Mechanical, Material, and Compositional Determinants of Human Trabecular Bone Quality in Type 2 Diabetes.

CONTEXT: Increased bone fragility and reduced energy absorption to fracture associated with type 2 diabetes (T2D) cannot be explained by bone mineral density alone. This study, for the first time, reports on alterations in bone tissue's material properties obtained from individuals with diabetes and known fragility fracture status. OBJECTIVE: To investigate the role of T2D in altering biomechanical, microstructural, and compositional properties of bone in individuals with fragility fracture. METHODS: Femoral head bone tissue specimens were collected from patients who underwent replacement surgery for fragility hip fracture. Trabecular bone quality parameters were compared in samples of 2 groups, nondiabetic (n = 40) and diabetic (n = 30), with a mean duration of disease 7.5 ± 2.8 years. RESULTS: No significant difference was observed in aBMD between the groups. Bone volume fraction (BV/TV) was lower in the diabetic group due to fewer and thinner trabeculae. The apparent-level toughness and postyield energy were lower in those with diabetes. Tissue-level (nanoindentation) modulus and hardness were lower in this group. Compositional differences in the diabetic group included lower mineral:matrix, wider mineral crystals, and bone collagen modifications-higher total fluorescent advanced glycation end-products (fAGEs), higher nonenzymatic cross-link ratio (NE-xLR), and altered secondary structure (amide bands). There was a strong inverse correlation between NE-xLR and postyield strain, fAGEs and postyield energy, and fAGEs and toughness. CONCLUSION: The current study is novel in examining bone tissue in T2D following first hip fragility fracture. Our findings provide evidence of hyperglycemia's detrimental effects on trabecular bone quality at multiple scales leading to lower energy absorption and toughness indicative of increased propensity to bone fragility.

Biglycan and chondroitin sulfate play pivotal roles in bone toughness via retaining bound water in bone mineral matrix.

Recent in vitro evidence shows that glycosaminoglycans (GAGs) and proteoglycans (PGs) in bone matrix may functionally be involved in the tissue-level toughness of bone. In this study, we showed the effect of biglycan (Bgn), a small leucine-rich proteoglycan enriched in extracellular matrix of bone and the associated GAG subtype, chondroitin sulfate (CS), on the toughness of bone in vivo, using wild-type (WT) and Bgn deficient mice. The amount of total GAGs and CS in the mineralized compartment of Bgn KO mouse bone matrix decreased significantly, associated with the reduction of the toughness of bone, in comparison with those of WT mice. However, such differences between WT and Bgn KO mice diminished once the bound water was removed from bone matrix. In addition, CS was identified as the major subtype in bone matrix. We then supplemented CS to both WT and Bgn KO mice to test whether supplemental GAGs could improve the tissue-level toughness of bone. After intradermal administration of CS, the toughness of WT bone was greatly improved, with the GAGs and bound water amount in the bone matrix increased, while such improvement was not observed in Bgn KO mice or with supplementation of dermatan sulfate (DS). Moreover, CS supplemented WT mice exhibited higher bone mineral density and reduced osteoclastogenesis. Interestingly, Bgn KO bone did not show such differences irrespective of the intradermal administration of CS. In summary, the results of this study suggest that Bgn and CS in bone matrix play a pivotal role in imparting the toughness to bone most likely via retaining bound water in bone matrix. Moreover, supplementation of CS improves the toughness of bone in mouse models.

Damage tolerance of lamellar bone.

Lamellar bone is known to be the most typical structure of cortical bone in large mammals including humans. This type of tissue provides a good combination of strength and fracture toughness. As has been shown by John D Currey and other researchers, large deformations are associated with the appearance of microdamage that optically whitens the tissue, a process that has been identified as a contribution to bone toughness. Using finite-element modelling, we study crack propagation in a material with periodic variation of mechanical parameters, such as elastic modulus and strength, chosen to represent lamellar bone. We show that a multitude of microcracks appears in the region ahead of the initial crack tip, thus dissipating energy even without a progression of the initial crack tip. Strength and toughness are shown to be both larger for the (notched) lamellar material than for a homogeneous material with the same average properties and the same initial notch. The length of the microcracks typically corresponds to the width of a lamella, that is, to several microns. This simultaneous improvement of strength and toughness may explain the ubiquity of lamellar plywood structures not just in bone but also in plants and in chitin-based cuticles of insects and arthropods.

