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124 Cards in this Set

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What is unmineralized bone called?
osteoid
Which cells synthesize, transport, arrange proteins of bone matrix?
osteoblasts
Which cells initiate mineralization?
osteoblasts
Which cells have cell surface receptors which bind numerous
hormones (PTH, Vitamin D, Estrogen)?
osteoblasts
Osteoblasts once surrounded by matrix are:
osteocytes
Which cells are responsible for bone resportion?
osteoclasts
How many bones in the human body?
206
Term for fusion of two adjacent digits:
Syndactylism
Term for development of long spider-like digits:
Arachnodactylism
Most common disease of growth plate:
Dwarfism (Achondroplasia)
Mode of inheritance of achrondroplasia:
autosomal dominant
Mutated gene in Achondroplasia:
FGFR3
Normal role of FGFR3?

What does mutation cause at cellular level?
Normally inhibits cartilage proliferation

1. Mutation leads to constant activation
2. Reduced chondrocyte proliferation in the growth plate
3. Premature deposition of bone seals the growth
plate
Clinical features of Achondroplasia:
1. Shortened proximal extremities
2. Trunk of relatively normal length
3. Enlarged head with bulging forehead
4. Depression at root of nose
5. Normal longevity, intelligence, reproductive
status
What disease is known as "brittle bone disease"?
osteogenesis imperfecta
What type of collagen is affected in osteogenesis imperfecta?
type I collagen
Mode of inheritance of osteogenesis imperfecta:
autosomal dominant

autosomal recessive (perinatal lethal form)
Clinical features of osteogenesis imperfecta:
1. Multiple fractures
2. Blue sclera
3. Small mis-shapen teeth
4. Deafness
Goals of treatment of osteogenesis imperfecta:
1. Maximize mobility/function
2. Minimize fracture risk
3. Pain control
4. Psychosocial
The inorganic component of bone is called:
calcium hydroxyapetite
Growth plate related to what type of bone formation?
endochondral
What is the #1 metabolic bone disease in U.S.?
osteoporosis
Osteoporosis is characterized by what change in bone density:
decrease in bone density
Underlying causes of secondary osteoporosis:
1. hyperthyroidism
2. hyperparathyroidism
3. corticosteroid use
4. immobilization
5. hypogonadism
6. anticonvulsants (Dilantin)
How much bone density is lost per year in men and women:
men: 0.2-1% per year

women: same as men before menopause; 3-5% after menopause
Risk factors for osteoporosis:
1. Age
2. Female
3. Caucasian
4. Asian
5. Family history
6. Small body frame
7. Calcium deficiency
8. Decreased exercise
9. Estrogen deficiency
Changes that occur in post-menopausal women which leads to osteoporosis:
1. decreased seroum estrogen
2. increased IL-1, IL-6, TNF-alpha
3. increased expression of RANK and RANKL
4. increased osteoclast activity
What bones are affected most by osteoporosis?

What happens to the bone?
Entire skeleton affected

Most affected: vertebra, wrist, ribs, pelvis

thinned trabeculae
What does RANK and RANKL do?
RANK (receptor) is on monocytes and preosteoclast cells. They bind RANKL which is on osteoblasts --> osteoclastogenesis.
Signs of vertebral fractures in osteoporotic patients:
1. Loss of height
2. kyphoscoliosis
3. Dowager’s hump
Complications of osteoporosis:
1. pulmonary embolism
2. pneumonia
Can we catch osteoporosis early?
1. Not detectable on X-Ray until 30-40% bone
mass lost

