Bone “mass” and the “mechanostat”: A proposal

The observed fit of bone mass to a healthy animal's typical mechanical usage indicates some mechanism or mechanisms monitor that usage and control the three longitudinal growth, bone modeling, and BMU-based remodeling activities that directly determine bone mass. That mechanism could be named a mechanostat. Accumulated evidence suggests it includes the bone itself, plus mechanisms that transform its mechanical usage into appropriate signals, plus other mechanisms that detect those signals and then direct the above three biologic activities. In vivo studies have shown that bone strains in or above the 1500–3000 microstrain range cause bone modelling to increase cortical bone mass, while strains below the 100–300 microstrain range release BMU-based remodeling which then removes existing cortical-endosteal and trabecular bone. That arrangement provides a dual system in which bone modeling would adapt bone mass to gross overloading, while BMU-based remodeling would adapt bone mass to gross underloading, and the above strain ranges would be the approximate “setpoints” of those responses. The anatomical distribution of those mechanical usage effects are well known. If circulating agents or disease changed the effective setpoints of those responses their bone mass effects should copy the anatomical distribution of the mechanical usage effects. That seems to be the case for many agents and diseases, and several examples are discussed, including postmenopausal osteoporosis, fluoride effects, bone loss in orbit, and osteogenesis imperfecta. The mechanostat proposal is a seminal idea which fits diverse evidence but it requires critique and experimental study.     

Bone's mechanostat: a 2003 update

The still-evolving mechanostat hypothesis for bones inserts tissue-level realities into the former knowledge gap between bone's organ-level and cell-level realities. It concerns load-bearing bones in postnatal free-living bony vertebrates, physiologic bone loading, and how bones adapt their strength to the mechanical loads on them. Voluntary mechanical usage determines most of the postnatal strength of healthy bones in ways that minimize nontraumatic fractures and create a bone-strength safety factor. The mechanostat hypothesis predicts 32 things that occur, including the gross anatomical bone abnormalities in osteogenesis imperfecta; it distinguishes postnatal situations from baseline conditions at birth; it distinguishes bones that carry typical voluntary loads from bones that have other chief functions; and it distinguishes traumatic from nontraumatic fractures. It provides functional definitions of mechanical bone competence, bone quality, osteopenias, and osteoporoses. It includes permissive hormonal and other effects on bones, a marrow mediator mechanism, some limitations of clinical densitometry, a cause of bone "mass" plateaus during treatment, an "adaptational lag" in some children, and some vibration effects on bones. The mechanostat hypothesis may have analogs in nonosseous skeletal organs as well.     

Adaptation of diaphyseal structure with aging and increased mechanical usage in the adult rat: a histomorphometrical and biomechanical study

The experimental increase in mechanical usage or overloading of the left hindlimb was produced by immobilization of the contralateral hindlimb. The right hindlimb was placed in a flexed position against the body and was immobilized using an elastic bandage. Some control animals were sacrificed initially at time zero and increased mechanical usage and age-matched control animals were sacrificed after 2, 10, 18, and 26 weeks of treatment. All animals received double bone fluorochrome labeling prior to sacrifice. Cortical bone histomorphometry and cross-sectional moments of inertia were determined. Marrow cavity enlargement and total cross-sectional area expansion represented the age-related cortical bone changes. Increased mechanical usage enhanced periosteal bone modeling in the formation mode and dampened endocortical bone remodeling and bone modeling in the resorption mode (resorption drift) to create a slight positive bone balance. These observations are in general agreement with Frost's postulate for mechanical effects on bone modeling and remodeling (Frost, H.M. 1987b. Bone "mass" and the "mechanostat." A proposal. Anat. Rec. 219: 1-9). The maximum moment of inertia did not change significantly in either control or overloaded tibial shafts. The minimum and polar moment of inertias in overloaded bones increases over those of controls at 18 and 26 weeks of the experiment.     

