Chapter 26: Developmental and Acquired Disorders of Bone Flashcards
Which osteoblast-derived protein is unique to bone and can serve as a sensitive and specific marker for osteoblast activity when measured in the serum?
Osteopontin (aka osteocalcin)
What is the function of osteopontin (aka osteocalcin) produced by osteoblasts?
Bone formation, mineralization, and calcium homeostasis
What are the roles of the inorganic moiety, hydroxyapatite, in the bone matrix?
- Responsible for the hardness of bones
- Repository for 99% of body’s calcium and 85% of phosphorus
Which 3 cytokines and 3 GF’s are produced by osteoblasts?
- Cytokines = IL-1 + IL-6 + RANKL
- GF’s = IGF-1 + TGF-β + PDGF
Differentiate the 2 histologic forms of bone matrix (woven vs. lamelllar) in terms of production, stability, and components
- Woven: produced rapidly; fetal period / fracture repair; haphazard collagen arrangement = less structural integrity; always abnormal finding in adults
- Lamellar: SLOW production: parallel collagen; stronger
What are 2 functions of osteocytes?
- Help to control calcium and phosphate levels
- Detect mechanical forces and translate them into biologic activity (mechanotransduction)
What type of cell are osteoclasts?
Specialized multinucleated macrophages
Osteoclasts attach to bone how; secrete what for bone resorption?
- Utilize cell surface integrins for attachment to bone matrix
- Secrete matrix metalloproteases (MMPs) which dissolves inorganic and organic components of bone
Differentiate endochondral ossification from intramembranous ossification?
- Endochondral: development of the long bones: new bone deposited at bottom of growth plates –> longitudinal growth
- Intramembranous: development of flat bones: new bone deposited on pre-existing surface –> appositional growth
When is peak bone mass achieved and when does the steady decline in skeletal mass begin?
- Achieved in early adulthood after cessation of skeletal growth
- 4th decade: resorption > formation –> ↓ skeletal mass
Briefly discuss the role of RANK, RANKL, and osteoprotegrin (OPG) in bone remodeling and homeostasis, including which cells are associated with each?
- RANKL expressed on osteoblasts stimulates RANK on osteoclasts –> activates NF-kB, essential for the generation and survival of osteoclasts; promotes breakdown
- OPG is a secreted “decoy” receptor made by osteoblasts; binds RANKL and prevents interaction w/ RANK; promotes building
How do WNT proteins and sclerostin play a role in bone homeostasis and remodeling?
- WNT proteins (prod. by osteoprogenitor cells) bind LRP5 and LRP6 receptors on osteoblasts –> activate β-catenin and prod. of OPG
- Sclerostin (prod. by osteocytes) inhibits the WNT/β-catenin pathway
How does M-CSF play a role in bone homeostasis and remodeling?
- Prod. by osteoblasts and binds M-CSF receptor on osteoclasts
- Stimulates a tyrosine kinase cascade crucial for generation of osteoclasts
Describe the paracrine crosstalk btw osteoblasts and osteoclasts in bone homeostasis and remodeling?
Breakdown of matrix by osteoclasts liberates and activates matrix proteins, GF’s, cytokines and enzymes; some of which stimulate osteoblasts
Brachydactyly types D and E are due to mutations of what gene; what is seen with this disorder?
- Mutations in homeobox HOXD13 gene
- Shortening of the terminal phalanges of thumb and big toe
Loss-of-function mutations in the RUNX2 gene result in what autosomal dominant disorder?
Cleidocranial dysplasia
What are the clinical manifestations of Cleidocranial Dysplasia?
- Patent fontanelles + Short height + Primitive clavicles
- Delayed closure of cranial sutures
- Wormian bones**: extra bones within cranial sutures
- Delayed eruption of 2’ teeth
*Dustin from Stranger Things*
Achondroplasia, the most common skeletal dysplasia has which type of inheritance pattern and is due to what mutation?
Autosomal dominant; gain-of-function in FGFR3
What are the clinical features of Achondroplasia?
- Retarded cartilage growth –> shortened prox. extremities + normal trunk length + enlarged head w/ bulging forehead
- NO change in longevity, intelligence or repro. status
What is the most common lethal form of dwarfism?
Thanatophoric dysplasia
Which mutation is associated with Thanatophoric Dysplasia; what is a frequent cause of death for these pt’s?
- Gain-of-function in FGFR3
- Pt’s have small chest cavity –> respiratory insufficiency
What is the most common inherited disorder of connective tissue?
