Bone Response Research Articles

A 20-week exercise program improved total body and legs bone mineral density in children with overweight or obesity: The ActiveBrains randomized controlled trial

ObjectivesThe aim of this study was to investigate the effect of a 20-week exercise program on bone mineral parameters in children with overweight or obesity. DesignRandomized controlled trial. MethodsThis study took part from November 21, 2014, to June 30, 2016, in Granada, Spain. A secondary analysis of this parallel-group randomized controlled trial was performed with 77 children with overweight or obesity (9.9 ± 1.2, 65 % boys) who were randomly allocated to exercise or control group. All participants received lifestyle recommendations. The control group continued their usual routines, whereas the exercise group attended a minimum of 3 supervised 90-minute sessions/week of aerobic plus resistance training for 20 weeks. A whole-body scan by dual-energy X-ray absorptiometry was carried out to obtain body composition at total body less head, arms, lumbar spine, pelvis, and legs. ResultsParticipants in the exercise group acquired significantly higher total body aBMD (mean z-score [95 % confidence intervals, CI], 0.607 [0.522–0.692]) compared with the participants in the control group (mean z-score, 0.472 [0.388–0.556]); difference between groups, 0.135 standard deviations [95 % CI 0.015–0.255], and legs aBMD (mean z-score, 0.629 [0.550–0.708]); control group (mean z-score, 0.518 [0.440–0.596]); difference between groups, 0.111 [0.001–0.222]; all p < 0.05. There were no significant differences between exercise group and control group at the remaining evaluated regions (p > 0.05). ConclusionsA 20-week non-specifically bone-targeted exercise program induced a small, yet significant, improvement on total body and legs aBMD in children with overweight or obesity. Future studies should investigate the interaction of weight status in the bone response to exercise programs. Trial registrationProspectively registered in ClinicalTrials.gov Identifier: NCT02295072.

Treatment of bone infections in children in low-income countries – A practical guideline based on clinical cases

In low-income countries (LIC), the management of bone infections is a huge challenge. A high number of patients are in the pediatric age group. Children and adolescents exhibit good bone healing potential offering treatment options that mainly rely on the biological response of the infected bone. The purpose of this article is to highlight treatment options for these patients in LIC, which is based on clinical cases that illustrate the principles of the treatment, focusing on bone reaction and healing potential.First, identification of emergency cases is of importance. Sepsis of the patient due to bone infections is a life-threatening disease that requires immediate surgical attention with abscess incision. It should be tailored to the surgeon's experience and local conditions to avoid unwanted complications, such as excessive bleeding, fracture or bone loss.In non-septic patients, uncomplicated cases should be distinguished from complicated cases as the first might often require only abscess incision, particularly in small children, without any other major surgical intervention.Biomechanical stability and bone formation capacity, soft tissue conditions and joint involvement are decisive factors differentiating uncomplicated from complicated cases. Central treatment column is the immobilization of the infected bone with simple methods, such as plaster of Paris, braces or external fixation. This is intended to provide sufficient stability to allow for new bone formation that subsequently downsizes the infection site and that can bridge previously infected non-union sites or bone defects. In most cases, antibiotic treatment is not performed as antibiotics are not available or affordable.Severe soft tissue defects remain a major challenge as microvascular surgical experience is often required for reliable coverage, for which referral to one of the very few specialized centers is recommended. Major bone defects should also be treated in centers with sufficient expertise for bone reconstruction procedures. Regular follow-ups are important to ensure healing and to avoid aggravation of the disease.Encouraging success rates can be achieved by these treatment principles. However, it should not be forgotten that poverty in these countries, including limited access to health care, remains one of the world's most important problems.

