Microstructural strain near osteocyte lacuna in cortical bone in vitro

Mechanical factors affect bone remodeling such that increased mechanical demand results in net bone formation, whereas decreased demand results in net bone resorption. Two proposed mechanical signals are stress-generated fluid flow forces acting on cells and bone matrix deformation itself. A prominent current theory is that bone cells are more responsive to fluid flow than to mechanical strain. Recent experiments support this conclusion: bone cells increase their production of osteopontin (OPN) mRNA, prostaglandin (PGE(2)), and nitric oxide (NO) in response to fluid flow in contrast to cells stimulated by mechanical strain levels similar to those measured in vivo. However, when cells are subjected to substrate strains levels many times greater than those measured in vivo, increased biological activity again results. We assert that it is neither fluid flow nor matrix deformation per se, but rather the resulting cell deformation that causes cell biological response. Machined specimens of undamaged bovine cortical bone were subjected to increasing levels of macroscopic strain while observed under an optical microscope at 220X. Continuum level strain was measured using a standard foil strain gauge attached to the back of the specimen and ranged from 500 to 6,000 microstrain. Images of the specimen surface at each strain level were captured. To determine the level of osteocyte deformation that results from fluid flow in vitro, MLO-Y4 cells were cultured on collagen coated 190 cm2 plastic sheets and subjected to steady fluid flow at 16 dynes/cm(2). Images representing the initial undisturbed cell configuration and the configuration of the cells after ten minutes of fluid flow were acquired from a videotape of the flow experiment. The captured unloaded vs. loaded image pairs were analyzed to determine the local deformation and strain fields using a digital stereoimaging system. When subjected to a nominal continuum strain level approximately equal to that measured in humans in vivo during rigorous activity (2,000 microstrain), the local, osteocyte level strains can be as high as 12,000 to 15,000 microstrain (1.2% to 1.5%). Average osteocyte strains due to fluid flow in vitro increase from 7,972 microstrains after 16 seconds of flow to 22,856 microstrains after 64 seconds of flow. In contrast, maximum strains measured in vivo are approximately 1,800 microstrain in humans and up to 3,000 microstrain in other species. These data may help to explain why bone cells are more sensitive to fluid flow than substrate strain; fluid forces result in cell deformations much higher than those considered to be "physiological".     

Measurement of microstructural strain in cortical bone

It is well known that mechanical factors affect bone remodeling such that increased mechanical demand results in net bone formation, whereas decreased demand results in net bone resorption. Current theories suggest that bone modeling and remodeling is controlled at the cellular level through signals mediated by osteocytes. The objective of this study was to investigate how macroscopically applied bone strains similar in magnitude to those that occur in vivo are manifest at the microscopic level in the bone matrix. Using a digital image correlation strain measurement technique, experimentally determined bone matrix strains around osteocyte lacuna resulting from macroscopic strains of approximately 2,000 microstrain (0.2%) reach levels of over 30,000 microstrain (3%) over fifteen times greater than the applied macroscopic strain. Strain patterns were highly heterogeneous and in some locations similar to observed microdamage around osteocyte lacuna indicating the resulting strains may represent the precursors to microdamage. This information may lead to a better understanding of how bone cells are affected by whole bone functional loading.     

A dynamical study of the mechanical stimuli and tissue differentiation within a CaP scaffold based on micro-CT finite element models

