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Osteoporosis (OP) represents a substantial public health issue and is associated with increasing rates of morbidity and mortality. It is characterized by reduced bone mineral density, deterioration of bone tissue quality, disruption of the microarchitecture of bones, and compromised bone strength. These changes may be attributed to the following factors: intercellular communication between osteoblasts and osteoclasts; imbalanced bone remodeling; imbalances between osteogenesis and adipogenesis; imbalances in hormonal regulation; angiogenesis; chronic inflammation; oxidative stress; and intestinal microbiota imbalances. Treating a single aspect of the disease is insufficient to address its multifaceted nature. In recent decades, traditional Chinese medicine (TCM) has shown great potential in the treatment of OP, and the therapeutic effects of Chinese patent drugs and Chinese medicinal herbs have been scientifically proven. TCMs, which contain multiple components, can target the diverse pathogeneses of OP through a multitargeted approach. Herbs such as XLGB, JTG, GSB, Yinyanghuo, Gusuibu, Buguzhi, and Nvzhenzi are among the TCMs that can be used to treat OP and have demonstrated promising effects in this context. They exert their therapeutic effects by targeting various pathways involved in bone metabolism. These TCMs balance the activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells), and they exhibit anti-inflammatory, immunomodulatory, anti-oxidative, and estrogen-like functions. These multifaceted mechanisms underlie the efficacy of these herbs in the management and treatment of OP. Herein, we examine the efficacy of various Chinese herbs and Chinese patent drugs in treating OP by reviewing previous clinical trials and basic experiments, and we examine the potential mechanism of these therapies to provide evidence regarding the use of TCM for treating OP.

Background: Cortical bone analysis has been investigated at the macroscopic level with mechanical tests and imaging techniques, but few studies have been done at the microscopic level (osteons). The purpose of this study is to measure the elastic modulus of thick lamellae of osteons exhibiting different degrees of mineralization. This study aims to provide clinicians with a better understanding of bone remodeling and help in assessing the different stages of bone healing. Methods: Six femoral human samples (5 mm × 5 mm × 5 mm) were cut transversally along the length of a human femur. Scanning electron micrographs were produced to reflect the composition of the microstructure. Three types of osteons were selected: white (high mineralization), gray (intermediate mineralization), and dark (low mineralization) osteons. Nanoindentation tests were performed on three locations of the thick lamella located in the middle of each osteon. The mechanical test induced three holdings and unloadings with a constant holding of 10 s. The maximal force was 2500 μN, which induced a maximal depth of about 400 nm. Results: Elastic modulus (E) and hardness (H) for the white (N = 61), gray (N = 17), and dark (N = 39) osteons were E_white = 21.30 GPa ± 3.00 GPa and H_white = 0.55 GPa ± 0.15 GPa, E_gray = 19.27 GPa ± 1.78 GPa and H_gray = 0.41 GPa ± 0.09 GPa, and E_dark = 12.95 GPa × 2.66 GPa and H_dark = 0.30 GPa ± 0.10 GPa, respectively. The variation of elastic properties within a lamella was approximately 2.6 GPa, depending on the level of mineralization. Conclusions: These results demonstrate the inhomogeneity of the lamella, suggesting that both the orientation of collagen fibers and the degree of mineralization may vary within the lamella. Our study shows a large range of elastic properties and hardness, reflecting different degrees of osteon mineralization.

Through the development of TGFβ-inducible early gene-1 (TIEG1) knockout (KO) mice, we have demonstrated that TIEG1 plays an important role in osteoblast-mediated bone mineralization, and in bone resistance to mechanical strain. To further investigate the influence of TIEG1 in skeletal maintenance, osteocytes were analyzed by transmission electron microscopy using TIEG1 KO and wild-type mouse femurs at one, three and eight months of age. The results revealed an age-dependent change in osteocyte surface and density, suggesting a role for TIEG1 in osteocyte development. Moreover, there was a decrease in the amount of hypomineralized bone matrix surrounding the osteocytes in TIEG1 KO mice relative to wild-type controls. While little is known about the function or importance of this hypomineralized bone matrix immediately adjacent to osteocytes, this study reveals significant differences in this bone microenvironment and suggests that osteocyte function may be compromised in the absence of TIEG1 expression.