Osteogenesis Imperfecta aka brittle bone disease (Type I Collagen)
What is the inheritance pattern and collagen defect associated with Type I Osteogenesis Imperfecta?
- Autosomal dominant***
- ↓ synthesis of pro-α1(1) chain of type I collagen
- Abnormal pro-α1(1) or pro-α2(1) chains of type I collagen
What are the clinical features of Type I Osteogenesis Imperfecta; life-span and stature of these pt’s?
- Most fractures occur before puberty (↓ frequency w/ ↑ age)
- _Normal lifespa_n and normal or near-normal stature
- Blue sclerae
- Loose joints + low muscle tone BUT absent or minimal bone deformity
- Brittle teeth and hearing loss = possible, w/ hearing loss usually manifesting in early 20s or 30s
What is the collagen defect seen with type II osteogenesis imperfecta; majority inherited how?
- Abnormally short pro-α1(1) chain
- Unstable triple helix
- Majority are inherited autosomal recessive
What are the clinical featues of Type II Osteogenesis Imperfecta?
- Death in utero or within days of birth
- Numerous fractures and severe bone deformity
- Small stature w/ underdeveloped lungs –> respiratory problems
What is the defect in collagen which causes Type I Osteogenesis Imperfecta?
Collagen structure is normal, but the amount is less than normal
Osteopetrosis is also known as what?
Marble bone disease and Albers-Schonberg disease
Most of the mutations underlying osteopetrosis interfere with what process?
Acidification of the osteoclast resorption pit, required for the dissoluation of the Ca2+ hydroxyapatite within the matrix
Describe the defect caused by the mutations in CA2 and CLCN7 associated with osteopetrosis?
- CA2: required to generate protons from CO2 and H2O –> absence prevents osteoclasts from acidifying the resporption pit and solubilizing hydroxyapatide, and also blocks the acidification of urine by renal tubular cells
- CLCN7, encodes a proton pump located on the surface of osteoclasts
Due to deficient osteoclast activity what is seen morphologically in the bones of osteopetrosis?
- Bones involved lack a medullary canal; instead contain primary spongiosa (which is normally removed during growth)
- Ends of long bones are bulbous (Erlenmeyer flask deformity)
- Neural foramina are small and compress exiting nerves
What is the inheritance pattern of the severe infantile form of osteopetrosis and what are the clinical features?
- Autosomal recessive
- Usually evident in utero or soon after birth
- Fracture, anemia, and hydrocephaly –> post-partum mortality
- Those who survive have CN defects: optic atrophy, deafness, and facial paralysis
What is the inheritance pattern of the mild form of osteopetrosis and what are the clinical features?
- Autosomal dominant
- Dx in adolescence or adulthood –> repeated fractures
- Mild CN defecits and anemia
How are osteopenia and osteoporosis defined radiographically?
- Osteopenia = bone mass 1.0-2.5 SD’s below the mean
- Osteoporosis = bone mass at least 2.5 SD’s below mean peak bone mass in young adults
Other than the decrease in peak bone mass at least 2.5 SD’s below the mean, the presence of what other findings signifies osteoporosis?
Presence of an atraumatic or vertebral compression fracture
What is the underlying pathophysiology of age-related changes leading to senile osteoporosis?
- Osteoblasts from older pt’s have ↓ proliferative and biosynthetic potential
- Cellular response to GF’s bound to extracellular matrix becomes attenuated as well
- This form is aka low-turnover variant
Who is most at risk for calcium-deficiency leading to future osteoporosis and why?
- Adolescent girls tend to have insufficient Ca2+ intake in the diet
- Typically occurs during a period of rapid bone growth, restricting the peak bone mass ultimately achieved
Why is post-menopausal osteoporosis categorized as a high-turnover variant of osteoporosis; which hormones play the greatest role?
- ↓ estrogen = major role –> leads to ↑ in bone resorption and formation; but formation < resorption
- ↓ estrogen –> ↑ inflammatory cytokines which stimulate osteoclast recruitment and ↑ RANKL, ↓ OPG –> ↓ osteoclast proliferation and apoptosis
What is the histologic hallmark of osteoporosis?
Normal bone that is decreased in quantity
Which bones are most often affected by the ↑ osteoclasts activity in post-menopausal osteoporosis and what is seen morphologically?
- Bones w/ ↑ SA (cancellous bones of vertebral bodies)
- Trabeculae: perforated, thinned and lose interconnections which —> microfractures and vertebral collapse
What is seen morphologically with senile osteoporosis?
Cortex thinned by subperiosteal** and **endosteal resorption, Haversian system widened (may mimic cancellous bone)
Vertebral fractures are common in osteoporosis and lead to what?
