New Horizons in Osteoporosis Management

Preface
Contents
Contributors
Part I: Bone Health: Towards Better Bones
	1: Bone Health: Basic and Applied Bone Biology
		Introduction
		Basic Bone Biology
		Cellular Composition
		Osteoblasts
		Bone Lining Cells
		Osteocytes
		Osteoclasts
		Bone Structure
		Cells Gaps
		Gap Junctions and Skeletal Development
		Bone Remodeling
		The Bone Remodeling Compartment
		The Remodeling Cycle – Cellular and Molecular Mechanisms
		Activation
		Resorption (Approximately Two Weeks in Duration)
		Reversal (Approximately Four to Five Weeks in Duration)
		Formation (Approximately Four Months in Duration)
		Termination
		The Remodeling Cycle – Major Signaling Pathways
		Receptor Activator of Nuclear Factor Kappa-B Ligand Signaling Pathway (RANKL/RANK/OPG Signaling)
		Wnt Signaling
		Hormonal Impact on Bone Remodeling
			Parathyroid Hormone (PTH)
			Estrogen
			Calcitonin
			Growth Hormone
			Glucocorticoids
			Thyroid Hormone
		Bone Modelling Vs. Remodeling
			Bone Modeling
			Bone Remodeling
		Applied Bone Biology
			Abnormalities of the Bone Remodeling Cycle
		Bone Modeling/Remodeling as Therapeutic Targets
			Antiresorptives
		Anabolic Agents
		Bone Formation-Sparing Antiresorptive Treatment
		Combined Anabolic and Antiresorptive Treatment
		Drugs that Act on the Bone Mineral/Matrix Composite
		Bone Turnover and Fracture Risk
		Building Better Bones: Sequential and Combination therapy for Osteoporosis
		Challenges in Developing Treatments for Osteoporosis
		References
	2: Muscle Health
		Introduction
		Muscles in Health
		Muscle Mass
		Muscle Bone Interaction
		Bone and Body Composition
		Relationships Between Muscle and Bone in Clinical Studies
			Bone and Muscle Interactions During Development
			Genetic Factors
			Endocrine Factors
			Vitamin D
			GH/IGF- I Axis
			Sex Hormones
			Glucocorticoid Excess
			Diabetes Mellitus
			Mechanical Factors
		Muscle and Bone Coupling
			Links from Muscle to Bone
				Data from Diseases and Gene Mutations
				Local Factors Affecting Muscle Ossification
				Myostatin
			Links from Bone to Muscle
		Techniques of Muscle Imaging: Measurement of Lean Body Mass and Muscle Mass
		Dual Energy X-Ray Absorptiometry
		Computed Tomography
		Magnetic Resonance Imaging
		Bioimpedance Analysis
		Emerging Techniques for the Assessment of Muscle Mass
		Towards a Reference Standard
		Different Indices to Express Lean Body Mass
		Nutrition and Muscle Health
		Proteins
		Dietary Protein Requirements for Optimal Muscle Mass and Strength
		Vitamin D
		Homocysteine Levels, Vitamin B12, and Folic Acid
		Acid-Producing Diets
		Muscle in Aging Adults and in Disease
			Muscle Health in Aging
		Measurement of Muscle Health in Aging
		Age-Related Change in Muscle or Lean Tissue Mass
		Age-Related Change in Muscle Quality
		Functional Capability
		Muscle and Inactivity/Bed Rest
		Muscle Health in Disease
		Muscles and the Acute Response to Critical Illness
		Muscles Role in Chronic Diseases
		Obesity and Muscle
		Muscle in Insulin Resistance and Diabetes
		Muscle and Osteoporosis
		Muscle and Kidney Diseases
		Approaches to Management of Muscle Loss?
			Hormonal Therapy
			Exercise
			Nutrition
		References
	3: Osteosarcopenia
		Introduction
		Aging Human Body
		Potential Mechanisms of Age-Related Sarcopenia
		Mitochondrial Reactive Oxygen Species and Mitochondrial Dysfunction
		Mitochondrial Apoptosis
		Mitochondrial Dynamics
		Mitochondrial Autophagy
		Myostatin
		Inflammatory Cytokines
		Bone–Muscle Crosstalks
		Biomechanical: The Mechanostat Theory and Biomechanical Coupling in the Musculoskeletal Unit
		Biochemical Communication between Muscle and Bone: Muscle and Bone as Endocrine Organs
		Indirect Links
		Nervous System
		Macrophages
		The Molecular Clock
		Sarcopenia Operational Definition
		Osteosarcopenia Clinic: Case Finding Practical Algorithm
		Validated Tests and tools for Current Use
		Finding Sarcopenia Cases
		Measuring Sarcopenia Parameters
		Muscle Strength
		Muscle Quantity
		Physical Performance
		Alternative or New Tests and Tools
		Lumbar Third Vertebra Imaging By Computed Tomography
		Mid-Thigh Muscle Measurement
		Psoas Muscle Measurement with Computed Tomography
		Muscle Quality Measurement
		Creatine Dilution Test
		Ultrasound Assessment of Muscle
		Specific Biomarkers or Panels of Biomarkers
		SarQoL Questionnaire
		How to Diagnose Osteosarcopenia?
