Bone Pathology

Question 1

Osteogenesis Imperfecta

Answer 1

• “imperfect formation of bone” AKA “brittle bone disease”
• a congenital disorder due to defective synthesis of type I collagen, leading to extreme skeletal fragility (because there’s simply too little bone)

Question 2

Apart from fragility, what do we see in patients with osteogenesis imperfecta?

Answer 2

• blue sclera (because of decreased collagen synthesis in the sclera, allowing visualization of the choroidal veins)
• hearing loss (auditory ossicles are weakened and malformed)
• small misshapen teeth

Question 3

Achondroplasia

Answer 3

• dwarfism; the most common type
• a congenital disorder that inhibits the proliferation of cartilage in growth plates
• mutations ACTIVATE FGFR3 (fibroblast growth factor receptor-3): activated FGFR3 inhibits chondrocyte proliferation

Question 4

Osteopetrosis

Answer 4

• “stone like bone”
• a congenital disorder resulting in defective osetoclasts (usually due to mutations in carbonic anhydrase II), leading to an inability to resorb bone
• bones become dense, solid, and stone-like, BUT the lack of turnover makes them very brittle (chalk-like)

Question 5

What is the term used for inadequate osteoids?

Answer 5

• osteopenia
• (osteoporosis is the end of this spectrum)
• T-score between 1 and -1 is normal, between -1 and -2.5 is osteopenia, equal to or less than -2.5 is osteoporosis

Question 6

What is osteoporosis? Which bones are primarily affected? How is it diagnosed?

Answer 6

• “porous bone”
• a weakening of the bones; resorption exceeds formation over time
• predominantly affects the vertebral column, hip, and distal radius
• diagnosis: DXA T-score equal to or less than -2.5

Question 7

Why does osteoporosis classically develop after menopause?

Answer 7

• because of the loss of estrogen
• estrogen inhibits certain cytokines such as IL-6 (IL-6 activates osteoclasts)
• it also inhibits RANKL
• therefore, with decreased estrogen we have increased osteoclast activity

Question 8

Patients taking which type of medication are at an increased risk of developing osteoporosis? Why?

Answer 8

• corticosteroids / anti-inflammatories

- corticosteroids induce osteoblast apoptosis, shifting the balance of bone remodeling to favor resportion

Question 9

What is paget disease? Is it a systemic disease or a more localized one? When does it typically present?

Answer 9

• AKA osteitis deformans
• repetitive episodes of frenzied regional osteoclastic activity (bone resorption), followed by bone formation, and an eventual exhaustion of cellular activity
• there is an increase in bone mass, but it is disordered and weak
• it is a localized process, affecting only certain bones (usually skull, spine, and pelvis)
• typically presents in late adulthood

Question 10

What may trigger Paget disease? What is pathognomonic of Paget disease?

Answer 10

• may be triggered from paramyxovirus infections of osteoclasts, causing their hyperactivity
• the bizarre bone remodeling yields a pathognomonic mosaic pattern (like rounded out puzzle pieces) of the bone because the pieces have not been properly connected due to the rapid rate

Question 11

What disease is associated with a vitamin D deficiency? Why?

Answer 11

• Rickets in children; osteomalacia in adults
• lack of vitamin D results in a loss of ability to absorb Ca2+ in the gut, so the body increases bone resorption to maintain Ca2+ levels

Question 12

What does hyperparathyroidism result in? What is a primary cause? A secondary cause? What can we use to treat it?

Answer 12

• results in hypercalcemia and hypophosphatemia: muscle weakness, neuro defects, skeletal deformities, calcium-containing kidney stones
• primary cause: hypersecretory tumor; secondary cause: chronic renal failure
• treat by removing the tumor or giving calcimimetic drugs (these act like Ca2+ and bind to calcium receptors to stop PTH secretion)

Question 13

What does hypoparathyroidism result in? What can cause it?

Answer 13

• results in hypocalcemia and hyperphosphatemia: muscle cramps, twitches, pins and needles
• death due to severe hypocalcemia if left untreated
• caused by removal of the parathyroid during surgery, autoimmune destruction of the parathyroid or of PTH, congenital disorders (such as DiGeorge’s syndrome)

Question 14

What is osteonecrosis?

Answer 14

• AKA avascular necrosis

- a complication of a fracture that compromises the vascular supply of the bone –> necrosis

Question 15

What is osteomyelitis? What are the more common causative agents?

Answer 15

• inflammation of the bone and the bone marrow (basically, infection)
• most common agents: pyogenic bacteria (especially Staph aureus) and Pseudomonas aeruginosa in IV drug users, prolonged catheters, or piercing injuries
• in neonates: S. aureus, group B strep, Gram negative bacilli (E. coli, Klebsiella)
• in everyone else: S. aureus, Strep pneumoniae
• in patients with hemolytic disorders, such as sickle cell: salmonella
• infection is most commonly due to an open injury, exposing the bone

Question 16

What percent of patients with pulmonary tuberculosis develop tuberculous osteomyelitis? What disease results when TB infects the __________?