The control of the mechanical stimuli transmitted to the cells is critical for the design of functional scaffolds for tissue engineering. The objective of this study was to investigate the dynamics of the mechanical stimuli transmitted to the cells during tissue differentiation in an irregular morphology scaffold under compressive load and perfusion flow. A calcium phosphate-based glass porous scaffold was used. The solid phase and the fluid flow within the pores were modeled as linear elastic solid material and Newtonian fluid, respectively. In the fluid model, different levels of viscosity were used to simulate tissue differentiation. Compressive strain of 0.5% and fluid flow with constant inlet velocity of 10 μm/s or constant inlet pressure of 3 Pa were applied. Octahedral shear strain and fluid shear stress were used as mechano-regulatory stimuli. For constant inlet velocity, stimuli equivalent to bone were predicted in 80% of pore volume for the case of low tissue viscosity. For the cases of high viscosity, fluctuations between stimuli equivalent to tissue formation and cell death were predicted due to the increase in the fluid shear stress when tissue started to fill pores. When constant pressure was applied, stimuli equivalent to bone were predicted in 62% of pore volume when low tissue viscosity was used and 42% when high tissue viscosity was used. This study predicted critical variations of fluid shear stress when cells differentiated. If these variations are not controlled in vitro, they can impede the formation of new matured tissue.     

An Analysis and Comparison of Convergence and Uniqueness of Time-Independent Bone Adaptation Models

Several stimuli are proposed in the bone remodeling theory. It is not clear, if a unique solution exists and if the result is convergent using a certain stimulus. In this study, the strain stimulus, strain energy stimulus and the von Mises stress stimulus for bone remodeling are compared and applied to a square plate model using the finite element method. In the plane stress state, the remodeling equilibrium equations are transformed into functions of only the principal strains and the graphs of these functions are drawn in a diagram using the principal strains as the variables of two coordinate axes. The equation of the sum of principal strain squared equal to a constant is a circle in the diagram. The remodeling equilibrium equation of the strain stimulus is a quadrangle fitting into the circle, the remodeling equilibrium equation of the strain energy stimulus is an ellipse and the remodeling equilibrium equation of the von Mises stress stimulus is also an ellipse close to the principal strains circle when we take the same constants in the above equations. Using the finite element method, two models are performed with the uniform initial elastic properties and with the semi-random initial distribution of the elastic properties. The principal strains as the final finite element results converge within 2% of the objective constant for all the different stimuli. The obtained Young's moduli of two models as the adaptation object are different but in equilibrium, i.e. the equilibrium solution of adaptation model is not unique. The principal strains can not be used to examine the uniqueness of solution, since two different solutions can have the same results of principal strains. Using a certain stimulus, certain initial properties and a certain iterative equation, the solution is unique in equilibrium. The results using the model in this study show also that the same results can be obtained using any of the three stimuli when a proper constant in each remodeling equilibrium equation is chosen.     

Local Mechanical Stimuli Regulate Bone Formation and Resorption in Mice at the Tissue Level

Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R² = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R² = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level.     

Interstitial fluid flow in canaliculi as a mechanical stimulus for cancellous bone remodeling: in silico validation

Cancellous bone has a dynamic 3-dimensional architecture of trabeculae, the arrangement of which is continually reorganized via bone remodeling to adapt to the mechanical environment. Osteocytes are currently believed to be the major mechanosensory cells and to regulate osteoclastic bone resorption and osteoblastic bone formation in response to mechanical stimuli. We previously developed a mathematical model of trabecular bone remodeling incorporating the possible mechanisms of cellular mechanosensing and intercellular communication in which we assumed that interstitial fluid flow activates the osteocytes to regulate bone remodeling. While the proposed model has been validated by the simulation of remodeling of a single trabecula, it remains unclear whether it can successfully represent in silico the functional adaptation of cancellous bone with its multiple trabeculae. In the present study, we demonstrated the response of cancellous bone morphology to uniaxial or bending loads using a combination of our remodeling model with the voxel finite element method. In this simulation, cancellous bone with randomly arranged trabeculae remodeled to form a well-organized architecture oriented parallel to the direction of loading, in agreement with the previous simulation results and experimental findings. These results suggested that our mathematical model for trabecular bone remodeling enables us to predict the reorganization of cancellous bone architecture from cellular activities. Furthermore, our remodeling model can represent the phenomenological law of bone transformation toward a locally uniform state of stress or strain at the trabecular level.     