动载荷作用下骨重建力学调控机制

目的探讨动载荷作用下骨重建的力学调控机制。方法对骨重建力学调控机制进行分析,吸纳力学疲劳强度理论思想,提出动载荷作用下骨重建力学调控机制;选取损伤作为力学激励,建立动载荷骨重建模型;分析动态载荷成骨效果优于静态载荷现象,数值模拟运动防治骨质疏松。结果动态载荷成骨效果优于静态载荷现象得到较为合理的解释;运动量增加10%~30%,骨密度增加3.13%~8.61%。结论动载荷作用下骨重建的力学调控机制可为机械振动防治骨代谢相关疾病提供理论指导,是骨重建力学调控理论的补充和完善。     

Perspectives: A vital biomechanical model of the endochondral ossification mechanism

Background: Mechanical usage effects could explain many features of endochondral ossification and related processes. Mineralization of growth plate cartilage could reduce its mechanical strains enough to make its resorption begin and to guide it in space. By removing most of its mineralized vertical septae, resorption could overload the remainder enough to increase woven bone formation on them and construct the primary spongiosa. After it finishes mineralizing, the primary spongiosa could become stiff enough to begin partial disuse in strain terms, so BMU-based remodeling would begin replacing it with lamellar bone. This would construct the secondary spongiosa. In transferring loads from the growth plate to the cortex, the central metaphyseal spongiosa becomes deloaded. This disuse would make remodeling remove it in the diaphyseal marrow space. Methods: The slow growth of epiphyses and apophyses gives their spongiosas more time to adapt to their loads than the metaphyseal spongiosa beneath faster growing growth plates. Compared to metaphyseal trabeculae, this leads to fewer and thicker epiphyseal trabeculae that turn over more slowly and should persist for life because they carry loads for life. Results: Rapid turnover of metaphyseal cortex in very young subjects could let it strain enough to form woven bone. Increased thickness and slower turnover of this cortex in older subjects could reduce its strains enough to make lamellar bone form there instead. This would compose this cortex mostly of woven bone in the very young and of lamellar bone in adults. Conclusions: This model assigns particular importance to the stiffness and strains of tissues (as distinguished from their strength and stresses), to the relative rates of some processes, and to responses of the skeleton's biologic mechanisms to a tissue's typical largest mechanical strains (as distinguished from their stresses). © 1994 Wiley-Liss, Inc.     

Skeletal structural adaptations to mechanical usage (SATMU): 2. Redefining Wolff's law: the remodeling problem

Basic multicellular unit (BMU)-based remodeling of lamellar bone causes bone turnover, net gains and losses of bone on some bone surfaces or "envelopes," and a remodeling space comprising bone temporarily absent due to evolving resorption spaces and incomplete refilling of them by new bone. Those features depend a) on how many new BMU arise annually, b) on how much bone each BMU has resorbed and c) formed upon its completion, and d) on how long the typical BMU takes to become completed. Because a, b, and c have limiting or maximal values in life that direct and/or indirect effects of mechanical usage of the skeleton can change, the theory presented here derives mechanical usage functions that express what fractions of those maxima a given mechanical usage history allows to happen. The theory predicts some changes in bone formation, resorption, balance, turnover, and remodeling space that depend on how remodeling responds to the vigor of a subject's mechanical usage. The theory can predict specific effects of specific mechanical challenges that experiments can test, and it fits abundant published evidence. As the kernel of a new approach to the problem it awaits critique and refinement by others. It plus the 3-way rule can redefine Wolff's law conceptually and also in mathematical and quantifiable form.     

