Mechanisms Of Bone Remodeling Research Articles

Bone Mineral Densities of the Vertebral Body and Intertransverse Fusion Mass After Instrumented Intertransverse Process Fusion

We used dual-energy x-ray absorptiometry to examine the bone mineral densities (BMDs) of the vertebral bodies at the fused level (the fused vertebral BMDs), at the unfused level (the unfused vertebral BMDs), and the intertransverse fusion mass (the fusion mass BMD) after instrumented intertransverse process fusion. We wanted to determine whether there are any relationships among the unfused vertebral BMDs, the fused vertebral BMD, and the fusion mass BMD after successful solid union. Device-related vertebral osteoporosis is a well-known phenomenon that occurs in an early adaptive phase after instrumented spinal fusion. However, any relationships among the unfused vertebral BMDs, the fused vertebral BMD, and the fusion mass BMD in a later phase after obtaining successful spinal union are unknown. This study included 17 female patients, who had a solid union after instrumented intertransverse process fusion at the L4-L5 level. The average patient age at the time of this study was 54 years (range: 46-69 years). The vertebral BMDs at the fused level (L4), the vertebral BMDs at the unfused levels (L1-L3), and the fusion mass BMD were measured at a mean follow-up period of 42 months (range: 24-131 months) after surgery. The reciprocal correlations among the vertebral BMDs and the fusion mass BMD were analyzed. RESULTS.: The vertebral BMDs (g/cm) at the fused level (L4), the unfused level (L1-L3), and the fusion mass BMD were 0.84 ± 0.27, 0.72 ± 0.23, 0.56 ± 0.19, 0.58 ± 0.21, and 0.54 ± 0.16, respectively. There were significant reciprocal correlations among the vertebral BMDs at the fused and unfused level. However, the fusion mass BMD had no significant correlations with any of the vertebral BMDs. The vertebral bodies at the fused level may undergo osteoporosis in a pattern similar to what naturally occurs in the vertebral bodies at the unfused level. However, the fusion mass BMD seems to be influenced by bone remodeling mechanisms that are different from those that influence the vertebral bodies.

Osteopontin is required for unloading-induced osteoclast recruitment and modulation of RANKL expression during tooth drift-associated bone remodeling, but not for super-eruption

Unloading of teeth results in extensive alveolar bone remodeling, causing teeth to move in both vertical (“super-eruption”) and horizontal direction (“drift”). In order to decipher the molecular mechanisms of unloading-induced bone remodeling during tooth movement, we focused on the role of osteopontin (OPN) in the un-opposed molar model, comparing wild-type (WT) and OPN-null mice. Our data indicated that OPN was not required for the continuous eruption of un-opposed teeth while OPN was necessary for the drift of teeth. OPN expression and osteoclast counts were greatly increased on alveolar bone surfaces facing the direction of the drift in WT mice, while osteoclast counts were diminished in OPN−/− mice. RANKL expression in the distal periodontal ligament of WT molars increased significantly by day 6 following unloading, while overall levels of RANKL expression were decreased in both WT and OPN-null mice. In vitro treatment of MC3T3 cells, WT BMCs and OPN−/− BMCs with recombinant OPN resulted in significantly increased RANKL expression in all three cell types. The PI3K and MEK/ERK pathway inhibitors Ly294002 and U0126 reduced RANKL expression levels in vitro. Treatment of BMCs and MC3T3 with OPN also resulted in increased ERK phosphorylation and reduced OPG levels. Together, our studies suggest that increased OPN expression during unloading-induced drifting of teeth enhances localized RANKL expression and osteoclast activity on drift-direction alveolar bone surfaces via extracellular matrix signaling pathways.

Changes in bone mechanical strength in response to physical therapy

Numerous unfavorable factors that disturb the balance between resorption and bone formation affect bone mechanical strength. Also mechanical loading (body mass and muscle tension) and risk factors for osteoporosis affect bone strength. Loading that can be applied to the bone is limited by bone structure. At the same time, loading applied to the bone may condition its structure. This is possible thanks to the cellular mechanisms of bone modeling and remodeling called adaptation. Physical therapy affects bone mechanical strength by stimulating bone cells. Movement increases muscle strength and restores muscle cooperation, thus improving functional state and movement activity, which, in turn, indirectly increase bone strength. The analysis of the studies on bone mechanical strength confirms the efficacy of physical exercise, which is an important element of comprehensive management. A lower risk of falls and fractures has been observed in patients who had received physical therapy apart from pharmacological treatment. It has also been observed that an increase in bone mechanical strength is not necessarily reflected in densitometric evaluation.

