26 Bones Joints And ST Flashcards
Bone matrix
Extracellular component of bone
35% osteoid: Type I collagen and other proteins (ie osteopontin allows formation and is measurable in serum)
65% mineral: Hydroxyapatite, causes bone to be hard and stores 99% of bodies calcium, 85% of phosphorous
Woven bone
Woven bone: Rapidly produced (fetal development, fracture) with less structural integrity due to haphazard arrangement of collagen and always abnormal in adults
Lamellar bone
Lamellar bone: Slowly produced with parallel fibers and more strength
Osteoblasts
On the matrix surface
Synthesize, transport and assemble matrix, regulating mineralization
May become inactive over time which is indicated by ↓ cytoplasm
Some may remain on the surface of trabecula, others become embedded in the matrix (osteocytes)
produce monocyte colony stimulating factor (M-CSF) that activates osteoclast precursors to become osteoclasts
Osteocytes
Help control calcium and phosphate levels
Detect mechanical forces translating them to biologic activity (mechanotransduction)
These cells are interconnected via a network of canaliculi (dendritic cytoplasmic processes passing through tunnels
Osteoclasts
Originate from HSCs rather than mesenchymal stem cells
Specialized multinucleated macrophages derived from circulating monocytes
Responsible for bone resorption
Attach to bone matrix via integrins → resorption pit (sealed extracellular trench)
Dissolution of bone components occurs due to secretion of acid and neutral proteases (MMPs) into the pit
Intramembranous ossification
Intramembranous ossification is responsible for the development of flat bones and facial bones
unaffected in achondroplasia
Endochondral ossification
Endochondral ossification is responsible for the development of long bones
this is what is defective in achondroplasia (activating mutations in FGFR3
Hormonal control of bone growth
ormonal Control of Bone Growth
Growth hormone stimulates chondrocytes to induce and maintain proliferation
Thyroid hormone (T3) stimulates chondrocyte proliferation
Indian Hedgehog coordinates chondrocyte proliferation and differentiation and osteoblast proliferation
PTHrP activates PTH receptor and maintains proliferation of chondrocytes
Wnt activates β-catenin signaling; can promote both proliferation and maturation of chondrocytes
Wnt proteins produced by osteoprogenitor cells bind to the LRP5 and LRP6 receptors on osteoblasts and trigger the activation of β-catenin and the production of OPG
sclreostin (produced by osteocytes) inhibits WNT/β-catenin signaling
SOX9 is essential for differentiation of precursor cells into chondrocytes
RUNX2 controls terminal chondrocyte and osteoblast differentiation
Fibroblast Growth Factors act on hypertrophic chondrocytes to inhibit proliferation and promote differentiation
Bone Morphogenic Proteins have diverse effects on chondrocyte proliferation and hypertrophy
Homeostasis and remodeling
RANK: transmembrane receptor; receptor activator for NFκB; expressed on osteoclast precursors
RANK signaling activates the transcription factor NF-κB
NF-κB is essential for the generation and survival of osteoclasts
RANKL: expressed on osteoblasts and marrow stromal cells
OPG (osteoprotegrin): a secreted “decoy” receptor made by osteoblasts and several other types of cells that can bind RANKL and thus prevent its interaction with RANK
RANKL and OPG oppose one another; RANK-to-OPG ratio determines bone resorption vs formation
PTH, estrogen, testosterone, and glucocorticoids, vitamin D, inflammatory cytokines (eg IL-1), and growth factors alter the ratio
Dysostosis
ocalized problems in the migration and condensation of mesenchyme; transcription factors, homeobox genes, cytokines and cytokine receptors
aplasia: complete absence of a bone or entire digit
supernumerary digit: extra bones or digits
syndactyly, craniosynostosis: abnormal fusion of bones
Dysplasia
dysplasia: global disorganization of bone and/or cartilage; mutations in genes that control development or remodeling of the entire skeleton
Brachydactylyl types D and E
Brachydactyly types D and E: shortening of the terminal phalanges of the thumb and big toe
gene: HOXD13
Cleidocranial dysplasia
