Frost's Mechanostat Research Articles

Exploring neuronal mechanisms of osteosarcopenia in older adults.

Until recently, research on the pathogenesis and treatment of osteoporosis and sarcopenia has primarily focused on local and systemic humoral mechanisms, often overlooking neuronal mechanisms. However, there is a growing body of literature on the neuronal regulation of bone and skeletal muscle structure and function, which may provide insights into the pathogenesis of osteosarcopenia. This review aims to integrate these neuronal regulatory mechanisms to form a comprehensive understanding and inspire future research that could uncover novel strategies for preventing and treating osteosarcopenia. Specifically, the review explores the functional adaptation of weight-bearing bone to mechanical loading throughout evolutionary development, from Wolff's law and Frost's mechanostat theory to the mosaic hypothesis, which emphasizes neuronal regulation. The recently introduced bone osteoregulation reflex points to the importance of the osteocytic mechanoreceptive network as a receptor in this neuronal regulation mechanism. Finally, the review focuses on the bone myoregulation reflex, which is known as a mechanism by which bone loading regulates muscle functions neuronally. Considering the ageing-related regressive changes in the nerve fibres that provide both structural and functional regulation in bone and skeletal muscle tissue and the bone and muscle tissues they innervate, it is suggested that neuronal mechanisms might play a central role in explaining osteosarcopenia in older adults.

Adding mechanobiological cell features to finite element analysis of an immediately loaded dental implant.

Finite element analysis (FEA) has been used to analyze the behavior of dental materials, mainly in implantology. However, FEA is a mechanical analysis and few studies have tried to simulate the biological characteristics of the healing process of loaded implants. This study used the rule of mixtures to simulate the biological healing process of immediate implants in an alveolus socket and bone-implant junction interface through FEA. Three-dimensional geometric models of the structures were obtained, and material properties were derived from the literature. The rule of mixtures was used to simulate the healing periods-immediate and early loading, in which the concentration of each cell type, based on in vivo studies, influenced the final elastic moduli. A 100 N occlusal load was simulated in axial and oblique directions. The models were evaluated for maximum and minimum principal strains, and the bone overload was assessed through Frost's mechanostat. There was a higher strain concentration in the healing regions and cortical bone tissue near the cervical portion. The bone overload was higher in the immediate load condition. The method used in this study may help to simulate the biological healing process and could be useful to relate FEA results to clinical practice.

Clinical challenges of biomechanical performance of narrow-diameter implants in maxillary posterior teeth in aging patients: A finite element analysis.

This study evaluated the biomechanical performance of narrow-diameter implant (NDI) treatment in atrophic maxillary posterior teeth in aging patients by finite element analysis. The upper left posterior bone segment with first and second premolar teeth missing obtained from a patient's cone beam computed tomography data was simulated with cortical bone thicknesses of 0.5 and 1.0 mm. Three model groups were analyzed. The Regimen group had NDIs of 3.3 × 10 mm in length with non-splinted crowns. Experimental-1 group had NDIs of 3.0 × 10 mm in length with non-splinted crowns and Experimental-2 group had NDIs of 3.0 × 10 mm in length with splinted crowns. The applied load was 56.9 N in three directions: axial (along the implant axis), oblique at 30° (30° to the bucco-palatal plane compared to the vertical axis of the tooth), and lateral load at 90° (90° in the bucco-palatal plane compared to the vertical axis of the tooth). The results of the von Mises stress on the implant fixture, the elastic strain, and principal value of stress on the crestal marginal bone were analyzed. The axial load direction was comparable in the von Mises stress values in all groups, which indicated it was not necessary to use splinted crowns. The elastic strain values in the axial and oblique directions were within the limits of Frost's mechanostat theory. The principal value of stress in all groups were under the threshold of the compressive stress and tensile strength of cortical bone. In the oblique and lateral directions, the splinted crown showed better results for both the von Mises stress, elastic strain, and principal value of stress than the non-splinted crown. In conclusion, category 2 NDIs can be used in the upper premolar region of aging patients in the case of insufficient bone for category 3 NDI restorations.