NF-kappaB responds to mechanical strains in osteoblast-like cells, and lighter strains create an NF-kappaB response more readily

This study was to examine the early responses of nuclear factor kappa B (NF-kappaB) to mechanical strains in MG-63. MG-63 cells were subjected to cyclic uniaxial compressive or tensile strain, produced by a four-point bending system, at 1000 microstrain or 4000 microstrain for 5 min, 15 min, 30 min and 1h, respectively. Control cells received the same treatment with no mechanical stress loading. Expression of NF-kappaB (p60) was measured by Western blotting. NF-kappaB responded rapidly to mechanical stimuli in MG-63 cells. NF-kappaB was activated by cyclic uniaxial stretch at 1000 microstrain while it was restrained under a compressive strain environment at 1000 microstrain (P<0.001). The effects reversed for tension and compression at 4000 microstrain (P<0.001). Furthermore, strains at 1000 microstrain affected NF-kappaB expression much easier than those at 4000 microstrain. This indicates that there may be different responding mechanisms or mechanotransduction pathways for different mechanical stimuli.     

The skeleton in primary hyperparathyroidism: a review focusing on bone remodeling, structure, mass, and fracture.

The mechanisms behind the influence of PHPT on the skeleton are closely connected with bone turnover. Throughout life, the skeleton is continuously renewed by bone remodeling, a process which serves the purpose of repairing damaged bone and adapting the skeleton to changes in physical load. In this process, old bone is removed by osteoclastic resorption and new bone is laid down by osteoblastic formation. Bone mass increases with growth in the first decades of life, and around the age of 30 years the peak bone mass is reached. Thereafter, as a result of mechanisms involving bone remodeling, a net bone loss is seen: 1) A reversible bone loss because of increase in the remodeling space, i.e., the amount of bone resorped but not yet reformed during the remodeling cycle. This mechanism leads to decrease in average trabecular thickness and cortical width, and to increase in cortical porosity. 2) An irreversible bone loss caused by negative bone balance, where the amount of bone formed by the osteoblasts is exceeded by the amount of bone resorbed by the osteoclasts at the same remodeling site. Consequently, progressive thinning of trabecular elements, reduced cortical width and increased cortical porosity is seen. 3) Finally, perforation of trabecular plates by deep resorption lacunae leads to complete irreversible removal of structural bone components. Parathyroid hormone, together with vitamin D, are the principal modulators in calcium homeostasis. The main actions of PTH are executed in bone and kidneys. In the kidneys, PTH increases the tubular re-absorption of calcium, thereby tending to increase serum calcium. PTH also induces increased conversion of 25(OH)-D to 1,25(OH)2-D. This last action, enhances intestinal calcium absorption and increased skeletal calcium mobilization, which further adds to the circulating calcium pool. In bone, the "acute" regulatory actions of PTH on serum calcium are probably accompliced via activation of osteocytes and lining cells. A second mechanism of PTH in bone is the regulation of bone remodeling. The action seems to be an increased recruitment from osteoblastic precursor cells and activation of mature osteoclasts. It is supposed that these responses are predominantly mediated indirectly through actions on osteoblast-like or nonosteoblast-like stromal cells, as osteoclasts themselves to not have PTH receptors. Bone metabolism and bone mass are studied by biochemical bone markers, bone histomorphometry, and densitometry. As bone markers and bone histomorphometry give information on bone metabolism from different points of view, these methods are preferably combined. Histomorphometry gives detailed information about bone turnover on cellular level, the whole remodeling sequence is described, and the bone balance can be calculated. However, they focus on a small volume, and may, therefore, not be representative for the whole skeleton. On the other hand, studies of bone markers supply general information about turnover in the whole skeleton, but they do not give facts on the bone turnover on the cellular or tissue level and bone balance. Bone densitometry is the principal method in studying bone mass, but valuable information concerning bone structure also comes from histomorphometry. Bone remodeling is considerably increased in PHPT. Studies of bone markers show increase in both resorptive and formative markers, and the increases seem to be of equivalent size. This is in agreement with histomorphometric findings and shows that the coupling between resorption and formation is preserved. By histomorphometry on iliac crest biopsies, trabecular bone remodeling is found increased by 50%, judged by the increase in activation frequency; a measure of how often new remodeling is initiated on the trabecular bone surface. In PHPT, such remodeling activity is repeated about once every year. Reconstruction of the whole remodeling sequence does not show major deviations in lengths of the resorptive and formative periods compared to normal. Furthermore, the amount of bone removed by the osteoclasts during the resorptive phase is matched by the amount of new bone formed by the osteoblasts leading to a bone balance very close to zero. Compared with trabecular bone, the turnover rate in cortical bone is considerably lower, around 10%. Remodeling of the cortical bone takes place at the endocortical, the pericortical, and the Haversian surfaces. Endocortical bone remodeling activities are very similar to trabecular remodeling activities with good correlation between individual parameters. Periosteal remodeling activity is negligible in PHPT, as it is in the normal state. Cortical porosity, which reflects the remodeling activity on the Haversian surface, is increased by 30-65% in PHPT. (ABSTRACT TRUNCATED)     