Cleidocranial Dysplasia: patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra bones that occur within a cranial suture) delayed eruption of secondary teeth, primitive clavicles, and short height
loss of function mutations in the RUNX2
autosomal dominant
Dustin from Stranger Things
Achondroplasia
the most common skeletal dysplasia
major cause of dwarfism
gain-of-function mutations in the FGF receptor 3 (FGFR3); autosomal dominant; retarded cartilage growth
shortened proximal extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose
no changes in longevity, intelligence, or reproductive status
Thanatophoric dysplasia
most common lethal form of dwarfism
micromelic shortening of the limbs, frontal bossing, relative macrocephaly, a small chest cavity (–> respiratory insufficiency), and a bell-shaped abdomen
gain-of-function mutations in FGFR3 that differ from those in achondroplasia
Osteoporosis
Too little bone
Ostteopetrois
Too much bone
Type 1 collagen diseases
Type 1 Collagen Diseases == Osteogenesis Imperfecta (brittle bone disease)
Definition
Most common inherited disorder of connective tissue
Improper collagen formation leads to brittle bones (brittle bone disease)
places where type I collagen is found: joints, eyes, ears, skin, and teeth
four subtypes vary in severity based on location of the mutation in the protein
Type I == normal life span but experience childhood fracture that decrease following puberty
Type II == uniformly fatal in utero or during the perinatal period
Mutations and pathogenesis type 1 collagen disease
Autosomal dominant mutations of COL1A1 and COL1A2 mutations (α1 and α2 chains of type I collagen)
Many mutations replace glycine with another amino acid in the triple helical domain → defective assembly of higher order collagen peptides
Loss of function due to misfolding of the polypeptides and improper assembly of wild type collagen chains
Clincial presentation type 1 collagen disease
fundamental abnormality == too little bone → extreme skeletal fragility
Blue sclera: ↓ collagen = translucent sclera and partial visualization of the underlying choroid
Hearing loss: related to both sensorineural deficit and impeded conduction due to bone abnormalities in the middle and inner ear
Dental imperfections: Small, misshapen, blue-yellow teeth secondary to deficiency in dentin
Subtype I
↓ synthesis of proα1(1) chain Abnormal proα1(1) or proα2(1) chains ahem Autosomal dominant Normal life-span with childhood fractures that decrease at puberty Postnatal fracture Blue sclera Normal stature, skeletal fragility, joint laxity Dentinogenesis imperfecta Hearing impairment
Subtype II
Abnormally short proα1(1) chain
Abnormal or insufficient proα2(1)
Unstable triple helix
Autosomal recessive (some dominant or new mutations)
Perinatal lethal: Death in utero or within days of birth
Skeletal deformity with excessive fragility and multiple in utero fractures
Blue sclera
Subtype III
Subtype III Altered structure of propeptides of proα2(1) Impaired formation of triple helix 75% autosomal dominant Progressive, deforming disease Growth retardation, progressive kyphoscholiosis Multiple fractures Blue sclera at birth → white Hearing impairment Dentinogenesis imperfecta
Subtype IV
Subtype IV Short proα2(1) chain Unstable triple helix Autosomal dominant Compatible with survival Postnatal fractures Moderate skeletal fragility Short stature Normal sclera (+/-) dentiginogenesis imperfect
Mutations of types
Mutations of Types
II, IX, I, XI collagen type mutations are related to abnormal hyaline cartilage synthesis
Severe disorders: absence of type II leads to insufficient bone formation
Mild disorders: reduced synthesis of type II
Osteopetrosis
AKA: Marble Bone Disease or Albers-Schonberg Disease
Bones are “stone-like”, brittle and fracture easily like chalk
↓ bone resorption with diffuse symmetric skeletal sclerosis due to impaired formation or function of osteoclasts
Pathogenesis osteopetrosis
Mutations affect acidification of the osteoclast resorption pit, which is necessary for the dissolution of calcium hydroxyapatite within the matrix
ahem CA2 (carbonic anhydrase 2) autosomal recessive: acidification of urine is blocked with the lack of acidification of the pit –> metabolic acidosis
CLCN7: encodes the proton pump on the surface of osteoclasts
Morphology osteopetrosis
due to deficient osteoclast activity, bone lacks a medullary canal