		Osteosarcopenia in Standard Clinical Practice
		Categories of Sarcopenia and Sarcopenia-like Conditions
			Primary and Secondary Sarcopenia
			Acute and Chronic Sarcopenia
			Sarcopenic Obesity
			Frailty
			Malnutrition-Associated Sarcopenia
		Therapeutic Intervention
		Exercise
		Nutrition
		Drug Therapy
		Vitamin D
		Sex Hormones
		Estrogens
		Insulin and Insulin-Like Growth Factor-1
		Growth Hormone
		Myostatin Inactivation
		Urocortins
		Angiotensin 1–7 and Angiotensin-Converting Enzyme Inhibitors
		Selective Androgen Receptor Modulators (SARMs)
		Future Therapies
		Patient-Centered Approach for Sarcopenia Management
		References
	4: Bone Health in Women
		Introduction
		Young and Adulthood
		Pregnancy and Lactation
		Premenopausal Women
		Postmenopausal Osteoporosis (Type I Osteoporosis)
		Osteoporosis in Elderly Females
		Definition of Osteoporosis
		Physiologic Changes in the Bone Mass in Association with Pregnancy and Lactation
		Clinical Approach to Patient Identification and Diagnosis
			Young/Premenopausal Females
		Postmenopausal Females
		Approach 1: Quantitative Assessment
		Approach 2: Probability-Based Assessment
		Specific Clinical Situations
			Idiopathic Osteoporosis in the Young
		References
	5: Bone Health in Men
		Introduction
		Why Bone Health in Men Is Important?
		Epidemiology
		Bone Development and Loss in Men
			Childhood through to Young Adulthood
		Ages: 20–60 Years
		Age 70 Years and Onwards
		Pathogenesis: The Role of Hormones
		Causes of Osteoporosis in Men
		Hypogonadism
		Steroids
		Alcohol Consumption
		Smoking
		Diabetes-Related Osteoporosis
		Hypercalciuria
		Immobilization
		Gastrointestinal Disorders
		Idiopathic Osteoporosis
		Diagnosis
		Clinical Approach
		DXA Scan Interpretation
		Laboratory Tests
		Vertebral Fracture Assessment
		References
	6: Bone Health in the Transgenders
		Introduction
		Sex Hormones and Bone Health
		Bone Mass Effects of Cross-Sex Hormone Therapy in Transgender People
		Practical Guidelines for Transgender Hormone Treatment
		Osteoporosis Risk in Transgender Individuals
		Screening for Osteoporosis in Transgender Individuals
		Implications for Standard Clinical Practice
		References
Part II: Diagnosis: Clinician’s Guide
	7: Osteoporosis Risk Assessment Tools
		Introduction
		The Evidence
		Benefits and Harms of Early Detection of Osteoporosis
		Risk Assessment Tools
			FRAX
				FRAX in Patients’ Management
			QFracture
			Garvan
				Comparative Features
				Comparison of Input
				Comparison of Output
				Osteoporosis Self-Assessment Tool
				Osteoporosis Self-Assessment Tool (OST)
				Index of Risk (OSIRIS)
		Performance of Fracture Risk Model
		The Concept of Very High Fracture Risk
		Thresholds for Intervention
			Closing the Gap: Intervention Thresholds of Very High vs High Fracture Risk
				National Osteoporosis Guideline Group (NOGG)
				European Society of Endocrinology
		Fracture Risk Assessment Tools: Room for Improvement
			Genetic Profiling
			Trabecular Bone Score
			Bone Turnover Markers
			Fracture Type-Specific Prediction
			Artificial Intelligence
			Time-Variant Predictions
			Ethnic-Specific Models
		References
	8: Current Imaging Techniques
		Introduction
		Importance of Osteoporosis Imaging
		Dual X-ray Absorptiometry (DXA) Scan
		DXA Technology
		Nomenclature
		Clinical Applications of DXA
		Vertebral Fracture Assessment
		DXA Additional Parameters
		Quantitative Computed Tomography (QCT)
		Clinical Applications of QCT
		Standard QCT
		Single-Slice QCT
		Volumetric QCT
		High-Resolution Peripheral Quantitative CT (HR-)pQCT)
		Projectional QCT: Hip
		Discordance in Diagnosis of Osteoporosis by QCT and DXA
		Ultrasound Scanning
		MRI
		Bone Marrow Fat Imaging
		Positron Emission Tomography (PET)
		Bioengineering: Using an Electronic Stethoscope and Machine Learning to Detect Osteoporosis from Percussion Responses
		References
	9: The Challenges and Limitations of Osteoporosis Diagnosis
		Introduction
		Challenge 1: Underdiagnosis of Osteoporosis (Even after Fractures)
		Challenges 2: From T-Score to Bone Strength and Quality
			Changes in Density Account Partially for the Decrease in Fractures
		Challenge 3: The Scanning Process
		Challenge 4: Patient Awareness
		Challenge 5: The Missed Falls Risk Assessment