Loss of height and deformities, such as lumbar lordosis and kyphoscoliosis
What are 2 frequent complications associated with fractures of the femoral neck, pelvis, or spine seen with osteoporosis?
Pulmonary embolism and Pneumonia
Up to 50% of familial paget disease and 5-10% of sporadic cases harbor which mutation?
Mutations of SQSTM1 —> ↑ NF-kB –> ↑ osteoclast activity
What is the hallmark histologic pattern seen with Paget Disease of bone?
- Mosaic pattern of lamellar bone, seen in the sclerotic phase (late stage)
- Jigsaw-like appearance w/ prominent cement lines = haphazardly oriented units of lamellar bone
What is seen morphologically in the 3 phases of Paget Disease of bone?
1) Lytic phase: large osteoclasts** w/ 100 nuclei
2) Mixed phase: clasts persist, but lots of blasts also; primarily osteoblastic** at end of stage
3) Final: burned-out quiescent osteosclerotic stage
Which bones are involved in 80% of cases of Paget Disease?
Axial skeleton and proximal femur
What are some of the common presentations and complication of Paget Disease of bone?
- Chalk-stick type fractures: long bones of legs
- Anterior bowing of femur and tibia, distorts fibular head –> 2’ osteoarthritis
- Enlargement of craniofacial skeleton –> “lion facies“
- Hypervascularity of Pagetic bone –> warms overlying skin
Which complication may arise from the hypervascularity of Pagetic Bone?
↑ blood flow acting as AV shunt leading to high-output heart failure
What are the levels of serum calcium, phosphorus and ALP like in Paget Disease?
- ↑ ALP w/ normal calcium and phosphorus
- MOST COMMON cause of isolated ↑ ALP in adult
Paget disease of bone is relatively common in whom?
Whites in England, France, Austria, regions of Germany, Austrailia, New Zealand and the U.S.
PTH is responsible for activating which cells in bone?
Osteoclast activation –> ↑ bone resorption and Ca2+ mobilization; effect mediated indirectly through ↑ RANKL expression on osteoblasts
Symptomatic, untreated primary hyperparathyroidism manifests as what 3 interrelated skeletal abnormalities?
- Osteoporosis
- Brown tumors
- Osteitis fibrosa cysticab
Combination of ↑ bone cell activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of?
Severe hyperparathyroidism and is known as generalized osteitis fibrosa cystica (von Recklinghausen disease of bone)
The osteoporosis seen with hyperparathyroidism is most severe in which bones and the ↑ osteoclast activity is most prominent where?
- Most severe in the phalanges, vertebrae and prox. femur
- ↑ osteoclast activity is most prominent in cortical bone (subperiosteal and endosteal surfaces), but medullary bone is also affected
In hyperparathyroidism the osteoclasts may tunnel into and dissect centrally along the length of trabeculae, producing what?
Dissecting osteitis; looks like “railroad track“
Kidney disease causes skeletal abnormalities (renal osteodystrophy) through what 3 mechanisms?
- Tubular dysfunction: renal tubular acidosis –> ↓ pH dissolves hydroxyappatite
- Generalize renal failure: ↓ phosphate excretion, chronic hyperphosphatemia, hypocalcemia, and 2’ hyperparathyroidism
- ↓ prod. of secreted factors: kidney converts Vit D to active form (1,25-D3) and secretes proteins BMP-7 and Klotho
What is the fundamental defect in osteomalacia (adults) and rickets (children)?
Impairment of mineralization and resultant accumulation of unmineralized matrix
What is a simple vs. compound vs. comminuted fracture?
- Simple = overlying skin intact
- Compound = bone communicates w/ the skin surface
- Comminuted = bone is fragmented
What is a “Greenstick” fracture?
Extending only partially through the bone, common in infants when bones are soft
What is a pathologic fracture?
Involving bone weakened by an underlying disease process, such as tumor
What occurs immediately post bone fracture?
- Rupture of blood vessels results in a hematoma which fills the fracture gap and surrounds area of bone injury
- Clotted blood —> fibrin mesh seals site and creates framework for influx of inflammatory cells and ingrowth of fibroblasts + new capillaries
What are the major changes seen at the end of the first week following a bone fracture?
- Organization of the hemaoma + matrix prod. in adjacent tissues + remodeling of the fractured ends of the bone
- Fusiform and predominantly uncalcified tissue aka soft tissue callus or procallus
- Provides some anchorage between the ends of fracture bone but NOT structural rigidity
After 2 weeks of fracture repair what occurs?