Orthodontic appliances induce bone remodeling by acting as systems of forces and moments onto the crown of a tooth. These forces and moments should be within low physiological range to avoid resorptions. This is often realized by the use of superelastic wires or springs. For improving the design of these devices, we use the Finite Element Method (FEM) to simulate the behavior of teeth and devices. Great advantages were made in simulating the bone remodeling during the movement of a single tooth. Due to the lack of element types implementing hysteresis in the stress/strain graph, it is difficult to simulate the non-linear material properties of the superelastic wires made of NiTi-alloys. For this reason, we integrated the measurement of the devices into the calculation of the tooth movement. In this study we simulate the orthodontic long-term tooth movement of the canine retraction, using the new hybrid retraction spring.⁵ This spring allows a well-defined adjustment of the acting force system. The result of this study provides an example of how this approach can be used for future comparison of different orthodontic devices.

Weightlessness environment (also microgravity) during the exploration of space is the major condition which must be faced by astronauts. One of the most serious adverse effects on astronauts is the weightlessness-induced bone loss due to the unbalanced bone remodeling. Bone remodeling of human beings has evolved during billions of years to make bone tissue adapt to the gravitational field of Earth (1g) and maintain skeleton structure to meet mechanical loading on Earth. However, under weightlessness environment the skeleton system no longer functions against the pull of gravity, so there is no necessity to keep bone strong enough to support the body's weight. Therefore, the balance of bone remodeling is disrupted and bone loss occurs, which is extremely deleterious to an astronaut's health during long-term spaceflight. Bone remodeling is mainly orchestrated by bone mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Here, we review how these bone cells respond to microgravity environment.

Bone remodeling is defined as the coupling of bone formation and resorption on the bone surface. Numerical simulations of the remodeling in cancellous bone were performed to reproduce the change in the trabecular structure. Assuming that the formation/resorption in cancellous bone could be generated on the trabecular surface, where the local stress under the mechanical load was larger/smaller than the averaged stress on the surrounding surface, voxel trabecular elements in a numerical model of bovine cancellous bone were added/removed. An ultrasound continuous wave in the frequency range 0.1–1.0 MHz was applied as the mechanical load, and then, the local stress was analyzed using a finite-difference time-domain (FDTD) method. Using the remodeling simulations, both changes in the trabecular structure could be reproduced with decreasing and increasing porosity. In changes, the trabecular elements and the pore spaces became strongly oriented in the direction of ultrasound propagation. In addition, the remodeling simulations indicated that both bone formation and resorption lessened as the frequency increased.

This work aims to evaluate the prediction efficiency of a recently developed numerical approach in the mandible bone tissue remodeling process. The remodeling algorithm, seeking the minimization of the strain energy density, includes a phenomenological anisotropic material law capable of predicting the bone tissue mechanical properties based on the bone apparent density. The key factor of the proposed numerical approach is the inclusion of a flexible and efficient meshless method, which is used to obtain the strain energy density field. The inclusion of this advance discretization technique in the process is an asset since meshless methods produce smoother and more accurate strain energy density fields when compared with other numerical approaches. The bone tissue remodeling process of the molar region of the mandible, due to the inclusion of an implant system, is studied. The obtained results are in accordance with other numerical approach results available in the literature.