Impact of local delivery of allogeneic chondrocytes on the biological response and healing of the sternum bones after sternotomy

Median sternotomy is the surgical method of choice for many procedures where one of the main problems is the long post-operative wound healing process leading to sternal dehiscence and the development of infection. This leads to prolonged hospital stay and increased mortality due to post-operative complications. A promising solution seems to be the use of allogeneic chondrocytes for wound treatment, whose properties in the field of cartilage reconstruction are widely used in medicine, mainly in orthopedics. In the present study, we investigated the effect of local delivery of allogeneic chondrocytes on the biological response and healing of the sternum after sternotomy. We optimized the culture conditions for the isolated chondrocytes, which were then applied to the sternal incision wound. Chondrocytes in the culture were assessed on the basis of the presence of chondrocyte-specific genes: Sox9, Aggrecan and Collagen II. In turn, the histopathological and immunohistochemical evaluation was used to assess the safety of implantation. In our work, we demonstrated the possibility of obtaining a viable culture of chondrocytes, which were successfully introduced into the sternal wound after sternotomy. Importantly, implantation of allogeneic chondrocytes showed no significant side effects. The obtained results open new possibilities for research on the use of allogeneic chondrocytes in the process of accelerating wound healing after median sternotomy.

Sexual dimorphism of the synovial transcriptome underpins greater PTOA disease severity in male mice following joint injury

Osteoarthritis is a disease with sex-dependent prevalence and severity in both humans and animal models. We sought to elucidate sex differences in synovitis, mechanical sensitization, structural damage, bone remodeling, and the synovial transcriptome in the anterior cruciate ligament rupture (ACLR) mouse model of post-traumatic osteoarthritis (PTOA). Male and female 12-week-old C57/BL6J mice were randomized to Sham or noninvasive ACLR with harvests at 7d or 28d post-ACLR (n=9 per sex in each group - Sham, 7d ACLR, 28d ACLR). Knee hyperalgesia, mechanical allodynia, and intra-articular MMP activity (via intravital imaging) were measured longitudinally. Trabecular and subchondral bone remodeling and osteophyte formation were assessed by µCT. Histological scoring of PTOA and synovitis and anti-MMP13 immunostaining were performed. NaV1.8-Cre;tdTomato mice were used to document localization and sprouting of nociceptors. Bulk RNA-seq of synovium in Sham, 7d, and 28d post-ACLR, and contralateral joints (n=6 per group per sex) assessed injury-induced and sex-dependent gene expression. Male mice exhibited more severe joint damage at 7d and 28d and more severe synovitis at 28d, accompanied by 19% greater MMP activity, 8% lower knee hyperalgesia threshold, and 43% lower hindpaw withdrawal threshold in injured limbs compared to female injured limbs. Females had injury-induced catabolic responses in trabecular and subchondral bone, whereas males exhibited 133% greater normalized osteophyte volume relative to females and sclerotic remodeling of trabecular and subchondral bone. NaV1.8+ nociceptor sprouting in subchondral bone and medial synovium was induced by injury and comparable between sexes. RNA-seq of synovium demonstrated similar injury-induced transcriptomic programs between the sexes at 7d, but only female mice exhibited a transcriptomic signature indicative of synovial inflammatory resolution by 28d, whereas males had persistent pro-inflammatory, pro-fibrotic, pro-neurogenic, and pro-angiogenic gene expression. Male mice exhibited more severe overall joint damage and pain behavior after ACLR, which was associated with persistent activation of synovial inflammatory, fibrotic, and neuroangiogenic processes, implicating persistent synovitis in driving sex differences in murine PTOA.

The effect of medical biodegradable magnesium alloy in vivo degradation and bone response in a rat femur model with long-term fixation.

It is of great significance to understand the effect of the different corrosion behaviors of magnesium (Mg) alloys manufactured using different casting methods and implanted with different methods on the long-term implantation to expand the application of Mg-based biomedical implants. The effects of four different casting and rolling speeds on the microstructure of an Mg-rare earth (Mg-Re) alloy were analyzed using electron backscatter diffraction (EBSD). Four Mg alloys were obtained using vertical two-roll casting (TRC) at 10m/min, 16m/min, 24m/min, and 30m/min, and their microstructure, corrosion behavior and bone reaction in vivo were studied. The corrosion resistance of the alloy increases with an increase in casting speed and finer grain size of the cast-rolled parts. The Mg-Re alloys with TRC-10m/min and TRC-30m/min were selected for animal experiments. The two Mg alloys were made into metal rods and inserted into the rat femur to simulate the effect of Mg-Re on femoral healing under an injury condition. The rods were implanted for a long time to judge the effects of the Mg-Re alloy on the body. The TRC-30m/min implants obtained highly mature new bone tissue in the case of bone injury. The in vivo experiments showed that the corrosion resistance of the TRC-30m/min implant was better than that of the TRC-10m/min implant. After 32 weeks of implantation, there were no pathological changes in the liver, heart, or kidney of rats in the TRC-30m/min group, and the cell structure was normal.

