IB Diseases Of The Bone PDF

IBSSD 1525/1513 DISEASES OF THE BONE LUIGI STRIZZI, MD, PhD DEPARTMENT OF PATHOLOGY MIDWESTERN UNIVERSITY CCOM, CDMI  Game plan… i. Osteogenesis Imperfecta A. Congenital diseases of Bone Development...

IBSSD 1525/1513 DISEASES OF THE BONE LUIGI STRIZZI, MD, PhD DEPARTMENT OF PATHOLOGY MIDWESTERN UNIVERSITY CCOM, CDMI  Game plan… i. Osteogenesis Imperfecta A. Congenital diseases of Bone Development ii. Osteopetrosis iii. Fibrous dysplasia i. Osteoporosis ii. Paget Disease (Osteitis Deformans) B. Acquired Diseases of Bone iii. Rickets and Osteomalacia iv. Complications of Bone fractures i. Changes that occur during osteomyelitis C. Pathology of bone infections ii. Pott’s disease D. Neoplasms of the bone i. Bone forming tumors ii. Cartilage forming tumors iii. Secondary metastatic bone tumors & CARTILAGE - that GarS ·SSIFIED  * Ossification of the bones of the head Bones of calvarium (skullcap) → Intramembranous ossification Maxilla and zygomatic bone → intramembranous ossification No Cartilage Involved Most of body of mandible → intramembranous ossification Anterior part of mandible → endochondral ossification Ossification of the bones of the head * → endochondral ossification * Ethmoid bone → endochondral ossification  BONE IS NOT A STATIC TISSUE Response to mechanical load: bone is added Bone remodeling It's An ACTIVE TISSUE - where needed and removed where not needed Replacing/reshaping bone during: - mechanical load: - Growth Bending - Following injury (fracture) Compression - Repair of microdamage Tension Torsion - Osteoblasts deposit bone Bone remodeling unit matrix - Osteoclasts resorb bone Not Enough BONE & improper bone remodeling leads to weak, sclerotic bone that L Oo can easily fracture! Much BONE CAISO WEAK BONE) Congenital diseases of Bone i. Osteogenesis Imperfecta → a.k.a. “brittle bone disease” - AD inherited defective synthesis of alpha1 & alpha2 chains of type I collagen compromised osteoblast activity → reduced trabecular and lamellar bone formation Net result → decreased number of trabeculae + decreased cortical thickness DECREASE In SIZE THAT DOESN'T OSSIFIED BONG. HAVE EMOUGL Congenital > KIDS - Different types → Type I – Type VIII > NOT ENOUGH - BONE BONE = WEAK - Osteogenesis Imperfecta Tarda (Type I) → most common and mildest type → fractures during childhood → become less frequent after puberty - Osteogenesis Imperfecta Congenita (Type II) → most severe type → multiple fractures in utero → usually fatal Intra Uterine fructures Osteogenesis Imperfecta (OI) Clinical manifestations: reduced thickness of bone → skeletal fragility/deformity Marro normal reduced, irregular & poorly TURBECULAR BONE ossified trabeculae in OI bowing of ulna and radius in patient with OI Osteogenesis Imperfecta …because of the ubiquitous nature of Type I collagen → extraskeletal manifestations are common in OI Scleva becomes so thin , you start sizing the blue sclera - CHOROLD THAT'S UNDERNEATH THAT GIVESTHAT BLUISH Hinge to sclera hearing loss dental malformation and discoloration  iii. Osteopetrosis (“marble-bone disease”) - inherited disorders of osteoclast function → osteoclasts have difficulty decalcifying and resorbing bone CASY HAVE TO REMOVE THAT CALCIUM) osteoclasts resorb bone by creating acidic environment in resorption bays (Howship lacunae) cast Osteo -- to s ↓ Most common causes → defect in bone acidification: - PROVIDE TE ALLD Helps the AR → defective carbonic anhydrase (CA) enzyme activity Osteoclast the AD → defective proton pump record bone AD → defective Cl- channels (Albers-Schönberg disease) + H + - HYDROCHLORIC ACID CNEED TO ABSORE FILE BONG) Retroviral infections (alter/destroy osteoclasts ?) - RARE - Defective bone remodeling (i.e., osteoblasts continue to produce osteoid which gets mineralized but osteoclasts can’t resorb mineralized bone) → accumulation of dense but structurally weak bone → “sclerotic bone” → can easily fracture much  ma · Osteopetrosis not of clasts - crawing up on A of the cartilage EBONE REPLACINg. normal osteopetrosis - Regular bone trabeculae separating bone marrow in normal - dense, irregular, sclerotic bone → structural failure → increased cancellous bone susceptibility to fracture - retention of cartilage core → lack of medulla → defective myelopoiesis → recurrent infections, anemia, mucosal bleeding in the bone > - No room for bone marrow ↑ cartilage > - tbone Marrow (Make RBCs WBCs , , platelets) Infection