MSK 4 Flashcards
(190 cards)
1
Q
list the functions of calcified tissues in the skeleton
A
- structural support for heart, lungs, and marrow
- endocrine regulation (bone cells release osteocalcin which contributes to the regulation of blood sugar)
- attachment sites for muscles allowing movement of limbs
- mineral reservoir for calcium and phosphorous
- defence against acidosis
- trap for dangerous minerals (i.e lead)
- blood cells production (site of hematopoiesis
2
Q
what is the function of osteocalcin
A
helps in the regulation of blood sugar
3
Q
what is the role of skeletal radiographs in evaluating skeletal health
A
useful in identifying factures
not very useful in visualizing bone mass–> must have 30% loss of bone mass to see it on an xray
4
Q
what are some risk factors for poor skeletal health
A
age sex vertebral compression fracture fragility fracture after age 40 either parent has a hip fracture >3 months of glucocorticoid drugs medical conditions that inhibit absorption of nutrients and other medical conditions contribute to bone loss
5
Q
what is the role of bone density testing in evaluating skeletal health
A
can only provide information about bone mineral content–cannot provide information about bone cell activity and bone turnover rate without a biopsy
6
Q
what is bone density testing
A
central dual-energy x-ray absorptiometry (central DXA test)
measures your bone mineral density and compares it to an established norm (T-score)
0 means BMD is equal to the norm for a health young adult
differences between BMD and healthy young adult are measured in standard deviations
7
Q
what blood test can be helpful in identifying excessive bone turnover
A
ALP
8
Q
how can you measure bone turnover
A
with blood tests
9
Q
what blood test indicate bone formation
A
BAP
collagen type I propeptides
osteocalcin
10
Q
what blood tests indicate bone resorption
A
calcium TRAcP BSP hydroxyproline hydroxylysine glycosides pyridinium crosslinks collagen type I telopeptides
11
Q
what is the role of bone biopsy in evaluating skeletal health
A
used an as invasive diagnostic procedure and a research method
data can be obtained from the bone histology
- rate of bone resorption and remodelling
- degree of bone mineralization
- bone structure
12
Q
where is the preferred site for bone biopsy
A
iliac crest
13
Q
when is bone biopsy indicated
A
for selected unusual clinical reasons
14
Q
why is bone biopsy not often performed
A
due to invasiveness pain cost specialized centre required
15
Q
to which populations does the T-score system of bone density measurement apply
A
to men over 50 and post-menopausal women
cannot apply same fracture risk correlation to those that are younger
16
Q
what system of bone density grading do you use for those younger than 50
A
the Z-score–> uses an age matched comparative (especially important in pediatrics when peak bone mass has not been achieved)
17
Q
what is a normal T-score
A
-1 or higher
18
Q
what T-score represents low bone mass
A
between -1 and -2.5
19
Q
what T score represents osteoporosis
A
equal to -2.5 or lower
20
Q
what T score represents severe osteoporosis
A
equal to -2.5 or lower with presence of fracture
21
Q
what is the WHO criteria for the densitometric diagnosis of osteoporosis
A
T-score of -2.5 or lower in populations over 50/postmenopausal women
22
Q
what is osteoporosis
A
a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequence of increase in bone fragility and susceptibility to fracture
hallmark of osteoporosis is histologically normal bone that is decreased in quantity
the entire skeleton is affected in post-menopausal and senile osteoporosis but certain bones can be more severely impacted
23
Q
what is the hallmark of osteoporosis
A
histologically normal bone that is decreased in quantity
24
Q
what does the clinical manifestation of osteoporosis depend on
A
which bones are involved
25
what % of bone mass must be lost to detect osteoporosis on plain radiograph
30-40%
26
are blood levels of calcium, phosphorous and ALP diagnostic of osteoporosis
no
27
what tools offer the best estimates of bone loss in the setting of osteoporosis
specialized radiographic imaging:
| dual energy xray absorptiometry and quantitative computed tomography (measure bone density)
28
describe the clinical presentation of osteoporosis
can vary depending on which bones are involved
vertebral fractures that frequently occur in the thoracic and lumbar regions are painful and can cause significant height loss and deformities (i.e lumbar lordosis and kyphoscoliosis)
29
what is the recommended amount of calcium per day for the maintenance of bone health
1000 mg/day
30
what is the mineralization of bone dependent upon
vitamin D
31
what can result from vitamin D deficiency
accumulation of unmineralized bone that in the adult is called osteomalacia
32
what is the recommended dietary intake of vitamin D for adults over 70 years
800 IU
33
under what conditions is the physiological regulation of absorption optimal?
when intakes of both calcium and vitamin D are adequate
34
why is exercise important for bone health and fracture prevention?
