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Metabolic Bone Diseases

Normal Bone Bones

Mechanical Support Woven Lamellar
Mineral Homeostasis Fetal Skeleton Replace Woven Bone (Growth)
Hemopoietic Elements Formed by Growth of Plates Deposited Slowly
Protect Viscera Produced Quickly Stronger (than Woven Bone)
Determine Body Size, Shape Resists all Forces Equally from 4 Types
All Directions • Circumferential
Biochemically Presence of Woven Bone in Adult • Concentric
Inorganic (65%) Organic (35%) (Always indicate Pathological State) • Interstitial (Cortex)
Calcium Hydroxyapatite Cells • Trabecular
Small proportion in circulation • Osteoprogenitor Cells
Maintain critical level in blood • Osteoblasts
• Hormones PTH • Osteocytes
• Vitamin D • Osteoclasts
• Sex Steroid Protein
• Thyroid Constitute 2% of Bone Weight
• Glucocorticoid Formation, Maintenance of Bone
Strong Bone, Hardness
Store house for 99% Body
Ca2+, P, Na, Mg
Rate for mineralization varies
12 – 15 days between
Formation of Matrix and
its Mineralization
Unmineralized Bone – Osteoid Basic Multicellular Unit (BMU)
Bone Turnover is coupled with
Bone Forming Cells • Osteoclasts mediated Bone Resorption
Osteoprogenitor Osteoblast Osteocytes Osteoclast • Osteoblast stimulated Bone Formation
Pluripotential On Surface of Bone Control Daily Bone Balance in Bone Remodelling – No Net Change in Bone Mass
Mesenchymal Synthesize, Ca, P Resorption Basic 6 Steps in Bone Remodelling
Stem Cells Transport, Arrange Fluctuation Multinucleated
Located in Matrix Protein Commu nicate Breaks bone
Vicinity of All Initiate with surface down into its
Bony Surface Mineralization cells, osteocytes elements unit
Stimulated, Have Receptors via network
Differentiate • PTH canaliculi
into Osteoblasts • Vitamin D
Vital to Bone • Estrogen
• Growth • Cytokines
• Remodelling • Growth Factors
• Repair Remodelling
Microcrack
Osteocytes senses the damage (send signal into marrow spaces)
Pre-Osteoclasts – Multinucleated Osteoclast
Start Resorption
Pre-Osteoblast → Osteoblast → Forming Osteoid → Mineralization

Metabolic Bone Disease (MBD)

Definition
Combination of
• Altered Osteoblastic, Osteoclastic Activity
• Abnormal Remodelling
Protein of Bones • Altered Calcification
Family of Non-Collagenous Protein Types
Type 1 Collagen Osteoclasts Abnormal Mineral
(mainly from Osteoblasts) Abnormal Matrix
90% of Organic Component Osteoblasts deposit Collagen Dysfunction Homeostasis
Forms Backbone of Matrix Woven Bone Lamellar Bone Osteoporosis Osteopetrosis Hyperparathyroidism
Random Weave Orderly, Layered Osteogenesis Paget’s Disease Renal Osteodystrophy
Manner Imperfecta (Osteitis Deformans) Osteomalacia
(Brittle Bone) Rickets
Mucopolysaccharidose s
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Abnormal Matrix

Osteoporosis Osteogenesis Imperfecta (Brittle Bone)