In this paper, the theory of bone mechanoregulation under physiological loading was evaluated. The entire right tibiae of wild type (WT, $N=5$) and parathyroid hormone (PTH, $N=5$) treated C57BL/6J female mice were scanned using an in vivo$\mu$CT imaging system at 14, 16, 17, 18, 19, 20, 21, and 22 weeks. The PTH intervention started from week 18 until week 22. Subject-specific finite element (FE) models were created from the $\mu$CT images and physiological loading condition was defined in the FE models. The rates of changes in bone mineral content (BMC), bone mineral density (BMD), and bone tissue density (TMD) were quantified over 40 anatomical compartments across the entire mouse tibia. The resulting values were then correlated to the average 1st principal tensile strain (${\epsilon }_1$) and the strain energy density (SED) for every compartment at weeks 18, 20, and 22. It was found that: in both groups, ${\epsilon }_1$ had a minimal effect on the variability of $\mathrm{\Delta }$BMC ($p>0.01$); SED had a significant effect on the variability of $\mathrm{\Delta }$BMC only in the WT group ($p<0.01$); ${\epsilon }_1$ had a significant effect on the variability of $\mathrm{\Delta }$BMD only in the PTH group ($p<0.01$); SED had a significant effect on the variability of $\mathrm{\Delta }$BMD in both groups ($p<0.01$); neither SED nor ${\epsilon }_1$ had a significant effect on the variability of $\mathrm{\Delta }$TMD ($p>0.01$). These results are the first to reveal the mechanism of bone mechanoregulation in the physiological loading scenario.

The change in mechanical properties of the femoral bone tissue surrounding hip endoprosthesis stems during the post-operative period is one of the causes of implant instability, and the mathematical description of this phenomenon is the subject of much research. In the present study, a model of bone adaptation, based on isotropic Stanford theory, is created for further computer investigation. The results of implementation of such a mathematical model are presented regarding the choice of cement mantle rational thickness in cemented hip arthroplasties. The results show that for cement mantle thicknesses ranging from 1–1.5mm, a peak stress value in the proximal part of the mantle exceeds the limit of durability of bone cement. Moreover, results show that high reduction in the bone density of distal and proximal regions was observed in cases of cement mantle thicknesses varying from 1–3mm. No significant changes in bone density of the abovementioned regions were obtained for 4mm and 5mm. The outcome of numerical investigations can be treated as valuable and will lead to the improvement of cemented hip replacement surgery results.

Bone remodeling is a physiological phenomenon coupling resorption and formation processes that are mainly mediated by osteoclasts and osteoblasts, in response to mechanical stimuli transduced by osteocytes to biochemical signals activating the bone multicellular unit. Under normal loading conditions, bone resorption and formation are balanced by a homeostasis process. When bone is subjected to overstress, microdamaging occurs, which induces a modification of the structural integrity and microarchitecture. This has drawn significant attention to the mechanical properties of bone. In this context, the current study has been carried out with the aim of numerically investigating the impact of the mechanical properties on the remodeling process of the trabecular bone under cyclic loading, highlighting the effects of different values of the mineral density and the Young’s modulus. This was performed using a mechanobiological model, coupling mechanical and biological approaches, allowing to numerically simulate the effect of the selected parameters for a 20-year-period of cyclic loading for 2D and 3D models of a human femur head. The current work is an explorative numerical study, and the obtained results revealed the changes in the overall stiffness of the bone according to the mechanical properties.

Background: Several analytical models have been developed in the past to analyze the specific role of osteocytes in the process of bone remodeling, which can be considered as the response of bone material to functional requirements. Most of them considered both the number of osteocytes and their spatial distribution in one area of influence, while others suggested in addition to include considerations of the size of the basic multi-cellular unit. Methods: Taking advantage of previous works, the standard model equation is revisited by incorporating two complementary parameters: (a) the possibility of resorption of osteocytes, apoptosis or function inhibition during remodeling process triggered by the transduction phase of osteocytes embedded within the bone matrix and; (b) the interference of influence zones for the same osteocyte. Results: Bone density evolution has been calculated starting with a medical imaging of an implanted femur. It is shown that the management of interference zone and the possibility of resorption or inhibition of osteocytes have a direct impact upon the value of the mechanical stimulus and hence on the recruitment of Bone Multicellular Units (BMUs). From a mathematical point of view, this effect has been considered by modifying mechanical stimulus of the standard model such that it is impacted by a scalar factor ranged in the interval (0.5–1). Conclusion: It is clearly demonstrated that predicted of the added bone mass amount shows that the new model is more active in low density regions where requiring rapid adaptation to the behavior of the implant, and that the standard model takes the lead in the regions with high density.

