Disease of Bone Development (Handy Pants) Flashcards
What are bones made up of?
65% Inorganic: calcium hydroxyapatite
35% Organic: collagen
What gives bone its strength/hardness? structure?
strength/hardness = calcium hydroxyapatite
structure = collagen
bone that has not mineralized
osteoid
How long does it take to mineralize bone
12 - 15 days
puripotential mesenchymal stem cells
osteoprogenitor cells
CBFA-1
stimulates osteoprogenitor cells to become osteoblasts
What cells form bone?
osteoblasts
What cells reabsorb remodel bone?
osteoclasts
What cells sense mechanical stress and regulate serum calcium and phosphorus?
osteocytes
What is osteoid made of? What makes osteoid?
type I collagen
Osteoblasts
Multinucleated bone cell
osteoclast
Cells have PTH receptors to mediate osteoclast activity
osteoblast
cells that are encased in bone
osteocytes
canaliculi
contain osteocytic cell processes to allow osteocytes to communicate
howship lacunae
resorption pit containing osteoclast
osteoblasts that are surrounded by matrix =
osteocyte
What cells initiate mineralization
osteoblasts
ostoclast
osteoblast
osteocyte
Osteoclasts are derived from the same stem cells that produce _______.
macrophages
i.e. both from mesenchymal stem cells
Describe the interactions needed for osteoclast differentiation
RANK ligand on osteoblast membrane assc with RANK receptor on osteoclast precursor cell surface
\+
M-CSF binds M-CSF receptor on osteoclast precursor cell surface
Osteoprotegerin (OPG)
secreted by stromal cells/osteoblasts to prevent the binding of RANK ligand to the RANK receptor –> inhibits osteoclast differentiation and therefore bone reabsorption
What other cytokines are needed for osteoclast differentiation?
IL-1, 3, 6, 11
GM-CSF and M-CSF
anlage
cartilaginous model of the future bone
Growth plate
cartilage between ossification centers
____ –> cartilage –> bone
mesenchyme
Describe the normal long bone structure/its parts
Diaphysis: central portion
Metaphysis: between diaphysis and epiphysis
Epiphysis: end of long bones
What part of the long bone contains growth plates?
epiphysis
Why are children more prone to osteomyelitis than adults?
children have a richer blood supply (or is it the other way around? the pic makes me think it might be but I cannot tell from the wording…)
How is mature bone different than growing bone?
- epiphyseal plate stopped growing
- metaphyseal vessels penetrate the cartilage plate
- transverse bars of bone separate the growth plate from the metaphysis
A family of diseases having in common mutations in the type I collagen genes.
OSTEOGENESIS IMPERFECTA (“brittle bone diseases“)
Briefly describe the collagen defects assc with each type of OI (I-IV)
I. make too little pro-α1(1)
II. Pro-α1(1) is too short = collagen made but degraded intracellularly
III. Triple helix doesn’t form well
IV. Pro-α2(1) is too short
in what type of OI are bones break in utero or during birth, killing the child
II
= Pro-α1(1) is too short and collagen made but degraded intracellularly
In what type of OI do pts have normal statue, lax joints, and are hard of hearing?
type I = make too little pro-α1(1)
In what type of OI do pts have short stature and somewhat fragile bones?
type IV = Pro-α2(1) is too short
mode of inheritance for OI
autosomal dominant (type II may by AR or AD)
4 major clinical criteria for diagnosis of OI
2 of the following are needed for Dx:
- osteoporosis
- blue sclera
- dentingenesis imperfecta (=abnl teeth)
- premature otosclerosis (causes hearing loss)
characteristically associated with heritable disorders of connective tissue?
blue sclera OI > pseudoxanthoma elasticum, Ehlers-Danlos syndrome, and Marfan disease >>> iron deficiency, rheumatoid arthritis, or myasthenia gravis
What causes the blue discoloring of the sclera?
thinning of the sclera allows the underlying choroid to become visible
OI congenita vs OI tarda
congenita = is clinically severe, and survival beyond childhood is uncommon.
tarda = much milder course, and patients may live to an advanced age.
