Patho: Exam 2 Osteoporosis/Pagets Disease/Hyperparathyroidism Flashcards
(84 cards)
1
Q
What is Osteoporosis:
A
Poris bone and reduced bone mass
2
Q
What is the cause of Osteoporosis?
A
There are multiple causes ( Senile- primary type 2, Postmenopausea- primary type 1, Secondary)
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Q
What are some causes of secondary Osteoporosis?
A
Endocrine- Cushing disease, Neoplastic- Multiple myloma eating away at the bone, GI- any malabsorption of calcium, Drugs- steroids decrease calcium absorption and misc.
4
Q
Stats
A
in the Unitied states 15% of people by the age of 80 have a hip fracture, 25% by age 90 have hip fracture.
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Q
Pathology of Osteoporosis
A
Decreased thickness of cortex
Reduction in number and size of trabeculae of cancellous bone
Type 1(postmenopausae): disrupted connections between trabeculae- increased osteoclast activity.
Type 2(senile): reduced trabecular thickness- loss of osteoblast activity
6
Q
What does DEXA scan stand for?
A
Dual Energy X ray absorptiomety
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Q
Normal bone density:
A
Normal: Bone Mineral Density no lower than 1 SD below mean for young adult women: T>-1
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Q
Osteopenia
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(Low bone mass): BMD 1.0-2.5 SD below the mean for young adults (T=-1 to -2.5)
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Q
Osteoporosis
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BMD more than 2.5 SD below young adult mean (T<-2.5)
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Q
What is T versus Z score
A
T score- refers to the average bone density of a 30 y/o female
Z score- age and gender match.
11
Q
Who needs to get a dexa scan?
A
Women >65, Men >70
If you break a bone after the age of 50
Women of menopausal age with risk factors
Man age 50-69 with risk factors
Other: An xray showing bone loss Back pain with possible break in spine Height loss > .5 in or more in one year Total heigh loss of greater than 1.5 in. from original
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Q
What is the most common location they look at on DEXA?
A
Dual Energy X ray absorptiomety
13
Q
What can osteoperosis in the spine lead to?
A
Kyphosis or a dowager’s hump.
14
Q
what is a Dowagers hump?
A
the type of kyposis seen in osteoporosis due to shorter vertebral does in the spine
15
Q
What are some known factors that lead to osteoperosis?
A
oHereditary factors oPhysical activity oMuscle strength oDiet oHormonal state oAge related loss: 0.5% -0.7%/year
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Q
Primary Type 2- Age related loss AKA senile Osteoporosis
A
Primary Type 2- Age related loss AKA senile Osteoporosis
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Q
What is the problem in senile Osteoporosis
A
Reduced poligeration of the Osteoblast –they become sluggish
Proteins bound to matrix (Growth factors) lose biologic activity (Beta Catenin_)
Net result: decreased compasity to make bone
Both Trabecular and cortical bone is decreased
18
Q
What are the Other causes of senile Osteoporosis?
A
Reduced physical activity- Mechanical forces stimulate bone remodeling
19
Q
What evidence supports physical activity reduction leading to low bone density?
A
o Immobilized extremity
o Astronauts in zero gravity
oAthletes have higher bone density
20
Q
Genetic factors leading to Osteoporosis
A
o Associated genes: RANK ligand, OPG, RANK
o Other implicated genes: Vit D receptors, LPR5, Estrogen receptor gene.
21
Q
How can ones Nutritional state lead to Osteoporosis?
A
decreased vit d or Ca
22
Q
What are the Ca+ intake recommendations?
A
o Adults under 50- 1,000 mg/day
o Adults over 50-1,200 mg/day
23
Q
What are the Vit D intake recommendations?
A
o Adults under 50- 400-800 IU
o Adults over 50- 800-`1000IU
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Q
•What type of vit D should you order?
A
o Calcidiol- 25 hydroxyvitamin D not 125, because 125 has a short ½ life and wont give you a good reading
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There are two types of measurement on lab what are they?
Nmol/L or ng/ml
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What are the deficent, inadequate, adequate and bad levels of Vit D
o 50 nmol/L (> 30 ng/ml)= adequate
| o >125nmol/L (>50 ng/ml)=bad- tooMUCH!