BLEEDING Osteoclasts → marrow monocyte precursors → bone marrow transplant Tx > Anemia - , ,  Osteopetrosis and Thick Sclerotic Bone - > - impinge cranial nerves compress - affected bones: retention of 1ary cartilage cores → Clinical variability… delayed cavitation of metaphysis + thick sclerotic cortex Ex. cranial nerve deficits (deafness, blindness, palsies) = long bone malformation (Erlenmeyer flask deformity) caused by compression from surrounding sclerotic bone  MOVECULE THAT IS AFFECTED * CELLS ARE PROLIFERATING BUT is Arways Fibrous Dysplasia (FD) THEY'RE , DIFFERENTIATING T By the Mutation NOT. - ↳ FunctionuNG ANTERED Growth - caused by gain-of-function mutation in guanine nucleotide alpha stimulating (GNAS) gene → constitutively active G protein → increased cell proliferation at the expense of decreased osteoblast differentiation - end result → lack of bone formation → fibrous tissue accumulates where bone should be → bones fracture easily DEPOSIT OSTEOLD FOR OSTIFICATION 7 Doorly Functioning > - tissue osBons many bons - scar - AstactED Affected Benign muscle - monostotic and polyostotic clinical manifestations →↑ Neoplasms Mazabraud syndrome (FD of skull, ribs, legs and myomas, usually thighs), McCune-Albright syndrome (FD of face, spine, legs) Deposite h - FIBROBUASTS SSUE clie & All the bone is - by replaced Fibrous tissue Frous tissue Histopathology: small islands of irregular woven bone (magenta) surrounded by fibrous craniofacial FD involving FD of the femur tissue that has replaced the bone marrow orbit and maxilla Acquired Diseases of Bone i. Osteoporosis imbalance between osteoclast (bone resorption) and osteoblast (bone forming) activity in SIDERY INDIVIDUALS foccurs - senile osteoporosis: reduction in osteoblast (bone forming) activity relative to normal - osteoclast (bone resorbing) activity → incomplete filling of resorption bays 1ary - postmenopausal osteoporosis: low estrogen → increases levels of osteoclast- activating cytokines (RANK, M-CSF, etc.) → increased osteoclast (bone resorbing) activity relative to osteoblast (bone forming) activity → increased bone resorption * INCOMpLSTE BONE Deposition To CAUSE WEAK BONES IS GOING 2ary - other causes: endocrine disorders, malabsorption, malignancies (express osteoclast stimulating factors), alcohol, smoking, lack of exercise Morphologically: thinning of the trabeculae and widening of the Haversian canals osteoporosis normal Osteoporosis Net result: reduced bone mass → increased bone fragility and susceptibility to fractures trabecular bone particularly susceptible (ex. spine, femoral neck) Bone density scans (T-score) to determine bone loss Several regions of notable bone loss during osteoporosis are centered around the nasal, maxillary, zygomatic and frontal bones → posterior displacement of the midface… alveolar bone (A) in normal versus reduced alveolar bone density in osteoporosis → tooth loss normal osteoporosis ii. Paget Disease (Osteitis Deformans) M>F; patients in their 40s – 50s Resorption) EXCESS Estrocytic Activity (Bons - Starts with osteolytic stage → exaggerated bone turnover (a.k.a. “matrix madness”) - followed by excess irregular bone formation with very little bone remodeling to adapt to weight bearing stress! Causes: VIRAL - genetic predisposition (…maybe?) PARTICI - environmental factors: ex. viral infection (measles, RSV) → release of osteoclast activating cytokines (IL-1 and M-CSF) Paget Disease Net result of irregular bone formation → increased volume Bone histology: irregular, poorly mineralized of irregularly mineralized, sclerotic bone → that can easily cement lines → mosaic (“jigsaw”) pattern fracture → “chalkstick fracture” cures omitstresses - preysical normal OF CHARACTERISTIC PACET DISSASS - * ZIG-IAG MOSAI PATTERN Paget disease ERREGULAR DOORWY MINERALIZED CEMENT WINES Clinical features in Paget Disease: - can be asymptomatic or bony overgrowth can compress tissues/nerves (cranial nerves!) → severe skeletal and neuromuscular pain - skeletal deformities: thick deformed facial bones face (leontiasis ossea → ‘lion face’) & An EXAGGERATED CURVATURE OF THE SIDE TO SIDE - deformity of vertebral column: kyphosis, scoliosis, - - lordosis - exAGUERATED An CURVATURE OFTHE An exAGERATED CURVATURE OF THE THORACIC VERTEBRATE LUMBAR VERTEBRAE iii. Rickets (children) and Osteomalacia (adults) - decreased maturation and mineralization of cartilage at the growth plates, and of osteoid in areas of