1. Congenital 1. Achondroplasia* 2. Osteogenesis imperfecta* 3. Osteopetrosis * 2. Metabolic bone diseases 1. Osteoporosis* 2. Osteitis fibrosa cystica* 3.

Rickets and osteomalacia 4. Renal osteodystrophy 3. Disease caused by osteoclast dysfunction 1. Pagets disease* 4. Osteonecrosis (avascular necrosis) ** 5. Infections* 6. Fractures 7. Miscellaneous

Non-neoplastic disorders of bone

Congenital disorders of bone

1. Achondroplasia (long bones not formed properly) 2. Osteogenesis imperfecta (Defective synthesis of type I collagen) 3. Osteopetrosis: (Replacement of marrow cavity by bone due to defective osteoclast function)
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Achondroplasia
An autosomal dominant condition in which there is impaired formation of the long bones due to Impaired proliferation of cartilage at growth plate. Is one of the MC causes of dwarfism Clinical findings: Normal sized head and vertebral column Shortened arms and legs (dwarfism) Normal intelligence, life span and reproductive ability. Normal GH and insulin growth factor -1 levels. 3

Achondroplasia
Molecular basis: point mutation in gene coding for fibroblast growth factor receptor 3 (FGFR3) Inhibits cartilage synthesis at growth plate Decreased growth of long bones
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Osteogenesis imperfecta
AKA "brittle bone diseases or fragilitas ossium. A group of diseases having in common defective synthesis of type I collagen. Due to mutations in genes coding for 1 & 2 chains of collagen. Pathology: Generalized osteopenia (brittle bone) Resulting in recurrent fractures and skeletal deformity. Disease affects skeleton and other tissues 5 rich in type I collagen.

Osteogenesis imperfecta
Types: Several types are known (Type I-IV) Most are autosomal dominant***. Clinical findings: pathological fractures** at birth blue sclera** : due to reflection of underlying choroidal veins. Deafness : involvement of bone of inner and middle ear Thin dermis easy bruising. Dental imperfections. 6 Type II is lethal in utero

Osteogenesis imperfecta

Blue sclera

Osteogenesis imperfecta

Osteopetrosis ("marble bone disease")

Group of genetic diseases characterized by: decreased osteoclast function, leading to Decreased resorption, and Greatly increased density* of bone. Pathology: Increased bone density and thickening of bone cortex Marrow cavity replaced by bone The thickened bones are brittle and fracture easily.
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Obliteration of the marrow space

Dense bones of the lower extremities

Absence of marrow
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Osteopetrosis
X-ray findings:

Osteosclerosis

Broadened metaphysis

Erlenmeyer flask shaped deformity

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 Occurs in two forms autosomal dominant (usually mild) or autosomal recessive (usually severe). Clinical findings: Pathologic fractures Pancytopenia and leukoerythroblastic blood picture: Replacement of marrow cavity by bone. Extramedullary hematopoiesis: hepatosplenomegaly Cranial nerve compression: Due to narrowing of cranial foramina May result in blindness, deafness and facial nerve palsies. 13 Treatment: bone marrow transplant

Metabolic diseases of bone

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Osteoporosis
Refers to increased porosity of skeleton. Occurs due to: Loss of organic bone matrix and minerals. Resulting in : decreased bone mass and density. decreased thickness of cortical and trabecular bone. Osteoporotic bones: thin and fragile and are susceptible to fracture.
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Osteoporosis
Pathogenesis: Osteoporosis results from a slight excess of bone resorption over bone deposition, continuing over many years. Epidemiology: Is the most common metabolic abnormality of bone. MC occurs in postmenopausal Caucasian women and the elderly.
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TYPES of osteoporosis
A: Localized : e.g. disuse OP of a limb B: Generalized: involves entire skeleton. Two types 1. Primary: Old age (Senile) Osteoblasts with diminished capacity to make new bone Physical inactivity Estrogen deficiency (postmenopausal) 2. Secondary: due to underlying disease Cushings disease (hypercortisolism) Drugs (heaprin and steroids) Space travel 17

Postmenopausal osteoporosis Pathogenesis

Is secondary to estrogen deficiency. Normally Estrogen: Stimulates OPG production Decreases production of M-CSF Decreases response of osteoclasts to RANK ligand. Net result: Decreased formation of osteoclasts Decreased bone resorption
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Postmenopausal osteoporosis Pathogenesis

Estrogen deficiency results in: production of IL1 and TNF by monocytes Increased activity of RANK ligand and MCSF osteoclast activity bone loss.

