Pathology of Bone and Joint

Dr.Djumadi Achmad, SpPA(K)

Normal bones consist of :

Cells : 1. Osteoprogenitor cells

2. Osteoblasts 3. Osteocytes 4. Osteoclasts

Bone matrix :
1. Inorganic component (65 %) : Calcium hydroxyapatite Ca10(PO4)6(OH)2 2. Organic component (35 %) : type I collagen (90 %)

* Unmineralized bone matrix = Osteoid

Osteoprogenitor cell

Osteoblast

Bone matrix Osteocyte

Active osteoblasts synthesizing bone matrix. The surrounding spindle cells represent osteoprogenitor cells.

Two osteoclasts resorbing bone

Osteoblasts

Produce bone matrix. Have surface receptors for :

Hormones (parathyroid hormone, vit.D, estrogen) Cytokines Growth factors

Osteoclasts

Responsible for bone resorption. Its differentiation and maturation initiated by :

Interleukin : IL-1, IL-3, IL-6, IL-11 Tumor necrosis factor (TNF) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Macrophage colony-stimulating factor (M-CSF)

Release enzymes to disassemble the matrix and to solubilize the mineral.

Woven bone

Osteocytes

Lamellar bone

Woven bone (top) deposited on the surface of preexisting lamellar bone (bottom).

Woven bone :

Produced quickly. Collagen deposited in random weave. Numerous osteocytes haphazardly arranged. Normally formed at growth plate in the fetal skeleton. Its presence in the adult is always pathologic.

Lamellar bone :

Produced slower but stronger than woven bone. Collagen deposited in orderly layered manner. Less osteocytes which paralelly arranged. Gradually replaces woven bone.

Bone Modeling and Remodeling

Modeling = bone growing and anlarging. Remodeling = the breakdown and renewal of bone for skeletal maintenance. Conducted by osteoblasts and osteoclasts which considered as functional unit of bone (Basic multicellular unit). The activities of osteoblasts and osteoclasts are coupled processes and they cooperate in maintain the bone mass.

Bone remodeling. Bone resorption and formation are coupled processes and are controlled by systemic factors and local cytokine, some of which are deposited in the bone matrix.

1. Reserve zone

2. Zone of proliferation

3. Zone of hypertrophy 4. Zone of mineralization

5. Primary spongiosa

Active growth plate with ongoing enchondral ossification

Developmental Abnormalities
Malformation

Absence of a phalanx, rib, or clavicle. Formation of extra bones (supernumerary ribs or digits). Fusion of two adjacent digits (syndactylism). Long spider-like digits (arachnodactylism).

Caused by alterations in homeobox gene which responsible for production of localized cellular condensation of primitive mesenchyme as the precursor of the skeleton.

Developmental Abnormalities
Achondroplasia
The major cause of dwarfism.
Abnormality in the growth plate where proliferation

of chondrocytes is reduced. Defect in cell signaling point mutation in gene that codes for FGF receptor-3.

Developmental Abnormalities
Achondroplasia

Shortened extremities Relative normal trunk Enlarged head No disturbance in intelligence and reproductive

Radiograph of a fetus with achondroplasia

A couple of achondroplasic patients

Abnormality in the matrix

Osteogenesis Imperfecta (brittle bone disease)

Deficiency in the synthesis of type I collagen. Mutations in the genes that code for 1 and 2 chains of the collagen molecule. An autosomal dominant inherited disease. Four major subtypes : Type I IV.

Osteogenesis Imperfecta type I

Compatible with survival Normal stature Skeletal fragility Dentinogenesis imperfecta Hearing impairment Joint laxity Blue Sclerae

Osteogenesis Imperfecta type II

Severe lethal type Death in utero or within days of birth Skeletal deformity with excessive fragility and multiple fractures Blue Sclerae

Radiograph of a fetus with lethal type II osteogenesis imperfecta. Note the numerous fractures of bones, resulting in shortening of the limbs

Osteoporosis

Increased porosity of the skeleton resulting from a reduction in bone mass. May be localized or generalized. Most common forms are postmenopausal and senile osteoporosis. Women >> men. Critical loss of bone mass makes the skeleton vulnarable to pathologic fractures.