1. strengthen bones via bone remodelling (wolffs law)--> the body constantly monitors the strain on bones caused by muscle action--> any substantial increase in these forces signals the need to build more bone
2. improve balance and coordination which decreases likelihood of falls
3. helps to increased BMD in post-menopausal women
4. promotes gaining of muscle mass--> "muscle mass and bone are linked"
- -> psoas muscle size correlates with the bone mineral in the nearby vertebrae
- -> lean body mass is the strongest cross sectional predictor of BMD in younger women
- -> low BMI (fat and muscle) is associated with increased fracture risk
35
what determines osteoblast activation? how is it controlled? why dies this support the idea that exercise is beneficial for bone health?
the amount of Wnt signalling determines osteoblast activation and is controlled by SCLEROTIN
sclerotin is a protein made by osteocytes when the bone is not stressed (sclerotin is inhibited by stress on the bone and by PTH)
therefore, weight bearing exercises that stress the bone reduce sclerotin, and this allows osteoblasts to produce new bone
36
describe sclerotin expression in states of bed rest/in outer space
in these states, the bone is not stressed and sclerotin is over-expressed causing bone loss
37
what are the general recommendations to family practitioners regarding the evaluation and management of bone health in the family practice setting
1. premenopausal women should consume at least 1000 mg of calcium//postmenopausal women should consume 1200 mg (in total diet plus supplementation)
2. should not consume more than 2000 mg calcium per day due to risks of side effects
3. recommend that men over age 70 and postmenopausal women consume at least 800 IU of vitamin D per day
4. calcium and vitamin D supplements alone are insufficient to prevent age-related bone loss although they may be beneficial for some subgroups
38
what are primary sources of dietary calcium
milk
dairy products
green veggies
cereals
39
why do we need vitamin D
decreases bone loss and lowers the risk of fracture especially in older men and women
must be present for body to absorb calcium
40
what is a fragility fracture
fractures occurring from a fall from standing height or less without major trauma
41
how many women will suffer an osteoporotic fracture in their lifetime? men?
1/3 women and 1/5 men
42
what % of women will due within a year following a hip fracture? men?
women: 28%
men: 37%
43
how do bone mineral densities and fracture risks correlate?
measurements of BMD can predict fracture risk but cannot identify individuals who will have a fracture
all measuring sites had similar predictive abilities for decreased BMD except for measurement at the spine for predicting vertebral fractures and measurement at the hop for hip fractures
44
what is the epidemiology of fragility fractures
Fracture risk is ultimately determined by the relation between bone strength and propensity to trauma.
Bone density is a key determinant of bone strength, and depends on the bone gained during growth and consolidation, and the subsequent rate of bone loss.
Many factors (both genetic and environmental) influence the risk of future fracture through effects on these key intermediary mechanisms.
Fracture risk increases greatly with AGE and is generally higher in WOMEN than in men and in WHITES than in other races. Around 30% to 40% of the variance in peak bone mass is GENETICALLY determined, and polymorphisms for several candidate genes are currently being identified. Sex hormone deficiency after the menopause is a key factor in the pathogenesis of osteoporosis in women. In addition, however, there are environmental influences that affect bone density, such as cigarette smoking, alcohol consumption, physical inactivity, and nutrition.