Answer 16

• only 1-3% of patients

- Pott’s disease = TB in the lumbar vertebrae

Question 17

Are primary or metastatic tumors more common in bone?

Answer 17

• metastatic

Question 18

Name two benign and one malignant bone tumors that form new bone.

Answer 18

• benign: osteoma, osteoid osteoma (and osteoblastoma)

- malignant: osteosarcoma

Question 19

Where are osteomas usually found; how do patients present? What syndrome is related to multiple osteomas?

Answer 19

• (osteoma is a benign bone-forming tumor)
• most common in the head and neck (facial bones)
• patients present with a hard mass on a bone surface
• Gardner syndrome: FAP + multiple osteomas + fibromas (soft tissue tumors)

Question 20

Osteoid osteoma vs. osteoblastoma

Answer 20

• (both are benign bone-forming tumors of osteoblasts)
• osteoid osteoma: smaller, most common in proximal femur and tibia, patients present with localized pain (especially at night) that responds to aspirin
• osteoblastoma: larger, most common in the vertebral column, diffuse pain that does not respond to aspirin

Question 21

Where do osteosarcomas most commonly develop? Which patients have the greatest incidence? Which gene mutations are they associated with? Risk factors?

Answer 21

• (osteosarcomas are malignant proliferations of osteoblasts)
• much more common in the knee than anywhere else (distal femur and proximal tibia, so it affects long bones); developed in metaphysis
• commonly presents as pathological fractures or bone pain with swelling; look for Codman’s angle/triangle on x-ray (expansion of tumor pulls the peiosteum away from the bone)
• peak incidence is in teenagers (incidence increases again in the elderly)
• associated with the retinoblastoma TSG mutations
• risk factors: familial RB, Paget disease, radiation

Question 22

Name two benign and one malignant bone tumors that form cartilage. What type of cartilage is usually formed by these tumors?

Answer 22

• benign: osteochondroma and chondroma
• malignant: chondrosarcoma
• usually form hyaline or myxoid cartilage (elastic cartilage and fibrocartilage are rare)

Question 23

What are osteochondromas? What syndrome is associated with them? What gene?

Answer 23

• (benign cartilage-forming tumor)
• the most common benign tumor of bone
• these are cartilage-capped tumors that are attached to the underlying skeleton via a bony stalk
• loss of the EXT genes result in multiple hereditary osteochondromas (the name of the syndrome is simply multiple hereditary osteochondromas)

Question 24

What are chondromas? What disease and what syndrome are associated with them?

Answer 24

• (benign cartilage-forming tumor)
• a neoplasm of hyaline cartilage, usually occurs in small bones of the hands and feet
• Ollier disease: multiple chondromas (usually) on one side of the body
• Maffucci syndrome: multiple chondromas + hemangiomas (also an increased risk for ovarian carcinomas and gliomas)

Question 25

Where do chondrosarcomas most commonly develop?

Answer 25

• (malignant cartilage-forming tumor)
• most common in the pelvis, shoulder, and ribs (axial skeleton)
• (these are about half as common as the other malignant tumor, osteosarcomas)

Question 26

What are three “miscellaneous” types of bone tumors?

Answer 26

• Ewing sarcoma, primitive neuroectodermal tumor (“PNET”), and giant cell tumor

Question 27

Ewing Sarcomas; is there a genetic component?

Answer 27

• Ewing sarcomas are undifferentiated or poorly differentiated sheets of MALIGNANT tumor cells (small, round, and blue) arising from nerual crest cells
• classically arises in long bones of male children; commonly metastasizes; look for “onion-skin” appearance on x-ray
• 90-95% have the classic and characteristic t(11;22) translocation
• it is practically absent in black populations

Question 28

What are giant cell tumors?

Answer 28

• benign “miscellaneous” bone tumors
• characterized by multinucleated osteoclast-type giant cells, BUT it is actually the mononucleated cells that are neoplastic (they also express RANK)
• these arise in the epiphyses of long bones (the only malignancy from the epiphyses!)
• classic “soap bubble” appearance on x-ray

Question 29

Where do more than 75% of bone metastases come from? Which bones are most commonly affected?

Answer 29

• mainly from prostate, breast, kidney, and lung cancers

- most commonly affects the axial skeleton, followed by the proximal femur, followed by the humerus

Question 30

In achondroplasia, why do patients have shortened extremities, but a normal sized head?

Answer 30

• because the impaired chondrocytes result in a loss of endochondrial ossification potential
• the head is spared because these bones grow via intramembranous ossification

Question 31

What mutation is involved in achondroplasia?