Osteoporotic vertebral body (right) shortened by compression fractures

Osteoclast Dysfunction
Osteopetrosis

Marble bone disease Albers-Schonberg disease Stonelike bones, but are brittle and fracture like a piece of chalk. Variants are based on the mode of inheritance and the clinical findings. The autosomal dominant : benign type. The autosomal recessive : malignant type.

Pathogenesis The precise nature is unknown. One variant is associated with deficiency of carbonic anhydrase II, which result in failure of osteoclasts to resorb matrix. In animal models : infection by a retrovirus that cause mutation in gene for M-CSF and c-src gene. (The same mechanisms in human ?)

Morphology The ends of long bones are misshapen and bulbous (Erlenmeyer flask deformity). Cranial foramina are small. Persistent woven bone (no remodeling) brittle bone. Medullary cavity is abnormally filled with primary spongiosa. The number of osteoclast may be increased, normal, or decreased.

Clinical features Fracture easily Anemia Hydocephalus Cranial nerve disturbances (blindness, deafness, facial paralysis) Repeated infections Hepatosplenomegaly

Radiograph of the upper extremity in a patient with osteopetrosis. The bones are diffusely sclerotic, and the distal metaphyses of the ulna and radius are poorly formed (Erlenmeyer flask deformity).

Osteoclast Dysfunction
Paget Disease of Bone (Osteitis deformans)

First described by Sir James Paget in 1876. Rare in Asia and Africa. Caracterized by repetitive and overlapping sequence of speedy bone resorption followed by recurrent bone formation. The newly formed bone is disordered and poorly organized.

Paget Disease of Bone is divided into three phases or stages : 1. Osteolytic phase : osteoclastic activity 2. Mixed phase : osteoclastic-osteolytic later : osteoblastic activity 3. Osteosclerotic phase : osteoblastic activity

Diagrammatic representation of Paget disease of bone demonstrating the three phases in the evolution of the disease.

Morphology

Focal multiple lesions with variation in its stage in different sites. In the initial lytic phase, numerous resorptive pits and large osteoclasts with > 10-12 nuclei. Mosaic pattern of lamellar bone with prominent cement lines (like jigsaw puzzle). In mixed phase, osteoclasts persist + prominent osteoblasts in bone surfaces. The marrow is replaced by vascular rich connective tissue.

Cement line

Mosaic pattern of lamellar bone pathognomonic of Paget disease.

Morphology

In sclerotic phase, the mosaic pattern unfolds and the fibrovascular tissue is replaced by normal marrow. The bone become larger than normal, composed of coarsely thickened trabeculae and porous cortices, result in increased vulnerability to deformation under stress and fracture.

Paget disease of the humerus A. The three stages of the disease : 1. Lytic 2. Mixed 3. Sclerotic B. Area 1 : The lytic stage with part of mixed stage in the upper portion. C. Area 3 : The sclerotic stage reveals irregular thickening of both cortical and trabecular bone.

Abnormality in Mineral Homeostasis Rickets and Osteomalacia 2. Hyperparathyroidism 3. Renal Osteodystrophy

1.