Short-range intercellular calcium signaling in bone

The regulation of bone turnover is a complex and finely tuned process. Many factors regulate bone remodeling, including hormones, growth factors, cytokines etc. However, little is known about the signals coupling bone formation to bone resorption, and how mechanical forces are translated into biological effects in bone. Intercellular calcium waves are increases in intracellular calcium concentration in single cells, subsequently propagating to adjacent cells, and can be a possible mechanism for the coupling of bone formation to bone resorption. The aim of the present studies was to investigate whether bone cells are capable of communicating via intercellular calcium signals, and determine by which mechanisms the cells propagate the signals. First, we found that osteoblastic cells can propagate intercellular calcium transients upon mechanical stimulation, and that there are two principally different mechanisms for this propagation. One mechanism involves the secretion of a nucleotide, possibly ATP, acting in an autocrine action to purinergic P2Y2 receptors on the neighboring cells, leading to intracellular IP3 generation and subsequent release of calcium from intracellular stores. The other mechanism involves the passage of a small messenger through gap junctions to the cytoplasm of the neighboring cells, inducing depolarization of the plasma membrane with subsequent opening of membrane bound voltage-operated calcium channels. Next, we found that osteoblasts can propagate these signals to osteoclasts as well. We demonstrated that paracrine action of ATP was responsible for the wave propagation, but now the purinergic P2X7 receptor was involved. Thus, the studies demonstrate that calcium signals can be propagated not only among osteoblasts, but also between osteoblasts and osteoclasts in response to mechanical stimulation. Thus, intercellular calcium signaling can be a mechanism by which mechanical stimuli on bone are translated into biological signals in bone cells, and propagated through the network of cells in bone. Further, the observations offer new pharmacological targets for the modulation of bone turnover, and perhaps even for the treatment of bone metabolic disorders.     

Modeling of biological doses and mechanical effects on bone transduction

Shear stress, hormones like parathyroid and mineral elements like calcium mediate the amplitude of stimulus signal, which affects the rate of bone remodeling. The current study investigates the theoretical effects of different metabolic doses in stimulus signal level on bone. The model was built considering the osteocyte as the sensing center mediated by coupled mechanical shear stress and some biological factors. The proposed enhanced model was developed based on previously published works dealing with different aspects of bone transduction. It describes the effects of physiological doses variations of calcium, parathyroid hormone, nitric oxide and prostaglandin E2 on the stimulus level sensed by osteocytes in response to applied shear stress generated by interstitial fluid flow. We retained the metabolic factors (parathyroid hormone, nitric oxide and prostaglandin E2) as parameters of bone cell mechanosensitivity because stimulation/inhibition of induced pathways stimulates osteogenic response in vivo. We then tested the model response in terms of stimulus signal variation versus the biological factors doses to external mechanical stimuli. Despite the limitations of the model, it is consistent and has physiological bases. Biological inputs are histologically measurable. This makes the model amenable to experimental verification.     