Mg-Zn-Ca Alloy (ZX00) Screws Are Resorbed at a Mean of 2.5 Years After Medial Malleolar Fracture Fixation: Follow-up of a First-in-humans Application and Insights From a Sheep Model.

In the ongoing development of bioresorbable implants, there has been a particular focus on magnesium (Mg)-based alloys. Several Mg alloys have shown promising properties, including a lean, bioresorbable magnesium-zinc-calcium (Mg-Zn-Ca) alloy designated as ZX00. To our knowledge, this is the first clinically tested Mg-based alloy free from rare-earth elements or other elements. Its use in medial malleolar fractures has allowed for bone healing without requiring surgical removal. It is thus of interest to assess the resorption behavior of this novel bioresorbable implant. (1) What is the behavior of implanted Mg-alloy (ZX00) screws in terms of resorption (implant volume, implant surface, and gas volume) and bone response (histologic evaluation) in a sheep model after 13 months and 25 months? (2) What are the radiographic changes and clinical outcomes, including patient-reported outcome measures, at a mean of 2.5 years after Mg-alloy (ZX00) screw fixation in patients with medial malleolar fractures? A sheep model was used to assess 18 Mg-alloy (ZX00) different-length screws (29 mm, 24 mm, and 16 mm) implanted in the tibiae and compared with six titanium-alloy screws. Micro-CT was performed at 13 and 25 months to quantify the implant volume, implant surface, and gas volume at the implant sites, as well as histology at both timepoints. Between July 2018 and October 2019, we treated 20 patients with ZX00 screws for medial malleolar fractures in a first-in-humans study. We considered isolated, bimalleolar, or trimalleolar fractures potentially eligible. Thus, 20 patients were eligible for follow-up. However, 5% (one patient) of patients were excluded from the analysis because of an unplanned surgery for a pre-existing osteochondral lesion of the talus performed 17 months after ZX00 implantation. Additionally, another 5% (one patient) of patients were lost before reaching the minimum study follow-up period. Our required minimum follow-up period was 18 months to ensure sufficient time to observe the outcomes of interest. At this timepoint, 10% (two patients) of patients were either missing or lost to follow-up. The follow-up time was a mean of 2.5 ± 0.6 years and a median of 2.4 years (range 18 to 43 months). In this sheep model, after 13 months, the 29-mm screws (initial volume: 198 ± 1 mm 3 ) degraded by 41% (116 ± 6 mm 3 , mean difference 82 [95% CI 71 to 92]; p < 0.001), and after 25 months by 65% (69 ± 7 mm 3 , mean difference 130 [95% CI 117 to 142]; p < 0.001). After 13 months, the 24-mm screws (initial volume: 174 ± 0.2 mm 3 ) degraded by 51% (86 ± 21 mm 3 , mean difference 88 [95% CI 52 to 123]; p = 0.004), and after 25 months by 72% (49 ± 25 mm 3 , mean difference 125 [95% CI 83 to 167]; p = 0.003). After 13 months, the 16-mm screws (initial volume: 112 ± 5 mm 3 ) degraded by 57% (49 ± 8 mm 3 , mean difference 63 [95% CI 50 to 76]; p < 0.001), and after 25 months by 61% (45 ± 10 mm 3 , mean difference 67 [95% CI 52 to 82]; p < 0.001). Histologic evaluation qualitatively showed ongoing resorption with new bone formation closely connected to the resorbing screw without an inflammatory reaction. In patients treated with Mg-alloy screws after a mean of 2.5 years, the implants were radiographically not visible in 17 of 18 patients and the bone had homogenous texture in 15 of 18 patients. No clinical or patient-reported complications were observed. In this sheep model, Mg-alloy (ZX00) screws showed a resorption to one-third of the original volume after 25 months, without eliciting adverse immunologic reactions, supporting biocompatibility during this period. Mg-alloy (ZX00) implants were not detectable on radiographs after a mean of 2.5 years, suggesting full resorption, but further studies are needed to assess environmental changes regarding bone quality at the implantation site after implant resorption. The study demonstrated successful healing of medial malleolar fractures using bioresorbable Mg-alloy screws without clinical complications or revision surgery, resulting in pain-free ankle function after 2.5 years. Future prospective studies with larger samples and extended follow-up periods are necessary to comprehensively assess the long-term effectiveness and safety of ZX00 screws, including an exploration of limitations when there is altered bone integrity, such as in those with osteoporosis. Additional use of advanced imaging techniques, such as high-resolution CT, can enhance evaluation accuracy.