Changes in adipose bone marrow and bone morphology in X-linked hypophosphatemic rickets

IntroductionX-linked hypophosphatemic (XLH) rickets causes significant bone deformities in the lower limbs resulting from a bone mineralization defect. According to Frost's Mechanostat theory, compensatory modeling of the bones takes place during increased mechanical loads. In addition, mechanical stimuli modulate the differentiation of mesenchymal stem cells; common precursors to bone marrow adipocytes and osteoblasts. HypothesisBone deformities of the lower limbs lead to increased femoral bone mass and decreased fatty infiltration of the bone marrow (FIBM) in children with XLH rickets compared to a control group. Patients and methodsEleven children (10.3years [6–17]) with XLH rickets and 22 healthy children (10.2years [5–15.5]) underwent lower limb Magnetic Resonance Imaging. A calculation of FIBM was performed at the mid-femur, as well as a calculation of the total bone cross-sectional area (CSA), the cortical CSA, the anteroposterior and mediolateral axes of the femur, bone marrow and the thickness of the femoral cortices. ResultsTotal bone CSA, total cortical CSA and bone marrow CSA were higher in the XLH group than in the control group (p<0.05). The mid-lateral diameters of the femur and bone marrow were more elongated than those of the control group (p<0.001). Only the anterior cortex was thinned in the XLH group (p=0.001), while there was no difference with the control group for the posterior, medial and lateral cortices. The total percentage of FIBM was 72.81% [±3.95] and 77.4% [±5.52] for the XLH and control groups respectively (p<0.001). DiscussionThe increase in bone mass in the XLH population reflects an adaptation of bone tissue to the bone deformities present in this pathology. The decrease in FIBM indicates a lower risk of osteoporosis in the XLH population and may constitute a new monitoring parameter in this pathology. Level of studyIII; Case-control study.

Combined Effects of Exercise and Denosumab Treatment on Local Failure in Post-menopausal Osteoporosis-Insights from Bone Remodelling Simulations Accounting for Mineralisation and Damage.

Denosumab has been shown to increase bone mineral density (BMD) and reduce the fracture risk in patients with post-menopausal osteoporosis (PMO). Increase in BMD is linked with an increase in bone matrix mineralisation due to suppression of bone remodelling. However, denosumab anti-resorptive action also leads to an increase in fatigue microdamage, which may ultimately lead to an increased fracture risk. A novel mechanobiological model of bone remodelling was developed to investigate how these counter-acting mechanisms are affected both by exercise and long-term denosumab treatment. This model incorporates Frost's mechanostat feedback, a bone mineralisation algorithm and an evolution law for microdamage accumulation. Mechanical disuse and microdamage were assumed to stimulate RANKL production, which modulates activation frequency of basic multicellular units in bone remodelling. This mechanical feedback mechanism controls removal of excess bone mass and microdamage. Furthermore, a novel measure of bone local failure due to instantaneous overloading was developed. Numerical simulations indicate that trabecular bone volume fraction and bone matrix damage are determined by the respective bone turnover and homeostatic loading conditions. PMO patients treated with the currently WHO-approved dose of denosumab (60 mg administrated every 6 months) exhibit increased BMD, increased bone ash fraction and damage. In untreated patients, BMD will significantly decrease, as will ash fraction; while damage will increase. The model predicted that, depending on the time elapsed between the onset of PMO and the beginning of treatment, BMD slowly converges to the same steady-state value, while damage is low in patients treated soon after the onset of the disease and high in patients having PMO for a longer period. The simulations show that late treatment PMO patients have a significantly higher risk of local failure compared to patients that are treated soon after the onset of the disease. Furthermore, overloading resulted in an increase of BMD, but also in a faster increase of damage, which may consequently promote the risk of fracture, specially in late treatment scenarios. In case of mechanical disuse, the model predicted reduced BMD gains due to denosumab, while no significant change in damage occurred, thus leading to an increased risk of local failure compared to habitual loading.

The Segond fracture occurs at the site of lowest sub-entheseal trabecular bone volume fraction on the tibial plateau.

