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5. Formation of bones a. Intramembranous bone i. Direct bone formation without a "cartilage model"

ii. Flat bones such as the cranial bones, clavicles, vertebrae, wrist, and ankle bones iii. Also involved in appositional bone growth b. Enchondral bone i. Indirect bone formation from a "cartilage model"

ii. Bone is formed from cartilage at the epiphyseal growth plates iii. Long bones such as femur, humerus, tibia, fibula, etc. Hereditary Bone Disorders

1. Achondroplasia a. Most common form of inherited dwarfism b. Hereditary defect i. Autosomal dominant ii. Mutation in fibroblast growth factor receptor 3 (FGFR3)

c. Pathogenesis i. Activation of FGFR3 inhibits cartilage synthesis at the epiphyseal growth plate, resulting in decreased enchondral bone formation and premature ossification of the growth plates.

d. Long bones are short and thick —> short extremities —> dwarfism e. Cranial and vertebral bones spared —> relatively large head and trunk f. Normal intelligence, life span, and reproductive ability

2. Osteogenesis imperfecta (OG1) ("brittle bone disease")

a. Hereditary defect: abnormal synthesis of type I collagen b. Pathology i. Generalized osteopenia (brittle bones), resulting in recurrent fractures and skeletal deformity ii. Most patients have an abnormally thin sclera with a blue hue iii. Laxity of joint ligaments leads to hypermobility iv. Involvement of the bones of the inner and middle ear produces deafness v. Some patients have dentinogenesis imperfecta: small, fragile, and discolored teeth due to a deficiency of dentin vi. The dermis may be abnormally thin, and the skin is susceptible to easy bruising c. Treatment: supportive

Table 26-1. Clinical Phenotypes of OG1

Four clinical phenotypes of varying severity. All are rare. Type I

(1) Autosomal dominant ! (2) Fractures

(3) Blue sclerae

(4) Hearing loss

(5) Little progression after puberty

(1) Autosomal recessive

(2) Stillborn infant or death after birth with generalized crumpled bones Type III

! (1) Autosomal dominant or recessive

(2) Progressive

(3) Multiple fractures

(4) Severe skeletal deformity

(5) Dentinogenesis Imperfecta

(6) Hearing loss

Type IV

(1) Autosomal dominant

(2) Variable severity

3) Fractures

4) Skeletal deformity (5) Normal sclerae

6) Sometimes dentinogenesis imperfecta

3. Osteopetrosis a. Synonyms: marble bone disease, Albers-Schonberg disease b. Hereditary defect: decreased osteoclast function, leading to decreased resorption and thick sclerotic bones c. Pathology i. Increased bone density and thickening of bone cortex ii. The thickened bones are brittle and fracture easily iii. Myelophthisic process

• Due to narrowing and fibrosis of the medullary cavities

• May lead to pancytopenia iv. Extramedullary hematopoiesis v. Cranial nerve compression

• Due to narrowing of cranial foramina

■ May result in blindness, deafness, and facial nerve palsies vi. Hydrocephalus due to obstruction of CSF

d. X-ray findings i. Symmetrical generalized osteosclerosis ii. Long bones may have broadened metaphyses, resulting in an "Erlenmeyer flask"-shaped deformity e. Major clinical forms i. Autosomal recessive (malignant type)

■ Affects infants and children ' Multiple fractures

■ Early death due to anemia, infection, or hemorrhage ii. Autosomal dominant (benign type)

• Affects adults

• Cranial nerve impingement iii. Carbonic anhydrase II deficiency

• Autosomal recessive

• Renal tubular acidosis and cerebral calcification f. Treatment: bone marrow transplantation Paget Disease (Osteitis Deformans)

1. Definition: localized disorder of bone remodeling, resulting in excessive bone resorption followed by disorganized bone replacement, producing thickened but weak bone that is susceptible to deformity and fracture

2. Epidemiology a. Begins after age 40

b. Common in those of European ancestry

3. Etiology a. Possible slow virus infection with paramyxovirus b. Possible genetic predisposition

4. Forms of involvement a. Monostotic (15%): involving one bone b. Polyostotic (85%): involving multiple bones c. Common sites include the skull, pelvis, femur, and vertebrae.