This paper assesses the effectiveness of vibration in accelerating bone remodeling and orthodontic tooth movement. Databases of PubMed, Web of Science, and ScienceDirect were searched from January 2017 to March 2019 for randomized or quasi-randomized controlled trials that evaluated the effectiveness of vibration in accelerating bone remodeling and orthodontic tooth movement. The inclusion criteria were as follows: (i) studies that assessed the efficacy of vibration (cyclic loading) in bone remodeling and orthodontic tooth movement and (ii) those that employed groupings (experimental vs. control/placebo groups) on the basis of the use of vibration (cyclic loading). Eight clinical trials were included in this short review. Five studies met the eligibility criteria for bone remodeling and orthodontic tooth movement. Four studies found that low-magnitude high-frequency vibration could accelerate bone remodeling. However, contradictory results were obtained with regard to the acceleration of orthodontic tooth movement by vibration in human participants. Low-magnitude high-frequency vibration can accelerate bone remodeling and orthodontic tooth movement. However, this acceleration is dependent on the magnitude and frequency. Further research is necessary to determine the most feasible protocols for investigating the effects of magnitude and frequency of vibration on the acceleration of orthodontic tooth movement in human participants.

Taking advantage of the well-known Komarova’s type model, it is proposed here to analyze again the bone dynamics process within the context of a new parameter introduced in order to act only on the production/removal activities of osteoblasts and osteoclasts (BMU) while saving the net effectiveness of osteoclast-or-osteoblast-derived autocrine or paracrine factors. The effects of this new parameter upon simulation of the bone remodeling cycle as well as stable, intrinsically regulated oscillatory changes in bone cell numbers and bone mass are analyzed and from which unstable oscillations, similar to pathologically accelerated bone remodeling of Paget’s disease appear. One can say that the introduced d parameter, with $0\le d<1$, can be viewed as a new parameter driven by Pathological conditions. On the other hand, the parameter d can probably be linked to the complex mechanisms that regulate communication between osteoblasts and osteoclasts, which are known as critical to bone cell biology.

Background: CAR-T cells are chimeric antigen receptor (CAR)-T cells; they are target-specific engineered cells on tumor cells and produce T cell-mediated antitumor responses. CAR-T cell therapy is the “first-line” therapy in immunotherapy for the treatment of highly clonal neoplasms such as lymphoma and leukemia. This adoptive therapy is currently being studied and tested even in the case of solid tumors such as osteosarcoma since, precisely for this type of tumor, the use of immune checkpoint inhibitors remained disappointing. Although CAR-T is a promising therapeutic technique, there are therapeutic limits linked to the persistence of these cells and to the tumor’s immune escape. CAR-T cell engineering techniques are allowed to express interleukin IL-36, and seem to be much more efficient in antitumoral action. IL-36 is involved in the long-term antitumor action, allowing CAR-T cells to be more efficient in their antitumor action due to a “cross-talk” action between the “IL-36/dendritic cells” axis and the adaptive immunity. Methods: This analysis makes the model useful for evaluating cell dynamics in the case of tumor relapses or specific understanding of the action of CAR-T cells in certain types of tumor. The model proposed here seeks to quantify the action and interaction between the three fundamental elements of this antitumor activity induced by this type of adoptive immunotherapy: IL-36, “armored” CAR-T cells (i.e., engineered to produce IL-36) and the tumor cell population, focusing exclusively on the action of this interleukin and on the antitumor consequences of the so modified CAR-T cells. Mathematical model was developed and numerical simulations were carried out during this research. The development of the model with stability analysis by conditions of Routh–Hurwitz shows how IL-36 makes CAR-T cells more efficient and persistent over time and more effective in the antitumoral treatment, making therapy more effective against the “solid tumor”. Findings: Primary malignant bone tumors are quite rare (about 3% of all tumors) and the vast majority consist of osteosarcomas and Ewing’s sarcoma and, approximately, the 20% of patients undergo metastasis situations that is the most likely cause of death. Interpretation: In bone tumor like osteosarcoma, there is a variation of the cellular mechanical characteristics that can influence the efficacy of chemotherapy and increase the metastatic capacity; an approach related to adoptive immunotherapy with CAR-T cells may be a possible solution because this type of therapy is not influenced by the biomechanics of cancer cells which show peculiar characteristics.