Postmortem change in bone biomechanical properties: Loss of plasticity.

Bone is a hierarchical composite material composed primarily of collagen molecules, mineral crystals, and water. The mineral phase confers strength and stiffness while the organic matrix provides toughness. As a result, living bone is very capable of absorbing energy and resisting fracture. After death, the bone often becomes dehydrated and the collagen degrades causing greater stiffness and reduced toughness. These changes in mechanical properties are augmented due to the combined effects of water loss and collagen degradation. As a result, bone becomes more brittle postmortem, which causes the changes in fracture characteristics that are commonly used to estimate the timing of the fracture. However, because the loss of moisture and collagen degradation are influenced by taphonomic conditions, anthropologist must use caution when interpreting the timing of fractures based solely on fracture characteristics. As part of this special volume on hard tissue alterations associated with trauma, the aim of this article is to provide an overview of the mechanical changes that occur in bone postmortem and summarize major works in bone biology and anthropology examining the cause and timing of plasticity loss in bone after death.

Deformation Mechanisms of "Two-Part" Natural Adhesive in Bone Interfibrillar Nano-Interfaces.

Noncollagenous proteins at nanoscale interfaces in bone are less than 2-3% of bone content by weight, while they contribute more than 30% to fracture toughness. Major gaps in quantitative understanding of noncollagenous proteins' role in the interfibrillar interfaces, largely because of the limitation of probing their nanoscale dimension, have resulted in ongoing controversies and several outstanding hypotheses on their role and function, arguably going back to centuries ago to the original work from Galileo. Our results from the first detailed computational model of the nano-interface in the bone reveal "synergistic" deformation mechanism of a "double-part" natural glue, that is, noncollagenous osteopontin and osteocalcin at the interfibrillar interface. Specifically, through strong anchoring and formation of dynamic binding sites on mineral nanoplatelets, the nano-interface can sustain a large nonlinear deformation with ductility approaching 5000%. This large deformation results in an outstanding specific energy to failure exceeding ∼350 J/g, which is larger than the most known tough materials (such as Kevlar, spider silk, and so forth.).

Bone toughness at the molecular scale: A model for fracture toughness using crosslinked osteopontin on synthetic and biogenic mineral substrates.

The most prominent structural components in bone are collagen and mineral. However, bone additionally contains a substantial amount of noncollagenous proteins (most notably of the SIBLING protein family), some of which may act as cohesive/adhesive "binders" for the composite hybrid collagen/mineral scaffolding, whether in the bulk phase of bone, or at its interfaces. One such noncollagenous protein - osteopontin (OPN) - appears to be critical to the deformability and fracture toughness of bone. In the present study, we used a reconstructed synthetic mineral-OPN-mineral interface, and a biogenic (natural tooth dentin) mineral/collagen-OPN-mineral/collagen interface, to measure the fracture toughness of OPN on mineralized substrates. We used this system to test the hypothesis that OPN crosslinking by the enzyme tissue transglutaminase 2 (TG2) that is found in bone enhances interfacial adhesion to increase the fracture toughness of bone. For this, we prepared double-cantilever beam substrates of synthetic pure hydroxyapatite mineral, and of narwhal dentin, and directly apposed them to one another under different intervening OPN/crosslinking conditions, and fracture toughness was tested using a miniaturized loading stage. The work-of-fracture of the OPN interface was measured for different OPN formulations (monomer vs. polymer), crosslinking states, and substrate composition. Noncrosslinked OPN provided negligible adhesion on pure hydroxyapatite, whereas OPN crosslinking (by the chemical crosslinker glutaraldehyde, and TG2 enzyme) provided strong interfacial adhesion for both hydroxyapatite and dentin using monomeric and polymeric OPN. Pre-coating of the substrate beams with monomeric OPN further improved the adhesive performance of the samples, likely by allowing effective binding of this nascent OPN form to mineral/matrix components, with this pre-attachment providing a protein layer for additional crosslinking between the substrates.