2. Blood calcium, phosphorous, alkaline phosphatase levels NOT diagnostic
Prevention and treatment of osteoporosis (5):
1. Exercise
2. Calcium and vitamin D
3. Bisphosphonates
4. Estrogen replacing agents
5. Recombinant PTH (Forteo) - given in a pulsatile fashion; high levels all the time favors bone resorption
Etiology of rickets/osteomalacia:
Etiology = Vitamin D deficiency
Pathology of rickets (kids) and osteomalacia (adults):
1. bone mineralization defect
2. decreased mineral content of bone
3. relative increase in osteoid*
4. bones are soft
Explain Vitamin D deficiency (figure 9-24):
There is inadequate substrate for the renal hydroxylase (1), yielding a deficiency of 1,25(OH)2D (2), and deficient absorption of calcium and phosphorus from the gut (3), with consequent depressed serum levels of both (4). The hypocalcemia activates the parathyroid glands (5), causing mobilization of calcium and phosphorus from bone (6a). Simultaneously, the parathyroid hormone (PTH) induces wasting of phosphate in the urine (6b) and calcium retention. Consequently, the serum levels of calcium are normal or nearly normal, but the phosphate is low; hence, mineralization is impaired (7).
What is bone process is abnormal due to vitamin D deficiency?
bone modeling/remodeling
What problem would cause fractures and microfractures?
vitamin D deficiency --> rickets/osteomalacia
Lab findings in adults with osteomalacia:
1. Low normal calcium
2. Low (to low normal phosporous)
3. Decreased vitamin D
4. Elevated alkaline phosphatase
Rickets causes a problem with:
GROWING BONES
Where is the problem with rickets:
Deficient mineralization of the growth plate
Signs of Rickets:
1. Enlarged joints
2. Rachitic Rosary
3. Pigeon Breast Deformity
4. Bowing of legs
5. Occipital bones flattened
6. Parietal bones buckled inward
7. Frontal bossing/squared appearance of head (excess osteoid)
Treatment of rickets:
vitamin D
Causes of primary hyperparathyroidism (3):
Hyperplasia
Adenoma
Carcinoma
Causes of secondary hyperparathyroidism:
Prolonged hypocalcemia stimulates PTH hypersecretion
How does increased PTH cause bone resorption?
increased PTH levels are detected by receptors on osteoblasts which initiate release of mediators that stimulate osteoclast activity
Pathology of hyperparathyroidism:

1. what causes the skeletal manifestations?
2. what bone type is affected?
3. what is dissecting osteitis?
1. skeletal issues due to unabated osteoclastic bone resoption

2. affects cortical bone (thinned cortex) more than cancellous bone

3. Dissecting osteitis - osteoclasts tunnel into trabeculae (“railroad tracks”)
Findings in hyperparathyroidism:
1. microfractures
2. Brown tumors - microfractures and secondary hemorrhages eleicit influx of macrophages and ingrowth of reactive fibrous tissue
What is the hallmark of severe hyperparathyroidism?
Generalized osteitis fibrosa cystica (von Recklinghausen disease of bone) = increased bone cell activity, peritrabecular fibrosis, cystic brown tumors
Signs/symptoms of hyperparathyroidism:
1. Decreased bone mass
2. Pain
3. Fractures: stress fractures
Control of hyperparathyroidism can lead to:
bone changes regress
Cause of scurvy:
vitamin C deficiency
Why is vitamin C needed important for bone formation?
Vitamin C deficiency causes defect in hydroxylation of procollagen (formation of hydroxyproline) and suppressed rate of collagen synthesis.

In growing kids, vitamin C deficiency causes defect in formation of osteoid matrix resulting in deformed bones.
Problems associated w/ vitamin C deficiency (fig 9-30):
1. defective and insufficient formation of osteoid which leads to deformation of bones (usually kids)

2. weakness in blood vessel walls --> hemorrhages, purpura, ecchymoses

3. gingiva w/ hemorrhages, swelling
4. wound healing impaired
sources of vitamin C:
Milk
liver
fish
fruits
vegetables
Who is at risk of vitamin C deficiency?
1. Elderly
2. Alcoholics
3. Food faddists
4. Infants – formulas without supplementation
5. Sailors
Scurvy treatment:
vitamin C supplementation
Disease characterized by "matrix madness" or a "mosaic pattern" and its pathology:
Paget Disease of bone (Osteitis Deformans):
-initially there is increased haphazard bone destruction (osteolysis)
-eventually bone is replaced by vascular connective tissue and poorly organized bone --> increased* thickness of cortex and trabeculae, but the bone is soft b/c the matrix is poor (bone lacks structural strength)
Outcome of Paget Disease:
1. Increased bone mass
2. Disordered bone stx
3. Structurally unsound
3 stages of Paget Disease:
1. Osteolytic
2. Mixed osteolytic-osteoblastic
3. Osteosclerotic
Etiology of Paget Disease:
Slow virus infection of osteoclasts: Paramyxovirus

Induce IL-6 secretion
Stimulate osteoclast activity
What dz produced bones with "jigsaw-like" appearance?
Paget disease
When does Paget disease begin?
mid-adulthood (50-60)
Bones affected by Paget disease:
Monostotic (15%): Tibia, ilium, femur, skill, vertebra, humerus

Polyostotic (85%): Pelvis, spine, skull

(i.e. usually multiple bones affected)

descending order of affected bones: tibia, pelvis, femur, skull, spine
Why do people w/ Paget dz have pain?
1. Microfractures
2. Bone overgrowth compressing nerves, spinal
Problems caused by Paget disease (3):
1. Secondary arthritis
2. High output heart failure* - heart is working fine, but blood detours to bone (increased blood flow causes arteriovenous shunt)
3. Sarcoma development: 5-10%; osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma
4. bone overgrowth (i.e. leontiasis ossea: thickening of the skull and craniofacial bones) --> bone deformities
5. involvement of the ossicles --> hearing loss
How can Paget disease be recognized?
1. radiographs
2. bone scan
Lab signs of Paget Disease:
Elevated serum alkaline phosphatase**

Serum calcium, phosphorous unaffected
Treatment of Paget Disease:
1. Acetaminophen, NSAIDS
2. Bisphosphonates
3. Calcitonin
What causes osteonecrosis (avascular necrosis)?