骨功能适应性重建模型及数值模拟

骨骼会受到力学因素的影响和调控,发生骨功能适应性重建。建立模拟骨重建的数值模型,定量地研究骨重建过程,有着重要的临床应用价值。目前,骨功能适应性重建模型可分为两大类：力学模型和生理模型。对这两类重建模型的原理、算法和应用等做详细论述。力学模型通过假设力学环境与骨结构之间的函数关系来预测骨重建,但不考虑其真实的生物学过程。基于不同的重建激励主要有两种力学模型：骨力学稳态模型和骨损伤修复模型。生理模型则试图从微观层次阐明骨重建的力学-生物学机制,骨重建是由破骨细胞、成骨细胞等各种骨组织细胞完成,有以基本多细胞单位的形式作用或细胞独立分开作用两种观点。这些重建模型结合有限元法应用在许多有关骨重建问题的数值计算中。通过比较分析多个数值应用的模拟结果,还讨论了重建控制方程中各参数值的设置对重建结果的影响。     

带有力学调控系统的各向异性骨再造模型

目前，骨再造数值模型在生理上和力学上都不能复制骨再造的实际生理过程。本文引入了骨再造的生理机制和骨力学性质的各向异性，在损伤修复理论的基础上，建立了带有力学调控系统的各向异性骨再造模型，使骨再造的数值模拟趋向和生理过程一致，并以二维方板模型为例进行了计算机模拟，得到了和实际较为一致的结果。本模型可用于在一定力学环境下或力学环境改变后．骨结构的模拟，还可用于植入物植入后骨结构发生结构变化的模拟。     

Mechanobiological model of bone remodeling based on mechano-growth factors北大核心

BACKGROUND: Mechanotransduction is an issue of concern in the study on the relationship between stress and growth. Mechano-growth factor (MGF) holds stress sensitivity, and exerts similar effect with stress in bone metabolism regulation. OBJECTIVE: To explore the mechanotransduction during bone remodeling, and investigate the relationship between stress and growth at molecular level. METHODS: The governing equations about the relationship between MGF and mechanical stimulation, regulation of MGF on osteoblasts and osteoclasts, regulation of MGF on RANK-RANKL-OPG signaling axis were established, and then the MGF-mediated bone reconstruction model was established to simulate the bone remodeling process under mechanical stimulation. RESULTS AND CONCLUSION: Under the condition of disuse, there was a decrease in osteoblasts/osteoclasts ratio, bone mass and bone volume fraction, and bone resorption was more than bone formation. Under the condition of overload, there was an increase in osteoblasts/osteoclasts ratio, bone mass and bone volume fraction, and bone formation was more than bone resorption. The simulation results were in accordance with Frost mechanostat theory. These findings show that the mechanobiological model of bone remodeling based on MGF can simulate the bone remodeling process under mechanical stimuli, and achieve mechanotransduction. © 2017, Journal of Clinical Rehabilitative Tissue Engineering Research. All rights reserved.     

Bone mass,bone strength,muscle-bone interactions,osteopenias and osteoporoses

Densitometrically, the skeleton is currently conceived as 'a systemically regulated mass of mineralized material that is born, grows, reaches a more or less high peak, and then declines faster or slower as to develop a correspondingly high or low fracture risk'. Alternatively, from a biomechanical point of view, the skeleton can be conceived as 'a biomechanically-regulated structure that can be systemically disturbed (in the cybernetic sense), the strength of which depends on the intrinsic stiffness (material properties) and the spatial distribution (architectural properties) of the mineralized tissue'. The biomechanical feedback system involved (bone 'mechanostat') would not control bone mass to optimize bone strength; it would rather control bone material quality and architecture (through a modulation of bone modeling and remodeling) in order to optimize bone stiffness. The natural stimuli for the bone mechanostat would be the customary strains of bone tissue (sensed by osteocytes) that are induced by gravitational forces and, more importantly, the contractions of regional muscles. According to this view, the development of any bone-weakening disease should be related to either (1) an intrinsic illness of the system (primary disturbances of bone cells), (2) a lack of mechanical stimulation (disuse-induced bone losses), or (3) a systemically-induced shift of the system's setpoint (systemic or secondary bone diseases). This short review aims to conciliate those views: (1) taking profit of the diagnostic possibilities provided by densitometric bone 'mass' determinations; (2) proposing other resources to assess bone mechanical properties; and (3) analyzing the muscle-bone interactions. These are crucial for achieving a differential diagnosis between disuse and primary or secondary bone disturbances, based either (1) on the densitometric determination of bone and muscle masses that would provide an anthropometric diagnosis of osteopenia (not osteoporosis because no extrapolations to bone strength can be made this way) or (2) on the cross-sectional analyses of bone structure or strength and muscle strength provided by bone tomography, magnetic resonance or other techniques that could afford a diagnosis of osteoporosis according to biomechanical criteria.     