Microstructural fatigue fracture behavior of glycated cortical bone.

The current study aims to simulate fatigue microdamage accumulation in glycated cortical bone with increased advanced glycation end-products (AGEs) using a phase field fatigue framework. We link the material degradation in the fracture toughness of cortical bone to the high levels of AGEs in this tissue. We simulate fatigue fracture in 2D models of cortical bone microstructure extracted from human tibias. The results present that the mismatch between the critical energy release rate of microstructural features (e.g., osteons and interstitial tissue) can alter crack initiation and propagation patterns. Moreover, the high AGEs content through the increased mismatch ratio can cause the activation or deactivation of bone toughening mechanisms under cyclic loading. The fatigue fracture simulations also show that the lifetime of diabetic cortical bone samples can be dependent on the geometry of microstructural features and the mismatch ratio between the features. Additionally, the results indicate that the trapped cracks in cement lines in the diabetic cortical microstructure can prevent further crack growth under cyclic loading. The present findings show that alterations in the materials heterogeneity of microstructural features can change the fatigue fracture response, lifetime, and fragility of cortical bone with high AGEs contents. Cortical bone models are created from microscopy images taken from the cortical cross-section of human tibias. Increased glycation contents in the cortical bone sample can change the crack growth trajectories.

Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion.

Diabetes is a chronic metabolic disorder that can lead to diabetic myopathy and bone diseases. The etiology of musculoskeletal complications in such metabolic disorders and the interplay between the muscular and osseous systems are not well understood. Exercise training promises to prevent diabetic myopathy and bone disease and offer protection. Although the muscle-bone interaction is largely biomechanical, the muscle secretome has significant implications for bone biology. Uncoupling effects of biophysical and biochemical stimuli on the adaptive response of bone during exercise training may offer therapeutic targets for diabetic bone disease. Here, we have developed an in vitro model to elucidate the effects of mechanical strain on myokine secretion and its impact on bone metabolism decoupled from physical stimuli. We developed bone constructs using cross-linked gelatin, which facilitated osteogenic differentiation of osteoprogenitor cells. Then muscle constructs were made from fibrin, which enabled myoblast differentiation and myotube formation. We investigated the myokine expression by muscle constructs under strain regimens replicating endurance (END) and high-intensity interval training (HIIT) in hyperglycemic conditions. In monocultures, both regimens induced higher expression of Il15 and Igf1, whereas END supported more myoblast differentiation and myotube maturation than HIIT. When co-cultured with bone constructs, HIIT regimen increased Glut4 expression in muscle constructs more than END, supporting higher glucose uptake. Likewise, the muscle constructs under the HIIT regimen promoted a healthier and more matured bone phenotype than END. Under static conditions, myostatin (Mstn) expression was significantly downregulated in muscle constructs co-cultured with bone constructs compared with monocultures. Together, our in vitro co-culture system allowed orthogonal manipulation of mechanical strain on muscle constructs while facilitating bone-muscle biochemical cross-talk. Such systems can provide an individualized microenvironment that allows decoupled biomechanical manipulation, help identify molecular targets, and develop engineered therapies for metabolic bone disease. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

The Effects of Different Femoral Component Materials on Bone and Implant Response in Total Knee Arthroplasty: A Finite Element Analysis.