Biomecánica de las fracturas por stress / Biomechanical features of stress fractures

Se define como estrés (stress) tanto la fuerza que una carga externa ejerce sobre un cuerpo sólido como la fuerza reactiva que acompaña a la primera (Ley de Newton), por unidad de área imaginaria transversal a su dirección. Las cargas internas reactivas inducen deformaciones proporcionales del cuerpo. La resistencia del cuerpo a deformarse se llama rigidez. La deformación puede resquebrajar el cuerpo y, eventualmente, producir una fractura por confluencia de trazos. La resistencia del cuerpo a separarse en fragmentos por esa causa se llama tenacidad. La resistencia del cuerpo a la fractura es proporcional al stress que puede soportar sin separarse en fragmentos por deformación (no hay fractura sin deformación y sin stress previo). El stress máximo que un cuerpo puede soportar sin fracturarse resulta de una combinación de ambas propiedades: rigidez y tenacidad, cada una con distintos determinantes biológicos. Una o varias deformaciones del cuerpo pueden provocarle resquebrajaduras sin fracturarlo. La acumulación de resquebrajaduras determina la "fatiga" del material constitutivo del cuerpo, que reduce su rigidez, tenacidad y resistencia a la fractura para la próxima ocasión ("fragilidad por fatiga"). En el caso de los huesos, en general, los términos stress y fatiga tienen las connotaciones amplias referidas, respecto de todas las fracturas posibles. La fatiga predispone a fracturas a cargas bajas, que se denominan (correctamente) "fracturas por fatiga" y también (incorrectamente) "fracturas por stress", para distinguirlas de las que ocurren corrientemente, sin resquebrajaduras previas al trauma, que se denominan (incorrectamente) "fracturas por fragilidad, o por insuficiencia". En realidad, todas las fracturas se producen por stress y por fragilidad o insuficiencia (en conjunto); pero la distinción grosera entre fracturas "por fatiga, o por stress", por un lado, y "por fragilidad" o "por insuficiencia", por otro, aceptando las amplias connotaciones referidas antes, tiene valor en la práctica clínica. Este artículo intenta explicar esas particularidades biomecánicas y describir las distintas condiciones que predisponen a las fracturas "por fatiga o por stress" en la clínica, distinguiéndolas de las fracturas "por fragilidad o por insuficiencia" (manteniendo estas denominaciones) y detallando las características de interés directo para su diagnóstico y tratamiento. (AU)

The term "stress" expresses the force exerted by an external load on a solid body and the accompanying, opposed force (Newton's Law), expressed per unit of an imaginary area perpendicular to the loading direction. The internal loads generated this way deform (strain) proportionally the body's structure. The resistance of the body to strain expresses its stiffness. Critical strain magnitudes may induce micro-fractures (microdamage), the confluence of which may fracture the body. The body's resistance to separation into fragments determines its toughness. Hence, the body's resistance to fracture is proportional to the stress the body can support (or give back) while it is not fractured by the loadinduced strain (no stress, no strain -> no fracture). Therefore, the maximal stress the body can stand prior to fracture is determined by a combination of both, its stiffness and its toughness; and each of those properties is differently determined biologically. One or more deformations of the body may induce some microdamage but not a fracture. Microdamage accumulation determines the fatigue of the material constitutive of the body and reduces body's toughness, leading to a "fatigue-induced fragility". In case of bones, in general, both stress and fatigue have the referred, wide connotations, regarding any kind of fractures. In particular, bone fatigue predisposes to low-stress fractures, which are named (correctly) "fatigue fractures" and also misnamed "stress fractures", to distinguish them from the current fractures that occur without any excess of microdamage, that are named (wrongly) "fragility" or "insufficiency" fractures. In fact, all fractures result from all stress and fragility or insufficiency as a whole; however, the gross distinction between "fatigue or stress fractures", on one side, and "fragility or insufficiency fractures", on the other, accepting the wide connotations of the corresponding terminology, is relevant to clinical practice. This article aims to explain the above biomechanical features and describe the different instances that predispose to "fatigue or stress fractures" in clinical practice, as a different entity from "insufficiency or fragility fractures" (maintaining this nomenclature), and describe their relevant features to their diagnosis and therapy. (AU)

Remodeling in bone without osteocytes: billfish challenge bone structure-function paradigms.