5. Three stages of Paget disease a. Osteolytic: osteoclastic activity predominates b. Mixed osteolytic-osteoblastic c. Osteosclerotic: osteoblastic activity predominates "burnout stage"

6. Pathology a. Micro: haphazard arrangement of cement Unes, creating a "mosaic pattern" of lamellar bone b. Involved bones are thick but weak and fracture easily c. Skull involvement i. Increased head size ii. Foraminal narrowing causes impingement of cranial nerves, often leading to deafness iii. Involvement of facial bones may produce a lionlike facies

7. Clinical features a. Clinical presentation i. Asymptomatic in most cases ii. Bone pain and deformity iii. Fractures iv. Warmth of the overlying skin due to bone hypervascularity b. X-rays: bone enlargement with lytic and sclerotic areas i. Highly elevated serum alkaline phosphatase ii. Increased levels of urinary hydroxyproline ; 8. Complications a. AV shunts within marrow may result in high-output cardiac failure.

b. Osteosarcoma c. Other sarcomas

D. Osteoporosis Note

1. Definition: decreased bone mass (osteopenia)> resulting in thin, fragile bones that are a. Most common bone disorder in the United States b. Most commonly occurs in postmenopausal Caucasian women and the elderly

3. Pathogenesis a. Primary causes include i. Estrogen deficiency (postmenopausal, Turners syndrome)

ii. Genetic factors (low density of original bone)

iii. Lack of exercise iv. Old age v. Nutritional factors b. Secondary causes i. Immobilization ii. Endocrinopathies (e.g., Cushing disease, thyrotoxicosis)

iii. Malnutrition (e.g., deficiencies of calcium, vitamins C and D> protein)

iv. Corticosteroids v. Genetic disease (e.g., OGI, Gaucher disease)

4. Clinical features a. Clinical presentation i. Patients may experience bone pain and fractures ii. Weight-bearing bones are predisposed to fractures

■ Vertebrae (compression fracture)

■ Femoral neck (hip fracture)

• Distal radius (CoIJes fracture)

iii. Loss of height and kyphosis c. Lab susceptible to fracture 2. Epidemiology

In osteoporosis, bone is formed normally but in decreased amounts.

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b. Radiographic i. X-rays: generalized radiolucency of bone (osteopenia)

ii. Dual-energy x-ray absorptiometry (DEXA)

c. Lab: normal serum calcium, phosphorus, and alkaline phosphatase d. Micro: thinned cortical and trabecular bone 5. Treatment a. Estrogen replacement therapy b. Calcitonin c. Weight-bearing exercise Osteomalacia and Rickets

1. Genera]

a. Definition: both diseases are characterized by decreased, mineralization of newly formed bone, usually caused by deficiency or abnormal metabolism of vitamin D

b. Etiology i. Dietary deficiency of vitamin D

ii. Intestinal malabsorption iii. Lack of sunlight iv. Renal and fiver disease c. Treatment: vitamin D and calcium

2. Rickets (children)

a. Occurs in children prior to closure of the epiphyses b. Both remodeled bone and bone formed at the epiphyseal growth plate are under-mineralized c. Enchondral bone formation is affected, leading to skeletal deformities i. Craniotabes and frontal bossing: skull deformities ii. Rachitic rosary: deformity of the chest wall as a result of an overgrowth of cartilage at the costochondral junction iii. Pectus carinatum (pigeon breast deformity): outward protrusion of the sternum iv. Lumbar lordosis: spinal curvature v. Bowing of the legs; curvature of femur/tibia due to weight bearing d. Fractures may also occur

3. Osteomalacia (adults)

a. Impaired mineralization of the osteoid matrix results in thin, fragile bones that are susceptible to fracture.

b. Clinical presentation i. Bone pain ii. Fractures of the vertebrae, hips, and wrist c. X-rays: diffuse radiolucency of bone (osteopenia)

d. Lab i. Low serum calcium and phosphorus ii. High alkaline phosphatase

Osteomyelitis 1. Pyogenic osteomyelitis a. Routes of infection i. Hematogenous spread