Definition Definition
↑ Porosity of Skeleton Deficiency in Type 1 Collagen Synthesis
Resulting in ↓ Bone Mass Affect Structures rich in Collagen
Predispose bone to Fracture • Joints
Localized (Disuse Limb) Generalized (Metabolic Bone Di sease) • Eyes
Primary • Ears
Secondary • Skin
• Teeth
Qualitatively ↓ in Amount of Normal Collagen
Severe Cases
Genetic Defects produce Abnormal Polypeptide Chains
(Cannot assemble into Triple Helix Configuration)
Basic Abnormality
Too Little Bone → Osteoporosis
(with marked Cortical Thinning, Attenuation of Trabeculae)
Clinical
Spectrum of Diseases
All Marked by Extreme Skeletal Fragility
4 Major Subtypes
Pathogenesis
Peak Bone Mass achieved during Childhood
Determined Largely by Hereditary Factors
(Vitamin D Receptor Allele, Genes for Collagen 1A1, ER, IGF-1, Binding Protein)
Acquired
• Physical Activity
• Muscle Strength
• Diet
• Hormonal State
Pathogenesis (Hypothesis )
Age Related ↓ Physical Activity Hormonal Influences
Osteoblasts in Elderly Mechanical Forces Yearly Reduction
↓ Replicative, (Stimuli for Normal • Cortical Bone (2%)
Biosynthetic Potential Bone Remodelling) • Cancellous Bone (9%)
Lose Biologic Potency Bone Loss Accelerated Bone Loss
over Time (Immobilized Patients) (Hormonal Dependent)
Diminished Capacity to (↓ Skeleton Mass) (After Menopause)
Make Bone ↑ Bone Mass Density Estrogen Deficiency
↓ Turnover Variant (in Athletes) Estrogen Replacement is
Aging Protective against Bone
(Senile Osteoporosis) Loss
↓ Estrogen Mucopolysaccharidoses
↑ Cytokines Secretion Definition
↑ RANK, RANKL Group of Lysosomal Storage Disease
(Stimulator of Osteoclast Deficiency in Enzymes that Degrade
Recruitment, Activity) • Dermatan Sulfate
↑ Bone Resorption • Heparan Sulfate
↓ Bone Mass • Keratan Sulfate
Implicated enzymes are mainly Acid Hydrolases
Mesenchymal Cells severely affected
(especially Chondrocytes, play a major role in Metabolism of Extracellular
Matrix Mucopolysaccharides)
Skeletal Abnormality (resulted from Abnormality in Hyaline Cartilage)
Clinical
Short Stature
Chest Wall Deformities
Morphology
Malformed Bones
Entire Skeleton affected in
Senile, Post-Menopausal Osteoporosis
Post-Menopausal Senile
Trabeculae are Thinned, Cortex is Thinned
Lose Interconne ctions (Subperiosteal, Endosteal Resorption)
Progressive Microfracture Haversian System (HS) Widened
Vertebral Collapse (Very Severe) HS Enlarged that
Cortex mimics Can cellous Bone
Clinical Course
Depend on which bone involved
Fracture – Painful
Multilevel Fractures – Loss of Height, Various Deformities
Cannot be reliably detected in Plain Radiograph
(until 30 – 40% Bone Mass Lost)
Serum Ca, P, ALK – Not Diagnostic
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Osteoclasts Dysfunction

Osteopetrosis (Marble Bone Disease, Albers-Schonberg Disease) Paget’s Disease (Osteitis Deformans)
Definition Definition
Rare Hereditary Disease Periods of Bone Re sorption followed by Hectic Bone Formation
↓ Osteoclast Bone Resorption Later, Bone Cell Activity becomes markedly Diminished
Result in Diffuse Symmetrical Skeletal Sclerosis Result in ↑ Bone Mass
Brittle Bone, Fracture (like a piece of chalk) (but Newly Formed Bone Disordered)(Abnormal Architecture)
Types Common in Whites (England, France, Austria)
Malignant Benign Not Serious Life Threatening Disease in Absence of Malignant Transformation
Autosomal Recessive Autosomal Dominant 3 Phases
Morphology Osteosclerotic
Osteolytic Mixed Osteoclastic – Osteoblastic
Precise Nature (Remains Unknown) (Burnt Out)
Deficient Osteoclast Activity Ends with predominance of
• Bones Lack a Medullary Canal Osteoblastic Activity
• End of Long Bones – Bulbou s, Misshapen Pathogenesis
Initial Lytic Phase
1° Spongiosa Persists ↓

Fills in Medullary Cavity → No Hemopoetic Marrow Waves of Osteocla sts, Numerous Reso rptive P its
Osteoclasts Abnormal ly Large (up to 100 nucle i)
(Prevent Mature Trabeculae) ↓

Mixed Phase
Bones – Not Remodelled, Woven in Architecture ↓

No of Osteoclasts Osteoclast Per sist but Admixed w ith

Prominent O steoblast s (l ining surface)
• Normal ↓

Marrow (adjacent to bone forming s urface)

• Increased Replaced by Loose Connective Ti ssue
• Decreased (contain Osteoprogen itor Ce ll s, Bloo d Ve ssel s)
Clinical Course (Transport Nutrie nt to and from
the Metabol ically Active Site s)
Infantile Malignant Autosomal Dominant (Benign) ↓

Osteosclerotic P hase
Detected in Utero, Soon after Birth Detected till Adolescent, Adulthood ↓

New Bone Formati on

Fracture, Anaemia, Hydrocephalus
Extramedullary Hematopoiesis
(Hepatosplenomegaly)
Fatal (often)
Repeated Fractures
Mild Cranial Nerve Deficit/ Anaemia
(Larger, composed of Coarsely Th ickened Trabeculae)
(Remodelled t o Lamellar B one)
(Haphazardly arranged – form Mosaic Patter n) Slow Virus Infection by Paramyxovirus
↓
In Situ Hybridi zation
Mosaic Pattern Unfo lds
(Localize the viru s in Osteoclast)
(Cell Activity ↓, Fibr ovascular Tis sue Recedes)
↓ Target Osteoblast
Bones become Car icature of itself (with Transm iss ion to Osteoclast)
Viruse s can Induce Secretion of IL-6
↓
(Potent Stimulator s of O steoclast
Cortices Soft, Porou s, Unstable
Recruitment, Resorpt ive Activity)
(Vulnerable to Deformation under stres s)