Due to the high stiffness of the biomaterials used in total knee arthroplasty, stress shielding can lead to decreased periprosthetic bone mineral density and bone resorption. As different materials and 3D-printed highly porous surfaces are available for knee femoral components from the industry nowadays, this study aimed to compare the effects of two same-design cruciate-retaining femoral components, made with CoCr and titanium alloy, respectively, on periprosthetic bone stresses through a finite element model of the implanted knee in order to evaluate the induced stress shielding. Moreover, the effect of the cementless highly porous surface of the titanium implant was analyzed in comparison to the cemented interface of the CoCr implant. The von Mises stresses were analyzed in different periprosthetic regions of interest of the femur with different configurations and knee flexion angles. The titanium component induced higher bone stresses in comparison with the CoCr component, mostly in the medial compartment at higher knee flexion angles; therefore, the CoCr component led to more stress shielding. The model was revealed to be effective in describing the effects of different femoral component materials on bone stress, highlighting how a cementless, highly porous titanium femoral component might lead to less stress shielding in comparison to a cemented CoCr implant with significant clinical relevance and reduced bone resorption after total knee arthroplasty.

Compressive mechanical behavior and failure of the pig bone rib and correlation to its morphological characteristics

The mechanical and failure properties of bones are well documented from a structural perspective. By contrast, less is known about those properties from the material and microstructural point of view. This study combines mechanical compression of pig bone rib slices, comprising both cortical and trabecular components, together with digital image correlation records. For monotonic loading, the three classical phases of the bone response, namely elastic, plateau/softening, and hardening are observed. The first phase is characterized by a uniform state of deformation which becomes heterogeneous in the following phases, through the appearance of well-defined domains. Failure is initiated in the trabecular bone at the interfaces between those domains, where the prevailing heterogeneous deformation indicates the operation of shear or uniaxial strain components. From a microstructural point of view, using micro-CT (computed tomography) it was noticed that sub-regions with relatively combined low BV/TV (bone material volume divided by total volume) and anisotropy, whose structure is oriented perpendicularly to the loading direction, are prone to failure at the interface between heterogeneously deforming domains. A globally similar behavior is reported for aluminum foams without cortical components.Repeated loading cycles reveal a previously un-noticed response of the bone, consisting of elastic shakedown without ratcheting, with diminishing hysteretic load-displacement loops, which indicate that most of the damage is achieved during the first loading cycle.The observations reported in this paper are believed to provide important physical evidence to be included in numerical models at the verification and/or validation stages.

Surface Corrosion from Implant–Abutment Couplings with Different Connection Designs Influences Osteoblasts’ Function: A Novel Technique

The improved peri-implant bone response demonstrated when utilizing the platform-switching concept may result from the reduced levels of metal ions released from implant–abutment surfaces to the surrounding tissues. These corrosion products may play a major role in crestal bone remodeling around dental implants. This study evaluated the effect of different implant–abutment couplings (platform-matched vs. platform-switched) on osteoblasts’ function. Titanium alloy and cobalt–chrome alloy abutments were coupled with titanium cylinders, forming either platform-switched or platform-matched groups, and were incubated in human osteoblast cultures utilizing a novel direct-exposure technique. Viability was evaluated over 21 days using Alamar Blue assay. Apoptosis was measured after 24 h using flow cytometry. The expression of genes related to bone resorption was analysed over 21 days using a real-time quantitative polymerase chain reaction assay. Cell viability was reduced from day 4 to day 21 (p &lt; 0.05), with higher rates of early apoptosis (p &lt; 0.05) compared to the controls. Apoptosis was higher in the platform-matched groups (p &lt; 0.05). The tested genes’ expression was up-regulated after 1 and 3 days of exposure to implant–abutment couplings (p &lt; 0.05). The upregulation was more pronounced in platform-matched groups (p &lt; 0.05). Exposure of osteoblasts to implant–abutment couplings induced adverse biological responses, which were more pronounced with platform-matched couplings. These reactions might be related to the increased amounts of metal ions released from the platform-matched couplings, highlighting the possible role of corrosion products in the mediation of crestal bone loss around dental implants.

Altered Caveolin-1 Dynamics Result in Divergent Mineralization Responses in Bone and Vascular Calcification.

