Robbins - Bone (Ch. 26) Flashcards
Bone matrix is made of an organic component called ___ and a mineral component. It is made of predominantly type ___ collagen.
Osteoid
Type 1
Which type of bone is common in neonates, but abnormal in adults?
Which type of bone is normal in adults?
Woven bone
Lamellar bone
Within bone, multinucleated macrophages derived from circulating monocytes…
Cell type?
Osteoclasts
Osteoclasts use what to resorb bone?
Acid and matrix metalloproteases (MMPs)
In neonates, long bones are formed though a process called ____
In neonates, flat bones are formed through a process called ____
Endochondral ossification
Intramembranous ossification
Where are RANK, RANKL, and OPG expressed?
What is OPG?
RANK activation causes what?
RANK = osteoclasts RANKL = osteoblasts OPG = osteoblasts
Decoy receptor that can bind RANKL and prevent its interaction w/ RANK
NFkB activation, maintaining osteoclast survival
Peak bone mass is achieved when?
Resorption begins when?
Early adulthood, after cessation of skeletal growth
30s
Dystoses vs. Dysplasia
Dystoses = abnormal mesenchymal cell migration or differentiation during fetal growth (LOCALIZED)
Dysplasia = mutations in signal molecule or matrix constituents, causing GLOBAL disorganization of bone
Examples of dystoses (4)
Aplasia (bone or digit)
Supernumary digit
Syndactyly (abnormal fusion)
Craniosynostosis (abnormal fusion)
Examples of dysplasias (5 diseases)
Brachydactyly types D, E Cleidocranial dysplasia Achondroplasia Osteogenesis imperfecta Osteopetrosis
Short, broad terminal phalanges of 1st digits
Gene mutation? What is is?
Brachydactyly types D, E
HOXD13 – transcription factor
Abnormal clavicles, multiple small bones around the skull symphyses (Wormian bones), supernumerary teeth, patent fontanelles
Gene mutation? What is it?
Cleidocranial dysplasia
RUNX2 – transcription factor
Short stature, short proximal limbs, normal thorax, large head with frontal bossing, depression of root of nose
Most common cause of ____
Gene mutation? What is it?
Achondroplasia
Dwarfism
FGFR3 – receptor
Osteogenesis imperfecta – due to what?
Other name?
Deficiency in synthesis of COLLAGEN TYPE 1
Brittle bone disease
Describe collagen type 1 structure
Packs of fibers made of fibrils. Each fibril is packs of triple helices that are crosslinked
Osteogenesis imperfecta – genetic mutations
Results in what structural abnormality?
COL1A1 (alpha-1) and COL1A2 (alpha-2) – chains of type 1 collagen
Defective assembly of higher order collagen polypeptides
Which subtype of osteogenesis imperfecta is fatal in utero?
Tend to develop multiple ____
Subtype 2
Intrauterine fractures
Multiple fractures (maybe postnatal or prepubertal), blue sclerae, hearing loss, dental imperfections
Osteogenesis imperfecta
Reduced bone resorption, diffuse symmetric skeletal sclerosis…disease?
Due to what?
Other names? (2)
Osteopetrosis
Abnormal osteoclasts
Marble bone disease, Albers-Schönberg disease
Although dense, bones in osteopetrosis are abnormally ___, and they ___ easily
Brittle, fracture
Osteopetrosis – mutation?
Result?
Carbonic anhydrase 2 (CA2)
Impaired acidification of osteoclastic resorption pit, thus impaired solubilization of hydroxyapatite
Osteopetrosis – other association?
What to expect on routine labs?
Renal tubular acidosis
Hyperchloremic (normal anion gap) metabolic acidosis
3 bone-related findings in osteopetrosis
- Diffuse sclerosis (brittle), especially of ends of long bones
- No medullary canal
- Narrowed neural foramina
What are the significant findings that correlate w/ the bone defects in osteopetrosis?