A dynamic pattern of mechanical stimulation promotes ossification in avian embryonic long bones

We have performed a set of finite element analyses of embryonic chick hindlimb skeletal rudiments at several time points during development, around the time of initial bone formation. Using optical projection tomography, we created anatomically accurate rudiment and muscle morphologies for each stage. The changes in pattern and magnitude of biophysical stimuli (such as stress, strain, hydrostatic pressure and fluid flow) were computed, and were found to transform as bone formation proceeded in the rudiment. For each biophysical stimulus, a single concentration of the stimulus was predicted at the mid-diaphysis some time before initial bone formation begins. Then, several hours before ossification, two concentrations of the stimuli were predicted distal and proximal to the prospective bone collar. Once bone formation had begun, high concentrations of the stimuli were maintained proximal and distal to the bone collar. We propose the hypothesis that patterns of biophysical stimuli resulting from mechanical loading due to muscle contractions initiate and propagate ossification in avian embryonic long bones, whereby a region of the perichondrium experiences a period of time under high cyclic stimulus levels, promoting chondrocyte hypertrophy at the core and prompting bone collar formation some hours later.     

Fluid-induced osteolysis: modelling and experiments

A model to calculate bone resorption driven by fluid flow at the bone–soft tissue interface is developed and used as a basis for computer calculations, which are compared to experiments where bone is subjected to fluid flow in a rat model. Previous models for bone remodelling calculations have been based on the state of stress, strain or energy density of the bone tissue as the stimulus for remodelling. We believe that there is experimental support for an additional pathway where an increase in the amount of the cells directly involved in bone removal, the osteoclasts, is caused by fluid pressure, flow velocity or other parameters related to fluid flow at the bone–soft tissue interface, resulting in bone resorption.     

Capturing microscopic features of bone remodeling into a macroscopic model based on biological rationales of bone adaptation

To understand Wolff’s law, bone adaptation by remodeling at the cellular and tissue levels has been discussed extensively through experimental and simulation studies. For the clinical application of a bone remodeling simulation, it is significant to establish a macroscopic model that incorporates clarified microscopic mechanisms. In this study, we proposed novel macroscopic models based on the microscopic mechanism of osteocytic mechanosensing, in which the flow of fluid in the lacuno-canalicular porosity generated by fluid pressure gradients plays an important role, and theoretically evaluated the proposed models, taking biological rationales of bone adaptation into account. The proposed models were categorized into two groups according to whether the remodeling equilibrium state was defined globally or locally, i.e., the global or local uniformity models. Each remodeling stimulus in the proposed models was quantitatively evaluated through image-based finite element analyses of a swine cancellous bone, according to two introduced criteria associated with the trabecular volume and orientation at remodeling equilibrium based on biological rationales. The evaluation suggested that nonuniformity of the mean stress gradient in the local uniformity model, one of the proposed stimuli, has high validity. Furthermore, the adaptive potential of each stimulus was discussed based on spatial distribution of a remodeling stimulus on the trabecular surface. The theoretical consideration of a remodeling stimulus based on biological rationales of bone adaptation would contribute to the establishment of a clinically applicable and reliable simulation model of bone remodeling.     

