Microdamage Accumulation In Bone Research Articles

Serum exosomes from young rats improve the reduced osteogenic differentiation of BMSCs in aged rats with osteoporosis after fatigue loading in vivo

BackgroundOsteoporosis is a major public health concern for the elderly population and is characterized by fatigue load resulting in bone microdamage. The ability of bone mesenchymal stem cells (BMSCs) to repair bone microdamage diminishes with age, and the accumulation of bone microdamage increases the risk of osteoporotic fracture. There is a lack of effective means to promote the repair of bone microdamage in aged patients with osteoporosis. Exosomes have been shown to be related to the osteogenic differentiation of BMSCs. Here, we aimed to evaluate the changes in the osteogenic differentiation capacity of BMSCs in aged osteoporotic rats after fatigue loading and the treatment potential of serum exosomes from young rats.MethodsThe tibias of six aged osteoporotic rats were subjected to fatigue loading in vivo for 2 weeks, and the bone microdamage, microstructures, and mechanical properties were assessed. Subsequently, BMSCs were extracted to evaluate their proliferation and osteogenic differentiation abilities. In addition, the BMSCs of aged osteoporotic rats after fatigue loading were treated with serum exosomes from young rats under osteogenic induction conditions, and the expression of osteogenic-related miRNAs was quantified. The osteogenetic effects of miRNA-19b-3p in exosomes and the possible target protein PTEN was detected.ResultsObvious bone microdamage at the fatigue load stress point, the bone microstructure and biomechanical properties were not obviously changed. A decreased osteogenic differentiation ability of BMSCs was observed after fatigue loading, while serum exosomes from young rats highly expressing miRNA-19b-3p improved the decreased osteogenic differentiation ability of BMSCs. Transfection with miRNA-19b-3p mimic could promote osteoblastic differentiation of BMSCs and decreased the expression of PTEN. After transfection of miRNA-19b-3p inhibitor, the promotional effect of exosomes on bone differentiation was weakened. Treatment with transfected exosomes increased the expression of PTEN.ConclusionSerum exosomes derived from young rats can improve the decreased osteogenic differentiation ability of BMSCs in aged rats with osteoporosis after fatigue loading and can provide a new treatment strategy for the repair of bone microdamage and prevention of fractures.

Neuropeptide Y1 receptor antagonist promotes osteoporosis and microdamage repair and enhances osteogenic differentiation of bone marrow stem cells via cAMP/PKA/CREB pathway

Osteoporosis is a common metabolic bone disorder in the elderly population. The accumulation of bone microdamage is a critical factor of osteoporotic fracture. Neuropeptide Y (NPY) has been reported to regulated bone metabolism through Y1 receptor (Y1R). In this study the effects and mechanisms of Y1R antagonist on prevention for osteoporosis were characterized. In the clinical experiment, compared with osteoarthritis (OA), osteoporosis (OP) showed significant osteoporotic bone microstructure and accumulation of bone microdamage. NPY and Y1R immunoreactivity in bone were stronger in OP group, and were both correlated with bone volume fraction (BV/TV). In vivo experiment, Y1R antagonist significantly improved osteoporotic microstructure in the ovariectomized (OVX) rats. And Y1R antagonist promoted RUNX2, OPG and inhibit RANKL, MMP9 in bone marrow. In vitro cell culture experiment, NPY inhibited osteogenesis, elevated RANKL/OPG ratio and downregulated the expression of cAMP, p-PKAs and p-CREB in BMSCs, treated with Y1R antagonist or 8-Bromo-cAMP could inhibit the effects of NPY. Together, Y1R antagonist improved the bone microstructure and reduced bone microdamage in OVX rats. NPY-Y1R could inhibit osteoblast differentiation of BMSCs via cAMP/PKA/CREB pathway. Our findings highlight the regulation of NPY-Y1R in bone metabolism as a potential therapy strategy for the prevention of osteoporosis and osteoporotic fracture.

Ground reaction force metrics are not strongly correlated with tibial bone load when running across speeds and slopes: Implications for science, sport and wearable tech.