- Erlenmeyer flask deformities, repeated fractures
- Anemia, leukopenia (repeated infections, hepatosplenomegaly)
- Compression of spinal nerves 2, 7, and/or 8 (optic atrophy, deafness, facial paralysis)
- Hydrocephaly
Elderly (70+) caucasian w/ a disorder of increased, but disordered and structurally unsound, bone mass
Other name?
Paget disease
Osteitis Deformans
Paget disease - most common genetic cause
Molecular result?
Juvenile Paget disease – genetic causes (2)
SQSTM1 gene activating mutation
Enhanced RANK signaling, increasing activity of NF-kB
RANK activating mutation
OPG inactivating mutation
Paget disease - 3 phases
- Osteolytic phase
- Mixed clast-blast phase
- Sclerotic (burned-out) phase
Mosaic pattern of dense lamellar bone with prominent cement lines that conjoin poorly-oriented units of lamellar bone
What phase is this?
In osteolytic phase, what do osteoclasts look like? What do they form on the bone?
In the mixed phase, what do you see?
Paget disease
Sclerotic (burned-out) phase
Abnormally large, multi-nucleated (10-100 nuclei)
Many resorption pits
Osteoclasts AND osteoblasts lining the surface of the bones, marrow replaced by connective tissue
Paget disease - most commonly involves what bones?
Axial skeleton, proximal femur
Localized severe bone pain w/ overlying skin warmth, can’t hold head up, enlarged facial features, invagination of skull base, anterior bowing of femurs and tibias
Paget disease
Paget disease - associated disease
Why?
High-output heart failure
AV shunt within increased blood flow to hyper-vascular bone
Paget disease - possible benign tumors
Bad tumor?
Giant cell tumors, giant cell granulomas, extra-osseous masses of hematopoietic tissue
Sarcoma
Painful bone, thick coarsened cortices and cancellous bone, wedge-shaped lytic leading edge
Paget disease
3 clinical signs of osteoporosis (only need 1)
- BMD > 2.5 SDs below mean PBM in young adults
- Atraumatic fracture(s)
- Vertebral compression fracture(s)
Most common 2 forms of osteoporosis (w/ cause for each)
- Senile (reduced osteoblast replication and activity in older age)
- Post-menopausal (reduced estrogen –> increased osteoclast activity and inflammatory cytokines and RANK/RANKL)
Hallmark of osteoporosis histologically
Typically affects which bone type the most?
Normal bone, reduced in quantity
Cancellous
Painful thoracic and lumbar regions, increased lumbar lordosis and thoracic kyphosis, multiple/easy fractures
Most common fractures
Most serious complications (major causes of death)
Osteoporosis
Femoral neck, pelvis, spine
PE and pneumonia – from hospitalization and immobility
Best way to diagnose osteoporosis
Can it be diagnosed w/ labs?
What about plain X-ray?
Dual energy X-ray absorptiometry (DEXA)
NO
ONLY if lost 30-40%
Define fracture types:
- Simple
- Compound
- Comminuted
- Displaced
Simple = intact overlying skin
Compound = bone communicates w/ skin surface
Comminuted = bone is fragmented
Displaced = ends are not aligned
Define fracture types:
- Stress
- Greenstick
- Pathologic
Stress = slow-developing after increased physical activity w/ repetitive load forces
Greenstick = extending only partially through the bone (infants w/ soft bones)
Pathologic = bone weakened by underlying disease process
By the end of the 1st week after a fracture, what has formed?
Phases it took to get there
Soft tissue callus (procallus)
Hematoma organization, matrix production in adjacent tissues, remodeling of fractured ends into UNCALCIFIED fusiform tissue
By the end of 2 weeks after a fracture, what has formed?
How did it get there?
Bony callus
Woven bone formed by osteoprogenitor cells, w/ some mesenchymal cells becoming chondrocytes that make fibrocartilage and hyaline cartilage which undergoes endochondral ossification
How does the bone eventually become strong lamellar bone again?