妇女骨质疏松过程及运动防治模拟

应用带有力学调控系统的各向异性骨再造模型结合有限元法,进行妇女骨质疏松过程及运动防治的模拟。研究结果表明:在骨量下降初始阶段,下降平缓,绝经后骨量丢失加速,60岁时,骨量下降25.84%~28.63%,80岁时,骨量下降38.50%~40.44%,运动使外荷提高10%~20%后,可使骨量增加3.05%~10.26%,上述结果与临床观察结果基本一致。证明了肌力下降是妇女骨质疏松的主要因素,绝经则加快了妇女骨质疏松的过程。运动可减缓骨质疏松。     

Biomechanical properties of anuran long bones: correlations with locomotor modes and habitat use

Long bones are subjected to mechanical loads during locomotion that will influence their biomechanical properties through a feedback mechanism (the bone mechanostat). This mechanism adapts the spatial distribution of the mineralized tissue to resist compression, bending and torsion. Among vertebrates, anurans represent an excellent group to study long bone properties because they vary widely in locomotor modes and habitat use, which enforce different skeletal loadings. In this study, we hypothesized that (a) the cortical bone mass, density and design of anuran femur and tibiofibula would reflect the mechanical influences of the different locomotor modes and habitat use, and (b) the relationships between the architectural efficiency of cortical design (cross-sectional moments of inertia) and the intrinsic stiffness of cortical tissue [cortical mineral density; the 'distribution/quality' (d/q) relationship] would describe some inter-specific differences in the efficiency of the bone mechanostat to improve bone design under different mechanical loads. To test this hypothesis, we determined tomographic (peripheral quantitative computed tomography) indicators of bone mass, mineralization, and design along the femur and tibiofibula of four anuran species with different modes of locomotion and use of habitat. We found inter-specific differences in all measures between the distal and proximal ends and mid-diaphysis of the bones. In general, terrestrial-hopper species had the highest values. Arboreal-walker species had the lowest values for all variables except for cortical bone mineral density, which was lowest in aquatic-swimmer species. The d/q relationships showed similar responses of bone modeling as a function of cortical stiffness for aquatic and arboreal species, whereas terrestrial-hoppers had higher values for moments of inertia regardless of the tissue compliance to be deformed. These results provide new evidence regarding the significant role of movement and habitat use in addition to the biomechanical properties of long bones within a morpho-functional and comparative context in anuran species.     

基于应力状态的细胞分子水平骨重建力生物学模型

目的建立基于应力状态的细胞分子水平骨重建力生物学模型。方法从工程角度分析骨重建过程和力学激励,吸纳力学强度设计理论思想,选取相当应力作为力学激励,基于应力状态选取合适的力学激励计算公式,提出基于应力状态的细胞分子水平骨重建力生物学模型;应用模型进行口腔临床正畸牙槽骨的模拟预测。结果张力区孔隙度降低,骨量增加;压力区孔隙度增加,骨量减少,与牙槽骨特性一致。结论基于应力状态的细胞分子水平骨重建力生物学模型考虑应力状态对骨组织失效形式的影响,体现骨重建过程是力学激励下细胞水平的自优化强度设计,有助于在细胞分子水平探讨应力状态对骨重建的影响,是骨重建理论的补充和完善,可为口腔正畸的治疗提供理论指导。     

Adaptation of diaphyseal structure to aging and decreased mechanical loading in the adult rat: a densitometric and histomorphometric study