Computer modelling of bone’s adaptation: the role of normal strain,shear strain and fluid flow

Bone loss is a serious health problem. In vivo studies have found that mechanical stimulation may inhibit bone loss as elevated strain in bone induces osteogenesis, i.e. new bone formation. However, the exact relationship between mechanical environment and osteogenesis is less clear. Normal strain is considered as a prime stimulus of osteogenic activity; however, there are some instances in the literature where osteogenesis is observed in the vicinity of minimal normal strain, specifically near the neutral axis of bending in long bones. It suggests that osteogenesis may also be induced by other or secondary components of mechanical environment such as shear strain or canalicular fluid flow. As it is evident from the literature, shear strain and fluid flow can be potent stimuli of osteogenesis. This study presents a computational model to investigate the roles of these stimuli in bone adaptation. The model assumes that bone formation rate is roughly proportional to the normal, shear and fluid shear strain energy density above their osteogenic thresholds. In vivo osteogenesis due to cyclic cantilever bending of a murine tibia has been simulated. The model predicts results close to experimental findings when normal strain, and shear strain or fluid shear were combined. This study also gives a new perspective on the relation between osteogenic potential of micro-level fluid shear and that of macro-level bending shear. Attempts to establish such relations among the components of mechanical environment and corresponding osteogenesis may ultimately aid in the development of effective approaches to mitigating bone loss.     

Fluid-induced osteolysis: modelling and experiments

A model to calculate bone resorption driven by fluid flow at the bone-soft tissue interface is developed and used as a basis for computer calculations, which are compared to experiments where bone is subjected to fluid flow in a rat model. Previous models for bone remodelling calculations have been based on the state of stress, strain or energy density of the bone tissue as the stimulus for remodelling. We believe that there is experimental support for an additional pathway where an increase in the amount of the cells directly involved in bone removal, the osteoclasts, is caused by fluid pressure, flow velocity or other parameters related to fluid flow at the bone-soft tissue interface, resulting in bone resorption.     

Measurement of local strain on cell membrane at initiation point of calcium signaling response to applied mechanical stimulus in osteoblastic cells

In adaptive bone remodeling, it is believed that bone cells such as osteoblasts, osteocytes and osteoclasts can sense mechanical stimuli and modulate their remodeling activities. However, the mechanosensing mechanism by which these cells sense mechanical stimuli and transduce mechanical signals into intracellular biochemical signals is still not clearly understood. From the viewpoint of cell biomechanics, it is important to clarify the mechanical conditions under which the cellular mechanosensing mechanism is activated. The aims of this study were to evaluate a mechanical condition, that is, the local strain on the cell membrane, at the initiation point of the intracellular calcium signaling response to the applied mechanical stimulus in osteoblast-like MC3T3-E1 cells, and to investigate the effect of deformation velocity on the characteristics of the cellular response. To apply a local deformation to a single cell, a glass microneedle was directly indented to the cell and moved horizontally on the cell membrane. To observe the cellular response and the deformation of the cell membrane, intracellular calcium ions and the cell membrane were labeled using fluorescent dyes and simultaneously observed by confocal laser scanning microscopy. The strain distribution on the cell membrane attributable to the applied local deformation and the strain magnitude at the initiation point of the calcium signaling responses were analyzed using obtained fluorescence images. From two-dimensionally projected images, it was found that there is a local compressive strain at the initiation point of calcium signaling. Moreover, the cellular response revealed velocity dependence, that is, the cells seemed to respond with a higher sensitivity to a higher deformation velocity. From the viewpoint of cell biomechanics, these results provide us a fundamental understanding of the mechanosensing mechanism of osteoblast-like cells.     

Osteocyte lacunae tissue strain in cortical bone

Current theories suggest that bone modeling and remodeling are controlled at the cellular level through signals mediated by osteocytes. However, the specific signals to which bone cells respond are still unknown. Two primary theories are: (1) osteocytes are stimulated via the mechanical deformation of the perilacunar bone matrix and (2) osteocytes are stimulated via fluid flow generated shear stresses acting on osteocyte cell processes within canaliculi. Recently, much focus has been placed on fluid flow theories since in vitro experiments have shown that bone cells are more responsive to analytically estimated levels of fluid shear stress than to direct mechanical stretching using macroscopic strain levels measured on bone in vivo. However, due to the complex microstructural organization of bone, local perilacunar bone tissue strains potentially acting on osteocytes cannot be reliably estimated from macroscopic bone strain measurements. Thus, the objective of this study was to quantify local perilacunar bone matrix strains due to macroscopically applied bone strains similar in magnitude to those that occur in vivo. Using a digital image correlation strain measurement technique, experimentally measured bone matrix strains around osteocyte lacunae resulting from macroscopic strains of approximately 2000 microstrain are significantly greater than macroscopic strain on average and can reach peak levels of over 30,000 microstrain locally. Average strain concentration factors ranged from 1.1 to 3.8, which is consistent with analytical and numerical estimates. This information should lead to a better understanding of how bone cells are affected by whole bone functional loading.     