Though vascular smooth muscle cells adopt an osteogenic phenotype during pathological vascular calcification, clinical studies note an inverse correlation between bone mineral density and arterial mineral-also known as the calcification paradox. Both processes are mediated by extracellular vesicles (EVs) that sequester calcium and phosphate. Calcifying EV formation in the vasculature requires caveolin-1 (CAV1), a membrane scaffolding protein that resides in membrane invaginations (caveolae). Of note, caveolin-1-deficient mice, however, have increased bone mineral density. We hypothesized that caveolin-1 may play divergent roles in calcifying EV formation from vascular smooth muscle cells (VSMCs) and osteoblasts (HOBs). Primary human coronary artery VSMCs and osteoblasts were cultured for up to 28days in an osteogenic media. CAV1 expression was knocked down using siRNA. Methyl β-cyclodextrin (MβCD) and a calpain inhibitor were used, respectively, to disrupt and stabilize the caveolar domains in VSMCs and HOBs. CAV1 genetic variation demonstrates significant inverse relationships between bone-mineral density (BMD) and coronary artery calcification (CAC) across two independent epidemiological cohorts. Culture in osteogenic (OS) media increased calcification in HOBs and VSMCs. siRNA knockdown of CAV1 abrogated VSMC calcification with no effect on osteoblast mineralization. MβCD-mediated caveolae disruption led to a 3-fold increase of calcification in VSMCs treated with osteogenic media (p < 0.05) but hindered osteoblast mineralization (p < 0.01). Conversely, stabilizing caveolae by calpain inhibition prevented VSMC calcification (p < 0.05) without affecting osteoblast mineralization. There was no significant difference in CAV1 content between lipid domains from HOBs cultured in OS and control media. Our data indicate fundamental cellular-level differences in physiological and pathophysiological mineralization mediated by CAV1 dynamics. This is the first study to suggest that divergent mechanisms in calcifying EV formation may play a role in the calcification paradox. The online version contains supplementary material available at 10.1007/s12195-023-00779-7.

Simulation of ultrasonically induced electrical potentials in bone.

Low-intensity pulsed ultrasound treatment is known to shorten the healing period of bone fractures by 30%-40%, but the initial mechanism of the healing process remains unknown. One possible mechanism is related to the piezoelectricity of bone. However, the complex geometry of bones results in inherent challenges to evaluating electric fields induced therein. Therefore, in this study, we investigate the piezoelectric responses of bones by using simulations to study the wave propagation and induced potentials in bone, according to the piezoelectric finite-difference time-domain (PE-FDTD) method. First, we verify the suitability of the PE-FDTD method by comparing the simulated electric field results with the experimental data obtained by an ultrasound receiver using bone as the piezoelectric element. Next, ultrasound irradiation into a real bone model (the radius of a 66-year-old woman) is simulated at different incident angles. At normal incidence and off-axis incidence (45°), the maximum electric field strength was 4.3 and 5.6 mV/cm, respectively. We also present evidence of significant shear wave contribution to the induced potential. The results of this study confirm the existence of ultrasonically induced potentials in heterogenous bones with complex shapes, equal in magnitude to potentials generated in electrically stimulated bone healing.

Palaeoecological deductions from osteohistology.

Palaeoecological deductions are vital for understanding the evolution and diversification of species within prehistoric environments. This review highlights the multitude of ways in which the microanatomy and microscopic structure of bones enables palaeoecological deductions. The occurrence of growth marks in bones is discussed, and their usefulness in deducing the ontogenetic status and age of individuals is considered, as well as how such marks in bones permit the assessment of the growth dynamics of individuals and species. Here osteohistology is shown to provide insight into the structure of past populations, as well as ecological relationships between individuals. In addition, the response of bones to trauma, disease and moulting is considered. Finally, I explore how osteohistology can give insight into ecomorphological adaptations, such as filter feeding, probe feeding and saltatorial locomotion. Methodological advances in three-dimensional microtomography and synchrotron scanning bodes well for future studies in osteohistology and despite some compromises in terms of tissue identity, circumvents the crucial issue of destructive analyses.