Nine-month-old female rats were subjected to right hindlimb immobilization or served as controls for 0, 2, 10, 18, and 26 weeks. They were double-labeled with bone markers prior to sacrifice. Experimental unloading was produced by immobilizing the right limb against the abdomen with an elastic bandage. Single-photon absorptiometry was performed on the intact femurs; static and dynamic histomorphometry were performed on 20-micron thick toluidine blue-stained, undecalcified cross sections of the tibial shafts. Changes in the continuously immobilized tibiae were compared to those in both tibiae of age-matched controls. Unloading shut off nearly all periosteal bone formation and accelerates bone marrow expansion over that which occurs in age-related controls. The effect of unloading appeared to be mediated by recruiting fewer osteoblasts which showed inhibited activity. Furthermore, unloading increased endocortical percentage eroded surface. These histological changes lowered cortical bone mass by inhibiting diaphyseal cross sectional expansion and enlarging the bone marrow cavity. The results support Frost's suggestion that decrease mechanical usage depresses bone modeling-dependent bone gain by decreasing activation of modeling in the formation mode. It also stimulates bone remodeling-dependent bone loss by increasing activation of remodeling in the resorption mode.     

不同力学激励对骨重建数值模拟的影响

目的研究采用应变能密度、等效应力、等效应变3种不同力学激励对骨重建数值模拟结果的影响。方法建立股骨近端的二维有限元模型,基于力学稳态理论的重建控制方程并结合有限元法,分别用3种不同力学激励模拟股骨近端的内部结构及密度分布,并与CT数据计算得到的骨密度值进行定量分析比较。结果 3种力学激励模拟得到的重建结果均能反映出股骨近端的主要特征结构,但采用等效应力作为激励时得到的股骨密度曲线图的趋势和数值都与CT图像数据更为一致。结论在骨重建力学调控机制中,应力可能起主导作用。准确预测和模拟骨重建过程将对矫形外科、骨伤治疗、人工假体的优化和个体化设计等临床实践提供理论依据。     

Age‐related Changes in Marmoset Trabecular and Cortical Bone and Response to Alendronate Therapy Resemble Human Bone Physiology and Architecture

In older humans, bone elongation ceases, periosteal expansion continues, and bone remodeling remains a dominant metabolic process. An appropriate animal model of type I and type II osteoporosis would be a species with sealed growth plates and persistence of bone remodeling. The rat is commonly used as a primary model, but due to delayed epiphyseal closure with continuous modeling and lack of Haversian remodeling, Food and Drug Administration guidelines recommend assessment of bone quality in an additional, nonrodent, remodeling species. This study investigated the skeletal characteristics of senescent marmosets to evaluate their suitability as an osteoporosis model. Animals were randomized across three experimental groups; controls for both sexes and marmosets receiving alendronate for either 30 or 60 days (28 μg/kg, sc, twice per week). Outcome measures included serum chemistry and bone biomarkers, DEXA, histomorphometry, micro‐computed tomography, and histopathology. Results showed that the adult marmoset skeleton has similar anatomical characteristics to the adult human, including the absence of growth plates, presence of Haversian system, and true remodeling of cancellous and cortical bone. Structural analyses of senescent marmoset cancellous bone demonstrated loss of trabecular mass and architecture similar to skeletal changes described for elderly men and women. Treatment with alendronate improved trabecular volume and number by reducing bone resorption, although bone formation was also reduced through coupling of bone remodeling. The common marmoset may provide a valuable model for research paradigms targeting human bone pathology and osteoporosis due to skeletal features that are similar to age‐related changes and response to bisphosphonate therapy reported for humans. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.     