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what is a side effect of taking to much Calcium?
The Ca+ suppliments are like candy, so people where taking in so much Ca+ but the side effect of SPIKED ca+ ( random increases) will lead to depositis of ca+ athrosclerosis in the vessels – new recommendations is just to get Ca in the diet.
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Vitamin D can be obtained by the sun, how?
You need to spend 20 min in direct sunlight in the peak sun light everyday.
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What are the two types of vit d and what is the difference between them?
D3: Cholecalciferol- what you actually make ( needs to go to the liver to become a hormone)
D2: Ergocalciferol
D3 has a longer half life.
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For every 1000 units per day, after 1 mo, how much will it raise your vit D?
10 ng/ml.
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What happeneds to Vit D levels as you age?
As one ages there is a decrease in renal 1 alpha-hydroxylase and less conversion of vitamin D to its active form
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What are normal Vit D levels?
75 nmol/L or higher
| 30 ng/ml or higher but less than 50ng/ml
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Primary Type I Osteoporosis- Hormonal Women:
Loss of 35% of cortical bone and 50% of their trabecular bone within 30-40 years after menopause: recognizable within 10 years after the onset of menopause.
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Pathogenesis of type 1
Decreased estrogen
Increased secretion of inflammatory cytokines by monocytes and bone marrow cells
Cytokines stimulate osteoclast recruitment by increasing RANKL while diminishing expression of OPG.
Osteoblastic activity does not keep pace with the oseoclast
High Turn over frooom ostoporosis break down faster than it can build
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Treatment of Osteoporosis
* Non-pharmacologic: exercise
* Pharmacologic
* Calcium/Vitamin D
* Estrogen/progesterone
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Estrogen/progesterone
controversial due to its increased risk for CA
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Estrogen receptor modulator:
raloxifene (Evista)
Acts like estrogen in the bones and increases OPG molecules to decreased the osteoclast activation
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Bisphosphonates
Inhibits osteoclasts
o Affects a protein pump within in the osteoclast to inhibit the acid PH production.
o Atypical features in proximal humoral shaft and in the femur have been seen this is due the fact that remodeling is not the same, to much building and not breaking down
o Bisphosphonates stay in the bone for LONG time ( 5 years)
* Alendronate (Fosamax)/week
* Risedronate (Actonel, Atelvia)/week
* Ibandronate (Boniva)/month
* Zoledronic acid (Reclast, Zometa);/year
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Forteo
rPTH (intermittent exposure – stimulates osteoblasts)
Recombinent parathryroid hormone- it is the first 34 AAwhich has the active site for osteoblast
Typically parathyroid hormone will bind to the osteoblast receptor which ill make a lot of RANK ligand to activate osteoclast to demineralize bone, BUT when given an injection of PTH all at once it does not have the noral affect only affects osteoblast to just build and not simulate the break down
Side effet: Risk of bone cancer, necrosis, osteosarcoma, can only be given for 2 years.
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Denosumab
Antibody to RANKL binds like OPG to block lignad
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Secondary causes of Osteoporosis
Secondary causes of Osteoporosis
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Endocrine conditions
Corticosteroids ( Cushings) –Endogenous production of cortisol
Inhibit osteoblasts & Ca++ absorption
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Hyperparathyroidism-
Increased parathyroid hormone production which will lead to Osteoclast recruitment
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Hyperthyroidism
Increaed Osteoclast activity
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Hypogonadism
Hematologic malignancies:
Multiple myeloma
Malabsorption:
Alcoholism: Inhibitor of osteoblasts:
Hematologic malignancies-Multiple myeloma
Malabsorption: Irritable Bowl, crohns Dieases ( decreased absorption)
Alcoholism: Inhibitor of osteoblasts
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Explain the FRAX calculation tool
Assess 10 year risk for fractures by looking at age, previous fractures, RA, smoking, secondary osteoporosis, alcohol, steroids, COPD
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What is Paget’s disease (Osteitis Deformans)
OSTEOBLAST GONE WILD!
Osteoblast are laying down bone like crazy but it is not in a lamellar fashion, very unstable.
Disease of bone remodeling (breaking down) with osteoclast mediated bone resorption followed by new bone formation (Too much bone growth)!