W/ weight bearing, unstressed bone is reabsorbed while stressed bone become lamellar
Osteonecrosis - what is it?
2 most common causes? Others?
Infarction (avascular necrosis) of the medullary cavity or entire bone segment
FRACTURE, CORTICOSTEROIDS, bisphosphonate therapy, alcohol abuse, pregnancy, infection, radiation sickle cell, CT diseases, etc.
What actually causes the infarction in osteonecrosis? (4)
Vascular insufficiency from injury, thromboembolism, external pressure, or venous occlusion
Localized bone pain w/ activity that over time becomes constant
2 infarct types
Osteonecrosis
Subchondral (wedge-shape)
Medullary
Osteomyelitis - what is it?
Inflammation of bone and marrow, secondary to infection
Pyogenic osteomyelitis in otherwise healthy individual – most common organism?
Staph. aureus
Healthy child that develops pyogenic osteomyelitis – most likely mode of spread
Most common site of infection w/in the bone?
How does the bacteria usually get in (in this case)?
Hematogenous
Metaphyseal plate
Trivial mucosal injuries (defecation, vigorous chewing, minor skin infections)
Adult develops pyogenic osteomyelitis – most likely methods of infection (3)
Open fractures
Surgical procedures
Diabetic feet sores
Adult has GU tract infection or IV drug abuser, develops osteomyelitis – most likely organisms? (3)
E. coli
Pseudomonas
Klebsiella
Neonate develops osteomyelitis – most likely organisms? (2)
Group B strep
H. influenzae
Adult w/ sickle cell disease develops osteomyelitis – most likely organism?
Salmonella
Fever, malaise, chills, leukocytosis, intense throbbing pain over specific area. Lytic focus of bone destruction surrounded by zone of sclerosis
Osteomyelitis
Potential subtle presentations of osteomyelitis in:
- Baby
- Adult
Baby = unexplained fever
Adult = localized pain
Diagnosing osteomyelitis
Biopsy, bone culture
Localized pain, low-grade fever, chills, weight loss. Caseous necrosis and granulomas on CT of bone.
Will also have what?
Serious complication? What is it?
Serious complication will present how?
Mycobacterial (TB) osteomyelitis
Extra-osseous TB infection somewhere
Pott Disease – TB hematogenous spread into vertebrae and vertebral discs
Scoliosis or kyphosis w/ neurologic defects from cord/nerve compression
Mycobacterial osteomyelitis, Pott disease develops. Common associated soft tissue infection
Psoas muscle abscess
Child, saber shin, edematous granulation tissue w/ many plasma cells, necrotic bone
How to diagnose organism?
Skeletal (congenital) syphilis
Silver stain or immunohistochemistry
Skeletal metastases of cancer are generally ___ and located in the ____
Multifocal
Axial skeleton
Man w/ multiple osteoblastic lesions in axial skeleton…most likely underlying condition
Prostate carcinoma
Multiple osteolytic lesions in the axial skeleton…most common underlying cancers (4)
Kidney, lung, GI, melanoma
Common childhood cancers that metastasize to bone (5)
Neuroblastoma Wilms tumor Osteosarcoma Ewing sarcoma Rhabdomyosarcoma
Symptoms of bone mets (5)
Significant pain BM suppression Hypercalcemia Pathologic fracture Spinal cord/root compression
A primary bone tumor is likely to be (benign/malignant) in younger ages and (benign/malignant) in older ages
Benign (0-30)
Malignant
Cartilage-forming bone tumors usually produce what? (2)
Hyaline or myxoid cartilage
Adolescent male, solitary bone tumor that extends out from the metaphysis of the distal femur w/ a bony stalk, a hyaline cartilage cap, and a continuous medullary cavity
Undergoes ____
Other name for this tumor?