Morphology

Paget’s Disease

Paget’s Disease

Paget’s Disease
Mosaic Pattern of Lamellar Bone
Prominent Cement Lines
Jigsaw Puzzle Like
Clinical Course
One or More Bones
Sites – Axial Skeleton, Proximal Femur (up to 80%)
Unusual Sites – Ribs, Fibula, Small Bones of Hands
Clinical Manifestations
Bone Pain
Joint Pain
Deformity
Spontaneous Fractures
Alk Phos ↑
[Ca2+] Normal Unless I mmobilised
Complications
Fractures
2° Osteoarthritis (OA)
Bowing of Femoral, Tibia Bone
Nerve Entrapment (2° to Compression Fracture of Spine)
Spinal Stenosis
Cardiac Failure (↑ Blood Flow – behaves as AV shunt)
Bone Sarcoma – Osteosarcoma, MFH, Chondrosarcoma
Hypercalcaemia

Paget’s Disease Paget’s Disease

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Abnormal Mineral Homeostasis

Hyperparathyroidism Renal Osteodystrophy

Definition
All Skeletal Changes of Chronic Renal Disease
Skeletal Changes
• ↑ Osteoclastic Bone Resorption
• Delayed Matrix Mineralization (Osteomalacia)
• Osteosclerosis
• Growth Retardation
• Osteoporosis
Pathogenesis
Mix Skeletal Lesions (Many Patients)

Chronic Renal Failure

↓
P Retention
↓
Hyperphosphatemia
↓
2° Hyperparathyroidism
Primary (1°) Secondary (2°)
Parathyroid Hyperplasia/ Adenoma Prolonged Hypocalcaemia
(compensatory PTH Hypersecretion)
Pathogenesis
↑ PTH
↓
Detected by Osteoblasts Osteomalacia, Rickets
↓
Definition
Release Molecules that Stimulate Osteoclasts Activity
↓
Delayed, Inadequate Bone Mineralization (Excess of U nmineralized Matrix)
Unabated Osteoclastic Bone Resorption Persistence of Irregular Masses of Cartilage
↑ PTH Deposition of Osteoid Matrix
Entire Skeleton is Affected Deformation of Skeleton
Osteitis Fibrosa Cystica (Severe Hyperparathyroidism) Clinical Manifestations
(Rarely encountered – due to Diagnosed, Treated at Early Stage) Infancy, Childhood (Rickets) Adults (Osteomalacia)
2° Hyperparathyroidism – Presented with Milder Skeletal Abnormalities Softened, Flattened Occipital Bones Loss of Skeletal Mass
Morphology Frontal Bossing Osteopenia (Too Little Bone)
Chest Deformation Malaise
Pigeon Breast Bone Pain
(Anterior Protrusion of Sternum) Proximal Muscle Weakness
Lumbar Lordosis Alk Phos ↑
Bowing of Legs [Ca2+] ↓ or Normal
[PO4 2-] ↓ or Normal
Looser zones in X-ray
Pathology
Inadequate Mineralization of Bone
↓ Mineralization (per unit volume of bone)
Causes Tests
Vitamin D Deficiency [Ca2+] ↓
• ↓ Intake, Inadequate Sunlight Exposure [PO4 2-] ↓
Hyperparathyroidism • Malabsorption Alk Phos ↑
Osteoclasts boring into center of Abnormal Vitamin D Metabolism PTH ↑
Hyperparathyroidism
trabeculum (create appearance of Railroad • Liver Disease
Cortical Bone affected ↑
Tracks – Dissecting Osteitis) • Renal Disease
(compared to Cancellous Bone )
Marrow Space (around bone cell activity) • Drugs (Anticonvulsants)
Lesion along Radial Aspect of
replaced by Fibrovascular Tissue Hypophosphatasia
Middle Phalanges of
• ↓ Intake
Index, Middle Fingers
• Genetic
Bone Loss → Microfracture, 2° Hemorrhage
Morphology
Brown Tumour
• Haemorrhage, ↑ Vascularity, Hemosiderin Deposition
• Due to Influx of
o Multinucleated Macrophages
o Ingrowth of Reparative Fibrous Tissue
Generalized Osteitis Fibrosa Cystica (Von Recklinghausen Disease of Bone)
• ↑ Bone Cell Activity
• Peritrabecular Fibrosis
• Cystic Brown Tumours (Hallmark of Severe Hyperparathyroidism)

Rickets Rickets

Normal Osteomalacia