What areas are affected, which are spared?
bone infarction (bone and marrow)

affected: medullary cavity of metaphysis or diaphysis

spared: cortex is spared due to collateral blood flow
Causes of ischemia leading to osteonecrosis:
Mechanical (fracture)
Corticosteroids
Thrombosis/embolism
Vessel injury (vasculitis, radiation)
Vascular compression
Etiology of osteonecrosis:
Trauma
Corticosteroids
Infection
Dysbarism
Radiation therapy
Connective tissue
Sickle cell anemia*
Tumors
Pregnancy
Idiopathic
Signs of subchondral infarcts in osteonecrosis:
1. pain
2. collapse of bone
3. secondary arthritis
Signs of medullary infarcts (i.e. center of long bones):
most are clinically silent
What is Tuberculous Osteomyelitis?
TB goes to bone:
-spine: thoracic and lumbar > cervical and sacral (Pott disease)
-knees and hips most common sites of skeletal involvement

1-3% of patients w/ pulmonary TB get this
How can Tuberculous Osteomyelitis manifest itself?
1. Hematogenous spread
2. Direct extension
3. Spread via draining lymphatics

Usually solitary focus
AIDS - multifocal
Pott disease?
-Spine (Pott Disease)
-Thoracic and lumbar vertebra
-Intervertebral disks breached
-Multi-level involvement
-Soft tissue abscesses
-Knees, hips
Symptoms of Tuberculous Osteomyelitis:
1. Pain, fever, weight loss
2. Compression fractures
3. Scoliosis, kyphosis
4. Neurologic defects
Primary bone neoplasms:
common or uncommon?
who gets it?

Majority of bone neoplasms are benign or metastatic:
Uncommon
Children & adolescents > adults
Benign or malignant
Age, location, radiographic appearance tissue examination

majority of bone neoplasms are METASTATIC
Primary bone neoplasms arise where:

3 most common?
Hematopoietic 40%
Chondrogenic 22%
Osteogenic 19%
Histiocytic
Fibrogenic
Vascular
Lipogenic
Neurogenic
Unknown origin 10%
What is an osteoma?
-Benign tumor
-Composed of dense (sclerotic) well-formed bone
-Extends from surface of cortical bone
Who gets osteomas?
What bones are affected?
What problems can they cause?
Middle aged men
Cranial and facial bones
Slow growing
Often clinically insignificant

Obstructs sinus cavity
Eye impingement
Cosmetic issues
Disease associated w/ multiple osteomas:
Gardner's syndrome
What is an osteoid osteoma?
-Benign
-Haphazard bone and osteoid
-Haphazardly arranged trabeculae of woven bone -rimmed by osteoblasts
-Stroma - loose connective tissue, vascular
-Arises in cortex of femur, tibia
-Less than 2cm
Who gets osteoid osteoma?
What is the main symptom?
Men <25 years old (5-25)

PAIN!
Prostaglandin E2
Nocturnal
Relieved with aspirin
What is the most common primary malignant bone tumor?
osteosarcoma (osteogenic sarcoma)
Common sites of osteosarcomas?
Medullary cavity of the metaphysis of long bones

(60% arise close to knee: distal femur and proximal tibia)
Histo appearance of osteosarcoma:
anaplastic mesenchymal cells intermixed w/ osteoid (and sometimes cartilage)
What is Codman triangle?
an irregular radiographic shadow b/w cortex and raised end of periosteum
Mutations causing osteosarcoma?
RB gene mutations:
1. Hereditary retinoblastoma: 1000x risk of osteosarcoma
2. Sporadic mutations

P53, Cyclin D1, MDM2 mutations
Who gets osteosarcoma?