mature bone Most common causes: - vitamin D deficiency (insufficient dietary intake of vitamin D, inadequate exposure to sunlight, malnutrition) - altered vitamin D metabolism (defect in renal 1 α- hydroxylase activity, drugs that accelerate the degradation of sterols ex. phenobarbital, liver disease, renal disease) of bone tissue Loss Children: widening and lengthening of the growth plates, due to the accumulation of non-mineralized - Adults: loss of mineralization → irregular margins in the metaphysis and trabecular bone; osteopenia and pseudofractures (incomplete - - Histology: accumulation of unmineralized matrix (osteoid tissue) osteoid and cartilage; skeletal fractures or “Looser” zones) → partial deformities be bones - soft due are to excess lucencies usually at right angles to the involved cortex → thickening of periosteum & formation minerated& normal cartilage of callouses in the affected area common. thickening A lot O osteomalacia More - sendo-- of Parostium * Soft fracture Cotilage , Soft Osteoid  Bone Fractures START LECTURE  * Just Know for A REFERENCE D. Injury i. Bone Fractures Not on the EXAm *  Collection of blood cells+ growth factors Fracture healing Hematoma - of the fracture Going to trigger the healing - Cavitation of primary bone * + inflammatory reaction!! Movement of the bone fragments → poor immobilization, weightbearing too soon ① Alcohol, smoking (constricts blood vessels & decreases circulation + toxic effect on bone cells) Factors that can Medications: corticosteroids, immunosuppressants negatively affect Infections healing of bone Medical conditions: bone diseases, endocrine disorders (ex. PTH defect, diabetes mellitus) or fracture: vascular diseases (atherosclerosis) Advanced age (see osteoporosis, poor blood supply) Poor nutrition or impaired metabolism → low levels of calcium and vitamins C or D  angulated malunion looksLikeato Complications of bone fractures: * Pseudoarthrosis resulting from nonunion of a fracture Malalignment → sheering, twisting, bending, etc. of * fractured bone can cause deformity, delayed union, malunion or nonunion (a.k.a. pseudoarthrosis) Joint instability → osteoarthritis * Osteonecrosis (a.k.a avascular or ischemic or aseptic necrosis) - death of bone tissue due to a lack of blood supply. Can be a result of direct injury to blood vessels supplying a bone during injury/fracture or other factors that interrupt blood supply *Myositis ossificans - formation of bone tissue inside muscle tissue after a traumatic injury to the area Neuralgia – pain caused by nerve compression Pathologic Changes in Infected Bone  C. Infections Osteomyelitis = inflammation of the bone and marrow most often caused by an infectious agents: virus, fungus, bacteria or mycobacteria (TB osteomyelitis → widespread necrosis in the medullary canal) Pyogenic bacteria - hematogenous spread: ex. from GI or UG lesions, IV drug use (E. coli, Klebsiella, Pseudomonas), skin (S. aureus) etc. - extend from a contiguous site: ex. infected lymph nodes - direct implantation: ex. open fracture Clinic: fever, chills, leukocytosis and regional pain. In children, only fever may be present Infection most common in metaphysis where capillary flow is slowest Et will facilitate implantation of bacteria. Stages during osteomyelitis: Infection → inflammation and edema → subperiosteal or intraosseous abscess (‘Brodie abscess’) → periosteal reaction & lifting of the periosteum (‘involucrum’) → impairs blood flow → segmented ischemia → necrosis ↓ B V that feed. the bone go through it. necrotic bone fragment embedded in the abscess → ‘sequestrum’ SHEATH AROUND THE BONE ↳ involucrum involucrum sequestrum - sinus sequestrum ov training & Astula Brodie abscess (like from a cloaca puS the breeirs Though fistula Necrotic yone out to the Fragment abscess can destroy surrounding tissue forming a surface the of skin in the abscess draining fistula/sinus or ‘cloaca’ epithelialization of surface of cloaca can occur → increased risk of squamous cell carcinoma Osteomyelitis of the vertebra caused by TBC infection → “Pott Disease” - most common in thoracic and lumbar vertebra → necrosis → compression fracture → deformities like kyphosis +/- neurologic deficits - TB may affect knees and hip but less commonly Clinic: pain exacerbated with motion, local tenderness, low-grade fever, chills and weight loss. Direct diffusion to adjacent vertebra not common in Pott disease due to difficultly for mycobacteria