Reduced Limbic and Hypothalamic Volumes Correlate with Bone Density in Early Alzheimer's Disease

Accelerated bone loss is associated with Alzheimer's disease (AD). Although the central nervous system plays a direct role in regulating bone mass, primarily through the actions of the hypothalamus, there is little work investigating the possible role of neurodegeneration in bone loss. In this cross-sectional study, we examined the association between bone mineral density (BMD) and neuroimaging markers of neurodegeneration (i.e., global and regional measures of brain volume) in early AD and non-demented aging. Fifty-five non-demented and 63 early AD participants underwent standard neurological and neuropsychological assessment, structural MRI scanning, and dual energy x-ray absorptiometry. In early AD, voxel-based morphometry analyses demonstrated that low BMD was associated with low volume in limbic grey matter (GM) including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional GM volume was found in non-demented controls. The hypothesis-driven region of interest analysis further isolating the hypothalamus demonstrated a positive relationship between BMD and hypothalamic volume after controlling for age and gender in the early AD group but not in non-demented controls. These results demonstrate that lower BMD is associated with lower hypothalamic volume in early AD, suggesting that central mechanisms of bone remodeling may be disrupted by neurodegeneration.

Parametric study of control mechanism of cortical bone remodeling under mechanical stimulus

The control mechanism of mechanical bone remodeling at cellular level was investigated by means of an extensive parametric study on a theoretical model described in this paper. From a perspective of control mechanism, it was found that there are several control mechanisms working simultaneously in bone remodeling which is a complex process. Typically, an extensive parametric study was carried out for investigating model parameter space related to cell differentiation and apoptosis which can describe the fundamental cell lineage behaviors. After analyzing all the combinations of 728 permutations in six model parameters, we have identified a small number of parameter combinations that can lead to physiologically realistic responses which are similar to theoretically idealized physiological responses. The results presented in the work enhanced our understanding on mechanical bone remodeling and the identified control mechanisms can help researchers to develop combined pharmacological–mechanical therapies to treat bone loss diseases such as osteoporosis.

Protein Kinase C-δ Transactivates Platelet-derived Growth Factor Receptor-α in Mechanical Strain-induced Collagenase 3 (Matrix Metalloproteinase-13) Expression by Osteoblast-like Cells

Matrix metalloproteinase-13 (MMP-13, or collagenase 3) has been shown to degrade intact collagen and to participate in situations where rapid and effective remodeling of collagenous ECM is required. Mechanical strain induction of MMP-13 is an example of how osteoblasts respond to high mechanical forces and participate in the bone-remodeling mechanism. Using MC3T3-E1 osteoblast-like cells, we dissected the signaling molecules involved in MMP-13 induction by mechanical strain. Reverse transcription-PCR and zymogram analysis showed that platelet-derived growth factor receptor (PDGFR) inhibitor, AG1296, inhibited the mechanical strain-induced MMP-13 gene and activity. However, the induction was not affected by anti-PDGF-AA serum. Immunoblot analysis revealed time-dependent phosphorylation of PDGFR-alpha up to 2.7-fold increases within 3 min under strain. Transfection with shPDGFR-alpha (at 4 and 8 microg/ml) abolished PDGFR-alpha and reduced MMP-13 expression. Moreover, time-dependent recruitments of phosphoinositide 3-kinase (PI3K) by PDGFR-alpha were detected by immunoprecipitation with anti-PDGFR-alpha serum followed by immunoblot with anti-PI3K serum. AG1296 inhibited PDGFR-alpha/PI3K aggregation and Akt phosphorylation. Interestingly, protein kinase C-delta (PKC-delta) inhibitor, rottlerin, inhibited not only PDGFR-alpha/PI3K aggregation but PDGFR-alpha phosphorylation. The sequential activations were further confirmed by mutants DeltaPKC-delta, DeltaAkt, and DeltaERK1. Consistently, the primary mouse osteoblast cells used the same identified signaling molecules to express MMP-13 under mechanical strain. These results demonstrate that, in osteoblast-like cells, the MMP-13 induction by mechanical strain requires the transactivation of PDGFR-alpha by PKC-delta and the cross-talk between PDGFR-alpha/PI3K/Akt and MEK/ERK pathways.