ends of long bones are bulbous (Erlenmeyer flask deformity)
neural foramina are small, compressing exiting nerves II, VII, and VIII
primary spongiosa is not removed, filling the medullary cavity leading to no hematopoietic marrow and preventing the formation of mature trabeculae
woven architecture of newly deposited bone
diffuse skeletal sclerosis (bones look wider but they are brittle because increased woven bone) = fractures
Clincla osteopetrosis
autosomal recessive mutations (infantile form): fracture, anemia, and hydrocephaly may cause death shortly after birth surviving infants (autosomal dominant): Mild form presenting with cranial nerve defects (optic atrophy, deafness, facial paralysis). Recurrent infections (often fatal) due to leukopenia. Extramedullary hematopoiesis → hepatosplenomegaly
Treat osteopetrosis
HSC transplant
Osteoclasts are produced from donor stem cells and may reverse many of the skeletal anomalies
Mucopolysaccharisoses
group of lysosomal storage disease that are caused by deficiencies in the acid hydrolases that degrade dermatan sulfate, heparan sulfate, and keratan sulfate
mucopolysaccharides from the extracellular matrix accumulate inside the chondrocytes causing apoptosis
skeletal manifestations result from abnormalities in hyaline cartilage
Osteopenia
Osteopenia
↓ bone mass
Bone mass 1-2.5 standard deviations below mean peak bone mass in young adults
Osteoporosis s
Osteopenia that is severe enough to significantly ↑ risk of fracture
Bone mass 2.5 standard deviations below mean peak bone mass in young adults (2.5 and lower)
Can also be indicated by the presence of an atraumatic or vertebral compression fracture
May be primary or secondary
Most common types: senile and postmenopausal
May be localized (disuse) or involve the entire skeleton (manifestation of a metabolic disease
Osteoporosis risk factors
Age: Diminished capacity to form bone (senile form aka low turnover variant)
Reduced physical activity: Mechanical forces stimulate bone remodeling.: Weight training (load magnitude) exercise is better
Genetics: RANKL, RANK, OPG, HLA locus, estrogen receptor
Calcium nutritional state: impacts the bone density peak that can be achieved, especially affected are adolescent females
Hormones
Postmenopausal osteoporosis
characterized by an acceleration of bone loss
up to 2% per year for cortical bone and 9% per year for cancellous bone
Females may lose up to 35% of cortical bone and 50% of cancellous bone within 30-40 years
↓ estrogen
= ↑ secretion of inflammatory Cytokines (IL6, TNFα, IL1)
= ↑ RANKL
= ↓ osteoclast proliferation & ↓ osteoclast apoptosis
= resorption > formation
Morphology osteoporosis
Morphology
Histologically normal bone, but decreased quantity of trabecular bone
Morphology postmenopausal type I
Affects the bones/parts that have more surface area (eg cancellous compartment of vertebral bodies)
Trabecular plates become perforated, thinned and lose their interconnections leading to progressive micro-fractures and vertebral collapse
Morphology senile type 2
Cortex is thinned by sub-periosteal and endosteal resorption
Haversian systems are widened
Clincial course osteoporosis
Vertebral fracture (thoracic, lumbar): May be multiple and painful. Loss of height, altered lordosis and kyphosis that can lead to “dowager’s hump” fractures of the femoral neck, pelvis, or spine → pulmonary embolism and pneumonia
Diagnosis and treatment osteoporosis
Diagnosis: DEXA, or quantitative CT measure bone density. NO LABS for diagnosis
Treatment: exercise, Ca++/vitamin D intake, prescription (bisphosphonates, denosumab (anti-RANKL)
bisphosphonates reduce osteoclast activity and induce apoptosis
HRT → DVT, stroke
Paget disease
↑ but disordered and structurally unsound bone mass
Progresses through three stages:
Osteolytic stage
Mixed osteoclastic-osteoblastic stage –> ends with predominant osteoblastic activity
burned out quiescent osteosclerotic stage
Epidemiology paget
Diagnosed at 70 years old (many are asymptomatic)
Whites in England, France, Austria, Germany, Australia, NZ, USA
Rare: Scandinavia, China, Japan, Africa
Pathogenesis paget
50% of familial cases & 10% of sporadic
SQSTM1 mutations (familial) → ↑ NFκB activity = ↑ osteoclast activity
Juvenile cases
Activating RANK mutations