In a series of human cadaveric experiments, Dr. Paul Segond first described the avulsion injury occurring at the anterolateral tibial plateau that later took his name. The fracture is thought to arise as a consequence of excessive tibia internal rotation which often also elicits damage to other connective tissue of the knee. The exact mechanism behind the avulsion is, however, unclear. A number of ligamentous structures have been proposed in separate studies to insert into the Segond fragment. Suggestions include the iliotibial band (ITB), biceps femoris and the controversial ‘anterolateral ligament’ (ALL). Despite increasing knowledge of tibial plateau bony microarchitecture in both healthy and disease states, no studies have yet, to our knowledge, considered the role of tibial sub‐entheseal bone structure in pathogenesis of the Segond fracture. The goal of this study was thus to elucidate the differences in trabecular properties at regions across the tibial plateau in order to provide an explanation for the susceptibility of the anterolateral region to avulsion injury. Twenty human tibial plateaus from cadaveric donors were dissected and imaged using a Nikon‐XTH225‐μCT scanner with <80 μm isotropic voxel size. Scans were reconstructed using MicroView 3D Image Viewer and Analysis Tool. Subsequent virtual biopsy at ten anatomically defined regions of interest (ROI) generated estimates of bone volume fraction (‘bone volume divided by total volume’ (BV/TV)). The overall mean BV/TV value across all 20 tibiae and all 10 ROIs was 0.271. Univariate repeated‐measurements ANOVA demonstrated that BV/TV values differed between ROIs. BV/TV values at the Segond site (Sα, Sβ or Sγ) were lower than all other ROIs at 0.195, 0.192 and 0.193, respectively. This suggests that, notwithstanding inter‐ and intra‐specimen variation, the Segond site tends to have a lower trabecular bone volume fraction than entheseal sites elsewhere on the tibia. Since BV/TV correlates with tensile and torsional strength, the lower BV/TV at the Segond site could equate to a region of local weakness in certain individuals which predisposes them to an avulsion injury following the application of force from excessive internal rotation. The low BV/TV recorded at the Segond site also challenges the idea that the fracture occurs due to pull from a discrete ‘anterolateral ligament’, as the tension exerted focally would be expected to elicit a hypertrophic response in line with Frost's Mechanostat hypothesis. Our data would instead agree with the aforementioned reports of the fibrous band at the Segond site being part of a broader insertion of an ‘anterolateral complex’.

Effect of different biocompatible implant materials on the mechanical stability of dental implants under excessive oblique load.

Metallic implants such as titanium are much harder than the neighboring bone. This high difference may generate larger stress at the bone-implant interface during load transfer which leads to implant failure. The use of biocompatible polymer such as CRF-polyether ether ketone (PEEK) with strength comparable with the bone might lead to lower and better stress distribution to the supporting peri-implant bone. The aim of this study is to investigate the effect of using carbon reinforced PEEK composite material for fixture/abutment on stress distribution in peri-implant bone. Three-dimensional (3D) model of dental implant placed in the first mandibular molar is constructed from computed tomography scan. Five distinct models using a combination of titanium, CRF-PEEK, lithium disilicate for implant/abutment materials are studied. 3D finite element analysis (FEA) is used to evaluate the stress distribution at implant-bone interface under excessive oblique load. The physical interaction between several contacting bodies is numerically investigated. The effect of friction coefficients between the indenter and occlusal surface and between the implant and peri-implant bone is determined. FEA results show that there is no significant difference in the distribution pattern of stress at implant-bone interface among the different material models studied. The highest maximum and lowest minimum principal stresses were always located in the cortical bone and never in the cancellous bone which is consistent with the existing literature. Off-axis loading can result in unfavorable forces on the implant, jeopardizing the long-term success because of excessive lateral loads. Current FEA results agree with previously published work. Substitution of titanium implant by PEEK implant does not provide any advantages in regards to better stress distribution to the peri-implant bone. The strain thresholds of Frost's mechanostat theory that are suitable for long bone could not be applied for alveolar bone.

Number and localization of the implants for the fixed prosthetic reconstructions: On the strain in the anterior maxillary region

Resorption following tooth loss and poor bone quality affect the success of implants in the anterior maxilla. Inappropriate planning can cause implant loss and aesthetics problems that are difficult to resolve. There is a limited literature on the optimum number and location of implants in anterior maxilla for fabricating fixed prosthesis in biomechanical terms. This study investigated the effect of dental implant localizations in anterior maxilla on the strain values around implants using a three dimensional finite elements analysis method. Obtained strain values were compared to the data in Frost's mechanostat theory. The entire totally edentulous maxilla was modeled using computer tomography images and five models were prepared representing different implant localizations. The distribution of implants in the models was as follows: two canines in the first model, two canines and one central incisor in the second model, two canines and central incisor in the third model, two canines and one lateral incisor in the fourth model and two canines and two lateral incisors in the fifth model. Anatomic abutments with a gingival height of 2 mm and angle of 15° were used as the abutments to fabricate one piece cemented metal fused to porcelain restoration. A chewing strength of 100 N was applied to the cingulum of all crowns at a 45° angle. Maximum strain values in all models were measured in cortical bone in implant necks. The highest strain value was measured in the first model at the cortical bone area (3037 microstrain). Except the first model, all models showed micro strain values within 1000–3000 microstrain. The fifth model was the least risky method in biomechanical terms. The results of this study should be compared with different clinical scenarios (for example different implant designs and sizes). Due to the limitations of three-dimensional finite elements analysis studies, the findings of the study need to be supported by clinical studies.