Basic Synovial Biology and Immunopathology in Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy with a well recognized propensity for aggressive bone erosions. In some individuals, however, periarticular bone mineralization is maintained, and there is often associated new bone formation with periostitis and frank ankylosis; thus PsA manifests, in different individuals, reciprocal patterns of joint pathology suggesting a disorder of bone remodeling. Recent key scientific advances will be briefly reviewed including T cell, B cell, human leukocyte antigen associations; and the importance of neoangiogenesis, vascularity, and adhesion molecules in conjunction with inflammatory infiltrates and cytokine expression. Finally, the mechanisms of abnormal bone remodeling are discussed, including mediators of osteoclastogenesis such as RANK ligand and molecular signaling pathways including Dickkop-1 and bone morphogenetic proteins. Although much has been learned about the pathogenesis of PsA, much remains to be defined regarding the mechanisms linking synovial biology and immunopathology to different disease outcomes. Identifying key differentiating factors between the diverse PsA phenotypes, correlating findings with the rapidly advancing field of ultrasound image acquisition, and delineating the cellular and molecular mechanisms of abnormal bone remodeling in combination should enable the development of improved prognostic algorithms. This in turn should facilitate the targeting of expensive (about pound10k/patient/year) and potentially toxic yet effective biologics to patients most in need.

Hydrostatic pressures promote initial osteodifferentiation with ERK1/2 not p38 MAPK signaling involved

Mechanical stress has been considered to be an important factor in bone remodeling and recent publications have shown that mechanical stress can regulate the direction of stem cell differentiation. The exact mechanobiological effects of pressure on initial osteodifferentiation of mesenchymal stem cells (MSCs) have not been determined. These mechanobiological mechanisms may be important both in biological responses during orthodontic tooth movement and in the development of new mechanobiological strategies for bone tissue engineering. We investigated the effects of static (23 kPa) or dynamic (10-36 kPa and at 0.25 Hz frequency) pressure on MSCs during the initial process of osteoblastic differentiation following treatment with dexamethasone, beta-glycerophosphate and ascorbic acid (for 0, 3, and 7 days, respectively). The following parameters were analyzed in the ALPase activity, mRNA level of osteogenesis-related transcription factors (Runx2, Osterix, Msx2, and Dlx5), and phosphorylation of ERK1/2 and p38 MAPK. The results showed that exposure to either dynamic or static pressure induced initial osteodifferentiation of MSCs. Particularly both types of pressure strongly stimulated the expression of osteogenesis-related factors of totally undifferentiated MSCs. ERK signaling participated in early osteodifferentiation and played a positive but non-critical role in mechanotransduction, whereas p38 MAPK was not involved in this process. Furthermore, the undifferentiated MSCs were highly sensitive to pressure exposure; whereas after osteoinduction MSCs reacted to pressure in a lower response state. The findings should lead to further studies to unveil the complex initial biological mechanisms of bone remodeling and regeneration upon mechanical stimuli.

Application of Petri Nets in Bone Remodeling

Understanding a mechanism of bone remodeling is a challenging task for both life scientists and model builders, since this highly interactive and nonlinear process can seldom be grasped by simple intuition. A set of ordinary differential equations (ODEs) have been built for simulating bone formation as well as bone resorption. Although solving ODEs numerically can provide useful predictions for dynamical behaviors in a continuous time frame, an actual bone remodeling process in living tissues is driven by discrete events of molecular and cellular interactions. Thus, an event-driven tool such as Petri nets (PNs), which may dynamically and graphically mimic individual molecular collisions or cellular interactions, seems to augment the existing ODE-based systems analysis. Here, we applied PNs to expand the ODE-based approach and examined discrete, dynamical behaviors of key regulatory molecules and bone cells. PNs have been used in many engineering areas, but their application to biological systems needs to be explored. Our PN model was based on 8 ODEs that described an osteoprotegerin linked molecular pathway consisting of 4 types of bone cells. The models allowed us to conduct both qualitative and quantitative evaluations and evaluate homeostatic equilibrium states. The results support that application of PN models assists understanding of an event-driven bone remodeling mechanism using PN-specific procedures such as places, transitions, and firings.