		References
	10: Best Practice Recommendations for DXA Scans and Reports
		Introduction
		Basic Principles of DXA Scanning
		Best Practice of DXA
		How to Collect Local Reference Data
		Role of Healthcare Professionals in the DXA Scanning Service
		Radiographers
		Falls Service
		DXA Scanning in Standard Clinical Practice
			Referring for DXA Scanning
			Pre-scan Assessment
			Reporting DXA Scans
			Report Targets
			Demographics
		Medical History Used for Risk Determination
			Test Results
			Technical Notes
			Diagnostic Category
			Fracture Risk
			Interpretation
		Follow-Up Recommendation
			Limitations
		Follow-Up Adult BMD Report
			Follow-Up Referral Form
			Demographics
			Fracture Risk Category
			Changes in Density
			Interpretation
			Pediatric DXA Scanning
			Diagnostic Category
			Technical Comments
		Follow-Up Pediatric DXA Scanning
			Changes in Density
		References
	11: Pitfalls in DXA Scanning
		Principle of DXA Scanning
		Contraindications
		Who Should Have a DXA Measurement?
		Sites of Measurement of BMD
		Interpreting a DXA Scan
			Positioning
			DXA Scan Analysis
		Concordance Between Measurement Sites
			Prevalence and Risk Factors of T-Score Discordance
			Consequences of T-Score Discordance on Osteoporosis Management
		Monitoring of DXA
			Methods of Bone Mineral Density Reproducibility Measurement
			Clinical Implications of Bone Mineral Density Reproducibility Measurement
			Other Factors Influencing DXA Monitoring
		Vertebral Fracture Assessment (VFA)
		Trabecular Bone Score (TBS)
		Body Composition
		Conclusions
		References
	12: Osteopenia: Mind the Gap
		Introduction
		From T-score to Bone Health
		Bone Loss Is a Continuum, Not a T score
		The Burden of Fragility Fractures
		The Problem of Osteopenia
		The Challenge of Case Finding: Mind the Gap
		Case Finding Strategies
			Identification of Osteopenic Patients with High Fracture Risk
			Identification of Patients with Prevalent Fractures
			Identification of High-Risk Individuals Without History of Fracture
		Thresholds for Intervention
		Treatment Decisions
			Lifestyle Changes General
			Calcium and Vitamin Supplement Therapy
			Prevention of Falls and Protection Against Fall Trauma
			Pharmacotherapy
		Androgen Replacement Therapy in Males
		Management of Osteoporosis and Osteopenia in the Very Elderly
		Treatment Algorithm for Osteopenia
		References
Part III: Prevention: Recent Advances
	13: Imminent Fracture Risk
		Introduction
		Imminent Fracture Risk
		The Challenge of Identifying the Long-Term Risks of Fractures
		Imminent Risk and the Location of the Previous Fracture
			Central Versus Peripheral Sited Fractures
		Predicting Imminent Risk for Fracture
		Imminent Fracture Risk: Patient Perception
		Medication Adherence
		Imminent Fracture Risk Assessments and Fracture Liaison Service (FLS) Setting
		Gaps in Treatment
		Therapeutic Window of Opportunity
		References
	14: Fracture Liaison Service
		Introduction
		Fracture Liaison Service: The Concept
		Fracture Liaison Service Models
		Components of Fracture Liaison Service
		Identify
			Inpatient Fractures
			Outpatient Fractures
			Silent Vertebral Fractures
			Referrals
			Out of the Hospital FLS Setup
		Investigate
			Fracture Risk Assessment
			DXA Scans
			Vertebral Fracture Assessment (VFA)
			Trabecular Bone Score (TBS)
			Falls Risk Assessment
			Other Investigations
		Inform
		Intervention
			Osteoporosis Therapy
			Falls Management
		Improving Adherence
		Integrate
			Management Plan
		Quality
		FLS Outcomes
			Future Fracture Risk Reduction
			Vertebral Fragility Fractures
			Mortality
			Bone Health and Bone Mineral Density Assessment
			Osteoporosis Treatment Initiation and Adherence
			Cost-Effectiveness of an FLS
			Best Practice Framework for Fracture Liaison Services
		References
	15: Unmet Needs and Challenges in Osteoporosis
		Introduction
		Challenge 1: Fracture Risk Score and Absolute Risk of Fracture
		Challenge 2: Implementation of Health Economics into Clinical Guidelines
		Challenge 3: Treatment Thresholds
		Challenge 4: DXA
			Diagnosis of Osteoporosis: More Than Dual-Energy X-Ray Absorptiometry Alone
		Challenge 5: Measuring Bone Strength
		Challenge 6: Osteoporosis Treatment
		Challenge 6: Patient Education
			How to Improve Peak Bone Mass?