Inactivating OPG mutations
Chronic infection by measles or other RNA viruses affect vitamin D sensitivity and IL6 secretion by infected osteoclasts
Morphology paget
Initial lytic phase: waves of osteoclastic activity and lots of resorption pits. Osteoclasts are large and have many more nuclei than the 10-12 normally seen
Mixed phase: osteoclasts persist, but there are many more osteoblasts
Marrow next to the bone-forming surface is replaced by loose connective tissue with osteoprogenitor cells and lots of vessels
hallmark is a ahem mosaic pattern of woven and lamellar bone, seen in the sclerotic phase
“Jigsaw puzzlelike” due to unusually prominent cement lines orienting lamellar bone
Bone eventually exhibits coarsely thickened trabeculae with soft, porous cortices that lack structural stability = vulnerable to deformation under stress → easy fractures
“Cotton wool” appearance
Clincla course paget
Variable clinical presentation based on extent and site of disease
Most are asymptomatic and discovered incidentally
85% of cases are poly-ostotic (involve more than one bone)
80% involve the axial skeleton (head/trunk) or proximal femur
Pain localizes to the affected bone due to microfractures or bone overgrowth compressing spinal and cranial nerve roots
Bone pain/deformity (bowing of tibia) and/or nerve entrapment
Leontiasis ossea (lion face): enlargement of craniofacial skeleton (frontal bone) and a cranium so heavy that it is difficult to hold up
Platybasia: invagination of the skull base → compression of the posterior fossa
Weight bearing = anterior bowing of femurs and tibia → distortion of femoral heads –> 2˚ osteoarthritis
in the absence of malignant transformation, Paget disease is usually not a serious or life-threatening disease
Other changes paget
Chalk stick-type fractures: occur in long bones
Compression fracture of spine → kyphosis
High output cardiac failure may arise in severe cases
Hypervascularity of bone warms overlying skin (acts as arterio-venous shunt
Tumor like conditions paget
Benign: giant cell tumor, giant cell reparative granuloma, extraosseous hematopoietic tissue
Sarcoma: osteosarcoma or fibrosarcoma of the long bones, pelvis, skull, spine
Diagnose paget
Radiographic findings
Enlarged bone with thick, coarsened cortices and cancellous bone
Active disease: wedge shaped lytic leading edge progressing along the bone 1cm/year
ahem ↑ serum ALK phosphatase – most common cause of isolated elevated ALP
Normal calcium, phosphorous
Treat paget
mild symptoms readily suppressed with calcitonin and bisphosphonates
Rickets
Rickets (children)
Vitamin D deficiency or abnormal metabolism
Impaired mineralization → accumulation of under-mineralized matrix
disease of children (called osteomalacia in adults)
Interferes with deposition of bone in the growth plates
Osteomalacia
Vitamin D deficiency or abnormal metabolism
Impaired mineralization → accumulation of unmineralized matrix
Disease of adults (called rickets in children)
Bone formed during remodeling is under-mineralized → predisposition to fractures
PTH
↑ RANKL on osteoblasts
Osteoclast activation – hyperparathyroidism leads to significant skeletal changes related to unabated osteoclast activity
↑ bone resorption and calcium mobilization
↑ resorption of calcium by renal tubules
↑ urinary excretion of phosphates
↑ synthesis of active vitamin D by the kidneys
↑ calcium absorption from the gut
Net: ↑ serum calcium
Hyperparathyroidism
Excess levels of this hormone occur due to autonomous secretion (primary) OR
Renal disease (secondary): inadequate 1,25(OH)2D synthesis (altered GI absorption) & hyperphosphatemia suppression of α1-hydroxylase
Secondary hyperPTH is typically milder
Significant skeletal change due to unabated osteoclast activation
Entire skeleton affected
Bone changes are completely reversible with reduction of hormone levels
Morphology hyperparathyroidism
Osteoporosis: Most severe in the phalanges, vertebrae, and proximal femur
Osteoclasts more prominent in cortical bone (subperiosteal and endosteal)
Dissecting osteitis: tunnels along the length of the trabeculae (railroad tracks)
Brown tumors: Reactive tissue mass due to influx of macrophages and fibrous tissue that leads to hemorrhage and hemosiderin deposition. May have cystic degeneration.