Review of the Mechanism of Action and Use of Bisphosphonates in Horses

Bisphosphonates are a group of drugs that can reduce bone resorption by incorporating into the crystal structure of exposed hydroxyapatite where they are taken up by osteoclasts. Bisphosphonates have several other mechanisms of action including reducing pain and inflammation and altering macrophage function. There are two types of bisphosphonates - nitrogenous and non-nitrogenous, the latter of which is used in horses. This article provides a literature-based review of the proposed mechanisms of action and therapeutic uses of bisphosphonates including a brief review of bone response to disease. A review of the literature available in horses including safety data and current rules and regulations is also provided.

The application of an isotropic crushable foam model to predict the femoral fracture risk.

For biomechanical simulations of orthopaedic interventions, it is imperative to implement a material model that can realistically reproduce the nonlinear behavior of the bone structure. However, a proper material model that adequately combines the trabecular and cortical bone response is not yet widely identified. The current paper aims to investigate the possibility of using an isotropic crushable foam (ICF) model dependent on local bone mineral density (BMD) for simulating the femoral fracture risk. The elastoplastic properties of fifty-nine human femoral trabecular cadaveric bone samples were determined and combined with existing cortical bone properties to characterize two forms of the ICF model, a continuous and discontinuous model. Subsequently, the appropriateness of this combined material model was evaluated by simulating femoral fracture experiments, and a comparison with earlier published results of a softening Von-Mises (sVM) material model was made. The obtained mechanical properties of the trabecular bone specimens were comparable to previous findings. Furthermore, the ultimate failure load predicted by the simulations of femoral fractures was on average 79% and 90% for the continuous and discontinuous forms of the ICF model and 82% of the experimental value for the sVM material model. Also, the fracture locations predicted by ICF models were comparable to the experiments. In conclusion, a nonlinear material model dependent on BMD was characterized for human femoral bone. Our findings indicate that the ICF model could predict the femoral bone strength and reproduce the variable fracture locations in the experiments.

Comparison between bone–implant interfaces of microtopographically modified zirconia and titanium implants

The aim of this study was to investigate the surface characteristics and evaluate the bone–implant interfaces of injection molded zirconia implants with or without surface treatment and compare them with those of conventional titanium implants. Four different zirconia and titanium implant groups (n = 14 for each group) were prepared: injection-molded zirconia implants without surface treatment (IM ZrO2); injection-molded zirconia implants with surface treatment via sandblasting (IM ZrO2-S); turned titanium implants (Ti-turned); and titanium implants with surface treatments via sandblasting with large-grit particles and acid-etching (Ti-SLA). Scanning electron microscopy, confocal laser scanning microscopy, and energy dispersive spectroscopy were used to assess the surface characteristics of the implant specimens. Eight rabbits were used, and four implants from each group were placed into the tibiae of each rabbit. Bone-to-implant contact (BIC) and bone area (BA) were measured to evaluate the bone response after 10-day and 28-day healing periods. One-way analysis of variance with Tukey’s pairwise comparison was used to find any significant differences. The significance level was set at α = 0.05. Surface physical analysis showed that Ti-SLA had the highest surface roughness, followed by IM ZrO2-S, IM ZrO2, and Ti-turned. There were no statistically significant differences (p > 0.05) in BIC and BA among the different groups according to the histomorphometric analysis. This study suggests that injection-molded zirconia implants are reliable and predictable alternatives to titanium implants for future clinical applications.

Icariin, a phytoestrogen, exerts rapid estrogenic actions through crosstalk of estrogen receptors in osteoblasts.