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What is the location of pagets diease?
Solitary or multiple sites (axial skeleton, spine, skull, pelvis)
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Increased bone remodeling leads to what?
Disorganized mosaic pattern bone with increased vascularity and fibrosis
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what is the cause of Pagets?
Cause is unknown, possibly a virus – paramyxovirus, canine distemper
Virtually all patients exhibiting nuclear inclusions consistent with structure of a virus in osteoclasts.
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what race is most likely to have pagets?
what sex?
More common in Caucasian and less in China, japan, Africa
More common in males 3:2
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what % of adults over 70 have pagets?
10% of those 70 y.o.+ have Paget’s
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What are the phases of Pagets?
1:
2:
3:
Net Effect:
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Initial osteolytic stage
“Hot” resorptive stage: Lysis of the cortex (Trabecular and cortex of bone) osteoclast is super active breaking down
Mixed osteoclastic-osteoblastic stage
Osteoblasts replace broken down bone, cortex thickens. Cancellous bone thickens. This happens all the time until….
Burn out quiescent osteosclerotic stage
Osteoclasts are exhausted, little cellular reactivity, disorganized bone, > scar tissue (fibrotic)
Net Effect: Gain in bone mass with newly formed bone is disordered and architecturally unsound
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What are characteristics of Paget’s Disease?
Accelerated remodeling, numerous osteoclasts, large active osteoblasts, peritrabelular marrow fibrosis, collagen arranged in woven vs. lamellar pattern
Bone begins to bow outward
Lytic changes and thinning
“Osteoblasts gone crazy”
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Pathogenesis of Pagets
Environmental: viral?
Genetic
-Autosomal dominant pattern- incomplete penetrance ( shows up different in families)
- Mutations in SQSTM1 gene
- SQSTM 1 gene codes for protein P 62 which acts as a scaffold protein in the RANK signal pathway.
- Mutations cause Enhanced RANK signaling
- Leads to increased osteoclast activity
-RANKL and RANK/OPG mutations also found
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Severe Pagets disease:
o Tibia becomes bowed out
| o Affected portion is enlarged, sclerotic, and exhibits irregular thickening of both the cortical and cancellous bone.
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Pagets can be an incidental finding how often is it found?
`Incidental findings: ( on autopsy 3% of people have pagets)
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How will people with Pagets normally present?
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o Bone pain/Joint pain: due to small fractures that can occur in the bone
o Deformity: Axial skeleton( arm/legs) and femur involved in 80% of cases and Craniofacial enlargement
o Lysis in frontal and parietal bones: Osteoprosis circumscripta
o Spontaneous fractures
o Alk Phos high, increase urinary hydroxyproline ( Due to increased turn over form osteoblast and osteoclast break down products.
o [Ca2+] normal unless immobilized- kidneys help maintain.
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How does the affected bone appear?
Bowed, enlarged, sclerotic, irregular thickening of cortical and cancellous bone
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What do the fractures look like in pagets?
Usually transverse
| cInfractions: incomplete fractures without displacement
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Pagents usually has issues with hearing why?
Increased growth of Ossicles in the ear and impingemnt of CN 8 in the foramen
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You can also see Osteogenic sarcoma, how common is this?
0.7-0.9%
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Hypercalcemia
rare!
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Skull can become heavy and collapse over C1 vertebra resulting in:
oPlatybasia:
o Pagetic Steal:
compresses medulla and cord
oPlatybasia: flattening of the base of skull, impinges foramen magnum
Pagetic Steal: light headness due to shuniting of blood from the brain to thebone (skull ) the marrow is very vascular, so if you increase that space you increase the blood flow needed to the skull.
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Treatment of pagets:
stop the break down
| -Calcitonin, bisphospaonates, mithramycin.
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Hyperparathyroidism
PTH net effect: Increase Ca levels in the blood!
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How many Para thyroid glands do you have?
2-6 glands
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What is the effect of PTH?
Increase serum Ca2+ and PO42-
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What is the action of PTH in the Bone?