动态力学信号对人骨髓基质细胞、骨膜细胞生长和成骨表达的作用

目的 探讨动态力学信号对体外分离培养的人骨髓基质细胞、骨膜细胞生长与分化特征的生物学效应。方法 使用Flexcell应力系统，将频率为1Hz、振幅为5％变形、正弦波状力学信号作用于体外分离培养的正常人骨髓基质细胞和骨膜细胞，在不同时间段检测其对细胞DNA、总蛋白合成、碱性磷酸酶（ALP）表达和骨钙素分泌量的影响。结果 动态力学刺激对人骨髓基质细胞、骨膜细胞蛋白与DNA合成无明显作用。接受力学刺激信号后骨膜细胞受维生素D3刺激后分泌骨钙素显著增加，而骨髓基质细胞则显著下降。结论 动态力学信号能够促进人骨膜细胞向成骨细胞分化，这可能是其对骨的生物学作用的机制之一。     

成骨细胞和骨细胞的力学信号转导

背景:骨骼具有功能适应性的特点,骨骼细胞是力学信号敏感细胞,但细胞的力学信号转导功能是如何实现的,对骨骼如何调控仍不明确。 目的：了解成骨细胞和骨细胞的力学信号转导途径,为利用力学信号改善骨骼功能提供理论依据。 方法：应用计算机检索PubMed数据库2000-01/2011-03相关文献。英文检索词为“osteoblast,osteocyte,bone cells,mechanical stress”, 根据纳入标准共69篇文章进行综述,以此对骨骼细胞力学信号转导相关内容进行总结。 结果与结论：骨骼具有功能适应性的特点,骨骼细胞是力学信号敏感细胞,但细胞的力学信号转导功能是如何实现的,对骨骼具有怎样的调控仍不明确。研究表明,由于骨骼的结构特点和细胞位置,成骨细胞和骨细胞是最重要的力学敏感性细胞。力学信号在骨骼内的转导过程分为4个阶段：①力学偶联。②生化偶联。③信号的传递。④效应性细胞的反应。通过这4个阶段的作用,作用在骨骼上的应力信号转导为生物化学信号,并影响细胞的功能,最终导致骨骼组织出现相应的结构变化以适应应力环境的需要。对于力学信号在骨髓间充质干细胞中的调控机制还有待继续深入探索。     

Skeletal structural adaptations to mechanical usage (SATMU): 4. Mechanical influences on intact fibrous tissues

This paper proposes that the growth in length of living fibrous tissue structures (tendon, ligament, fascia) responds primarily to circulating systemic rather than mechanical factors. However, growth of the thickness of those structures responds primarily to their mechanical tension loads in the special sense that, when the tissue's typical peak mechanical strains exceed a threshold value, its cells begin to add new collagen to increase its thickness, strength, and tension stiffness. When subsequent peak strains reduce to the threshold value, then further additions of collagen stop. That process defines mechanically controlled modeling of fibrous tissues. The collagen in these tissues can also develop mechanical microdamage (MDx) under repeated tension load-deload cycles. Special maintenance mechanisms normally repair that MDx to prevent accumulations that would threaten structural integrity. As a result, spontaneous complete ruptures of these structures can happen when MDx production exceeds its repair. These maintenance mechanisms also prevent gradual stretching under continuous tension loads, a process the author suggests calling creep compensation. When the creep compensation mechanism becomes incompetent, structures can stretch under continuous loads; when it becomes overactive, contractures can occur. The above meld of fact and inference provides the kernel of a general theory for the responses of the architecture and mechanical competence of intact fibrous tissues to mechanical usage.     

Thermoelectroelastic solutions for surface bone remodeling under axial and transverse loads

Theoretical prediction of surface bone remodeling in the diaphysis of the long bone under various external loads are made within the framework of adaptive elastic theory. These loads include external lateral pressure, electric and thermal loads. Two solutions are presented for analyzing thermoelectroelastic problems of surface bone remodeling. The analytical solution that gives explicit formulation is capable of modeling homogeneous bone materials, while the semi-analytical solution is suitable for analyzing inhomogeneous cases. Numerical results are presented to verify the proposed formulation and to show the effects of mechanical, thermal and electric loads on surface bone remodeling process.