A remarkable property of tetrapod bone is its ability to detect and remodel areas where damage has accumulated through prolonged use. This process, believed vital to the long-term health of bone, is considered to be initiated and orchestrated by osteocytes, cells within the bone matrix. It is therefore surprising that most extant fishes (neoteleosts) lack osteocytes, suggesting their bones are not constantly repaired, although many species exhibit long lives and high activity levels, factors that should induce considerable fatigue damage with time. Here, we show evidence for active and intense remodeling occurring in the anosteocytic, elongated rostral bones of billfishes (e.g., swordfish, marlins). Despite lacking osteocytes, this tissue exhibits a striking resemblance to the mature bone of large mammals, bearing structural features (overlapping secondary osteons) indicating intensive tissue repair, particularly in areas where high loads are expected. Billfish osteons are an order of magnitude smaller in diameter than mammalian osteons, however, implying that the nature of damage in this bone may be different. Whereas billfish bone material is as stiff as mammalian bone (unlike the bone of other fishes), it is able to withstand much greater strains (relative deformations) before failing. Our data show that fish bone can exhibit far more complex structure and physiology than previously known, and is apparently capable of localized repair even without the osteocytes believed essential for this process. These findings challenge the unique and primary role of osteocytes in bone remodeling, a basic tenet of bone biology, raising the possibility of an alternative mechanism driving this process.

Reference point indentation is not indicative of whole mouse bone measures of stress intensity fracture toughness.

Bone fragility is a concern for aged and diseased bone. Measuring bone toughness and understanding fracture properties of the bone are critical for predicting fracture risk associated with age and disease and for preclinical testing of therapies. A reference point indentation technique (BioDent) has recently been developed to determine bone's resistance to fracture in a minimally invasive way by measuring the indentation distance increase (IDI) between the first and last indentations over cyclic indentations in the same position. In this study, we investigate the relationship between fracture toughness KC and reference point indentation parameters (i.e. IDI, total indentation distance (TID) and creep indentation distance (CID)) in bones from 38 mice from six types (C57Bl/6, Balb, oim/oim, oim/+, Phospho1(-/-) and Phospho1 wild type counterpart). These mice bone are models of healthy and diseased bone spanning a range of fracture toughness from very brittle (oim/oim) to ductile (Phospho1(-/-)). Left femora were dissected, notched and tested in 3-point bending until complete failure. Contralateral femora were dissected and indented in 10 sites of their anterior and posterior shaft surface over 10 indentation cycles. IDI, TID and CID were measured. Results from this study suggest that reference point indentation parameters are not indicative of stress intensity fracture toughness in mouse bone. In particular, the IDI values at the anterior mid-diaphysis across mouse types overlapped, making it difficult to discern differences between mouse types, despite having extreme differences in stress intensity based toughness measures. When more locations of indentation were considered, the normalised IDIs could distinguish between mouse types. Future studies should investigate the relationship of the reference point indentation parameters for mouse bone in other material properties of the bone tissue in order to determine their use for measuring bone quality.

Effect of long term use of bisphosphates on microdamage and mechanical properties of bone / 医用生物力学

Bisphosphates as a first line preferred drug for curing osteoporosis has been used for a long time in clinic since it can inhibit the bone remodeling to decrease the risk of bone fracture and increase the bone density. But recent studies show that bisphosphates could cause the accumulation of microdamage to decrease bone quality. The long term use of bisphosphates may reduce the bone toughness and weaken the mechanical properties of bone. Some clinical reports have indicated that patients with osteoporosis tend to have non traumatic fractures after their use of bisphosphates. This article will review the effect of bisphosphates on the microdamage and mechanical properties of bone.