• Seeding of bone after bacteremia

• Commonly affects the metaphysis ii. Direct inoculation iii. Spread from an adjacent site of infection b. Microbiology i. Staphylococcus aureus (most common)

ii. Escherichia coli iii. Streptococci iv. Go no cocci v. Haemophilus influenzae vi. Salmonella: common in sickle cell disease vii. Pseudomonas: common in intravenous drug abusers (IVDA) and diabetics c. Clinical features i. Fever and leukocytosis ii. Localized pain, erythema, and swelling d. X-ray i. May be normal for up to 2 weeks ii. May initially show periosteal elevation iii. Lytic focus with surrounding sclerosis e. Pathology i. Suppurative inflammation ii. Vascular insufficiency iii. Ischemic necrosis of bone iv. Sequestrum: the necrotic bone v. Involucrum: new bone formation that surrounds the sequestrum f. Diagnosis i. Blood cultures ii. Bone biopsy and culture g. Treatment: antibiotics ± surgical drainage h. Complications i. Fracture ii. intraosseous (Brodie) abscess iii. Amyloidosis iv. Sinus tract formation v. Squamous cell carcinoma of the skin at the site of a persistent draining sinus tract vi. Osteogenic sarcoma (rare)

2. Tuberculous osteomyelitis a. Occurs in 1% of cases ofTB

b. Pain or tenderness, fever, night sweats, weight loss c. Caseating granulomas with extensive destruction of the bones d. Common site: thoracic and lumbar vertebrae ("Pott disease")

e. Complications i. Vertebral compression fracture ii. Psoas abscesses iii. Amyloidosis Miscellaneous Bone Disorders

1. Avascular necrosis a. Synonyms: aseptic necrosis, osteonecrosis b. Definition: ischemic necrosis of bone and bone marrow c. Causes i. Trauma and/or fracture (most common)

ii. Idiopathic iii. Steroids iv. Sickle cell anemia v. Gaucher disease vi. Caisson disease vii. Other d. Complications: osteoarthritis and fractures

2. Osteitis fibrosa cystica a. Synonym: von Recklinghausen disease of bone b. Definition: excessive parathyroid hormone (hyperparathyroidism) causing osteoclast activation and generalized bone resorption c. Etiology i. Parathyroid adenoma ii. Parathyroid hyperplasia d. Clinical features i. Occurs more commonly in primary hyperparathyroidism ii. May cause bone pain, bone deformities, and fractures e. Pathology i. Excess bone resorption with increased number of osteoclasts ii. Fibrous replacement of marrow iii. Cystic spaces in trabecular bone (dissecting osteitis)

iv. "Brown tumors": brown bone masses produced by cystic enlargement of bones with areas of fibrosis and organized hemorrhage f Treatment: treat hyperparathyroidism

3. Hypertrophic osteoarthropathy a. Presents with painful swelling of wrists, fingers, ankles, knees, or elbows b. Pathology i. Ends of long bones have periosteal new bone formation ii. Digital clubbing iii. Arthritis of adjacent joints is commonly seen c. Etiology i. Bronchogenic carcinoma (a paraneoplastic syndrome)

ii. Chronic lung diseases iii. Cyanotic congenital heart disease iv. Inflammatory bowel disease d. Treatment: often regresses when the underlying disease is treated H. Benign Tumors of Bone

1. Osteoma a. Definition: benign neoplasm that frequently involves the skull and facial bones b. "Hyperostosis frontalis interna" describes an osteoma that extends into the orbit or sinuses.

c. Associated with Gardner syndrome

2. Osteoid osteoma a. Definition: benign, painful growth of the diaphysis of a long bone, often the tibia or femur b. Presentation i. Males > females; age 5-25 years ii. Pain that is worse at night and relieved by aspirin c. X-rays: central radiolucency surrounded by a sclerotic rim d. Micro i. Small (<2 cm) lesion of the cortex ii. Centra] nidus of osteoid surrounded by dense sclerotic rim of reactive cortical bone