IntroductionTibial stress fractures are a common overuse injury resulting from the accumulation of bone microdamage due to repeated loading. Researchers and wearable device developers have sought to understand or predict stress fracture risks, and other injury risks, by monitoring the ground reaction force (GRF, the force between the foot and ground), or GRF correlates (e.g., tibial shock) captured via wearable sensors. Increases in GRF metrics are typically assumed to reflect increases in loading on internal biological structures (e.g., bones). The purpose of this study was to evaluate this assumption for running by testing if increases in GRF metrics were strongly correlated with increases in tibial compression force over a range of speeds and slopes.MethodsTen healthy individuals performed running trials while we collected GRFs and kinematics. We assessed if commonly-used vertical GRF metrics (impact peak, loading rate, active peak, impulse) were strongly correlated with tibial load metrics (peak force, impulse).ResultsOn average, increases in GRF metrics were not strongly correlated with increases in tibial load metrics. For instance, correlating GRF impact peak and loading rate with peak tibial load resulted in r = -0.29±0.37 and r = -0.20±0.35 (inter-subject mean and standard deviation), respectively. We observed high inter-subject variability in correlations, though most coefficients were negligible, weak or moderate. Seventy-six of the 80 subject-specific correlation coefficients computed indicated that higher GRF metrics were not strongly correlated with higher tibial forces.ConclusionsThese results demonstrate that commonly-used GRF metrics can mislead our understanding of loading on internal structures, such as the tibia. Increases in GRF metrics should not be assumed to be an indicator of increases in tibial bone load or overuse injury risk during running. This has important implications for sports, wearable devices, and research on running-related injuries, affecting >50 scientific publications per year from 2015–2017.

Once-Weekly Teriparatide Treatment Prevents Microdamage Accumulation in the Lumbar Vertebral Trabecular Bone of Ovariectomized Cynomolgus Monkeys

The effect of teriparatide treatment on microdamage accumulation has yet to be examined in animal studies. The purpose of this study was to investigate the effect of once-weekly teriparatide treatment on bone microdamage accumulation and the relationship between microdamage parameters and bone mass, architecture, turnover, and collagen cross-linking in the lumbar vertebral trabecular bone of ovariectomized (OVX) cynomolgus monkeys. Female monkeys were divided into four groups (n = 18–20 per group): (1) SHAM group, (2) OVX group, (3) OVX with 1.2 µg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 µg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein for histomorphometry. L3 and L7 lumbar vertebrae were harvested and analyzed for differences in histomorphometry, microdamage, and collagen cross-linking. The iliac crest was also analyzed for differences in bone turnover. In the OVX group, cancellous bone mass was reduced and microdamage accumulation was increased as compared with the SHAM control. Once-weekly teriparatide at both doses prevented the decrease in bone mass and increase in microdamage accumulation, and improved the distribution of collagen cross-linkage types. Regression analyses indicated that decreased microdamage accumulation was associated with reduced non-enzymatic cross-link pentosidine rather than increased cancellous bone mass or enzymatic cross-links. These findings suggest that once-weekly teriparatide treatment decreases microdamage accumulation by recovering the balance in collagen cross-links.

Assessing bone quality through mechanical properties in postmenopausal trabecular bone

BackgroundThe inner structure of trabecular bone is a result of structural optimization provided by remodeling processes. Changes in hormonal status related to menopause cause bone tissue loss and micro-architectural deterioration with a consequent susceptibility to fracture. Accumulation of micro-damage in bone, as a function of the rate of production and rate of repair, underlies the development of stress fractures, increasing fragility associated to age and osteoporosis, especially in transmenopausal women. Patients and MethodsQuasi-static and nano-dynamic mechanical characterization were undertaken in trabecular bone from femoral neck biopsies of postmenopausal women. AFM (Atomic Force Microscopy) complementary studies were performed to determine nano-roughness (SRa) and the fibrils width of collagen. Nanoindentations were used to quantify transmenopausal changes in intrinsic mechanical properties of trabecular bone: hardness (Hi), modulus of Young (Ei), complex modulus (E*), tan delta (δ), storage modulus (E') and loss modulus (E"). ResultsAs result of the quasi-static measurements, 0.149 (0.036) GPa and 2.95 (0.73) GPa of Hi and Ei were obtained, respectively. As result of the nano-dynamic measurements, 17.94 (3.15), 0.62 (0.10), 13.79 (3.21 and 6.39 (1.28) GPa of E*, tan (δ), E' and E" were achieved, respectively. 101.07 SRa and 831.28 nm of fibrils width were additionally obtained. ConclusionsThis study poses a first approach to the measurement of bone quality in postmenopausal trabecular bone by combining quasi-static, nano-DMA analysis and tribology of dentin surface through AFM characterization.