Site and Sex Effects on Tibia Structure in Distance Runners and Untrained People

The purpose was to study the relationship between mechanical environment and bone structure by comparing the tibia in people with different physical activities. Indicators of bone mass (bone mineral content), bone material "quality" (cortical volumetric mineral density (vBMD)), and diaphyseal design (endocortical and periosteal perimeters (EcPm and PoPm, respectively), cortical thickness (CtTh), circularity, and bending and torsion cross-sectional moments of inertia (CSMIs)) were determined in serial peripheral quantitative computed tomography scans taken at 5% steps of the tibia in 40 voluntary men and women age 25-40 yr who were either physically inactive or experienced distance runners (n = 10-12 per group). Bone mass and design indicators were higher in runner than in nonrunner men, with a variable effect size along the tibia. In the distal tibia, runners had enhanced bone mineral content and CtTh (resistance to compression), but EcPm, PoPm, circularity, and CSMI were unaffected. In the midshaft, CSMIs (resistance to bending/torsion) were enhanced in runners, whereas bone mass was unaffected. In the proximal third, effects were observed for CtTh, EcPm, and PoPm. In female runners, these benefits were restricted to CSMIs only. Cortical vBMD, naturally lower in men than in women, was reduced in runners of either sex. Results are coherent with previous findings in physically inactive people and with Frost's mechanostat theory. The observed group differences in cortical vBMD could reflect an increase in intracortical porosity (enhanced remodeling for damage repair), eventually compensated biomechanically by CSMI improvements. The sex specificity of exercise effects may suggest the interference by the endocrine environment. Results confirm that the mechanical environment is a strong determinant of regional tibia structure and suggest that the endocrine environment may reduce the effects of physical interventions on bone health in fertile women.

A Semi-Empirical Cell Dynamics Model for Bone Turnover Under External Stimulus

The normal periodic turnover of bone is referred to as remodeling. In remodeling, old or damaged bone is removed during a 'resorption' phase and new bone is formed in its place during a 'formation' phase in a sequence of events known as coupling. Resorption is preceded by an 'activation' phase in which the signal to remodel is initiated and transmitted. Remodeling is known to involve the interaction of external stimuli, bone cells, calcium and phosphate ions, and several proteins, hormones, molecules, and factors. In this study, a semi-empirical cell dynamics model for bone remodeling under external stimulus that accounts for the interaction between bone mass, bone fluid calcium, bone calcium, and all three major bone cell types, is presented. The model is formulated to mimic biological coupling by solving separately and sequentially systems of ODEs for the activation, resorption, and formation phases of bone remodeling. The charateristic time for resorption (20 days) and the amount of resorption (~0.5%) are fixed for all simulations, but the formation time at turnover is an output of the model. The model was used to investigate the effects of different types of strain stimuli on bone turnover under bone fluid calcium balance and imbalance conditions. For bone fluid calcium balance, the model predicts complete turnover after 130 days of formation under constant 1000 microstrain stimulus; after 47 days of formation under constant 2000 microstrain stimulus; after 173 days of formation under strain-free conditions, and after 80 days of formation under monotonic increasing strain stimulus from 1000 to 2000 microstrain. For bone fluid calcium imbalance, the model predicts that complete turnover occurs after 261 days of formation under constant 1000 microstrain stimulus and that turnover never occurs under strain-free conditions. These predictions were not impacted by mean dynamic input strain stimuli of 1000 and 2000 microstrain at 1 Hz and 1000 microstrain amplitude. The formation phase of remodeling lasts longer than the resorption phase, increased strain stimulus accelerates bone turnover, while absence of strain significantly delays or prevents it, and formation time for turnover under monotonic increasing strain conditions is intermediate to those for constant strain stimuli at the minimum and maximum monotonic strain levels. These results are consistent with the biology, and with Frost's mechanostat theory.