Short extremities, normal trunk, large head, normal mentation
achondroplasia
What is the pathogenesis of achondroplasia
AD mutation in fibroblast growth factor 3 causing a reduction in chondrocytes at growth plate –> impaired formation of the LONG bones (endochondral process)
risk factor for new mutations leading to achondroplasia
advanced paternal age
Is sexuality or intelligence affected in achondroplasia
no
mode of inheritance for achondroplasia
AD and often due to a new mutation (advanced paternal age)
What is a danger to life in achondroplasia?
deformity at the foramen magnum, where minor trauma can dislocate the skull from the neck bones and compress the brainstem
long bones without medullary cavities and misshapen, bulbous ends and increased # of irregular bony trabeculae
osteopetrosis
T or F: there is an increased number of osteoclasts in osteopetrosis
F: dysfunctional osteoclasts
pathogenesis of osteopetrosis
carbonic anahydrase II deficiency –> osteoclast dysfunction
or
RANKL loss of function mutation –> osteoclasts are not activated –> low # of osteoclasts in bone
-> lacking ability to reabsorb tissue –> bone marrow is occluded with weak, woven bone
How is the bone different in osteopetrosis?
W - Woven bone occluding marrow
I - Increased # of Irregular bony trabeculae
B - Bulbous ends U - residual strips of
Unremodeled cartilage
M - lack of Meduallry canal/cavaties and trabeculaeor Marrow
S - diffusely Sclerotic bone
WI BUMS get osteoporosis from their cheese
NF-kB intracell signaling pathway activated by
RANKL binding RANKR to signal osteoclast differentiation
What is the definition of osteoporosis
- low bone mass
- microarchitectural deterioration of bone tissue
–> leading to bone fragility and increased fracture risk
What the the common fracture sites in osteoporosis?
wrist, hip, and spine
**30% of women 50+ will have one or more vertebral fractures
What are the major risk factors for osteoporosis?
- Age > 70
- Menopause < 45
- Hypogonadism
- Fragility Fracture
- Hip Fracture in Parents
- Glucocorticoids
- Malabsorption
- High Bone Turnover
- Anorexia Nervosa
- BMI < 18
- Immobilisation
- Chronic Renal Failure
- Transplantation
What are the moderate risk factors for osteoporosis?
- Estrogen Deficiency
- Calcium Intake < 500 mg/d
- Primary Hyperparathyroidism
- Rheumatoid Arthritis
- Bechterew Disease
- Anticonvulsants
- Hyperthyroidism
- Diabetes Mellitus
- Smoking
- Alcohol Excess
What is the pathogenesis of osteoporosis?
reabsorbed cavity too large + newly formed packet of bone too small –> formation does not match absorption + increased numbers of remodeling units = increased bone loss
How does menopause contribute to pathogeneis of osteoporosis?
decreased serum estrogen
increased IL-1, 6, and TNF
increased RANK expression –> increased osteoclast activity
How does aging contribute to the pathogenesis of osteoporosis?
- decreased replication of osteoprogenitor cells
- decreased synthetic activity of osteoblasts
- decreased biologic activity of matrix bound growth factors
- decreased physical activity
What is the mortality rate for:
1 year after hip fracture:
<75 yo
75-84 \>85 yo
10 years after hip fracture and >/= 85 yo
7%
21%
33%
95%
Unbalanced and excessive osteoclast and osteoblast function; increased bone turnover
paget disease of bone
What does paget disease of bone predispose a person to?