Prolonged high force high repetition pulling induces trabecular bone loss and microcracks, while low force high repetition pulling induces bone anabolism

We have an operant rat model of upper extremity reaching and grasping in which we examined the impact of performing a high force high repetition (High-ForceHR) versus a low force low repetition (Low-ForceHR) task for 18 weeks on the radius, compared to age-matched controls. High-ForceHR rats performed at 4 reaches/min and 50% of their maximum voluntary pulling force for 2 hrs/day, 3 days/wk. Low-ForceHR rats performed at 6% maximum voluntary pulling force. High-ForceHR rats showed decreased trabecular bone volume in the distal radius and increased catabolic indices (microcracks and increased osteocyte apoptosis), compared to controls. In contrast, Low-ForceHR rats showed increased trabecular bone volume, and no microcracks or osteocyte apoptosis. Thus, prolonged performance of an upper extremity reaching and grasping task is loading-dependent with high force loading leading to accumulation of bone microdamage. The target grasp force (1.27N) of the High-ForceHR rats was 50% of their mean maximum voluntary force of 2.45N, easily below the predicted maximum acceptable force (MAF) of 1.64N (predicted from published equations). The presence of microcracks and bone loss leads us to suggest that the published equations over-estimated the MAF on these tissues by 1.3 fold.

Bisphosphonates and atypical subtrochanteric fractures of the femur.

ObjectivesBisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs.MethodsWe present an evaluation of current literature relating to the pathogenesis and treatment of AFFs in the context of bisphosphonate use.ResultsSix broad themes relating to the pathogenesis and management of bisphosphonate-related AFFs are presented. The key themes in fracture pathogenesis are: bone microdamage accumulation; altered bone mineralisation and altered collagen formation. The key themes in fracture management are: medical therapy and surgical therapy. In addition, primary prevention strategies for AFFs are discussed.ConclusionsThis article presents current knowledge about the relationship between bisphosphonates and the development of AFFs, and highlights key areas for future research. In particular, studies aimed at identifying at-risk subpopulations and organising surveillance for those on long-term therapy will be crucial in both increasing our understanding of the condition, and improving population outcomes.Cite this article: N. Kharwadkar, B. Mayne, J. E. Lawrence, V. Khanduja. Bisphosphonates and atypical subtrochanteric fractures of the femur. Bone Joint Res 2017;6:144–153. DOI: 10.1302/2046-3758.63.BJR-2016-0125.R1.

The effect of low fluoride concentrations on microdamage accumulation in mouse tibias under impact loading

Microdamage accumulation in bone is one of the mechanisms for energy dissipation during the fracture process. Changes in the ultrastructure and composition of bone constituents due to aging or diseases could affect microdamage accumulation. Low concentration (1 mM) of sodium fluoride (NaF) has been used in this study to investigate the effect of ultrastructural changes on microdamage accumulation in mouse tibias following free-fall impact loadings. Twenty-two tibias were divided randomly into control and NaF-treated groups. Free-fall impact loading was conducted twice on each tibia to produce microdamage. The elastic modulus of NaF-treated tibias decreased significantly after the impact loadings, while there was no significant difference in the modulus of untreated samples between pre- and post-damage loadings. Microdamage morphology analysis showed that less and shorter microcracks existed in NaF-treated tibias compared with control bones. Meanwhile, more and longer microcracks were observed in tensile regions in untreated samples compared with that in compressive regions, whereas no significant difference was observed between tensile and compressive regions in NaF-treated bones. The results of this study indicate that more energy is required to generate microcracks in NaF-treated bone than in normal bone. A low concentration of fluoride treatment may increase the toughness of bone under impact loading. This study focused on the effect of ultrastructural changes on microdamage in bones under impact loadings. The elastic modulus of the NaF-treated tibias decreased significantly after impact loadings. Less and shorter microcracks existed in NaF-treated tibia bones. More energy is required to generate microdamage in NaF-treated bones. A low concentration of fluoride treatment may increase the toughness of bone.