Wolffの法則とFrostの理論からレーザー刺激と骨再生を考える

Recently, osteocytes embedded in mineralized matrix have attracted much research attention as they are thought to translate mechanical loading into biochemical signals that affect bone (re) modeling. In order to understand the biological mechanisms by which osteocytes control bone formation and resorption under mechanical force, we conducted a study in the light of Wolff's Law and Frost's mechanical thresholds theory. The findings indicate that mechanical stress can be used for bone regeneration therapy. We have demonstrated that carbon dioxide laser irradiation induces bone formation, and that laser irradiation is a kind of mechanical force and so could be used for bone regeneration therapy. Here, we review how laser irradiation influences bone metabolism via osteocytes on the basis of Wolff's Law and Frost's mechanostat thresholds theory.

Influence of tooth removal on mandibular bone response to mastication

The quantification of biomechanical response of mandibular bone to mastication is an integral component for a key in understanding the biological consequence of masticatory functions. Understanding the response of mandibular bone to external loading may also well explain the mechanisms of bone turnover. In this study, three finite element (FE) models simulating the lower second premolar, first and second molars along with their supporting structures were developed to determine stress/strain levels and distribution under different occlusal loading. The changes in stress/strain values and profiles have been investigated in three scenarios: pre-extraction of the lower first molar, post-extraction and after full healing of the extracted socket. The mastication induced equivalent strains within the supporting mandibular bone at each of these three scenarios were quantified and compared against the Frost's mechanostat theory. The results of stress/strain profiles show considerably lower magnitudes in the post-extracted and healed scenarios compared with the pre-extraction case. Following the Frost's MES hypothesis, the initial equivalent strains are related to local bone remodelling. It is found that in the extracted case the bone near the tooth socket undergoes resorption from lingual respect whilst filling the cavity, whereas in the healed case bone turnover reaches equilibrium. The results provide important data for clinical assessment of constructing dentures or other restorative devices.

Functional significance of strain distribution in the human mandible under masticatory load: Numerical predictions

A common feature of studies of mandibular morphology is the assumption that there is some functional relation between the form of the lower jaw and masticatory stress. It was noted that the local variation in cortical bone thickness in the mandibular corpus appears to be stereotypical among anthropoids. This occurs at sections under the molars, where the lingual cortical plate is thinner than buccal one. In this study we investigate and contrast the strain pattern along buccal and lingual surfaces of the mandibular corpus during mastication using a numerical model of a human mandible. We show that strain distribution differs in alveolar and mid-corpus segments of the mandible and that the latter develops an alternate pattern between the buccal and lingual aspects of the working and balancing sides of the jaw. We then relate the magnitude of these strains to Frost's mechanostat. Our results suggest that the cortical asymmetry of the human mandible is in fact not related to strain patterns generated during mastication.

The past, present, and future of bone morphometry: its contribution to an improved understanding of bone biology.

It was not until the 1950s that a better paradigm for bone biology evolved, which led to the birth of bone histomorphometry. Two clinicians, Harold Frost (1958-1964) and Lent Johnson (1964), were responsible for the paradigm stating that the primary function of bone is mechanical load bearing with subsidiary function to participate in plasma calcium homeostasis to support hematopoesis. Dynamic bone histomorphometry was born when Milch et al. (1958) discovered bone localization of tetracycline and Frost generated the methodology to study tetracycline-based dynamic histological analysis of cortical bone remodeling (1961-1965). Dynamic bone histomorphometry did not blossom until Frost, while a Sun Valley Workshop participant, developed it to address trabecular bone dynamics. The combination of Arnold (1948) producing thin sections of plastic-embedded undecalcified bone and Frost's (1977-1983) modification of dynamic cortical bone histology for cancellous bone made it possible to study tetracycline-based dynamic histomorphometry of cancellous bone. It led to the better understanding of basic metabolic unit (BMU) remodelling and to Frost's mechanostat hypothesis, and characterized the rat model to accelerate the development of several drugs in the treatment of bone diseases. Currently, dynamic bone histomorphometry has contributed to studies in bone's mechanical usage windows, mechanical usage setpoint hypothesis, muscle-bone relations, marrow-bone relations, the Utah paradigm of musculoskeletal physiology, apoptosis, genetics (transgenic mice) and bone structure, bone quality, the lacunocanalicular network and bone modelling, and remodeling hypothesis, osteocyte role as mechanosensory, chemosensory, and regulatory in bone maintenance, targeted and untargeted remodeling, the role of permissive agents, etc., items in bone biology expounded briefly by Lent Johnson (1965) and continuously by Harold Frost at the Sun Valley Workshop (1965-2003). Finally, "What's next?" covers how to improve and perpetuate the employing of qualitative histomorphometry in research opportunities in hard tissue research.