to penetrate the intervertebral disk → spread along tissue planes is more common CASE · steomyelitis ONE VERTEBRAS to the Next If they infect SARADThANSOTBRAE - One VERTEBRAE , an vertebral osteomyelitis caused by S. aureus there notgoingtowe throve Pott disease intervertebral disc. Bone tumors  1. Bone forming tumors Osteoma - slow growing, benign, “hamartomas” → common in the skull, face, sinuses, mandible and maxilla - not invasive and do not undergo malignant transformation - usually solitary, multiple osteomas in Gardner syndrome (multiple osteomas, colon polyps, skin and soft tissue tumors) Morphology: - round/oval, hard, sessile bone mass projecting from the cortical surface - insignificant except when they obstruct a sinus cavity or compress structures Histology: mixture of woven bone & compact (nerve tissue, teeth, eye, etc.) lamellar bone that's made of normal bone. - A mass up  Osteosarcoma most common primary malignancy of bone M > F; 75% of cases before age 20; older patients can be 2ary to Paget disease, radiation exposure → highly aggressive long bones of the extremities common → 60% of the cases near the knee mutations in p53 (sporadic) and Rb (hereditary → ~1,000X increased risk for osteosarcoma) * IRREGULAR S MAREIN - bore - ReactivaFormation * * Spicries X-ray: masses with radiolucent or radiodense regions; irregular margins 2ary to reactive bone formation (“sunray spicules” – red circle); aggressive growth can penetrate cortex and lift periosteum giving triangular shadow on X-ray (Codman triangle – white arrows)  Osteosarcoma large bulky tumors areas of hemorrhage, necrosis and cystic degeneration Can invade medullary canal → marrow replacement Histologically: vary in cellularity and bone/matrix production; some may have areas producing cartilage (chondroblastic osteosarcoma) unra inte low grade tumor: malignant cells produce advanced grade: less bone/matrix more pleomorphic cells with frequent mitoses and mineralized or unmineralized bone tumor giant cells  2. Cartilage forming tumors Osteochondroma (Exostosis) - Majority are sporadic, some are AD inherited → mutation of EXT gene (heparan sulphate biosynthesis → tumor suppression ?) - mushroom shaped benign outgrowths of endochondral origin near the epiphyseal growth plate of long tubular bones, especially near the knee - stop growing once normal skeletal growth is completed - can compress soft tissue/vessels/nerves → pain - stalk can fracture contains an outer layer of benign hyaline cartilage capping benign bony head and stalk may increase risk for chondrosarcomas especially for hereditary variants * CAN GO FROM OSTROCHONDROMA TO CHONDROSARCOMA.  Chondroma - consists of hyaline cartilage (rests of growth plate cartilage?) that does not undergo endochondral ossification - located in medullary canal (enchondroma) or on the surface of bone (juxtacortical chondroma) - usually solitary, more common in metaphyses of tubular bones especially of hands and feet Jux tactical chondroma Enchundroma “O-ring” sign benign neoplastic chondrocytes in hyaline matrix Enchondromatosis = multiple enchondromas - rare nonhereditary forms caused by sporadic mutations in the isocitrate dehydrogenase (IDH) genes Ollier disease Maffucci syndrome endochondromatosis + angiomas enchondromatosis increases risk for malignant transformation Chondrosarcoma normal low grade - patients usually > 40 years; M more than F - common sites → pelvis, femur and shoulder girdle Chondrocured - - large translucent, gray-white gelatinous areas with calcification and cystic necrosis are common - low grade tumors → reactive thickening of the cortex; consists of mild hypercellularity with rare mitosis - high grade tumors destroy the cortex and form soft tissue masses; show marked hypercellularity, pleomorphism, bizarre MORE DIFFERENTIATED giant cells, mitoses more frequent. ne I terrega Promorphic un - Less Nucle high grade DIFFERENTIATED Pleomorphism is Accentuated & MORE as , vess caraga  Secondary Metastatic Tumors Primary OSTEOSARCOMA common timor of the bone = The most *- most common tumor of bone - majority (75%) are carcinomas - lymphatic/vascular most common route of dissemination - direct extension (ex. ca. uterus → pelvis; ca. breast & lung → chest wall - osteoblastic (ex. prostate cancer), osteoclastic (ex. cancers of lung, thyroid, kidney) or mixed phenotype (ex. cancers of breast, testicle, ovary) - osteoblastic - ostes- Card > - Curs Hon Resort