			Proactive Non-pharmacological Measures to Prevent Fractures
		Multifaceted Osteoporosis Group Education
		References
	16: Osteoporosis Update for Primary Care Physicians
		Introduction
		Primary Care Perception About Osteoporosis
		Gaps in Care in the Primary Care Setting
			Gap 1: Failure to Implement and Follow Osteoporosis Screening Guidelines
			Gap 2: Failure to Address the Imminent Fracture Risk in the Primary Care Setting
			Gap 3: Insufficient Physician-Patient Communication/Poor Patient Education
			Gap 4: Poor Monitoring After Prescribing Osteoporosis Therapy
			Gap 5: Pitfalls in the Healthcare System
		Improving Osteoporosis Service in the Primary Care: Breaking Barriers Not Bones
		The Bone Health Team
		The Role of the Osteoporosis Nurse Specialist
		The Role of the Fracture Liaison Service (FLS) Nurse
		Components of Screening Interventions
			Rationale for Screening
			Assessment of Fracture Risk
			Treatment Thresholds and Decisions
		Osteoporosis Management Guidelines for the Primary Care
		References
Part IV: New Treatment Concepts
	17: Bone Modulation
		Introduction
		The Dynamic Skeleton
		Bone Modeling
		Bone Remodeling
		Coupling of Bone Remodeling
		Principles of Bone Modulation
		Implications from Research Studies and Clinical Practice
			Inhibitors of Bone Resorption
			Cathepsin K Inhibitors
		Stimulators of Bone Formation
		New Aspects of the Bone-Protecting Effects of Vitamin D
		Further Nontraditional Molecules with Anti-osteoporotic Potential
		Implications of Remodeling and Modeling on the Long-Term Effects of Osteoporosis Drugs on Bone Mass and Strength
		References
	18: Treat-to-Target in Osteoporosis
		Introduction
		Treat-to-Target as a Strategy in Osteoporosis
		Establishing Treatment Goals
		Bone Mineral Density/T-Score as a Goal
		Fracture Probability as a Goal
		Indices of Bone Strength as a Goal
		Bone Turnover Markers (BTM) as a Goal
		Comparison Between the Standard Treatment and Goal-Directed Treatment
		Goal-Directed Selection of Initial Therapy
		Goal-Directed Assessments and Treatment Decisions During Treatment
			Assessing Adherence to Treatment
			Monitoring Response to Therapy
		Drug Holiday
		Proposed Algorithm to Monitoring Osteoporosis Therapy
			Limitation and Expectations of Treat-to-Target Approach
		References
	19: Geroscience and Management of Osteoporosis in Older Adults
		Introduction
		Geroscience: The Intersection of Basic Aging Biology, Chronic Disease, and Health
		Aging and Bone Loss
		Mechanisms of Age-Related Bone Loss
			Role of Menopause in Women
			Role of Sex Steroid Deficiency in Men
		Bone Marrow Fat
		Secondary Hyperparathyroidism
		Other Contributing Factors
		Bone Changes with Aging
			Mechanical and Morphological Changes with Age
		Bone Protein Changes with Age
		Mineral Changes with Age
		Changes in BMD with Aging
		Approach to Management of Osteoporosis in the Older Adults
			Medications
			Calcium and Vitamin D
		Antiresorptive Osteoporosis Therapy
		Osteoanabolic Agents
		Osteoporosis by Aiming at Bone Marrow Stromal Cells (BMSCs)
		When to Repeat the BMD Testing
		The Onset of Anti-fracture Efficacy
		Safety of Anti-osteoporotic Drugs
		Gastrointestinal Effects
		Vascular Effects
		Musculoskeletal Pain
		Immune Reactions
		Nervous System Effects
		Cancer
		Cardiac Effects
		Impaired Fracture Healing and Induced Bone Weakening
		Renal Safety
		Optimizing Therapeutic Adherence in Osteoporosis
		Predictors of Nonadherence
		References
	20: Bone Healing and Osteoporosis
		Introduction
		Pathophysiology of Fractured Bone Healing