Osteochondroma
Endochondral ossification
Exostosis
Child, multiple osteochondromas
Genetics?
Multiple hereditary exostosis syndrome
EXT1 or EXT2
Small, solitary gray-blue bone lesion at the metaphyseal area of a metacarpal, metatarsal, or phalanx. Circumscribed lucency of hyaline cartilage w/ small irregular calcifications inside.
2 types of this
Chondroma
- Enchondroma (w/in medullary cavity)
- Juxtacortical chondroma (on surface of bone)
Multiple enchondromas
Genetics?
Ollier disease
IDH1 or IDH2
Multiple enchondromas + spindle cell hemangiomas
Increased risk of what other cancers? (2)
Maffucci syndrome
Ovarian carcinoma
Brain glioma
40+ y/o patient w/ painful enlarging mass in the pelvis, shoulder, or ribs. Large bulky tumors of glistening gray-white cartilaginous nodules. Foci of flocculent densities w/in the calcified matrix.
Variants? (4) Sub-variants? (2)
Most common?
Chondrosarcoma
Conventional (hyaline-producing) - Central (medullary) - Peripheral (juxtacortical) Clear cell Dedifferentiated Mesenchymal
Conventional central
Osteoid osteoma and osteoblastoma…What are they?
Symptom?
Compare and contrast…
- Size
- Location
- Content
- NSAIDs
- Treatment
Bone-producing tumors
Severe nocturnal pain
Osteoid osteoma
- under 2 cm
- appendicular (femur, tibia)
- cortex w/ thick rind of reactive bone
- Relieved by aspirin/NSAIDs
- Tx = radiofrequency ablation
Osteoblastoma
- over 2 cm
- posterior spine
- NO bony reaction
- NOT relieved by aspirin
- Tx = curettage or excision
Round/oval mass of hemorrhagic gritty tan tissue. Well-circumscribed, randomly interconnecting trabeculae of woven bone w/ prominent rim of osteoblasts. Many dilated and congested capillaries.
2 options?
Osteoid osteoma
Osteoblastoma
Most common primary malignancy of bone overall
Osteosarcoma
Teenager, painful progressively-enlarging bone mass or sudden fracture of the metaphyseal region of femur or tibia (or UE). Mixed osteolytic and osteoblastic mass w/ infiltrative margins. Multiple lesions in the lungs.
Other subjected populations?
Most common locations?
Osteosarcoma - metastatic
Older w/ Paget, bone infarct, or prior radiation
Metaphyseal region of long bones of extremities
Osteosarcoma – aggressive radiographic sign
Codman triangle – lifting of periosteum off of the bone surface
Osteosarcoma – most common genetic
RB mutation (70%)
Varied cell sizes and shapes, large hyperchromatic nuclei, bizarre giant cells w/ many abnormal (tripolar) mitoses. Vascular invasion. Osteoid deposition.
Osteosarcoma
Caucasian child, painful enlarging mass w/ tender, warm, swollen overlying skin. Fever, elevated sed rate, anemia, and leukocytosis. Undifferentiated primitive round cells that are cohesive.
Cell type?
Ewing sarcoma
Neuroectodermal
Destructive medullary lytic tumor w/ permeative margins that extend into the surrounding tissues. Reactive ONION-SKIN bone deposition
Ewing sarcoma
Ewing sarcoma – genetics
(11;22) EWS-FLI1
Early adolescent. Pain, fracture, limb length discrepancies. Well-circumscribed, intra-medullary lesion of curvilinear woven bone (Chinese characters). No osteoblastic rimming. Fibroblastic proliferation.
Genetics? Causes what?
Fibrous dysplasia
GNAS1 – Gs/cAMP mediated interruption of normal osteoblast differentiation from precursors
Fibrous dysplasia + intramuscular myxomas
Mazabraud syndrome
Polyostotic fibrous dysplasia, brown skin spots, precocious puberty
McCune-Albright syndrome