The parathyroid gland will sense a low Ca2+ in the body, causing the release PTH
PTH will go to the bone increase osteoclast activity (use acidic environment in the laminar bone to release Ca+ and Phosphate)
PTH will bind to a receptor on the osteoblasts causing them to synthesize and secrete RANKL
RANKL binds to RANK in osteoclast which will cause them to become very active (more active than the osteoblast)
large amounts of PTH and continued RANKL prevents osteoclast apoptosis
Osteoclastic activity releases Ca2+ and PO42-
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PTH in the Kidney:
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PTH will go to the kidney and make you pee out the phosphate and reabsorb the Ca+
•Increased PO42- excretion
• Increased Ca2+ reabsorption by increases transporter pumps that allow Ca+ reabosorption
PTH goes to the Kidney which increase formation of Vit D from the liver- goes to small intestines and increase ca+ absorption
•Increased hydroxylation of vitamin D
•Augments activity of 1alpha-hydroxylase- go to the gut and cause absorption of Ca within in the GI system
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Vitamin D formation
o Naturally in your body: 7-Dehydrocholesterol is stimulated by the sunlight to covert into Cholecalciferol ( Vit D 3)
o From your diet you get Cholecalciferol ( Vit D 3) and Egocalciferol (Vit D 2)
o Both Cholecalciferol ( Vit D 3) and Egocalciferol (Vit D 2) go to the liver and gets hydroxylated to become Calcidiol ( 25-Hydroxvitamin D)
o Calcidiol ( 25-Hydroxvitamin D) goes to the Kidney and gets hydroxylated again to become either Calcitriol (1-25 Dihydroxyvitamin D) or an inactive metabolite ( 24, 25 Dihydroxyvitamin D)
o The Calcitriol (1-25 Dihydroxyvitamin D) has 3 actions Increase intestinal absorption of Ca, increase bone resorption ( only wen dietary deficiency occurs) and decrease renal Ca+ and phosphate excretion.
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What is the big difference between Vit D2 and Vit D3?
Vit D 3 has a longer half life than vit D2.
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Hyperparathyroidism Types
Primary
secondary
Familial hyperparathyroidism
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Primary Hyperparathyroidism:
What is the cause of primary hyperparapthyroidim?
What type of tumor usually causes primary hyperparathyroidism?
Extremely high PTH release when it should not be high (normal Ca+ lvls). PTH raised inappropriately relative to Ca+ levels
Autonomous hyperplastia or tumor
Adenoma (85%) Benign!
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Secondary Hyperparathyroidism:
What is the most common cause of secondary hyperparathyroidism?
Excessive secretions of PTH due to prolonged states of hypocalcemia. The hypocalcemia is usually due to chronic renal failure. Can not regulate Ca+ so it goes out in the urine, and they can not hydroxlate the Vit D so they can no longer absorb Ca+ from the gut. Therefore the only place they can get the Ca+ from is the bone.
CKD – this means a lot of people with CKD will have osteoperosis too.
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Familial hyperparathyroidism
Mutation in the calcium sensing receptor gene (CASR)
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All three types: outcomes
* Excess PTH
* Binds to receptors on osteoblasts
* Release factors that stimulate osteoclast activity: RANKL
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In hyperparathyroidism what bone type is effected the most, resulting in what?
Cortical bone affected more severely than cancellous bone resulting in thinned cortices
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What are the anatomic changes of hyperparathyroidism know as?
Anatomic changes known as osteitis fibrous cystica- cyst like area where it has been degraded
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Sequence of events
Dissecting Osteitis: Osteon (early laminar bone) hallowed out by osteoclast-Osteoclast boaring into the center of the Trabeculum
Osteitis Fibrosa: Trabecular bone reabsorbed and marrow is replaces with fibrosis
Osteitis fibrosa cystica: Brown Tumor( Fibrosis and blood)
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How does stage 3 get the name brown tumor?
When hemoglobin gets oxidized into hemociderin it is a brown color.
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Manifestations
“Stones, Bones, Moans, Growins, Psy”
Stone: Renal stones due to increase Ca break down- getting in blood stream
Bones: Degradatons
Groins: GI irregularity because of the Ca+ levels
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Treatment - What is the treatment of Hyperparatyroidism?
Removal of the PT gland
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What is the treatment in Secondary Hyperparaptyroidism?
Remove the glands and freeze them, once the patient gets kidney transplant you put the glands back in (usually in the arm)