generalized osteitis fibrosa cystica (von Recklinghausen disease of bone): increased bone cell activity, peri-trabecular fibrosis, and cystic brown tumors
hallmark of severe hyperparathyroidism
Now rare due to early treatment
Renal osteodystrophy
Definition
Skeletal changes associated with renal disease (ie dialysis)
Manifestations are not unique and include things like: Osteopenia/osteoporosis, Osteomalacia, secondary hyperPTH, and growth retardation
Types of renal osteodystrophy
High turnover: characterized by increased bone resorption and bone formation, with resorption predominating Low turnover or aplastic: manifested by adynamic bone (little osteoclastic and osteoblastic activity), and, less commonly, osteomalacia Mixed pattern (area dependent: high/low turnover
Pathogenesis osteodystrophy
Tubular dysfunction: the major tubular disease that affects the skeleton is renal tubular acidosis
low pH –> demineralization –> osteomalacia
Generalized renal failure: chronic hyperphosphatemia, hypocalcemia, secondary hyper-PTH
↓ production of secreted factors: Vitamin D3, BMP7, FGF-23, Klotho
BMP-7: produced by renal tubular cells to induce osteoblast differentiation and proliferation
Klotho: membrane bound protein made by the kidney to cause osteocytes to make FGF-23 and help regulate phosphate and vitamin D in the kidney
aluminum from dialysis, oral phosphate binders, iron deposition, and diabetes mellitus may indirectly contribute to bone disease in the setting of renal failure
Fractures
Loss of bone integrity due to mechanical injury and/or diminished bone strength
Simple: overlying skin intact
Compound: bone communicates with skin surface
Comminuted: bone is fragmented
Displaced: ends of bone at site are not aligned
Stress: slowly develops with physical activity and repetitive loads
Greenstick: extending only partially through the bone, common in infants when bones are soft
Pathologic: associated with an underlying disease process (tumor
Fracture healing: ST callus/procallus week 1
acture Healing: Soft Tissue Callus /Procallus – WEEK 1
Fracture site hematomas are organized by an influx of inflammatory cells, fibroblasts and new vessels
Platelets and inflammatory cells release PDGF, TGFβ, FGF and IL’s to trigger osteoprogenitor cells and stimulate osteoclast and osteoblast activity
Matrix production in adjacent tissues has occurred by the end of the first week
The fracture ends of the bone have been remodeled
Some anchorage between the ends of the fracture bones but not structural rigidity for weight bearing
Fracture healing bony callus by end of week 2
Conversion of the procallus
activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone that are oriented perpendicular to the cortical axis and within the medullary cavity
Fibrocartilage and hyaline cartilage are also produced
Undergoes enchondral ossification → newly deposited bone in the medulla and beneath the periosteum
Allows fracture site stabilization by the end of the 2-3rd week with maximal girth
Fracture ends are bridged: as it mineralizes stiffness and strength of the callus increases allowing controlled weight bearing
Fracture healing maturation
Areas not physically stressed are resorbed, reducing the callus in size and shape
The outline of the fractured bone is reestablished as lamellar bone
Healing is complete with restoration of the medullary cavity
Fracture healing: deformity
Seen with displaced and comminuted fractures
Fracture healing: delayed or non union
acture Healing: Delayed or nonunion
Occurs with inadequate immobilization and movement of the callus
Nonunion persistence = cystic degeneration of callus with the luminal surface lined by synovial like cells → pseudoarthrosis (false joint
Fracture healing: infection nutrition
Common with open fractures
Malnutrition and skeletal dysplasia hinder healing
Fracture healing: kids vs adults
Children and young adults = perfect unions are the norm
Older adults may require surgical immobilization for adequate repair
Osteopetrosis
nfarction of bone and marrow
Cortex is typically not affected because there is collateral blood flow
Causes osteopetrosis
