Multiscale Mechanobiology of Bone Remodeling and Adaptation (eBook)

Preface 7
Contents 9
Contributors 10
Functional Adaptation of Bone: The Mechanostat and Beyond 12
1 Introduction 13
2 Functional Adaptation: Origins and Evolution of the Mechanostat and Its Physiological Properties 15
2.1 Why Should Bones Respond to Exercise? 15
2.2 What Happens When Bones Respond to Exercise or a Lack of It? 15
2.3 Wolff's Law and the Mechanostat 16
2.4 What Initiates and Controls Bone's Adaptive Response? 17
2.5 Cellular and Molecular Machinery of the Mechanostat 18
3 Animal Models for Structural Adaptations to Mechanical Loading 24
3.1 Physiological Models 25
3.2 Externally Applied Loading Models 26
3.3 Surgical Approaches 26
3.4 Non-invasive Approaches 27
4 Bone Cell Responses to Loading: Involved Regulatory Factors, Receptors and Environmental Factors 30
4.1 Early Responses: ATP, Calcium, PGE2, Nitric Oxide 31
4.2 Oestrogen Receptor Involvement in Load Sensing 35
4.3 Intermediate Responses: RANKL and Wnt 37
4.4 Sclerostin as a Master Regulator of Mechanical Loading 39
5 Loading Physiology: Translating Findings from Animal Models to Clinical Applications in Humans 40
5.1 Changes of Bone Mass with Age 40
5.2 Effective Loading Characteristics 42
5.3 Translating Controlled Loading to Physical Activity 44
5.4 Maximising Bone Strength 45
5.5 Persistence of Childhood Bone Adaptation 45
6 In Silico Models of Bone Adaptation 46
6.1 Cowin's Theory of Adaptive Elasticity 48
6.2 Stanford Model of Daily Stress Stimulus 48
6.3 Huiskes' Strain Energy Density Model 50
6.4 Turner's Model of Dynamic Loading Stimulus 50
6.5 Recent Theories of Bone Adaptation 53
7 Conclusion 56
References 57
Application of Disease System Analysis to Osteoporosis: From Temporal to Spatio-Temporal Assessment of Disease Progression and Intervention 72
1 Introduction 73
2 Relationship Between Structure and Function of Bone: An Overview 76
2.1 Bone Structure and Function 76
2.2 Bone Physiology 79
3 Biomarkers Characterising Mass, Quality and Turnover of Bone 86
3.1 Bone Structure and Bone Mineral Density 86
3.2 Bone Turnover Markers 87
3.3 Characteristic Time Scale and Variability of Bone Biomarkers 89
4 Bone Pathology: Osteoporosis and Treatments 92
4.1 RANK-RANKL-OPG Pathway 92
4.2 Risk Factors for Osteoporosis and Osteoporotic Fractures 94
4.3 Current Diagnosis of Osteoporosis and Whole Bone Strength 94
4.4 Current and Emerging Treatments 95
5 Basics of Disease System Analysis 99
5.1 PK/PD Modelling 99
5.2 Disease Progression Analysis 105
6 Disease System Analysis of Osteoporosis 112
6.1 Denosumab PK Model 113
6.2 Mechanistic PK/PD Model of Osteoporosis 115
6.3 Modelling Disease Progression in PMO 118
6.4 Modelling the Action of Denosumab 119
6.5 Numerical Simulations 120
7 Summary and Conclusions 122
References 123
3 Musculoskeletal Modelling and the Physiome Project 133
1 The Physiome Project 134
1.1 Introduction 134
1.2 History of the Physiome Project 134
1.3 Objectives of the Physiome Project 135
1.4 Recent Developments and Future Directions for the Physiome Project 137
2 Geometrical Musculoskeletal Modelling 139
2.1 Challenges in Subject-Specific Modelling 139
2.2 Geometry Development 140
2.3 Subject-Specific Customisation 142
2.4 Conclusions 145
3 Musculoskeletal Statistical Shape Analysis 145
3.1 Introduction 146
3.2 Training the Femur Shape Model 147
3.3 Automatic Femoral Cortex Segmentation 150
3.4 Model Generation and the Musculoskeletal Atlas Project 152
3.5 Conclusions 157
4 Modelling Towards a Clinical Tool 157
4.1 Introduction 157
4.2 Generation of FE Models from Clinical CT Datasets and Model Validation 158
4.3 Development and Validation of Retroacetabular Osteolytic Defect Model 160
4.4 Investigation of Osteolytic Defects with Clinical CT Data 162