osteogenic sarcoma
chondroscarcoma
malignant fibrous histiocytoma
epidemiology of paget disease of bone
mid adult
northern european
Clinical features of paget disease of bone
Thick skull
Deafness
Kyphosis
Pain
Bowed legs
irregular lamellar bone
sclerotic phase of paget
Irregular thick, coarse cortex
paget disease of bone
Describe vit D/Ca metabolism
ingest vit D or made in skin and enters the bloodstream. In the liver it is converted into 25(OH)D. This goes to the kidney where it is made into:
- 1, 25 (OH)2D –> intestine told to abs Ca –>
- 24, 25(OH)2D –> actives parathyroid to make PTH–> kidneys reabsorb Ca and bone releases Ca
==> Ca into the blood
Failure of the bone to mineralize properly in an adult
osteomalasia
of inadequate intake of vitamin D and/or calcium in childhood
rickets
Adults with dietary calcium deficiency or malabsorption are prone to …
osteomalasia –> bone pain and fractures
What will blood test reveal in a pt with renal osteodystrophy?
hypocalcemia
hyperphosphatemia
increased PTH
osteomalacia + Increased bone formation in spine and long bones but decreased TOTAL bone mass
renal osteodystrophy
What causes hypocalcemia in renal osteodystrophy?
loss of nephron mass –>
- decreased renal production of 1, 25(OH)2D –> decreased gut abs of Ca
- decreased renal excretion –> hyperphosphatemia –> hypocalcemia
secondary hyperparathyroidism
renal osteodystrophy due to hypocalemia
(from def 1, 25(OH)2D/loss of nephron mass)
primary hyperparathyroidism is due to…
secondary hyperparathyroidism is due to…
adenoma
prolonged hypocalcemia with compensatory hyper-secretion
Results in release of mediators that stimulate osteoclasts and bone resorption
PTH secretion
X-ray: railroad tracks along length of bone and decrease in bone density (osteopenia)
dissecting osteitis due to hyperparathydroidism (renal osteodystrophy)
brown tumor hyperparathyroidism (renal osteodeystrophy)
deformed teeth
OI
limb bones are short, with abnormally wide ends
achondroplasia
residual strips of unremodeled cartilage
osteopetrosis
Surfaces of bony trabeculae (black) are covered by a thicker than normal layer of osteoid (red) = osteomalasia/rickets
thin trabeculae that is typical of osteoporosis
affects skull and long bones
paget disease of bone
diffusely sclerotic bone
osteopetrosis
hyperparathyroidism (renal osteodeystrophy)
These photomicrographs of a brown tumor show fibroblasts admixed with osteoclasts and numerous activated osteoclasts at the edge of a trabecula.
blue gray within pink trabecular bone in osteopetrosis = unremodeled cartilage bc osteoclasts dysfunction
Osteolytic, mixed osteolytic-osteoblastic, osteoblastic and burnt-out stages
paget disease of bone
pts are usually neutropenic and anemic
osteopetrosis
von Kossa stain
osteomalasia/rickets
calcified tissue is black
Cortical bone resorption > cancellous bone
hyperparathyroidism (renal osteodeystrophy)
woven bone occluding marrow
osteopetrosis
Surfaces of bony trabeculae (black) are covered by a thicker than normal layer of osteoid (red)
osteomalasia
lack of meduallry canal and trabeculaeor marrow
osteopetrosis
trilineage hematopoiesis is markedly reduced
osteopetrosis
Osteitis fibrosa cystica showing numerous hemorrhagic cysts (middle) and brown tumors (far right)
Brown tumors
renal osteodeystrophy
=macrophages react to micro- fractures and hemorrhage
is replacement of normal cancellous bone with coarse, thick bundles of trabecular bone
paget disease of bone
Diagnosis?
Radiographs (anteroposterior and lateral views) of this 32 week male stillborn fetus indicate the following: Skull: Minimal mineralization at the skull base only. Long Bones: General demineralization; short, telescoped long bones secondary to in utero fractures. The provisional zones of calcification are preserved (ends of long bones are sharp). Ribs: Beaded appearance secondary to multiple fractures.
OI
Paget Disease of Bone Humerus showing lytic (1), mixed (2), and sclerotic (3) phases, all in the same bone.
osteitis fibrosis cystica WHY?
renal osteodeystrophy
=increased bone activity + peritrabecular fibrosis + cystic brown tumors DUE to hyperparathyroidism