45
in the absence of a fragility fracture, what is the best predictor of future fracture risk
BMD measurement
biomechanical studies show a strong association between mechanical strength and BMD measured by DXA
46
list the WHO risk factors for 10 year fracture risk
1. age (50-90), sex, clinical risk factors
2. BMI/DXA
3. prior fragility fracture
4. parental history of hip fracture
5. current tobacco smoking
6. long term use of glucocorticoids
7. rheumatoid arthritis or other secondary causes
8. alcohol intake 3 or more units per day
47
what is FRAX
fracture risk assessment tool
developed by the WHO to evaluate fracture risk of patients
used in patients between 50 and 70 years old
gives a 10 year probability of hip fracture and a 10 year probability of a major osteoporotic fracture (hip, spine, forearm, shoulder)
algorithm is based on femoral neck BMD
is the same as CAROC plus height, weight, family hx, smoking, alcohol and RA (most people however score the same on both assessments)
48
in what age group is FRAX used
50-70 years old
49
what does FRAX indicate
gives a 10 year probability of hip fracture and a 10 year probability of a major osteoporotic fracture (hip, spine, forearm, shoulder)
50
what BMD is used in the FRAX calculation
femoral neck BMD
51
what is CAROC
developed by osteoporosis Canada
used in patients between 50-85 years old
based on charts and tables
risk is determined based on BMD results in combination with age, sex, hx of fragility fracture and glucocorticoid use
--> if both glucocorticoid use AND hx of fragility fracture are present then the patient is automatically high risk status
52
in what age group do you use CAROC
50-85 years old
53
how much of the bodys calcium is stored in bone
99%
| continuous osteolysis and osteogenesis
54
what is the normal range for serum calcium
10mg/dL or 2.5 mmol/L
| very tightly controlled
55
how is calcium transported in the blood
1. 45% bound to albumin
2. 15% bound to anions (phosphate, citrate)
3. 40% free or ionized (**metabolically active form**)
56
why must you measure albumin levels with total serum calcium levels?
because 45% of calcium in the blood is bound to albumin
57
what anions does calcium bind to in the blood
phosphate
| citrate
58
what influences the distribution of calcium in the blood (i.e between protein bound, anion bound and free/ionized)
the pH of the plasma
acidemia increases the percentage of ionized calcium at the expense of calcium bound to proteins
alkalemia decreases the percentage of ionized calcium by increasing the calcium bound to proteins --> alkalemia makes the patient susceptible to tetani (hyperalbuminemia would also do this)
59
what metabolic condition makes a patient susceptible to tetani (due to disturbances in calcium transport)
alkalosis--> decreases amount of ionized calcium and increases calcium bound to protein
hyperalbuminemia would also have this effect
60
what effect does acidemia have on calcium transport
increases the percentage of calcium in the ionized versus protein bound form
61
what organ is responsible for excretion of calcium
kidneys
100-400mg/day
62
what is the role of calcium in the body
important co-factor for many enzymatic reactions
key second messenger
important role in excitability of nerve and muscle, signal transduction, blood clotting and muscle contraction
critical component of extracellular matrix, cartilage, teeth and bone
63
what happens in states of low ionized calcium?
(hypocalcaemia)
can lead to hypocalcaemia tetani
occurs because hypocalcaemia causes the threshold potential to shift more to NEGATIVE values (closer to the resting potential, therefore contracts more easily)
64
what happens in states of high ionized calcium?