The risk of osteoporosis and fragility fracture is increased in patients with autoimmune rheumatic diseases. Although the use of glucocorticoids is the major contributing factor, inflammation mediated by cytokines and growth factors and other medications, including the biologic and targeted disease-modifying antirheumatic drugs, also play important roles in bone remodeling. Pro-inflammatory cytokines such as IL-1, IL-6, IL-17, and TNF$\alpha$ increase RANK expression and promote osteoclast activity while inhibiting osteoblast-mediated bone formation through the Dickkopf-1 pathway. Certain autoantibodies stimulate differentiation of the osteoclasts, resulting in localized bone resorption. This article covers the prevalence and risk factors for osteoporosis in patients with common rheumatic diseases and the role of inflammatory cytokines and other clinical factors. Controlling disease-related inflammation and optimizing the diagnostic and therapeutic instrumentation is needed to reduce fragility fractures in patients with rheumatic diseases.

Mathematical modeling of biological processes has bridged the fields of experimental as well as theoretical research and has carried forward remarkable innovation. Sclerostin is a fundamental communication element for bone remodeling and its activity regulates the reabsorption and deposition of new bone tissue. During this research, we have presented several studies, which illustrate the function of sclerostin in communication with the Wnt signaling pathways. This article features the sclerostin-based pathological patterns related to diseases such as bone cancer. To have a good remodeling process, the osteocytes must recruit the pre-osteoblast cells from the mesenchymal stem cells with the help of the signal mechanism given by the Wnt pathway. The Wnt signal pathway is a complex transduction of a pool of well-conserved genes whose expression regulates various activities like gene translation, cell adhesion, cell differentiation, mitogenic stimulation and polarity cell. The complexity of the interaction of the Wnt pathway is due to the ligands of Wnt itself, to the proteins R-spondin and norrin. The receptors on the surface of the cell, then, activate a process of transduction of the intracellular signal that initiates gene transduction. The hypothesis of a sort of “steady state” has therefore proved indispensable to establish a sort of common base on which the two phases. This paper seeks to give a qualitative view of the action of sclerostin through a simple mathematical model. We use a logic related to stimulation and inhibition signals of new tissue production and illustrate the role of sclerostin in the mechanical and biochemical interaction during the bone remodeling process.

In recent years, mesenchymal stem cells (MSCs) have become more widely used in the treatment of bone fractures. Typically, MSCs are isolated from the bone marrow, expanded in cell culture, and implanted back into the subject using a polymeric material as the seeding scaffold. In the literature, there are a myriad of papers on the topic of MSC extraction, proliferation ability, and multipotency. As such, the characteristics of MSCs are not completely understood and their pluripotency is still being explored. The purpose of this chapter is to discuss the role of MSCs in bone remodeling and to highlight several methods for extracting, proliferating, and implanting MSCs into a defect.

This chapter introduces a Scion Image based on contact microradiography for evaluating the degree of secondary mineralization in basic structure units (BSUs) of cortical bone. The effects of long-term bis-phosphonate (incadronate disodium) administration on the degree of secondary mineralization in osteons in Beagle dogs are evaluated as an example of the application of this technique. The relevant evaluation parameters used and validated for comparison include the mean degree of secondary mineralization in osteons and the distribution curves of mineralization frequency. Scion Image based on contact microradiography is a simple and precise method that can accurately evaluate the mean degree of secondary mineralization in BSUs of bone. Experimental findings suggest that long-term incadronate administration significantly increases the degree and uniformity of secondary mineralization of osteons in a dose-dependent manner, but does not cause hypermineralization of bone tissue.