			The Inflammatory Phase
				Osteoimmunology in Older Adults
			The Repair Phase
			Bone Formation Phase
		Effects of Aging on Fracture Healing
		Implications of Osteoporosis Treatment for Fracture Healing
			Anti-catabolic Medications
				Bisphosphonates
				Local Application of Bisphosphonates and Its Effect on Bone Repair
				Denosumab
				Selective Estrogen Receptor Modulators: Raloxifene
			Anabolic Medications
				Parathyroid Hormone
				Romosozumab
				Management of Atypical Femoral Fractures
		References
Part V: Towards Optimized Practice
	21: Osteoporosis Management: Gaps in Patients’ Care and Treatment
		Introduction
		Osteoporosis: The Need to Treat
		Osteoporosis: Gaps in Care
			Gap 1: Failure to Follow Guidelines for Screening for Osteoporosis
			Gap 2: Failure of Secondary Fracture Prevention
			Gap 3: Patient-Physician Communication Failure
		Osteoporosis: Mind the Treatment Gap
		Fear of Rare Side Effects
		Concerns Regarding Long-Term Efficacy
		Osteoporosis: Closing the Gaps
			Closing Gap 1: Secondary Fracture Prevention
		Models of Care: Orthogeriatrics Services and Fracture Liaison Services
			Closing Gap 2: Medication-Induced Osteoporosis
		Steroids-Induced Osteoporosis
		Androgen Deprivation Therapy-Induced Osteoporosis
		Aromatase Inhibitor-Induced Osteoporosis
			Closing Gap 3: Diseases Associated with Osteoporosis
			Closing Gap 4: Primary Fracture Prevention
			Closing Gap 5: Adherence to Therapy
			Closing Gap 6: Public Awareness of Osteoporosis and Fracture Risk
			Closing Gap 7: Public Awareness of Benefits Versus Risks of Osteoporosis Treatment
			Closing the Gap 8: Access and Reimbursement for Osteoporosis Assessment and Treatment
			Closing the Gap 9: Prioritization of Fragility Fracture Prevention in National Policy
			Closing the Gap 10: The Burden of Osteoporosis in the Developing World
		Guidelines
		References
	22: Precision Medicine: Pharmacogenetics and Pharmacogenomics of Osteoporosis
		Introduction
		Terminology
		Elucidating Pharmacogenomic Mechanisms
		Bone Mass Pharmacogenetics
		Osteoporosis Pharmacogenomics and Fracture Prediction
		Pharmacogenomics of Osteoporosis Therapy
		Osteoporosis Pharmacogenomics: Recent Insights and Future Perspectives
		Pharmacogenomics of Adverse Drug Reactions
		Towards Personalized Medicine
		References
	23: Romosozumab: Optimizing the Anabolic Window
		Introduction
		Bone-Forming and Antiresorptive Effects of Romosozumab
		Bone Morphological Changes
		Time-Dependent Effects of Romosozumab
		Pharmacokinetics
		Clinical Trials
		Profile of Romosozumab and its Potential in the Management of Osteoporosis
		Phase II Trials: Efficacy and Safety of Romosozumab
		Phase III Trials: Efficacy, Effectiveness, and Safety of Romosozumab
		Antifracture Efficacy
		Adverse Events
		Sustainability
		The Clinical Potential of Romosozumab
		Guidelines
		Technical Remarks
		The Potential of Romosozumab Retreatment
		Treatment in Male Osteoporosis
		Sclerostin Antibody for Potential Healing Enhancement of Osteoporotic Fracture
		Romosozumab and Cardiovascular Events
		Romosozumab/Alendronate and Atherosclerosis
		ROMO and Renal/Vascular Disease
		References
	24: New Frontiers in Osteoporosis Management: Optimizing Sequential and Combination Therapy
		Introduction
		Unmet Needs in the Management of Bone Fragility
		Clinical Vs Radiologic Osteoporosis
		Pathophysiology: What Is and Is Not Achievable Using Different Osteoporosis Therapies?
		Therapeutic Implications
			Anti-resorptive Therapy
			Anabolic Therapy
		Does the Sequence Matter?