Mechanical injury to blood vessels: thromboembolism, external pressure on vessels, venous occlusion
Often due to fracture or corticosteroid administration
Alcohol abuse, Bisphosphonates (especially jawbones), pregnancy
Morphology osteopetrosis
Subchondral infarction: triangular/wedge shaped segment of tissue that has the subchondral bone plate as its plate undergoes necrosis
The overlying articular cartilage remains viable from nutrients in the synovial fluid
Dead bone is recognized as empty lacunae that are surrounded by ruptured adipocytes, which can have associated fat saponification (may remain for life)
Creeping substitution with new bone occurs from the margin of the infarct, but is too slow and collapses upon itself
Clincla course osteopetrosis
Subchondral infarcts: Pain initially associated with activity then becomes persistent. Articular cartilage collapses → severe, secondary osteoarthritis
Medullary infarcts: small, clinically silent except when they arise in the setting of Gaucher disease, dysbarism (the “bends”), and sickle cell anemia
Gaucher disease: inborn error of metabolism that leads to problems with glucocerebrosidase
more than 10% of the 500,000 joint replacements performed annually in the United States are for treatments of complications of osteonecrosis
Osteomyelitis
Inflammation of bone and marrow secondary to infection
Pyogenic bacteria and mycobacteria are most common
Pyogenic osteomyelitis causes
Due to bacterial infection reaching the bone via hematogenous spread (most common in children), extension from a contiguous site, direct implantation
Presentation in different age groups
Neonates: metaphyseal vessels penetrate the growth plate → infection of metaphysis, epiphysis or both.
Children: trivial mucosal injury (defecation, chewing), minor skin infection. Metaphysis localization.
Adults: open fracture, surgical procedure, diabetic infections of feet. Epiphyses and subchondral regions
Bacterial causes osteomyelitis
Staph Aureus: 80-90% of culture positive cases of osteomyelitis.
Cell wall proteins bind bone matrix components (collagen) facilitating adhesion
staph == coagulase positive (aureus only), catalase positive
coagulase positive == staph aureus and nothing else
strep == coagulase negative, catalase negative
E. Coli, Pseudomonas, Klebsiella: patients with genitourinary infections or IV drug users
Mixed infection: Direct spread or inoculation of organisms during surgery or into open fractures
Neonatal: H. Influenzae, group B strep
Sickle cell: Salmonella typhi
50% of cases = no organism can be isolated
Progression osteomyelitis
Changes are dependent on the chronicity and location
Entrapped bone becomes necrotic within 48 hours
Bacteria and inflammation percolate within the shaft and along the haversian systems to involve the periosteum
Lifting of the periosteum further compromises the vascular supply → zone of bone necrosis
Dead bone = sequestrum
Periosteum rupture → soft tissue abscess and a draining sinus to the skin
Attempt at healing osteomyelitis
Attempt at healing
Chronic inflammatory infiltrates stimulate osteoclastic bone resorption, ingrowth of fibrous connective tissue and deposition of reactive tissue after the first week
Involucrum: sub-periosteal new bone encasing the inflammatory focus; newly deposited bone can form a shell of living tissue, known as the involucrum
Brodie abscess: small, walled off intracortical abscess
Sclerosing osteomyelitis of Garre: extensive new bone formation of the jaw obscuring the underlying osseous structure
Clincial course osteomyelitis
Hematogenous: acute systemic illness presentation with malaise, fever, chills, leukocytosis, and throbbing pain over infected region
Others may present with unexplained fever (children) or localized pain (adults
Diagnosis and treatment osteomyelitis
nosis and Treatment
Lytic bone lesion surrounded by sclerosis on radiograph
Some untreated cases may have (+) blood culture
Pathogen identification requires biopsy and bone cultures
Treatment: antibiotics and surgical drainage = curative
Chronic pyogenic osteomyelitis