Answer 31

• an ACTIVATING mutation of FGFR-3

- it is autosomal dominant

Question 32

In osteopetrosis, a mutation in which gene results in impaired osteoclast activity?

Answer 32

• mutations in gene coding for carbonic anhydrase II

- (without CA, osteoclasts can’t generate the acidic environment needed for bone resorption)

Question 33

What can patients with osteopetrosis present with?

Answer 33

• bone fractures
• anemia, thrombocytopenia, and leukopenia (because the thickening of the bone reduces the medullary space where hematopoiesis occurs! patients will also have EMH: extramedullary hematopoiesis in the spleen as a result)
• vision and hearing impairment (because cranial nerves get compressed by the thickened bone)
• renal tubular acidosis resulting in metabolic acidosis (because of the loss of carbonic anhydrase in tubular cells = inability to generate a net gain of HCO3-)

Question 34

How can we treat osteopetrosis?

Answer 34

• with a bone marrow transplant!

- (remember that osteoclasts are from hematopoietic stem cells and are essentially macrophages)

Question 35

Both osteoporosis and osteomalacia are pathological processes that result in the weakening of the bone - how can we tell them apart?

Answer 35

• in a younger adult, osteoporosis is less likely
• if vitamin D is low, suspect osteomalacia
• *in osteomalacia, Ca2+ will be low, PO43- will be low, PTH will be high, and ALP will be high; in osteoporosis, these are all NORMAL

Question 36

What can patients with rickets present with?

Answer 36

• pigeon breast, frontal bossing (prominent forehead), bowing of legs, rachitic rosary (osteoid deposition at costochondral junctions), delayed fontanelle closure, lordosis/kyphosis/scoliosis, flaring of ribs and wrists, dental abnormalities
• low calcium and phosphate, high PTH and ALP

Question 37

What can patients with paget disease present with? What serum levels would we expect to see? What are two major complications of paget disease?

Answer 37

• bone pain, increasing hat size, hearing loss, lion-like face (from involvement of the skull and facial bones)
• we’d expect to see isolated elevated ALP (normal calcium, phosphate, and PTH)
• complications are an increased risk for osteosarcoma and cardiac failure (the constant bone remodeling generates many A-V shunts, which can result in high-output cardiac failure)

Question 38

What is avascular necrosis? What can cause it? What are some complications?

Answer 38

• AKA osteonecrosis and aspetic necrosis
• ischemic necrosis of bone and marrow due to trauma, fracture, sickle cell disease, coisson disease (gas emboli)
• increases risks for fracture and osteoarthritis

Question 39

What are the four stages of paget diesase?

Answer 39

• 1) lytic: osteoclast activity predominates
• 2) mixed: osteoclast and osteoblast activity
• 3) sclerotic: osteoblast activity predominates
• 4) quiescent: minimal cellular activity (burned out stage)

Question 40

What percentage of bone tumors occur in patients less than 45? What age group has the largest peak incidence?

Answer 40

• 60% occur in people less than 45
• peak incidence: 15-19
• (note that the most common neoplasms in adolescents and young adults are leukemia, then lymphoma, and then bone tumors)
• osteosarcomas and Ewing sarcomas have male, white predilections

Question 41

What are the most common primary benign and malignant tumors of the bone?

Answer 41

• benign: osteochondroma
• malignant: osteosarcoma, followed by Ewing Sarcoma, and then chondrosarcoma (however, ES is the most common malignant in patients less than 10)

Question 42

In patients with osteosarcoma, what seems to be the best prognositc factor? What about for patients with Ewing sarcoma?

Answer 42

• osteosarcoma: cases where at least 95% of the necrosis is removed via chemo before surgery tend to have very good prognoses
• ES: depends on the level of metastasis (this is a very malignant tumor)

Question 43

Where does osteomyelitis usually occur? How do patients present?

Answer 43

• usually involves the growing end of long bones (so children and adolescents are at an increased risk; infection can obliterate the growth plate)
• patients present with a painful local bone lesion and general febrile illness

Question 44

What is the sequestrum? What is the involucrum?

Answer 44

• these are terms related to chronic osteomyelitis
• sequestrum: the necrotic bone region
• involucrum: the area of new bone growth over the sequestrum

Question 45

How do we diagnose osteomyelitis? How do we manage it?

Answer 45

• diagnose w/ at least 2 of the following: pus aspirated from bone, positive blood culture, positive bone culture, local signs of inflammation, radiographic/bone scans
• (note that radiographs usually won’t detect until 2 weeks in, but bone scans can detect within 1 or 2 days)
• manage: antibiotics, monitor response and progress with ESR and CRP levels (these are not the best for assisting in diagnosis)