- Soft tissue callus is transformed into bony callus
- Activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone
- Bony callus reaches maximum girth at end of 2nd to 3rd week and helps stabilize the fracture site
Healing of a bone fracture is complete with restoration of what?
The medullary cavity
Most cases of osteonecrosis (avascular necrosis) are due to what 2 etiologies?
- Fractures or corticosteroid tx
- May also be seen w/ bisphosphonate tx (especially jaw!)
Regardless of etiology, medullary infarcts (osteonecrosis) are geographic and involve which parts of bone?
Trabecular bone & marrow
Why is the cortex not typically affected in medullary infarcts (osteonecrosis)?
Due to its collateral blood flow
What is the characteristic morphology seen with with subchondral infarcts of osteonecrosis?
Triangular or wedge-shaped segment of tissue that has the subchondral bone plate as its base undergoes necrosis
What does dead bone look like microscopically?
Empty lacunae surrounded by necrotic adipocytes which frequently rupture
What is seen with the trabeculae that remains in subchondral infarcts (osteonecrosis)?
- Acts as scaffolding for the deposition of new bone in process known as “creeping substitution”
- Pace is too slow to be effective, so there is collapse of the necrotic bone and distortion, fracture and even sloughing of the articular cartilage
What is the origin of most osteomyelitis in both healthy children and adults?
- Children: hematogenous spread from trivial mucosal injuries i.e., defecation or vigorous chewing of hard foods or from minor infections of skin
- Adults: more often arise as complication of open fractures, surgical procedures, and diabetic infections of the feet
Which 3 organisms are commonly cultured in osteomyelitis seen in pt’s with UTI’s are who are IV drug users?
E. coli + Pseudomonas + Klebsiella
Pt’s with C5, 6, 7, 8, and 9 deficiency have increased susceptibility to which organism causing osteomyelitis?
Neisseria
What is the seen in the acute phase of osteomyelitis?
Bacteria proliferate and induce neutrophilic inflammatory rxn; necrosis of bone cells and marrow ensues within first 48 hours
In children the periosteum is loosely attached to the cortex, so what is often seen in the acute phase of osteomyelitis?
Sizable subperiosteal abscesses may form, which dissect for long distances along the bony surface
What does the term sequestrum refer to in terms of osteomyelitis; what is seen with rupture of the periosteum?
- Dead bone following subperiosteal abscess
- Rupture of periosteum —> soft tissue abscess which can channel to become a draining sinus
What is seen commonly with epiphyseal infection (osteomyelitis) in infants?
Spread thru the articular surface or along capsular and tendoligamentous insertions into joints —> septic or suppurative arthritis
What is seen in the chronic phase (after first week) of osteomyelitis; what does the term involucrum refer to?
- Chronic inflammatory cells release cytokines that stimulate osteoclastic resorption, ingrowth of fibrous tissue and deposition of reactive bone at the periphery
- Newly deposited bone can form a shell of living tissue, known as involucum, around the segment of devitalized infected bone
Describe the morphological variants of osteomyelitis known as Brodie abscess and Sclerosis osteomyelitis of Garre?
- Brodie abscess: small interosseous abscess frequently involves cortex & is walled off by reactive bone
- Sclerosing osteomyelitis of Garre: in jaw and assoc. w/ extensive new bone formation that obscures much of the underlying osseous structure
Diagnosis of osteomyelitis is strongly suggested by what characteristic radiographic findings?
Lytic focus of bone destruction surrounded by zone of sclerosis
Unexplained fever vs. localized pain are more common findings of osteomyelitis in which age group (adults or children)?
- Unexplained fever = children
- Localized pain = adults
In mycobacterial osteomyelitis the organisms usually originate from where?
Blood borne, originating from a focus of active visceral disease during initial stages of primary infection; can be direct extension
What are some of the complications which may arise in the setting of tuberculous spondylitis (Pott disease)?
- Permanent compression fractures –> scoliosis or kyphosis & neurological deficits 2’ to spinal cord and nerve compression
- Other: tuberculous arthritis, sinus tract formation, psoas abscess & amyloidosis
How and when does skeletal syphillis present when congenital?
- Appear about 5th month gestation and fully developed at birth
- Saber shin: massive reactive periosteal bone deposition on medial and anterior surfaces of the tibia
In acquired syphillis when do the bone lesions typically present and how?
- May begin in early tertiary stage, 2-5 years after initial diagnosis
- Saddle nose, palate and extremities (esp. long tubular bones like tibia)