Develop in instances of delayed diagnosis, extensive bone necrosis, inadequate antibiotic therapy or surgical debridement, or due to weakened host defenses
May experience acute flare ups spontaneously after years of dormancy
May also have pathologic fractures, secondary amyloidosis, endocarditis, sepsis, squamous cell carcinoma development in draining sinus tracts and sarcoma of the infected bone
Mycobacteria osteomyelitis
Typically seen in developing countries
1-3% of patients with tuberculosis have osseous infection
Blood borne organisms that originate from a focus of active visceral disease during primary infection
May persist for years before diagnosis
Localized pain, low grade fever, chills, weight loss
Solitary infection unless immunocompromised
histology: caseous necrosis and granulomas (same as tuberculosis elsewhere)
Tends to be more destructive and resistant to control
Tuberculosis spondylitis pott disease
Spinal involvement (40%) via hematogenous spread usually infection breaks through intervertebral discs, affecting multiple vertebrae and extends into soft tissue Destruction of discs and vertebra → permanent compression fractures = scoliosis or kyphosis and neurological deficits secondary to spinal cord and nerve compression (paraplegia can happen) 75% of patients develop soft tissue infection, commonly in Psoas muscle If untreated, degeneration of vertebrae can herniate into cord space May also have: sinus tract formation, psoas abscess, tuberculosis arthritis, amyloidosis
Skeletal syphilis
Bone involvement is infrequent due to earlier diagnosis and treatment
Bone lesions appear in the 5th months of gestation and are fully developed at birth
Spirochetes localize to areas of active enchondral ossification (osteochondritis) and in the periosteum (periostitis)
Saber shin: massive reactive periosteal bone deposition on the medial & anterior surfaces of the tibia
(don’t forget about Hutchinson teeth)
If acquired, bone disease manifests 2-5 years after initial infection and involves the nose, palate, skull and extremities (long bones
Morphology skeletal syphilis
Morphology
Edematous granulation tissue containing lots of plasma cells and necrotic bone
Spirochetes are seen with silver stains
Gummas can also form
Osteosarcoma
Adolescents knee
Chondrosarcoma
Older adults pelvis and proximal extremities
Bone sarcoma
< 1% of all bone disease
50% are lethal
Found from bone pain or pathological fractures
Treatment is often disfiguring
Goal: optimize survival & maintain function of affected body parts
bone tumors are classified according to the normal cell or matrix they produce
lesions that do not have normal tissue counterparts are grouped according to their clinicopathologic features
Risk factors
Chronic injury and inflammation: bone infarcts, chronic osteomyelitis, Paget disease, radiation, metal prostheses
Prevelance of bone tumors
Primary tumors are far outnumbered by metastatic tumors and hematopoietic tumors
Benign tumors are much more common than malignant tumors
Benign tumors are more common in the first three decades, but malignant tumors are more common in adults
Of the malignant tumors: Osteosarcoma > chondrosarcoma > Ewing sarcoma
Bone forming tumors
2-6% of primary tumors involving bone
All tumors produce unmineralized osteoid matrix or mineralized woven bone
Benign: identical histologic features but differ in size, sites of origin, and symptoms; malignant transformation is rare
Osteoid osteoma
Osteodystrophy osteoma
Benign, bone forming tumor < 2cm
Severe nocturnal pain due to osteoblast production of PGE2, relieved by ASA
metaphysis of long bones (femur, tibia = 50%)
Thick rind of reactive cortical bone radiographically
10-20 year olds, male predominance
Presentations: severe nocturnal pain that is relieved by aspirin
Treatment: radiofrequency ablation
Osteoblast OA
Benign, bone forming tumor >2cm (larger) No bony reaction involves the posterior spine (laminae & pedicles) 10-20 year olds Pain is not responsive to aspirin Treatment: curetted or excised in bloc
Osteodystrophy osteoma and osteoblast OA morphology
Round, oval masses of hemorrhagic, gritty, tan tissue