A theoretical analysis of long-term bisphosphonate effects on trabecular bone volume and microdamage

Bisphosphonates increase bone mass and reduce fracture risk, but their anti-resorptive action may lead to increases in fatigue microdamage. To investigate how bisphosphonate effects influence changes in bone volume and microdamage in the long term, a strain-adaptive model of bone remodeling and microdamage balance was developed for a continuum-level volume of postmenopausal trabecular bone by invoking Frost's mechanostat hypothesis. Both disuse and fatigue microdamage were assumed to stimulate the activation frequency of basic multicellular units (BMUs) such that bone remodeling served to remove excess bone mass and microdamage. Bisphosphonate effects were simulated as follows: low, intermediate, high, or complete suppression of BMU activation frequency either without a change in resorption by the BMU or with an independent decrease in resorption while the bone formation process was unaffected (i.e., formation initially exceeded resorption). Of the bisphosphonate effects, a reduction in resorption relative to formation dictated the long-term gain in bone volume while the potency of activation frequency suppression controlled the rate of gain. A plateau in the bone mass gain that typically occurs in clinical studies of bisphosphonate treatment was predicted by the model because the resultant reduction in strain forced bone formation by the BMU to decrease over time until it matched the reduction in BMU resorption. A greater suppression of activation frequency proportionally increased microdamage, but the accumulation was limited over the long term as long as remodeling was incompletely suppressed. The results of the model suggest creating bisphosphonates that provide minimal suppression of remodeling and a large decrease in BMU resorption because this would minimize damage accumulation and increase bone mass, respectively.

The regulation of bone development as a biological system

A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often, events at the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost's mechanostat theory. In this model, the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone.

The developing bone: slave or master of its cells and molecules?

A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often events on the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost's mechanostat theory. In this model the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone. When mechanical challenges exceed an acceptable level (the mechanostat set point), bone tissue is added at the location where it is mechanically necessary. The main mechanical challenges during growth result from increases in bone length and in muscle force. Hormones, nutrition, and environmental factors exert an effect on bone either directly by modifying the mechanostat system or indirectly by influencing longitudinal bone growth or muscle force. Predictions based on this model are in accordance with observations on prenatal, early postnatal, and pubertal bone development. We propose that future studies on bone development should address topics that can be derived from the mechanostat model.

Modeling and remodeling in a developing artiodactyl calcaneus: a model for evaluating Frost's Mechanostat hypothesis and its corollaries.

The artiodactyl (mule deer) calcaneus was examined for structural and material features that represent regional differences in cortical bone modeling and remodeling activities. Cortical thickness, resorption and formation surfaces, mineral content (percent ash), and microstructure were quantified between and within skeletally immature and mature bones. These features were examined to see if they are consistent with predictions of Frost's Mechanostat paradigm of mechanically induced bone adaptation in a maturing "tension/compression" bone (Frost, 1990a,b, Anat Rec 226:403-413, 414-422). Consistent with Frost's hypothesis that surface modeling activities differ between the "compression" (cranial) and "tension" (caudal) cortices, the elliptical cross-section of the calcaneal diaphysis becomes more elongated in the direction of bending as a result of preferential (> 95%) increase in thickness of the compression cortex. Regional differences in mineral content and population densities of new remodeling events (NREs = resorption spaces plus newly forming secondary osteons) support Frost's hypothesis that intracortical remodeling activities differ between the opposing cortices: 1.) in immature and mature bones, the compression cortex had attained a level of mineralization averaging 8.9 and 6.8% greater (P < 0.001), respectively, than that of the tension cortex, and 2.) there are on average 350 to 400% greater population densities of NREs in the tension cortices of both age groups (P < 0.0003). No significant differences in cortical thickness, mineral content, porosity, or NREs were found between medial and lateral cortices of the skeletally mature bones, suggesting that no modeling or remodeling differences exist along a theoretical neutral axis. However, in mature bones these cortices differed considerably in secondary osteon cross-sectional area and population density. Consistent with Frost's hypothesis, remodeling in the compression cortex produced bone with microstructural organization that differs from the tension cortex. However, the increased remodeling activity of the tension cortex does not appear to be related to a postulated low-strain environment. Although most findings are consistent with predictions of Frost's Mechanostat paradigm, there are several notable inconsistencies. Additional studies are needed to elucidate the nature of the mechanisms that govern the modeling and remodeling activities that produce and maintain normal bone. It is proposed that the artiodactyl calcaneus will provide a useful experimental model for these studies.