How does it present?
men > women
majority < 20yo (but older peak associated w/ predisposing factors such as Paget disease)

presents as painful, enlarging mass
Where does osteosarcoma metastasize to?

what treatments used for osteosarcoma and how successful?
metastasizes to lungs

treatment: chemotherapy, limb salvage (60% long-term survival)
What is an enchondroma?:

Composed of what?
Arises where?
-Benign neoplasm
-Composed of hyaline cartilage
-Arises within metaphysis of short tubular bones of hands and feet
Symptoms of enchondroma:
-aymptomatic usually
-painful on occassion
Disease where people develop multiple enchondromas:
Ollier disease
What is a chondrosarcoma?
=Malignant neoplasm composed of malignant hyaline and myxoid cartilage
-Varies in degrees of differentiation
Central portion
-Arise in central portions of skeleton: pelvis, shoulder, ribs
histo of chondrosarcoma:
...
How is Chondrosarcoma graded?
Grade 1 – Low grade
Grade 2
Grade 3 – High grade: Very hypercellular, pleomorphic, bizarre tumor giant cells

grade is important for outcome
Who gets Chondrosarcoma?

How does it present?

Metastases and prognosis?

Treatments?
>40 years
Men > women

Painful enlarging masses
Metastases to lungs, skeleton
Prognosis related to grade, size

5 year survival:
90% - Grade 1; 43% - Grade 3

Surgery
Some variants chemotherapy
Chondrosarcoma...
...
What is Ewing Sarcoma/PNET?
=Malignant neoplasm composed of small, round mesenchymal cells resembling lymphocytes

-Occurs in medullary cavity of long bones: femur, flat bones of pelvis
What differentiates PNET from Ewing sarcoma?
Neural differentiation – PNET

No neural differentation – Ewing Sarcoma
Gene associated w/ Ewing Sarcoma?
t(11;22)(q24;q12)
-EWS-FLI1 fusion gene
-Oncogene
-Protein = active transcription factor
Who presents w/ Ewing Sarcoma?

How does it present?

Clinically can mimic?
<20 year old (most 10-15 years)
Boys > girls
African Americans rarely

Painful, enlarging masses
Warm, tender, swollen
Fever, leukocytosis

mimics:
Treatment of Ewing Sarcoma/PNET:

Survival?
Chemotherapy, surgery
Radiation in some cases

75% 5 year survival
50% long term cure
Majority of bone neoplasms are due to:
BONE METASTASES
What cancers can metastasize to bone?
Any cancer, any bone
-Red marrow of axial skeleton
-Adults: Prostate, breast, kidney, lung
-Children: Neuroblastoma, Wilm’s tumor, Ewing sarcoma,
Rhabdomyosarcoma
How can bone metastases spread?
Direct extension
Lymphatic or hematogenous spread
Intraspinal seeding (Batson plexus of veins)
Radiographic evidence of bone metastases? (3 types)
-Lytic: Prostaglandins, interleukins, parathyroid hormone- related hormones; Osteoclast bone resorption stimulated

-Blastic: Osteoblastic bone destruction

-Mixed lytic and blastic
What bone metastasis are mostly blastic?**
prostate
Mneumonic for lytic bone mets:
"Bacon Lettuce Tomoato Ketchup and Mayo"

=Breast, Lung, Thyroid, Kidney, Multiple myeloma
Mneumonic for blastic bone mets:
"PITTA"

=Prostate*, Infamous lymphoma, Transitional cell CA, Treated breast, APUDoma (carcinoid)
Problems assoc w/ bone metastases?

Treatments?
1. Pathologic fractures
2. Pain: NSAIDS, opiates, adjuvant treatments, radiation Therapy
Define: woven bone
=osteoblasts deposit collagen in a random weave

-seen in fetal skeletaon and formed at growth plates

-always pathological in the adult
Define: lamellar bone
=deposited collagen in an orderly layer

-gradually replaces woven bone during growth
Define: osteocyte
-most numerous bone forming cells
-occupies a lacuna and has cytoplasmic processes that extend into canaliculi and make contact w/ other osteocytes

i.e. an osteocyte is an osteoblast surrounded by matrix
Define: osteoblast
=bone-forming cell (mesenchymal origin)
-synthesize, transport, and arrange matrix proteins
Define: osteoclast
=large, multinucleated cell (monocytic origin) that absorbs and removes osteous bone
Define: callus
=composite mass of tissue that forms at a fracture site to establish continuity b/w both ends of bones
Define: osteopenia
=decreased calcification or density of bone (decreased bone mass)
Define: osteonecrosis
=extensive bone death

(not caries = molecular death)
Define: Rachitic rosary
=row of beading seen at junction of ribs w/ their cartilages
Define: renal osteodystrophy
=generalized bone changes occurring in renal failure that resemble osteomalacia
Define: frontal bossing
=prominent forehead