3. Osteoblastoma a. Similar to an osteoid osteoma but is larger (>2 cm) and often involves vertebrae

4. Osteochondroma (exostosis)

a. Definition: benign bony metaphyseal growths capped with cartilage that originates from epiphyseal growth plate b. Clinical presentation i. Adolescent males ii. Firm, solitary growths at the ends of long bones iii. They may be asymptomatic, cause pain, produce deformity, or undergo malignant transformation (rare)

c. Osteochondromatosis (multiple hereditary exostosis) i. Multiple, often symmetric, osteochondromas

5. Enchondroma a. Definition: benign cartilaginous growth within the medullary cavity of bone, usually involving the hands and feet b. Typically solitary and asymptomatic and require no treatment c. Multiple enchondromas (enchondromatosis) i. Oilier disease

• Nonhereditary syndrome ■ Multiple enchondromas in the hands and feet

■ Presents with pain and fractures

■ May undergo malignant transformation to chondrosarcoma ii. Maffucci syndrome

■ Multiple enchondromas

• Soft tissue hemangiomas

• Increased risk of malignant transformation, ovarian carcinoma, and brain gliomas

Malignant Tumors of Bone

1. Osteosarcoma (osteogenic sarcoma)

a. Most common primary malignant tumor of bone b. Incidence i. Males > females ii. Most occur in teenagers (ages 10-25)

iii. Patients with familial retinoblastoma have a high risk c. Clinical features: localized pain and swelling d. Classic x-ray findings i. Codmans triangle (periosteal elevation)

ii. "Sunburst" pattern iii. Bone destruction e. Grossly i. Often involves the metaphyses of long bones ii. Usually around the knee (distal femur and proximal tibia)

iii. Large, firm, white-tan mass with necrosis and hemorrhage f. Micro: anaplastic cells producing osteoid and bone g. Treatment: surgery and chemotherapy h. Prognosis i. Poor ii. Hematogenous metastasis to the lungs is common iii. Prognosis is improved with aggressive management, such as resecting single pulmonary metastases i. Secondary osteosarcomas i. Occur in elderly persons ii. Associated with Paget disease, irradiation, and chronic osteomyelitis iii. Highly aggressive

2. Chondrosarcoma a. Definition: malignant tumor of chondroblasts b. Males > females; age 30-60

c. Etiology: the tumor may arise de novo or secondary to a preexisting enchondroma, exostosis, or Paget disease d. Clinical presentation: enlarging mass with pain and swelling e. Typically involves the pelvic bones, spine, and shoulder girdle f. Micro: composed of atypical chondrocytes and chondroblasts, often with multiple nuclei in a lacuna

3. Giant-cell tumor of bone ("osteoclastoma")

a. Uncommon malignant neoplasm containing multinucleated giant cells admixed widi stromal cells b. Females > males; age 20-50

c. Clinical features: bulky mass with pain and fractures d. X-rays i. Expanding lytic lesion surrounded by a thin rim of bone ii. May have a "soap bubble" appearance e. Gross i. Often involves the epiphyses of long banes ii. Usually around the knee (distal femur and proximal tibia)

iii. Red-brown mass with cystic degeneration f. Micro: multiple osteoclast-like giant cells are distributed within a background of mononuclear stromal cells g. Treatment: surgery (curettage or en bloc resection)

h. Prognosis: locally aggressive with a high rate of recurrence

4. Ewing sarcoma a. Malignant neoplasm of undifferentiated cells arising within the marrow cavity b. Incidence i. Males are affected slightly more often than females ii. Most occur in teenagers (ages 5-20)

c. Clinical features are pain, swelling, and tenderness d. Genetics: classic translocation t(11;22), which produces the EWS-FL11 fusion protein e. X-ray: concentric "onion-skin" layering of new periosteal bone f. Gross i. Often affects the diaphyses of long bones ii. Most common sites are the femur, pelvis, and tibia iii. White-tan mass with necrosis and hemorrhage g. Micro i. Sheets of undifferentiated small round blue cells resembling lymphocytes ii. Homer Wright pseudorosettes iii. Tumor cells erode through the cortex and periosteum and invade surrounding tissues h. Treatment: chemotherapy, surgery, and/or radiation i. Prognosis: 5-year survival rate 75%

5. Metastasis to bone a. Much more common than primary bone tumors b. Common primary sites i. Prostate (often osteoblastic)

ii. Breast iii. Lung iv. Thyroid v. Kidney

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