(hypercalcaemia)
may decrease neuromuscular excitability or produce cardiac arrhythmias, lethargy, disorientation or death
occurs because shifts threshold potential to less negative values (further from resting potential)
65
what is the metabolically active form of calcium
ionized
| hyper and hypocalcemia should refer to ionized calcium levels not total calcium levels
66
how do the kidneys help regulate calcium minute-to-minute
by excreting the amount of calcium that is absorbed by the intestinal tract
normal bone remodelling results in no net addition of calcium to the bone or released from bone
if plasma concentrations decline substantially then intestinal absorption, bone resorption, and renal tubular reabsorption increase and return plasma concentrations to normal levels
67
what are the two factors on which calcium homeostasis is dependent
1. the total amount of calcium in the body
| 2. the distribution of calcium between the bones and ECF
68
how is total body calcium determined
by the relative amounts of calcium absorbed by the intestinal tract and excreted by the kidneys
69
how does the intestine absorb calcium
through an active carrier-mediated transport mechanism that is stimulated by CALCITRIOL which is an active metabolite of vitamin D produced in the proximal tubule of the kidneys
70
where is calcitriol produced
proximal tubule of the kidneys
71
what role does calcitriol have in the intestine
stimulates the absorption of calcium from the gut via an active, carrier mediated transport mechanism
72
how does bone contribute to the calcium needs of the body
cancellous/trabelular bone--> honeycomb-like, making up 20-30% of the skeleton with frequent remodelling
bone remodelling compartment is bathed in bone marrow and outer cortical bone
the role is MINERAL supply, response to mechanical forces, and to preserve bone strength and resilience--> it QUICKLY releases calcium when the body needs it
73
where are osteoblasts located
on the surface of the matrix--> synthesize, transport and assemble matrix and regulate mineralization
synthesis of matrix is tightly regulated by hormonal and local factors
74
list the osteoblast derived proteins
1. type I collagen
2. calcium binding protein--> osteonecin
3. cell adhesion proteins--> fibronectin
4. cytokines--> IL-1, IL-6, RANKL
5. enzymes--> alkaline phosphatase, collagenase
6. growth factors--> IGF-1, TNF-beta, PDGF
7. proteins involved in mineralization (osteocalcin)
75
what is osteonecin
a calcium binding protein produced by osteoblasts
76
what is fibronectin
a cell adhesion protein produced by osteoblasts
77
what cytokines are produced by osteoblasts
IL-1
IL-6
RANKL
78
what enzymes are produced by osteoblasts
alkaline phosphatase, collagenase
79
what growth factors are produced by osteoblasts
IGF-1, TNF-beta, PDGF
80
what are osteocytes
osteoblasts that have become inactive and become embedded in the matrix
81
what are osteocytes
inactive osteoblasts that are interconnected via a network of dendritic cytoplasmic processes through tunnels of cannaliculi
82
what is the function of osteocytes
help control calcium and phosphate levels in the microenvironment
detect MECHANICAL forces and translate them into biological activity--> "mechanotransduction"
83
what are osteoclasts
specialized multinucleated macrophages derived from monocytes that are responsible for bone resorption
84
how do osteoclasts carry out their function
are responsible for bone resorption by means of CELL SURFACE INTEGRIN
osteoclasts attach to the bone matrix and create a sealed extracellular trench
secretion of acid and neutral proteases (MMPs) into the pit results in dissolution of inorganic and organic components of bone
85
during bone remodelling, what controls events at the bone multicellular unit
cell-cell interactions and cytokines
86
how many pathways are involved in bone remodelling
three
87
what three factors are involved in the first pathway of bone remodelling
1. transmembrane receptor RANK
2. RANK ligand (RANKL)
3. osteoprotegerin (OPG)
88
what cells express the transmembrane receptor RANK
osteoclast precursors
89
what cells express the RANK ligand (RANKL)
expressed on osteoblasts
90
what os osteoprotegerin (OPG
part of the first pathway of bone remodelling
it is a secreted decoy receptor made by osteoblasts and several other cells that can bind RANKL and thus prevent its interaction with RANK
91
what is the RANK receptor's function?
it is the receptor activator for NK-kB
92
what is the function of NK-kB in the skeleton
it is activated via activation of the RANK transmembrane receptor
NF-κB controls the differentiation or activity of the major skeletal cell types – osteoclasts, osteoblasts, osteocytes and chondrocytes
works as a transcription factor in the nucleus once activated
93
Describe the events of the first pathway of bone remodelling
when stimulated by RANKL expressed on osteoblasts, RANK signalling activates the transcription factor NK-kB which is essential for the generation and survival of OSTEOCLASTS
94
what cells are involved in the second pathway of bone remodelling
involves monocyte colony stimulating factor (M-CSF) which is produced by osteoBlasts
95
describe the events of the second pathway of bone remodelling
activation of the monocyte-colony stimulating factor (M-CSF) receptor on osteoclast precursors stimulates tyrosine kinase cascade that is crucial for generation of osteoClasts
96
describe the events of the third pathway of bone remodelling
involves the WNT/B-catenin pathway
WNT proteins produced by osteoprogenitor cells bind to the LRP5 and LRP6 receptors on osteoBlasts and trigger the production of osteoprotegerin (OPG)
conversely, sclerostin, produced by osteocytes, inhibits the WNT/B-catenin signalling pathway
97
how is the balance between net bone formation and resorption modulated?