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Genetic factors Physical activity

Menopause estrogen IL1,TNF RANK ligand, M-CSF osteoclast activity

Peak bone mass

Nutrition

Aging activity of Osteoprogenitor cells activity of osteoblasts physical activity

Osteoporosis
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Normal Vertebral body

Osteoporotic vertebral body

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Fracture Osteoporosis

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Osteoporosis
Clinical findings: Bone pain Weight bearing bones predisposed to # Compression # of vertebral bodies (most common) Colles # of distal radius. # femoral neck. Loss of height and kyphosis

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Pathology
thin cortical bone and thin trabecular bone

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Diagnosis: Dual energy X ray absorptiometry (DEXA) evaluate bone density. Prevention of postmenopausal osteoporosis: weight bearing exercises: walking, not swimming calcium, vitamin D supplements estrogen replacement therapy Unopposed estrogen increases the risk of endometrial Ca. Prevented by addition of progesterone. Treatment: Bisphosphonates: inhibit bone resorption. Calcitonin: inhibits osteoclasts SERM: selective estrogen receptor modulators

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Osteitis Fibrosa Cystica ( von Recklinghausen disease of bone)

The cause is primary or secondary hyperparathyroidism 1. Primary hyperparathyroidism : Parathyroid adenoma PTH Parathyroid hyperplasia PTH 2. Secondary hyperparathyroidism : prolonged hypocalcemia (renal failure) increased PTH. Increased levels of PTH Activates osteoblasts, which in-turn activates osteoclasts resulting in bone resorption and hypercalcemia.
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Brown tumor of hyperparathyroidism

Osteoclasts

Fibrosis

Osteoclasts in a fibrous stroma

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Osteitis Fibrosa Cystica

Characterized by: Wide spread osteolytic lesions. Predisposing to Deformity , microfractures and Secondary hemorrhages with formation of cysts. OFC can manifest as Brown tumor of bone characterized by: Cystic spaces lined by multinucleated osteoclasts, filled with fibrous tissue, and with brown discoloration resulting from 32 hemorrhage.

Rickets and osteomalacia

Both diseases characterized by Decreased mineralization of newly formed bone. Usually caused by deficiency or abnormal metabolism of vitamin D. Osteomalacia: Cause is Vitamin D deficiency in adults Rickets: Cause is vitamin D deficiency in children See nutrition lectures***.

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Renal osteodystrophy
Osteomalacia secondary to chronic renal disease. Pathogenesis: Chronic renal failure causes Hypocalcemia Due to lack of conversion of inactive vitamin D into active vit.D Hypocalcemia results in secondary hyperparathyroidism PTH secretion stimulates osteoclast activity
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Pagets disease of bone

OSTEITIS DEFORMANS

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Paget disease of bone (osteitis deformans)

Skeletal disease characterized by episodes of: Excessive and disordered bone resorption by osteoclasts followed by Exuberant but disorganized bone formation, producing thickened but weak bone that is susceptible to deformity and #. Epidemiology: Primarily occurs in elderly men (>40 yrs). Etiology: Cause unknown ( ? paramyxovirus) 36

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Paget disease of bone

Forms of involvement: Monostotic: involving one bone Polystotic : involving multiple bones. Common bones include: pelvis >skull> femur.

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Pathogenesis
Three stages of Paget disease: 1.Osteolytic stage 2.Mixed osteolytic-osteoblastic stage 3.Osteosclerotic (burnt out stage)

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Paget disease of bone : Stages

Osteolytic Stage: osteoclastic resorption of bone predominates Mixed osteolytic and osteoblastic stage: characterized by Osteolytic and increased osteoblastic bone formation (usually woven bone). New bone: poorly mineralized, soft and weak. vulnerable to # and deformation. the bone is deposited in a tile like or mosaic pattern which is pathognomonic of Paget disease. increased alkaline phosphatase levels. Osteosclerotic stage: Osteoblastic activity predominates 41

Clinical findings: Asymptomatic in most cases Elevated alkaline phosphatase* Bone pain from Pathologic fractures* Skeletal deformities* (tibial bowing, skull enlargement; increased hat size) Hearing loss:* narrowing of foramina Warmth of overlying skin due to bone hypervascularity. High output cardiac failure (due to AV connections in vascular bone)* Increased risk of osteogenic sarcoma*.
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Pathology
Microscopic features: Haphazard arrangement of cement lines creating a mosaic pattern .

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Normal bone

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Mosaic pattern of lamellar bone

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Paget's disease of bone: Mosaic pattern

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Osteonecrosis (Avascular necrosis)

Ischemic infarction of bone & bone marrow. Causes of ischemia: Vascular interruption (fracture) (femoral neck # bleeds into capsule compromise medial femoral circumflex artery avascular necrosis) Corticosteroids* (most common) (SLE patients) Sickle cell disease, Caisson disease. Common sites include femoral head 47 Scaphoid bone.

Osteonecrosis: Morphology
Osteonecrosis: Can involve The medullary cavity or The subchondral region Medullary infarct: involves marrow and the cancellous bone. usually clinically silent. Remains stable Subchondral infarct: Involves the subchondral bone Wedge shaped area of necrosis with viable overlying articular cartilage Causes chronic pain Collapse predispose to osteoarthritis
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Osteonecrosis

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Osteonecrosis in children
May involve characteristic sites: Legg-Calve-Perthes disease: Aseptic necrosis involving the ossification center in the femoral head. Occurs most often in boys 3-10 years of age. Pain in knee or limp secondary osteoarthritis is common. Kohler bone disease: Aseptic necrosis of navicular bone
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Osgood-Schlatter disease
Inflammation of proximal tibial apophysis at insertion of patellar tendon. Affects physically active boys 11-15 yrs of age Produces permanent knobby appearing knees.
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