A Physical Mechanism for Coupling Bone Resorption and Formation in Adult Human Bone

During skeletal remodeling, pre-osteoclasts and pre-osteoblasts are targeted to critical sites of the bone to resorb and reconstruct bone matrix, respectively. Coordination of site-specific recruitment of these two cell types is a prerequisite to maintain the specific architecture of each bone within strict limits throughout adult life. Here, we determined that the bone marrow microanatomy adjacent to remodeling areas is a central player in this process. By using histomorphometry and multiple immunostainings, we demonstrated in biopsies exhibiting coupled bone resorption and formation that osteoclasts and osteoblasts on the bone surface were always covered by a canopy of flat cells expressing osteoblast markers. In contrast, in biopsies in which this canopy was disrupted, bone formation was deficient. Three-dimensional visualizations revealed that this canopy covered the entire remodeling site and was associated with capillaries, thereby forming a previously unrecognized microanatomical entity. Furthermore, pre-osteoclasts were positioned along these capillaries. These findings led to a model that implicates vasculature in the site-specific recruitment of osteoclasts and osteoblasts and embraces the current knowledge on the molecular mechanism of bone remodeling.

OPG and sRANKL Serum Concentrations in Osteopenic, Postmenopausal Women After 2-Year Genistein Administration

RANKL and its decoy receptor osteoprotegerin (OPG) constitute a complex physiological mediator system involved in the regulation of bone resorption and may be responsible for the homeostatic mechanism of normal bone remodeling. Genistein, an isoflavone representing 1-5% of total phytoestrogen content in soybean products, may positively regulate cellular bone metabolism, but its mechanism of action on bone is not yet fully understood. We studied the serum levels of both soluble RANKL (sRANKL) and OPG and the sRANKL/OPG ratio in 389 postmenopausal women (age, 49-67 yr) with a femoral neck BMD <0.795 g/cm(2) and no significant comorbid conditions after 24-mo therapy with genistein, (n = 198; 54 mg/d) or placebo (n = 191). Both intervention and placebo contained calcium and vitamin D(3). All patients received dietary instruction in an isocaloric fat-reduced diet. In comparison with placebo, sRANKL level was lower (p < 0.001 versus placebo) and OPG higher in genistein recipients (p < 0.001 versus placebo) at 1 and 2 yr, respectively. Moreover, at the end of 24 mo, genistein produced a significant reduction in the sRANKL/OPG ratio compared with placebo (genistein = -0.021, 95% CI, -0.020 to -0.022; placebo = +0.004, 95% CI, 0.003-0.005; difference = -0.020, 95% CI, -0.015 to -0.025, p < 0.001). Our findings suggest that genistein plus calcium and vitamin D(3) as part of a healthy diet is able to positively modulate bone turnover in a cohort of osteopenic, postmenopausal women and improve sRANKL-OPG balance after 24 mo of treatment.

Assessment of bone quality. Observation of lacuna-canalicular network in single trabecula

Osteocytes embedded in bone matrix, making a three-dimensional network system connected each other via cell processes, are considered as the mechanosensor cells that play important roles in the regulatory mechanism of adaptive bone remodeling. Three-dimensional network structure of the lacuna-canalicular system in a trabecula was fluorescently visualized by confocal laser-scanning microscopy, and the morphological characteristics of the network were quantitatively evaluated. The canalicular network orientation was determined by fitting the fabric ellipse, and the normal vector field was derived from the gradient of a distance function from trabecular surface. As a result, the network orientation was found to approximately coincide with the normal direction to the trabecular surface.

Building bone to reverse osteoporosis and repair fractures

An important, unfilled clinical need is the development of new approaches to improve fracture healing and to treat osteoporosis by increasing bone mass. Recombinant forms of bone morphogenetic protein 2 (BMP2) and BMP7 are FDA approved to promote spinal fusion and fracture healing, respectively, and the first FDA-approved anabolic drug for osteoporosis, parathyroid hormone, increases bone mass when administered intermittently but can only be given to patients in the US for two years. As we discuss here, the tremendous explosion over the last two decades in our fundamental understanding of the mechanisms of bone remodeling has led to the prospect of mechanism-based anabolic therapies for bone disorders.