		Optimizing Osteoporosis Therapy: Combination and Sequential Therapies
			Sequential Therapy
				Anti-resorptives After Anabolic Agents for the Treatment of Osteoporosis
				Anabolics After Anti-resorptive Agents for the Treatment of Osteoporosis
				Anti-resorptives Sequential to Anti-resorptives for the Treatment of Osteoporosis (Anastasia)
			Combination Therapy
				Combination Therapies with Anabolics and Anti-resorptive Agents
				Combination Treatment with Hormone Replacement Therapy
		Challenges with the Outcomes of Sequential and Combined Osteoporosis Therapy
		The Way Forward
		References
Part VI: Disparities in Bone Health
	25: Osteoporosis in Men
		Introduction
		Bone Changes Across the Men’s Life Span
		Epidemiology of Osteoporosis in Men
			Pathophysiology
			Secondary Osteoporosis
		Differences Between Men and Women
		Male Osteoporosis in the Elderly
		Risk Factors: Identifying Men at High Risk of Fracture
		The Journey Toward Making of the Diagnosis of Osteoporosis in Men
		Case Finding
			Screening
			Making the Diagnosis
		Absolute Risk Assessment
		BMD Vs FRAX in Men
		Management
			Gaps in Access to Osteoporosis Therapy
			Who to Treat
		Treatment Plan
		General Nonpharmacologic Treatment
		Pharmacological Agents
		Selection of Therapeutic Agent
			Bisphosphonates
			Alendronate
			Risedronate
			Zoledronic Acid
			Other Bisphosphonates
		Contraindications or Intolerance to Oral Bisphosphonates
			Teriparatide
			Denosumab
			Romosozumab
		Combination/Sequential Therapy
		Monitoring the Response to Therapy
		Duration of Therapy
		References
	26: Pediatric Osteoporosis and Optimizing Bone Health in Children
		Introduction
		Bone Acquisition During Childhood and Adolescence
		Definition of Pediatric Osteoporosis
		Etiology of Pediatric Osteoporosis
		Primary Bone Loss in Children
		Secondary Osteoporosis in Children
		Clinical Signs and Risk Factors for Osteoporosis in Children
		Predictors of Fractures in Children at High Risk
		Predictors of Vertebral Fractures
		Predictors of Nonvertebral Fractures
		Assessment of Bone Mass and Structure
		Mobility, Muscle, and Functional Tests
		DXA Scan Technical Aspects
		DXA Technicalities, Interpretation, and Reporting in Children and Adolescents
		Vertebral Fracture Assessment (VFA) in Pediatric Patients
		Densitometry in Infants and Young Children
		When Osteoporosis Should Be Suspected?
		Laboratory Tests
		Making the Diagnosis of Osteoporosis in Children
		Bone Health Monitoring in at-Risk Children
		Monitoring of Vertebral Fractures
		Spontaneous Recovery from Osteoporosis in the Absence of Osteoporosis Therapy
		The Management of Osteoporosis in Children
			Goals of Treatment
		General Measures for Optimization of Bone Health
		Calcium and Vitamin D Supplementation
		Bisphosphonates
		What About Nonosteogenesis Imperfecta Primary and Secondary Osteoporosis?
		Is There a Room for Individualized Treatment Approach?
		Novel Therapies
		Treatment Considerations in Specific Conditions
			Osteogenesis Imperfecta
		Glucocorticoids-Induced Osteoporosis
		Anorexia Nervosa
		Epilepsy and Antiepileptic Drug Therapy
		Consider Puberty and Nutrition
		Improving Muscle Strength, Mobility, and Rehabilitation
		Osteoporosis Diagnosis and Treatment Algorithm
		Initial Assessment
		Treatment: Stabilization Phase
		Maintenance Phase and Discontinuation of Osteoporosis Therapy
		References
	27: Atypical Femur Fractures
		Introduction
		Definition
		Terminology
		Epidemiology
		AFFs in Osteoporosis Patients Treated with Denosumab
			AFFs in Osteoporosis Patients Treated with Romosozumab
			AFF in Autoimmune Disease and Steroid Therapy
		AFFs in Cancer Patients Treated with Bisphosphonates and/or Denosumab
			Periprosthetic AFFs
			Pathogenesis of AFF
			Stress or Insufficiency Fracture
			Hip Geometry and AFF
		Genetic Predisposition
			Other Medications: Glucocorticoids, Proton Pump Inhibitors
		Bone Material Properties in Patients with AFFs
		Mechanisms of Impaired Fracture Healing in AFF
			Atypical Fractures in Other Bones
			Clinical Features and Diagnosis of Atypical Femur Fractures
		Management of Atypical Femoral Fractures
			Early Detection of AFFs
			Prophylactic Treatment
		Management of Patients After Atypical Femur Fractures
			Medical Management of AFF
			Time for a New Treatment Paradigm
		References
	28: Pregnancy, Lactation, and Bone Health
		Introduction
		The Calcium Demand During Pregnancy and Lactation
		Body Adaptation During Pregnancy and Lactation
		Mineral Ions During Pregnancy
		Intestinal and Renal Handling of Calcium
		Vitamin D
		Parathyroid Hormone
			IGF1 and Pituitary Growth Hormone (PGH)
		Other Regulators
		Pathophysiology and Lactation-Associated Osteocytic Osteolysis
		BMD Changes During Pregnancy and Lactation
			Methodological Problems for Evaluating BMD in Pregnant and Lactating Women
			Variation of the Confounding Factors That Can Influence BMD
		So, Are There Any Changes in BMD During a Pregnancy?