A THREE-DIMENSIONAL COMPUTER MODEL TO SIMULATE SPONGY BONE REMODELING UNDER OVERLOAD USING A SEMI-MECHANISTIC BONE REMODELING THEORY

Overload has been suggested as a contributing factor for bone loss, for instance at the bone implant interface. The objective of this study is to investigate spongy bone resorption under overload using a semi-mechanistic bone remodeling theory. Since overload can cause the accumulation of microdamage in bone, in this study, it is assumed that overload will increase the osteoclastic activity, and also will reduce the osteocyte influence distance. First, a previously proposed semi-mechanistic bone remodeling theory was extended by defining a new form for the resorption probability function, which is based on experimental evidence. Then, in order to investigate the validity of our hypothesis, a three-dimensional finite element model of spongy bone was developed. The simulation results show that, first, trabeculae adapt with the mechanical stimuli placed on them. Secondly, a sharp reduction in spongy bone density will be resulted, in agreement with experimental evidence, when bone is under overload.

Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0mg/mL) and low-density (<2.0mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality.

The role of water and mineral–collagen interfacial bonding on microdamage progression in bone

Microdamage would be accumulated in bone due to high-intensity training or even normal daily activity, which may consequently cause fragility fracture or stress fracture. On the other hand, microdamage formation serves as a toughening mechanism in bone. However, the mechanisms that control microdamage initiation and accumulation in bone are still poorly understood. Our previous finite element model indicated that different interfacial properties between mineral and collagen in bone may lead to distinct patterns of microdamage accumulation. Therefore, the current study was designed to examine such prediction and to investigate the role of water and mineral-collagen interactions on microdamage accumulation in bone. To address these issues, 48 mice femurs were divided randomly into four groups. These groups were dehydrated or treated with perfluorotripropylamine (PFTA) or NaF solution to change water distribution and mineral-collagen interfacial bonding in bone. After three-point bending fatigue tests, the types of microdamage (i.e., linear microcracks or diffuse damage) formed in bone were compared between different groups. The results suggested that (1) bone tissues with strong mineral-collagen interfacial bonding facilitate the formation of linear microcraks, and (2) water has little contribution to the growth of microcracks.

Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys

Suppression of bone remodeling by bisphosphonates leads to accumulation of microdamage in bone. If this microdamage develops due to suppressed repair of remodeling only, more potent bisphosphonates should cause more damage. In this study, we evaluated the effects of reduced bone turnover produced by a potent bisphosphonate, minodronic acid, on microdamage accumulation, the degree of mineralization and mechanical properties of bone in ovariectomized cynomolgus monkeys, and compared these effects with those of alendronate. Sixty female monkeys aged 9–17years old were divided into five groups. The sham group and the ovariectomized group were treated daily for 17months with lactose vehicle. The other three groups were treated daily with minodronic acid at a dose of 0.015mg/kg or 0.15mg/kg, or alendronate at 0.5mg/kg orally. After sacrifice, lumbar vertebrae and left femurs were subjected to histomorphometry, microdamage, mineralization analyses, and mechanical testing. Minodronic acid suppressed bone remodeling of cancellous and cortical bone in a dose-dependent manner and the higher dose of minodronic acid suppressed bone remodeling more strongly than alendronate. The lower dose of minodronic acid did not increase microdamage accumulation and compressive strength, but the higher dose of minodronic acid and alendronate resulted in similar increases in cancellous microdamage accumulation and ultimate load in lumbar vertebra. There were no significant differences among the groups in microdamage, degree of mineralization and mechanical properties in cortical bone of the femoral shaft; however, only alendronate showed a tendency to increase highly mineralized osteons and microdamage. These findings suggest that microdamage caused by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate although this was not reflected in any significant change of mechanical properties.

Is SSBT associated with atypical femoral fracture? SSBT is associated with atypical femoral fracture - pathophysiology of atypical femoral fractures -

Recently, atypical femoral fracture has emerged as potential complication of long-term bisphosphonate therapy. Before considering the potential harmful effects of oversupression of bone turnover, it has been supposed that suppressed bone turnover in postmenopausal skeleton has well documented beneficial effects on bone strength and fracture risk. However, the benefit of long-term use of bisphosphonate for the prevention of femoral fractures seems to be lower than previously speculated. There are several factors by which severely suppressed bone turnover may reduce bone mechanical properties. These include increased mineralization of bone and increased homogeneity of mineralization, changes in collagen cross linking and accumulation of bone microdamage.