Icariin, a flavonoid glycoside derived from Epimedium brevicornum Maxim, exerts bone protective effects via estrogen receptors (ERs). This study aimed to investigate the role of ER-α66, ER-α36, and GPER in bone metabolism in osteoblasts following treatment with icariin. Human osteoblastic MG-63 cells and osteoblast-specific ER-α66 knockout mice were employed. The ERs crosstalk in the estrogenic action of icariin was evaluated in ER-α66-negative human embryonic kidney HEK293 cells. Icariin, like E2, regulated ER-α36 and GPER protein expression in osteoblasts by downregulating them and upregulating ER-α66. ER-α36 and GPER suppressed the actions of icariin and E2 in bone metabolism. However, the in vivo administration of E2 (2 mg/kg/day) or icariin (300 mg/kg/day) restored bone conditions in KO osteoblasts. ER-α36 and GPER expression increased significantly and rapidly activated and translocated in KO osteoblasts after treatment with E2 or icariin. ER-α36 overexpression in KO osteoblasts further promoted the OPG/RANKL ratio induced by E2 or icariin treatment. This study showed icariin and E2 elicit rapid estrogenic responses in bone through recruiting ER-α66, ER-α36, and GPER. Notably, in osteoblasts lacking ER-α66, ER-α36, and GPER mediate the estrogenic effects of icariin and E2, while in intact osteoblasts, ER-α36 and GPER act as negative regulators of ER-α66.

Exercise training modifies the bone and endocrine response to graded reductions in energy availability in skeletally mature female rodents.

Reductions in energy availability leading to weight loss can induce loss of bone and impact important endocrine regulators of bone integrity. We sought to elucidate whether endurance exercise (EX) can mitigate bone loss observed in sedentary (SED) skeletally mature rodents subjected to graded energy deficits. Female virgin rats (n=84, 5-mo-old; 12/group) were randomized to baseline controls and either sedentary (SED) or exercise (EX) conditions, and within each exercise status to adlib-fed (ADLIB), or moderate (MOD) or severe (SEV) energy restriction diets for 12 weeks. Rats assigned to EX groups performed treadmill running to increase weekly energy expenditure by 10%. MOD-ER-SED, SEV-ER-SED, MOD-ER-EX and SEV-ER-EX were fed modified AIN93M diets with 20%, 40% 10%, and 30% less energy content, respectively, with 100% of all other nutrients provided. Energy availability (EA) was effectively reduced by ~14% and ~30% in the MOD-ER and SEV-ER groups, respectively. MOD-ER for 12 weeks resulted in few negative impacts on bone and, except for serum leptin in MOD-ER-SED rats, no significant changes in endocrine factors. By contrast, SEV-ER in SED rats resulted in significantly lower total body and femoral neck bone mass, and reduced serum estradiol, IGF-1 and leptin. EX rats experiencing the same reduction in energy availability as SEV-ER-SED exhibited higher total body mass, lean mass, total BMC, and higher serum IGF-1 at the end of 12 weeks. Bone mechanical properties at 3 bone sites (mid-femur, distal femur, femoral neck) were minimally impacted by ER but positively affected by EX. These findings indicate that combining increased EX energy expenditure with smaller reductions in energy intake to achieve a targeted reduction in EA provides some protection against loss of bone mass and lean mass in skeletally mature female rats, likely due to better preservation of circulating IGF-1, and that bone mechanical integrity is not significantly degraded with either moderate or severe reduced EA.

Elasticity and material anisotropy of lamellar cortical bone in adult bovine tibia characterized via AFM nanoindentation

The research focuses on the evaluation of the mechanical properties of osteonal cortical bone at the lamellar level. Elastic properties of the mid-diaphysis region of the bovine tibia are investigated via cantilever-based nanoindentation at the submicron length scale utilizing Atomic Force Microscopy, where the force-displacement curves are used for the elastic assessment using the Derjaguin-Muller-Toropov model to calculate indentation modulus. Variations of the modulus and the directional mechanical response of the osteonal bone at different distances from the Haversian canal are investigated. Additionally, the effects of demineralization on the indentation modulus are discussed. It was found that in the axial direction, the first and last untreated thick lamella layers show a significant indentation modulus difference compared to all other layers (4.26 ± 0.4 and 4.6 ± 0.3 GPa vs ∼3.5 GPa). On the other hand, the indentation modulus of transverse thick lamella layers shows a periodic variation between ∼3 ± 0.7 GPa and ∼4 ± 0.3 GPa from near the Haversian canal to near the interstitial bone. A periodic variation in the anisotropy ratio was found. Mineral content was quantified via energy-dispersive X-ray microanalysis at different levels of mineralization and shows a positive correlation with the indentation modulus.