Abnormality in Mineral Homeostasis Rickets and Osteomalacia

Caused by vitamin D deficiency. Rickets in growing children; Osteomalacia in adults May result from : 1. Deranged vitamin D absorption or metabolism 2. Disorders that affect the function of vit.D 3. Disorders that disturb calcium or phosphorus homeostasis

The Causes of Rickets and Osteomalacia

1. Inadequate Synthesis or Dietary Deficiency of Vitamin D

Inadequate exposure to sunlight Limited dietary intake of fortified foods Poor maternal nutrition Dark skin pigmentation

The Causes of Rickets and Osteomalacia

2. Decreased Absorption of Fat Soluble Vit.D

Cholestatic liver disease Pancreatic insufficiency Biliary tract obstruction Celiac sprue Extensive small bowel disease

The Causes of Rickets and Osteomalacia 3. Derangements in Vitamin D Metabolism

Increased degradation of vit.D and 25(OH)D Induction of cytochrome P-450 enzymes (phenytoin, phenobarbital, rifampin) Impaired synthesis of 25(OH)D Diffuse liver disease Decreased synthesis of 1,25(OH)2D Advanced renal disease Inherited deficiency of renal -1 hydroxylase (vitamin D-dependent rickets type I)

The Causes of Rickets and Osteomalacia

4. End-Organ Resistance to 1,25(OH)2D

Inherited absence of or defective receptors for metabolite of vitamin D (vitamin D-dependent

rickets type II)

5. Phosphate Depletion

Poor absorption of phosphate due to chronic use of antacids (binding by aluminum OH) Excess renal tubule excretion of phosphate (X-linked hypophosphatemic rickets)

Deficiency of Vitamin D Production of PTH

Hypocalcemia

1. Activates renal -1 hydroxylase

Amount of active vit.D Calcium absorption

2. Mobilizes calcium from bone 3. Decreases renal calcium excretion 4. Increases renal phosphate excretion Impaired bone mineralization Hypophosphatemia

Morphology of Rickets

Overgrowth of epiphyseal cartilage. Persistence of irregular masses of cartilage. Deposition of osteoid matrix on inadequately mineralized cartilage. Enlargement of osteochondral junction. Increased capillary vessels and fibroblasts because of microfractures. Deformation of the skeleton due to the loss of structural rigidity of the developing bones.

A. Costochondral junction in rickets. The cartilage is irregularly oriented and the bone trabeculae contain unmineralized matrix. B. Normal costochondral junction with orderly transition from cartilage to new bone formation.

Morphology of Rickets
Skeletal deformities : - Craniotabes - Frontal bossing &Squared appearance of the head - Rachitic rosary and Pigeon chest - Harrison groove at the lower margin of the ribs - Deformed pelvis - Lumbar lordosis - Bowing of the legs

A rachitic child with bowing of legs.

Morphology of Osteomalacia
-

Persistence osteoid matrix No alteration in bone contours The bone is weak and vulnerable to fractures or microfractures vertebral bodies and femoral necks Eventually leads to the loss of skeletal mass (osteopenia)

Abnormality in Mineral Homeostasis Hyperparathyroidism

Either primary or secondary. Increased parathyroid hormone stimulate osteoblast activity which in turn initiate the release of mediators that stimulate osteoclast activity. The skeletal manifestations of hyperpara-thyroidism are caused by intense osteoclastic bone resorption.

Abnormality in Mineral Homeostasis Hyperparathyroidism

The entire skeleton is affected, even though some sites are more severely affected affected than others. The morphologic changes of severe hyperparathyroidism (osteitis fibrosa cystica) are rarely encountered. The morphologic changes in secondary hyperparathyroidism are milder than those in the primary hyperparathyroidism.

Morphology

Affects cortical bone more severely than cancellous bone, leading to thinned cortices. Intracortical bone resorption conducted by osteoclasts that bore along haversian and Volkmann canals (cortical cutting cones) In cancellous bone, osteoclasts tunnel into and dissect centrally along the length of the trabeculae (dissecting osteitis)

Morphology

Inceased bone formation by osteoblasts. Microfractures with hemorrhages elicit an ingrowth of reactive fibrous tissue, hemosiderin deposition and multinucleated giant cells (brown tumor) which frequently undergo cystic degeneration. The increased bone cell activity + peritrabecular fibrosis + cystic brown tumors = generalized osteitis fibrosa cystica (von Recklinghausen disease).