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. Trabecular bone cores from donors of varying ages and bone volume fraction (BV/TV) were separated into high and low BV/TV groups. Samples were subjected to no load or uniaxial compression to 0.6% (pre-yield) or 1.1% (post-yield) strain. Microdamage was stained with lead uranyl acetate and specimens were imaged via microcomputed tomography to quantify microdamage and determine its morphology in three-dimensions (3D). Donors with high BV/TV had greater post-yield strain and were tougher than low BV/TV donors. High BV/TV bone had less microdamage than low BV/TV bone under post- but not pre-yield loading. Microdamage under both loading conditions showed significant correlations with microarchitecture and BV/TV, but the key predictor was structure model index (SMI). As SMI increased (more trabecular rods), microdamage morphology became crack-like. Thus, low BV/TV and increased SMI have strong influences on microdamage accumulation in bone through altered initiation.

Morphological analysis of bone dynamics and metabolic bone disease. Pathophisiology of Microdamage

Microdamage, small crack in bone, is a product of bone fatigue. Burden of microdamage in vivo bone is determined by balance of generation and repair of microdamage. It has been reported that aging, bone loss, coarse osteocyte network, reduced bone remodeling cause accumulation of microdamage in bone. It is suspected that insufficiency fractures of subtrochanteric femur in patients under long term bisphophonate treatment are caused by severely suppressed bone turnover.

Microdamage Accumulation Changes According to Animal Mass: An Intraspecies Investigation

The fatigue life of a structure is also influenced by its size. Statistically, a bone from a large animal is expected to bear a higher risk of stress fracture if compared to the same bone from a small animal of the same species. This is not documented in the dog, where individuals can have a 40 times difference in body mass. We investigated the effect of body size on cortical bone microdamage accumulation, cortical microstructural organization (porosity, osteon area, and osteocyte lacunar density), and turnover in dogs with a wide body mass range. The aim was to understand and mathematically model how the bone tissue copes with the microdamage accumulation linked to body mass increase. Calcified transverse cortical sections of 18 canine radii of remarkably different size were examined by means of a standard bulk-staining technique and histomorphometric standard algorithms. Relationships between the investigated histomorphometric variables age, sex and mass were analyzed by general linear multivariate models and exponential equations. Type and location of microdamage and bone turnover were not influenced by body mass. Gender did not influence any parameter. Age influenced bone turnover and activation frequency. Microcrack density was influenced by bone mass. Bones had a similar microstructural organization within the same species regardless of the subject's dimension. Microdamage accumulation is inversely related to bone mass, whereas bone turnover is mass-invariant. We theorize a mass-related change in the bone fracture toughness targeted to reach an optimal unique dimensionless curve for fatigue life.

Effect of mineral–collagen interfacial behavior on the microdamage progression in bone using a probabilistic cohesive finite element model

The interactions between mineral and collagen phases in the ultrastructural level play an important role in determining the mechanical properties of bone tissue. Three types of mineral–collagen interaction (i.e., ionic interactions, hydrogen/van der Waals bonds, and van der Waals/viscous shear in opening/sliding mode, respectively) have been simulated in this study, using cohesive zone-modeling techniques. Considering the inhomogeneity of bone, a probabilistic failure analysis approach has been also employed to account for the effect of mineral–collagen interfacial behavior on microdamage accumulation in lamellar bone tissues. The results of this study suggested that different interfacial behaviors cause different types of microdamage accumulation. The ionic interactions between the mineral and collagen phases lead to the formation of linear microcracks, while the van der Waals/viscous shear interactions may facilitate the formation of diffuse damage. In the case of hydrogen/van der Waals bonds, a transitional behavior of microdamage accumulation in bone was observed. The findings of this study may help in understanding the mechanisms of mineral–collagen interactions and its effects on the failure mechanism of bone.