Bone disease drug discovery: examining the interactions between osteoblast and osteoclast

Background: Existing drugs, including bisphosphonates and calcitonin, cannot meet the strong demand for a possible cure of bone diseases – the prevailing cause of human disabilities. Objectives: To understand on-going drug discovery activities, new trends and different opinions in the treatment of bone diseases. Methods: Search, summarize and analyze the recent literature up to August 2007, related to osteoporosis and joint diseases. Results/conclusion: The drug discovery based on the molecular mechanism of bone remodeling has made some progress, but there are challenges, difficulties and different opinions. Bone resorption by osteoclasts is directly regulated by osteoblasts via the receptor activator of NF-κB/receptor activator of NF-κB ligand/osteoprotegerin signaling pathway, whereas the regulation of bone formation is poorly understood. Several aspects, including the present state and future trends, are commented as the expert opinions in this paper.

Molecular mechanism of bone remodelling during mandibular distraction osteogenesis in rats

To study the expression profiles of osteoprotegerin (OPG) and receptor activator of nuclear factor-KB ligand (RANKL) in the distraction region and to investigate the mechanism of bone remodelling during mandibular distraction osteogenesis. Osteotomies were performed and external distractors were installed on the mandibles of 42 adult male SD rats. After a 5-day latency period, the distractors were activated at a rate of 0.4 mm/day for 6 days, followed by a 4-week consolidation period. Radiographs were taken, and specimens were harvested at the end of the latency period, when distraction was completed, and at of 1, 2, 3 and 4 weeks of the consolidation period. Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the activated osteoclasts. Temporospatial expression of OPG and RANKL was investigated by using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Semi-quantitative analysis was used to characterize OPG,RANKL and RANK/OPG ratio. In all time points, OPG and RANKL were co-localized in bone marrow lining cells, osteoblasts and newly embedded osteocytes. OPG mRNA expression increased to a peak level when distraction was completed and maintained the level until the end of 2nd week of the consolidation period. RANKL mRNA expression increased steadily until the end of 1 st week of the consolidation period and maintained a peak level until the end of 3rd week, with a slight decrease at the end of 2nd week. The RANKL/OPG ratio increased continuously and reached its highest level at the end of 3rd and 4th week of the consolidation period. TRAP positive osteoclasts were mainly detected at 2, 3 and 4 weeks of the consolidation period in bone marrow cavities and bone surfaces. The temporospatial expression patterns of osteoprotegerin and RANKL suggest that osteoblasts and the lineage cell network orchestrates bone remodelling during distraction. Osteogenesis and the most activated bone resorption takes place during 3rd and 4th week of the consolidation phase.

Investigation of cancellous bone architecture using structural optimisation

The optimality of bone's internal architecture and its remodelling is investigated by applying topological optimisation. The os-calcis (heel bone) which is subject to a relatively simple loading environment was used as the test problem. The solution is compared with X-ray and CT images of the os-calcis and is demonstrated to agree favourably with the bone's typical trabecular orientation in the coronal plane. The optimality of bone remodelling is further investigated by applying a perturbation during optimisation which leads to a different optimum topology. This is compared with in-vivo experimental results from a model in which the same perturbation was applied. The findings indicate that there may exist more than one optimum state for the same mechanical condition and that structural optimisation is able to find these multiple states. It is therefore suggested that structural optimisation can be used to investigate the mechanisms of bone remodelling.

A histological assessment on the distribution of the osteocytic lacunar canalicular system using silver staining