5 Understanding the Mechanical Aetiology of Musculoskeletal Injury and Disease using EMG-Informed Muscle Modelling and Medical Imaging 166
5.1 Introduction 166
5.2 Estimating Muscle Forces Using EMG 167
5.3 Anatomical Model of the Musculoskeletal System 167
5.4 EMG-to-Activation Model 169
5.5 Hill-Type Muscle Model 170
5.6 Calibration 171
5.7 Accounting for Missing EMGs and Errors in EMGs 172
5.8 Validation 173
5.9 Application 173
5.10 PET-CT Imaging 175
5.11 Conclusions 176
References 177
Review of ``Universal'' Rules Governing Bone Composition, Organization, and Elasticity Across Organizational Hierarchies 185
1 Introduction 188
2 Morphological Patterns of Bone 189
3 Mineral and Collagen Dosages in Extracellular Bone Matrix 191
4 Mineral Distribution in Extracellular Bone Matrix 203
5 Hydration-Dependent Evolution of Unmineralized Collagenous Tissues 206
6 Bone Tissue Evolution During Mineralization 210
7 Nano- and Microstructural Patterns Governing Anisotropic Tissue Elasticity 216
8 Concluding Remarks 231
References 233
Computational Biomechanics of Bone Adaptation by Remodeling 240
1 Introduction 240
2 From the Macroscopic Structure to the Microscopic Cellular Responses of Bone 241
2.1 Hierarchical Structure of Bone 241
2.2 Bone Remodeling Regulation by Mechanical Stimuli 241
2.3 The Mechanobiology of Osteocytes 242
3 The Mathematical Modeling and Computational Biomechanics Approach 243
3.1 Classic Mathematical Models of Mechanical Adaptation by Bone Remodeling 243
3.2 Mechanosensing and Communication of Osteocytes 243
3.3 Flow Analysis Within Bone Canaliculi Using an Image-Based Model 244
4 Modeling Mechanosensing Osteocytes in Bone Adaptation 244
4.1 Cellular Mechanosensing 244
4.2 Intercellular Signal Transmission 247
4.3 Trabecular Surface Movement 247
5 Adaptation of a Single Trabecula to a Bending Load 248
5.1 Voxel Finite Element Model of a Single Trabecula 248
5.2 Results: Changes in Single Trabecular Morphology 250
5.3 Discussion 252
6 Adaptation of Cancellous Bone Tissue 253
6.1 Voxel Finite Element Model of Cancellous Bone 254
6.2 Results: Changes in Cancellous Bone Morphology 255
6.3 Results: Distributions of Equivalent Stress 256
6.4 Discussion 257
7 Mathematical Modeling of Spatiotemporal Dynamics at Microscopic Level 259
7.1 Remodeling of Trabeculae and Osteons 260
7.2 An Example of Osteoclast Differentiation Signals 261
7.3 Mathematical Modeling of Signaling Molecules in Bone Remodeling 261
8 Computer Simulations of Trabecular and Osteonal Remodeling 262
8.1 Trabecular Remodeling Simulation 262
8.2 Osteonal Remodeling Simulation 262
9 Conclusion 264
References 264
Biology of Bone and the Interaction of Bone with Other Organ Systems 267
1 Introduction 268
2 Biology of Bone 268
2.1 Bone Tissue 268
2.2 Bone Matrix 269
2.3 Bone Cells 269
3 Interaction of Bone with Muscle 271
3.1 Integration of Muscle and Bone 271
3.2 Muscle Imparts Strain in Bone 272
3.3 Bone Loading and Bone Homeostasis 273
3.4 Mechanotransduction in Bone 274
3.5 Myokines and Bone 275
3.6 Muscle and Fracture Repair 276
4 Interaction of Bone with the Vasculature 276
4.1 Bone Tissue Vasculature 277
4.2 Relationship Between Blood Vessels and Bone Remodelling 277
4.3 Bone Vasculature in Fracture and Bone Regeneration 279
4.4 Bone Vasculature and Surgical Intervention 279
4.5 Bone Vasculature and Osteoporosis 280
4.6 Bone Vasculature and Osteoarthritis 280
5 Interaction of Bone with Cartilage 281
5.1 Cartilage: Bone Interface 281
5.2 Subchondral Bone Vasculature 281
5.3 Chondrocyte-Osteoblast Interaction 282
5.4 Bone Remodelling in OA 283
5.5 The Potential Role of TGF? in OA 283
5.6 The Significance of Bone Marrow Lesions 284
6 Interaction of Bone with the Central Nervous System 284
6.1 Nerves in Bone 284
6.2 Hypothalamic Control of Bone 285
6.3 Functions of Nerves in Bone 287
References 288