Hyperparathyroidism with osteoclasts boring into the center of the trabeculum (dissecting osteitis).

Resected rib with an expansile brown tumor adjacent to the costal cartilage.

Abnormality in Mineral Homeostasis

Renal Osteodystrophy
The skeletal changes in chronic renal disease. 1. Increased bone resorption (mimicking osteitis fibrosa cystica. 2. Delayed matrix mineralization (osteomalacia). 3. Osteosclerosis. 4. Growth retardation. 5. Osteoporosis.

Renal Osteodystrophy
Two major types : 1. High-turnover renal osteodystrophy : increased bone resorption and formation with predominance of the former. 2. Low-turnover renal osteodystrophy (aplastic disease) : marked reduction in the rate of bone mineralization, formation and resorption. Many patients have mixed pattern.

Pathogenesis of Renal Osteodystrophy

Renal Failure

Phosphate retention
Hyperphosphatemia

1,25-[OH]2D
Hypocalcemia 1,25-[OH]D Bone mineralization

Aluminum deposition

Secondary hyperparathyroidism Secretion of PTH

Bone resorption

Fractures

Deposition of subperiosteal and intramedullary trabeculae of woven bone. The activated mesenchymal cells may also differentiate into chondroblasts that make fibrocartilage and hyaline cartilage. This mixture of vascularized fibrous tissue, woven bone and cartilage is fully attained at the end of the second or third week.

Fractures

Enchondral ossification initiate formation of bony callus which communicate the fractured ends. During a period of months, the callus will be remodeled and the portion that are not physically stressed will be resorbed.

A. Recent fracture of the fibula.

B. Marked callus formation 6 weeks later.

Pyogenic Osteomyelitis
The causes : Staphylococcus aureus (80-90%), E.coli, pseudomonas, etc Microorganisms may reach the bone by :
1. Hematogenous spread 2. Extension from an adjacent site 3. Direct implantation

Pyogenic Osteomyelitis
The location within specific bones varies with age :

In neonate : metaphysis or epiphysis or both In children : metaphysis In adult : epiphysis and subchondral region

Morphology

The bacteria within the bone will proliferate, induce acute inflammatory reaction and cell death. The entrapped bone undergoes necrosis. Spreading of the bacteria and inflammation within the bone and may reach the periosteum subperiosteal abscess. Both suppurative and ischemic injuries may cause segmental bone necrosis (sequestrum).

Morphology

Rupture of the periosteum leads to the formation of soft tissue abscess and draining sinus.

Resected femur in a patient with draining osteomyelitis. The drainage tract in the subperiosteal shell of viable new bone (involucrum) reveals the inner necrotic bone (sequestrum).

ARTHRITIS

OSTEOARTHRITIS RHEUMATOID ARTHRITIS GOUT ARTHRITIS

OSTEOARTHRITIS

OSTEOARTHRITIS

OSTEOARTHRITIS

Severe osteoarthritis. 1. Eburnated articular surface. 2. Subchondral cyst. 3. Residual articular cartilage.

Severe osteoarthritis of the hip. The joint space is narrowed, and there is subchondral sclerosis with scattered oval radiolucent cysts and peripheral osteophytes (arrows).

RHEUMATOID ARTHRITIS

RHEUMATOID ARTHRITIS

Rheumatoid arthritis.

A. Synovial hypertrophy with formation of villi.

B. Subsynovial tissue containing a dense lymphoid aggregate.

Subcutaneuos rheumatoid nodule with an area of necrosis (top) surrounded by a pallisade of macrophages and scattered chronic inflammatory cells.

Gouty tophus. An aggregate of dissolved urate crystals is surrounded by reactive fibroblasts, mononuclear inflammatory cells, and giant cells.

GOUTY ARTHRITIS

Amputated great toe with white tophi involving the joint and soft tissue.

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