Contrast-enhanced micro-computed tomography of fatigue microdamage accumulation in human cortical bone

Conventional methods used to image and quantify microdamage accumulation in bone are limited to histological sections, which are inherently invasive, destructive, two-dimensional, and tedious. These limitations inhibit investigation of microdamage accumulation with respect to volumetric spatial variation in mechanical loading, bone mineral density, and microarchitecture. Therefore, the objective of this study was to investigate non-destructive, three-dimensional (3-D) detection of microdamage accumulation in human cortical bone using contrast-enhanced micro-computed tomography (micro-CT), and to validate micro-CT measurements against conventional histological methods. Unloaded controls and specimens loaded in cyclic uniaxial tension to a 5% and 10% reduction in secant modulus were labeled with a precipitated BaSO 4 stain for micro-CT and basic fuchsin for histomorphometry. Linear microcracks were similarly labeled by BaSO 4 and basic fuchsin as shown by backscattered electron microscopy and light microscopy, respectively. The higher X-ray attenuation of BaSO 4 relative to the bone extracellular matrix provided enhanced contrast for the detection of damage that was otherwise not able to be detected by micro-CT prior to staining. Therefore, contrast-enhanced micro-CT was able to nondestructively detect the presence, 3-D spatial location, and accumulation of fatigue microdamage in human cortical bone specimens in vitro. Microdamage accumulation was quantified on segmented micro-CT reconstructions as the ratio of BaSO 4 stain volume (SV) to total bone volume (BV). The amount of microdamage measured by both micro-CT (SV/BV) and histomorphometry (Cr.N, Cr.Dn, Cr.S.Dn) progressively increased from unloaded controls to specimens loaded to a 5% and 10% reduction in secant modulus ( p < 0.001). Group means for micro-CT measurements of damage accumulation were strongly correlated to those using histomorphometry ( p < 0.05), validating the new methods. Limitations of the new methods in the present study included that the precipitated BaSO 4 stain was non-specific and non-biocompatible, and that micro-CT measurements exhibited greater variability compared to conventional histology. Nonetheless, contrast-enhanced micro-CT enabled non-destructive imaging and 3-D spatial information, which are not possible using conventional histological methods.

Collagen mutation causes changes of the microdamage morphology in bone of an OI mouse model

Previous studies have postulated that ultrastructural changes may alter the pattern and capacity of microdamage accumulation in bone. Using an osteogenesis imperfecta (OI) mouse model, this study was performed to investigate the correlation of collagen mutation with the microdamage morphology and the associated brittleness of bone. In this study, femurs from mild OI and wild type mice were fatigued under four-point bending to create microdamage in the specimens. Then, the microdamage morphology of these specimens was examined using the bulk-staining technique with basic fuchsin. Similar with the results of previous studies, it was observed that linear microcracks were formed more easily in compression, whereas diffuse damage was induced more readily in tension for both wild-type and mild-type mice. However, less diffuse damage was found in the tensile side of mild OI mouse femurs (collagen mutation) compared with those of wild type mice, showing that the microdamage morphology is correlated to the brittleness of bone. The results of this study provide direct evidence that supports the prediction made by the previous numerical simulation studies, suggesting that microdamage morphology in bone is significantly correlated with the integrity of the collagen phase.

Teriparatide Reduces Bone Microdamage Accumulation in Postmenopausal Women Previously Treated With Alendronate

Suppression of bone turnover by bisphosphonates is associated with increased bone microdamage accumulation in animal models. Our objective was to study the effects of teriparatide treatment on changes in microdamage accumulation at the iliac crest in previously treatment-naïve patients or in those switched from alendronate to teriparatide. Sixty-six postmenopausal women with osteoporosis (mean age, 68.0 yr; and mean BMD T-score of -2.8 at lumbar spine and -1.7 at total hip; 62% with prevalent fractures) entered this prospective, nonrandomized study and started with 24-mo 20 microg/d subcutaneous teriparatide treatment in monotherapy: 38 patients stopped previous alendronate treatment (10 mg/d or 70 mg/wk for a mean duration of 63.6 mo) and switched to teriparatide, whereas 28 were previously treatment naïve. Thirty-one paired biopsies with two intact cortices were collected and analyzed for microstructure and microdamage accumulation at baseline and after 24 mo of teriparatide administration. After 24 mo of teriparatide treatment, crack density (Cr.Dn), crack surface density (Cr.S.Dn), and crack length (Cr.Le) were decreased in previously alendronate-treated patients, whereas only Cr.Le was reduced in former treatment-naïve patients. Patients with lower initial femoral neck BMD also showed a higher reduction of microdamage accumulation. Better bone microarchitecture correlated positively, whereas bone turnover markers and age did not correlate with reduced microdamage accumulation on teriparatide. In conclusion, teriparatide reduces microdamage accumulation in the iliac crest of patients previously treated with alendronate. There is insufficient evidence to suggest that age or bone turnover would be associated with this change.