			Variation of the Confounding Factors That Can Influence BMD During Lactation
		So, Are There Any Changes in BMD During Lactation?
			Parity and Bone Long-Term Effects of Pregnancy and Lactation on the BMD
		Pregnancy-Related Transient Osteoporosis of the Hip
		Pregnancy, Lactation, and Risk of Fracture
		Pregnancy, Lactation, and Bone Biomarkers
		Osteoporosis During Pregnancy
		Clinical Presentation
		Diagnosis
		Treatment
		Recovery of the Bone Health After Lactation
		Long-Term Effect of Pregnancy and Lactation on Bone Health
		References
Part VII: Bone Health as a Comorbidity
	29: Bone Health and Cancer Therapy
		Introduction
		Unique Aspects of Cancer Therapy-Associated Bone Loss
		Cancer, Hormones, and Bones
		Sex Steroids and Bone
		The Interaction Between Cancer, Sex Hormones, and Bones
		Prostate and Bone
		Pathophysiology of Cancer Treatment-Induced Bone Loss
		Pathophysiology of Bone Loss in Breast Cancer Patients
		Endocrine Therapy
		Ovarian-Ablative Therapies
		Effects of Breast Cancer and Its Therapies on Bone in Men
		Effects of Prostate Cancer Therapies on Bone
		Bone Metastases and Skeletal-Related Events (SRE)
		Cancer Treatment-Induced Fractures
		Screening for Bone Loss in Cancer Patients
		Diagnosis of Cancer Therapy-Induced Bone Loss
		Monitoring Bone Mineral Density
		Clinical Sequelae of Cancer Therapy-Induced Bone Loss
		Management
		Diet and Lifestyle Changes
		Specific Lifestyle Measures for CTIBL in Prostate Cancer
		Specific Lifestyle Measures for CTIBL in Breast Cancer
		Bone-Targeted Agents (BTAs)
		Prevention of Skeletal Morbidity in Metastatic Bone Disease
		Breast Cancer
		Prostate Cancer
		Prevention of Bone Loss in Prostate Cancer
		Prevention of Bone Loss in Breast Cancer
		Oophorectomy, GnRH Agonist (ASCO)
		Cessation of Ovarian Function (CIOF)
		Patients with Chronic (> 6 Months) Glucocorticoid Use
		Management of Bone Metastases
			Palliative Radiotherapy
			Multidisciplinary Management Approach of Bone Metastases
		Clinical Implications
		Age Considerations: Older Adults
		Safety Considerations
		Algorithm for Identifying and Managing Cancer Treatment-Induced Bone Loss
		References
	30: Bone Health in Chronic Kidney Disease
		Introduction
		Mechanisms Underlying the Development of Osteoporosis
			Dysregulation of RANK/RANKL/OPG System (Fig. 30.1)
			Excessive Wnt/β-Catenin Signaling Inhibitors
			Inflammatory Cytokine-Related Osteolysis
		Disturbed Bone Remodeling: High or Low Bone Turnover-Related Osteoporosis
			High Bone Turnover Disorder
				Secondary Hyperparathyroidism
				Chronic Inflammation
			Low Bone Turnover Disorders
				Adynamic Bone Disease and Osteomalacia in CKD
				Glucocorticoid-Induced Osteoporosis (GIO) (Fig. 30.2)
			Bone Quality Loss
		Bone Mineral Density in Patient with CKD
			Relationship Between BMD and Renal Osteodystrophy
			CKD Progression and BMD Changes
				Low BMD in CKD Not Yet Receiving Dialysis
				Influence of Comorbidities
				Influence of Treatments (Medications) on CKD-Related Osteodystrophy
				Influence of Age and Gender
		Dialysis Modalities on BMD
			BMD in Hemodialysis Patients
			BMD in Peritoneal Dialysis Patients
		Secondary Hyperparathyroidism and Renal Osteodystrophy
			The Pathophysiology of Secondary Hyperparathyroidism (SHPT)
			Impact of SHPT on BMD
		Vitamin D Deficiency in Bone Loss
			The Alteration of Vitamin D Metabolism in CKD
				Decrease Vitamin D Synthesis and Increase Vitamin-D Catabolism in CKD
				Nutritional Vitamin D Hunger in the Parathyroid Gland
			Vitamin D Deficiency: Effect on Bone Quantity and Quality Loss
				Vitamin D Deficiency and Bone Quantity Loss
				Vitamin D Deficiency and Bone Quality Loss
		Role of Vitamin D Supplementation in High and Low Bone Turnover Disorders
			Treatment of High Bone Turnover Disorder
				Effect of Vitamin D Supplementation on Bone Quantity Loss (Fig. 30.4)
				Effect of Vitamin D Supplementation on Bone Loss: Bone Quality
				Extraskeletal Effect of Vitamin D in Treating Osteoporosis: Alleviating Inflammation and Oxidative End Products