Mechanisms of sex steroid effects on bone

Sex steroids play a major role in the regulation of bone turnover. Thus, gonadectomy in either sex is associated with an increase in bone remodeling, increased bone resorption, and a relative deficit in bone formation, resulting in accelerated bone loss. Recent physiological studies have established an important role for estrogen in regulating bone turnover not only in females, but also in males. Studies in mice with knock out of the estrogen receptor, aromatase, or androgen receptor have provided important insights into the in vivo mechanisms of sex steroid action on bone. The cellular and molecular mediators of sex steroid effects on the bone-forming osteoblasts and bone-resorbing osteoclasts are also being increasingly better defined. Estrogen inhibits bone remodeling by concurrently suppressing osteoblastogenesis and osteoclastogenesis from marrow precursors. Both estrogen and androgens inhibit bone resorption via effects on the receptor activator of NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, as well as by reducing the production of a number of pro-resorptive cytokines, along with direct effects on osteoclast activity and lifespan. Sex steroid effects on bone formation are also likely mediated by multiple mechanisms, including a prolongation of osteoblast lifespan via non-genotropic mechanisms, as well as effects on osteoblast differentiation and function. These pleiotropic actions of sex steroids on virtually all aspects of bone metabolism belie the importance of the skeleton not only in providing structural support for the body and in locomotion, but also as a dynamic tissue responsive, among other things, to the reproductive needs of the organism for calcium.     

Bone remodeling: A review of the bone microenvironment perspective for fragility fracture (osteoporosis) of the hip

Bone remodeling is an active process throughout the skeleton. The concept of bone turnover surface has been developed and reported in the peer reviewed literature as the quotient of formation surface/resorption surface and is significantly lower in hip fracture. It is necessary to identify the molecular drivers of these changes in bone turnover. Factors that have been strongly implicated in bone metabolism are therefore divided into three categories, "Vascular", "Anabolic" and "Catabolic". Further data is required from the bone tissue-level microenvironment, of fragility fracture patients, on the variation in molecular signals, and the associated changes in bone structure and remodeling.     

Prediction of bone density around orthopedic implants delivering bisphosphonate

The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant bone may resorb shortly after the surgery. This resorption is directly followed by new bone formation and implants fixation strengthening, the so-called secondary fixation. If the initial stability is not reached, the resorption continues and the implant fixation weakens, which leads to implant loosening. Studies with rats and dogs have shown that a solution to prevent peri-implant resorption is to deliver bisphosphonate from the implant surface.The aims of the study were, first, to develop a model of bone remodeling around an implant delivering bisphosphonate, second, to predict the bisphosphonate dose that would induce the maximal peri-implant bone density, and third to verify in vivo that peri-implant bone density is maximal with the calculated dose.The model consists of a bone remodeling equation and a drug diffusion equation. The change in bone density is driven by a mechanical stimulus and a drug stimulus. The drug stimulus function and the other numerical parameters were identified from experimental data. The model predicted that a dose of 0.3 μg of zoledronate on the implant would induce a maximal bone density. Implants with 0.3 μg of zoledronate were then implanted in rat femurs for 3, 6 and 9 weeks. We measured that peri-implant bone density was 4% greater with the calculated dose compared to the dose empirically described as best.The approach presented in this paper could be used in the design and analysis processes of experiments in local delivery of drug such as bisphosphonate.