Giving the complexity that characterizes the mechanisms of bone remodeling and the number of events that have to be in absolute harmony for it to occur flawlessly, the postulation that temporospatial distribution of osteocytes and their lacunar canalicular system might influence and be influenced by bone remodeling can be regarded, at least, as feasible. In this study, using Schoen's silver staining, we have examined the distribution of the osteocytic lacunar canalicular system (OLCS) in bones of developing mice. Trabecular bones of 3-day-old, 2-week-old, and 3-week-old mice displayed osteocytic cytoplasmic processes without any perceptible alignment. Also, many plump osteocytes were embedded in the mineralized bone matrix in a disorderly manner. At 4 weeks of age, however, mice bones showed some osteocytic processes that reached the bone surface on a right angle, while other osteocytes displayed the same features seen on 3-week specimens. Samples at 8 weeks of age featured osteocytes with their usual spindle shape, organized so as to parallel the longitudinal axis of trabecular bone. They also extended their cytoplasmic processes perpendicularly to the bone surface. However, several osteocytes immersed in older bone, i.e., a residual mix of cartilage and bone matrices, still showed a random pattern of distribution of their cytoplasmic processes. Up to 12 weeks of age, the majority of the osteocytes became flattened and were shown to be aligned with their long axis paralleling the bone surface. This tendency for such a gradual arrangement was also observed in cortical bones. We have further demonstrated that 8-week-old osteoprotegerin-deficient mice, which demonstrated histological evidence of higher than average bone turnover, revealed a disorganized OLCS. Given the data gathered in this work, the OLCS appears to assume an organized, probably function-related spatial distribution as normal bone remodeling goes on.

Poster 246: Synovial Cells Derived From Human Temporpmandibular Joint Have the Ability of Supporting Differentiation of Monocytes Into Osteoclasts Through a Mechanism Involving Cell-to-Cell Contact

Although a lot of arthroscopic, histological, and biochemical researches of the temporomandibular joint (TMJ) disorders (TMDs) have reported, the details of the cellular mechanism of bone destruction and remodeling remain unknown. Recently, we reported that induced and characterized osteoclast (OC)-like cells from the synovial fluid of patients with TMD and investigated the participation of these cells in the pathogenesis of TMD (Takano et al, Osteoarthritis and Cartilage, 2006). However, the relation to the OC inducement by the synovial cells of TMD is unknoun.

Biological mechanisms of bone and cartilage remodelling—genomic perspective

Rapid advancements in the field of genomics, enabled by the achievements of the Human Genome Project and the complete decoding of the human genome, have opened an unimaginable set of opportunities for scientists to further unveil delicate mechanisms underlying the functional homeostasis of biological systems. The trend of applying whole-genome analysis techniques has also contributed to a better understanding of physiological and pathological processes involved in homeostasis of bone and cartilage tissues. Gene expression profiling studies have yielded novel insights into the complex interplay of osteoblast and osteoclast regulation, as well as paracrine and endocrine control of bone and cartilage remodelling. Mechanisms of new bone formation responsible for fracture healing and distraction osteogenesis, as well as healing of joint cartilage defects, have also been extensively studied. Microarray experiments have been especially useful in studying pathological processes involved in diseases such as osteoporosis or bone tumours. Existing results show that microarrays hold great promise in areas such as identification of targets for novel therapies or development of new biomarkers and classifiers in skeletal diseases.

Skeletal stem/osteoprogenitor cells: Current concepts, alternate hypotheses, and relationship to the bone remodeling compartment

Plastic adherent bone marrow stromal cells have become synonymous with skeletal stem cells, and perhaps rightfully so, as these cells have been extremely well characterized over the past four decades, since their original description by Friedenstein. However, although this cell population is useful as an experimental model of precursors for osteoblasts and other mesenchymal lineages, the precise role of bone marrow stromal cells in bone remodeling, fracture repair, or repair of non-skeletal tissues remains unclear. Moreover, there is a conceptual problem in terms of postulating that these cells are osteoblast precursors at sites of bone remodeling on trabecular surfaces adjacent to red marrow and yet having to posit potentially entirely different mechanisms for the origins of osteoblasts at sites of cortical bone remodeling distant from red marrow. Thus, the identification and characterization in recent years of non-adherent stem and osteoprogenitor cells in the bone marrow, of similar cells in the peripheral circulation, and of stem/osteoprogenitor cells arising either from the perivascular compartment (pericytes) or within the developing vascular wall itself, has suggested alternative candidate cell populations that may help to resolve the problem of postulating different mechanisms of remodeling in trabecular versus cortical bone. When coupled with our evolving understanding of the bone remodeling compartment (BRC), a closed cavity penetrated by capillaries which appears to be the site of remodeling in both trabecular and cortical bone, it is likely that our conceptual understanding of the fundamental mechanisms of bone remodeling will need to be modified.