Biomechanical implications of mineral content and microstructural variations in cortical bone of horse, elk, and sheep calcanei.

Artiodactyl and perissodactyl calcanei have been recently introduced as models for examining bone for mechanically mediated adaptation. We have reported substantial regional variations in cortical bone microstructure and mineral content within the same cross-section of mule deer calcanei. In part, these variations may be adaptations accommodating the customary presence of predominantly tension, compression, and shear strain modes in mutually exclusive cortical locations. Calcanei from skeletally mature horses, elk, and sheep were examined in order to corroborate these previous findings. From each species, one calcaneus was obtained from each of 13 animals. Each bone was cut transversely near mid-shaft into two segments and examined for mineral (ash) content. From each species, an additional segment obtained from each of 7 of the original 13 bones was examined for microstructure using 50x backscattered electron images. Regions examined included the compression (cranial), tension (caudal), and medial and lateral (shear) cortices. Periosteal (P), middle (M), and endosteal (E) regions were also examined separately within the compression and tension cortices. Quantified microstructural parameters included: (1) secondary osteon population density (OPD), (2) fractional area of secondary bone (FASB), (3) porosity, (4) population density of new remodeling events (NRE = resorption spaces and newly forming secondary osteons), and (5) secondary osteon diameter and minimum-to-maximum chord ratio. Results in each species showed variations that are considered to be mechanically important and are similar to those reported in mule deer calcanei. Mineral content data suggest that remodeling activity in the compression, medial, and lateral cortices was occurring at a slower rate than remodeling in the tension cortex. In comparison to the tension cortices, the compression cortices have approximately 6.0% higher mineral content (P < 0.007) and 35% higher OPD (P < 0.01). Additionally, the compression cortices have more nearly perfectly round osteons and lower FASB, porosity, NRE, and osteon diameter (P < 0.05; except for FASB in horse where P = 0.087 and NRE in sheep where P = 0.520). However, patterns of microstructural variations between intracortical regions (P, M, E) are inconsistent when compared to data reported in mule deer calcanei. Microstructural characteristics between the medial and lateral cortices were similar although some significant differences were identified. In general, the microstructure of the medial and lateral cortices differ from the neighboring compression and tension cortices. Differences in mineral content and microstructure between opposing compression and tension cortices of these three species resemble differences previously reported in mule deer calcanei. The majority of the microstructural variations can be explained in the context of strain-magnitude-based rules of Frost's Mechanostat Theory of mechanically induced bone adaptation. These variations may also be strongly influenced by the strain mode predominating in each cortical location. The hypothesis that intracortical material adaptations are correlated with progressive transcortical strain magnitude variations is not supported by the inconsistent transcortical variations in material organization. These interpretations do not preclude the possibility that other specific strain features may contribute to a complex adaptive signal.

Skeletal adaptations to mechanical usage: results from tibial loading studies in rats.

Wolff's law defines a static relationship between stress trajectories and trabecular architecture. More recent theories have attempted to describe the dynamic relationship between the form of bone and its mechanical environment. Frost's mechanostat theory is unique among these in its distinction between modeling and remodeling processes, lamellar and woven bone formation, mechanical usage windows for activation and its application to disorders of bone and mineral metabolism. Our studies suggest that lamellar and woven bone formation are very different not only in histological appearance, but in the temporal characteristics of their formation. Thus, it is important to distinguish these two histological types when interpreting studies of adaptive bone formation. Studies using the in vivo 4-point bending model in rat tibiae show that static loads do not play a role in mechanotransduction and that bone formation is threshold-driven and dependent on strain rate, amplitude and duration of loading. They have also provided strong indirect evidence that mechanical strains cause interstitial fluid flow that, in turn, activates the bone cell response. Based on these observations, we hypothesize that strain rate determines the vigor of osteoblastic activity and the regularity of loading bouts determines osteoblast recruitment in a "quantum" fashion.