Well circumscribed nodules of radiologically translucent cortical, interlacing woven bone (nidus) rimmed by osteoblasts
Surrounded by highly vascular (congested, dilated), loose connective tissue enclosed by radiologically dense, reactive, sclerotic bone
Seen in the diaphysis of bone
Osteosarcoma
Malignant, bone forming tumor
Most common primary malignant bone tumor, exclusive or myeloma and lymphoma
Epidemiology
Bimodal: 10 - 20 year olds (growth spurt), and older adults who suffer from conditions known to predispose to osteosarcoma (Paget’s, bone infarcts, and prior radiation)
Think Chondrosarcoma in adults, Osteosarcoma in kids
Male predominance
peak in incidence around the time of the adolescent growth spurt and occur most frequently in the region of the growth plate in bones with the fastest growth
Location osteosarcoma
Can occur in any bone, but most commonly occur in the metaphysis of distal femur or proximal tibia, especially in the growth plate since there is faster cell proliferation there
Presentation osteosarcoma
Painful, progressively enlarging mass, may present as a fracture
Extends from medulla to lift periosteum = reactive periosteal bone formation
Radiographically: large, destructive, lytic & blastic mass with infiltrative margins
Codman triangle: triangular shadow between the cortex & raised ends of the periosteum; indicates an aggressive tumor; non-specific (characteristic but not diagnostic)
Pathogenesis osteosarcoma
RB (70% of sporadic) 1,000x ↑ risk
TP53: the guardian of the genome
Li-Fraumeni patients have ↑ risk
INK4a: encodes p16 (negative regulator of CDKs) and p14 (augments p53 function)
MDM2 (inhibits p53) & CDK4 (inhibits RB): overexpressed in low grade osteosarcomas via amplification of 12q13-q15
Classification
Site of origin (intramedullary, intracortical, surface) Primary (underlying bone is unremarkable) or secondary (signs of past chronic disease) Histologic grade (low, high) Histologic features (osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, giant cell) Most common subtype: primary, intramedullary, osteoblastic and high grade arising in the metaphysis of long bones
Morphology
Formation of bone by tumor cells is diagnostic
Large, destructive, grey-white, gritty +/- hemorrhage and cystic degeneration
Large, hyperchromatic, pleomorphic, mitotically active tumor cells
Neoplastic bone has a fine, lace-like pattern
Osteoblastic, chondroblastic, or fibroblastic differentiation
Treatment
Neoadjuvant chemotherapy + surgery
assume that all patients have occult metastases at the time of diagnosis
Prognosis
60-70% 5 year survival
Hematogenously spread to lungs (seen at diagnosis in 10-20%)
Of those who die: 90% have metastases to the lungs, bones, brain, etc
Outcome with metastases, recurrence or secondary disease is poor (< 20% 5 year survival
Cartilage forming tumors
30% (majority) of primary tumors involving bone (both malignant and benign)
osteosarcoma == most common primary malignant bone tumor
cartilage tumor == majority of primary bone tumors (both benign and malignant)
Benign
Osteochondroma (exostosis) == EXT1 or EXT2
Chondroma == IDH1 and IDH2
Ollier disease
Maffucci syndrome
Chondroblastoma
Chondromyxoid fibroma
30% (majority) of primary tumors involving bone (both malignant and benign)
osteosarcoma == most common primary malignant bone tumor
cartilage tumor == majority of primary bone tumors (both benign and malignant)
Benign
Osteochondroma (exostosis) == EXT1 or EXT2
Chondroma == IDH1 and IDH2
Ollier disease
Maffucci syndrome
Chondroblastoma
Chondromyxoid fibroma
Ok
Malignant
Chondrosarcoma (conventional)
Formation of hyaline or mixed cartilage
Osteochondroma (exostosis)
Most common benign bone tumor
Benign, cartilage capped tumor attached to the underlying skeleton via a bony stalk
Slow growing solitary masses
Painful if impinge on a nerve or stalk is fractured, but generally found incidentally
Male predominance
Late adolescence and early adulthood
Location osteochondroma
bones of endochondral origin, most commonly at the metaphysis of long bones (especially near the knee)
If they arise from the pelvis, scapula, or ribs they are sessile and have short stalks