			Vitamin D for Treating Low Bone Turnover Disorder: Combination with Anabolic Agents
		Treatment of Osteoporosis: According to Bone Turnover (Fig. 30.7)
			High Bone Turnover Disorder: Enhance Osteoclastogenesis Couple With More Increased in Osteoblast Viability
				Antiresorptive Agents
					Bisphosphonates
					Anti-RANKL Antibody
					Calcimimetics
			Low Bone Turnover Disorder: Rescute the Osteoblast Viability: Anabolic Agents: PTH Analogs, Monoclonal Antibodies Against Wnt Pathway Inhibitors
			Parathyroid Hormone
				Monoclonal Antibodies Against Wnt Pathway Inhibitors
		Effect of Nutritional Vitamin D on Osteoporosis
		Conclusions
		References
	31: Glucocorticoids and Musculoskeletal Health
		Introduction
		Epidemiology
		Pathophysiology
			Mechanism of Action of Glucocorticoids
			Role of Underlying Inflammation
		Effect on the Bone
			Direct Effect on the Bone
			Indirect Effects on Bone
			Effect on the Muscles
		Clinical Correlations of Glucocorticoid-Induced Osteoporosis
		Glucocorticoids Pharmacologic Preparation
		Risk Stratification, Screening, and Assessment
		Glucocorticoid-Induced Changes in BMD and Bone Microarchitecture
		Monitoring BMD Changes/Response to Therapy
		Fracture Risk Assessment in Individuals Treated with Steroids
		Glucocorticoid-Induced Osteoporosis in Children and Adolescents
		Management of Glucocorticoid-Induced Osteoporosis
		General Measures
		Nutrition/Calcium and Vitamin D Supplementation
		Pharmacologic
		Antiresorptive Agents
			Bisphosphonates
			Denosumab
		Anabolic in the Management of Glucocorticoid-Induced Osteoporosis
			Romosozumab
			Third-Line Agents
			Follow-Up
		Algorithm for Assessment and Management of GIO
			High Fracture Risk
			Moderate Fracture Risk
			Low Fracture Risk
		References
	32: Osteonecrosis of the Jaw
		Introduction
			Osteonecrosis of the Jaws: A Review and Update in Etiology and Treatment
		Definition
		Incidence of MRONJ
		Characteristics of the Jawbone
		Pathophysiology
			Hypothesis 1: Bone Remodeling Inhibition
			Hypothesis 2: Inflammation, Infection, and the Biofilm
			Hypothesis 3: Angiogenesis Inhibition
			Hypothesis 4: Soft Tissue Toxicity
			Hypothesis 5: Innate or Acquired Immunity Dysfunction
		Diagnosis and Stages of MRONJ
		Risk Factors for MRONJ
		Differences in Antiresorptive Functions Between Bisphosphonates and Denosumab
		Duration of Medication Therapy as a Risk Factor for MRONJ
		Imaging and Diagnosis
		Imaging in Patients with Bisphosphonate-Associated Osteonecrosis of the Jaws (MRONJ)
			Anatomical Imaging
				Panoramic Radiographs
				Cone-Beam Computed Tomography (CBCT)
				Computed Tomography
				Magnetic Resonance Imaging
			Functional Imaging
				Bone Scan (Skeletal Scintigraphy)
				18F-FDG Positron Emission Tomography/Computed Tomography (PET/CT)
			Fluorescence-Guided Bone Resection/Visually Enhanced Lesion Scope (VELscope®)
			Clinical Application of MRONJ Imaging
				Defining the Area of Inflammation
				Monitoring of the Disease Course
				Providing Useful Imaging Findings for Surgery
				Predicting Disease Prognosis
				Lab Investigation: Bone Markers in MRONJ
				Bone Markers as Predictors of MRONJ
				Association Between Periodontitis and ONJ
				Prevention, Management, and Treatment of MRONJ
				Preventive Measures Taken Before Antiresorptive Therapy
				Discussing Medication-Related Osteonecrosis of the Jaw with  Patients
				Oral Assessments and Other Preventive Measures
				Preventive Measures Taken During Antiresorptive Therapy
			Managing Oral Infections Before and During Antiresorptive Therapy
		Treatment
			Asymptomatic Patients
				Asymptomatic Patients Receiving IV BP or Antiangiogenic Drugs for Cancer
				Asymptomatic Patients Receiving Antiresorptive Therapy for Osteoporosis
			Patients with Established MRONJ
			Stage-Specific Management Approach
			Teriparatide as a Treatment Modality of MRONJ (PTH in OJN)
			Drug Holiday and Treatment
			MRONJ and the Need for Multiprofessional Teamwork
		References
Index