by the signals that connect RANK and WNT signalling pathways
because OPG and RANKL oppose one another, either bone resorption or bone formation can be favored by tipping the RANK-to-OPG ratio
systemic factors that affect this are hormones (parathyroid hormone, estrogen, testosterone and glucocorticoids), vitamin D, inflammatory cytokines (IL-1) and growth factors
98
what affect to PTH, IL-1 and glucocorticoids have on the bone resorption/formation balance
promote bone turnover and osteoclast differentiation
99
what affect to bone morphogenic proteins and sex hormones have on the bone resorption/formation balance
generally block osteoclast activity by favoring OPG expression
100
which two hormones regulate the distribution of calcium between bone and the ECF
PTH and calcitriol
101
where is PTH produced
the parathyroid glands
102
what stimulates PTH release
decrease in the plasma concentration of calcium
103
describe how plasma calcium concentration affects PTH release (mechanism)
plasma calcium is an agonist of the calcium-sensing receptor (CaSR) which is located in the plasma membrane of the chief cells in the parathyroid glands
hypercalcemia activates the CaSR which decreases PTH release
hypocalcemia reduces CaSR activation and increases PTH release
104
what effect does increased PTH have on calcium homeostasis
results in more calcium released into the blood
105
how does PTH increase plasma calcium concentrations
1. stimulating bone resorption
2. increasing calcium reabsorption by the distal tubule of the kidney
3. stimulating production of calcitriol (from kidney) which increases calcium absorption from the intestinal tract and promotes PTH
106
what is the clinical significance of diseases that cause lower parathyroid hormone levels
these lower PTH levels can reduce plasma calcium concentration and cause hypocalcemic tetani
107
what are the most common causes of hypercalcemia
primary hyperparathyroidism (i.e from benign tumor in parathyroid gland) and malignancy-associated hypercalcemia
108
what % of all patients with cancer have malignancy associated hypercalcemia
10-20%
109
what is the mechanism of malignancy associated hypercalcemia
caused by secretion of parathyroid hormone related peptide--> a peptide secreted by carcinomas in various organs
increased levels of PTH and parathyroid hormone related peptide cause hypercalcemia and hypercalciuria
110
what is the major source of vitamin D for humans and how is vitamin D produced
endogenous synthesis from a precursor 7-dehydrocholesterol in a photochemical reaction that requires solar or artificial UV light in the range of UVB radiation
results in synthesis of cholecalciferol --> vitamin D3 (prehormone)
vit D3 binds to plasma alpha-a-globulin (DBP) and is transported to the liver
in the liver, vit D3 is converted into 25-hydroxycholecalciferol (25-OH-D)
then in the KIDNEY 25-OH-D is converted into its active form (1, 25-dihydroxyvitamin D) by the enzyme 1-alpha-hydroylase
111
how is the production of 1, 25-dihydroxyvitamin D controlled in the kidney
1. hypocalcemia stimulates PTH which augments conversion by activating 1-alpha-hydroxylase
2. hypophosphatemia directly activates 1-alpha-hydroxylase
3. feedback mechanisms down regulate synthesis through 1-alpha-hydroxylate
112
what are the effects of vitamin D on calcium and phosphorous homeostasis
1. stimulation of intestinal calcium absorption in the duodenum via nuclear receptors which encode a calcium transport channel
2. stimulation of calcium reabsorption in the kidney--> increases calcium influx in the distal tubules of the kidney though increased protein channel expression
3. interaction with PTH in the regulation of blood calcium --> maintains calcium and phosphorus at supersaturated levels in the plasma and both of these enhance the expression of RANKL on osteoblasts--> RANKL binds RANK receptor on pro-osteoclasts thereby maturing them into mature osteoclasts
4. MINERALIZATION of bone--> contributes to the mineralization of osteoid matrix and epiphyseal cartilage in both flat and long bones--> stimulates osteoblasts to synthesize the calcium binding protein osteocalcin
113
how does vitamin D affect bone mineralization
contributes to it--> stimulates osteoblasts to synthesize calcium binding protein osteocalcin
114
what effect does vitamin D have on RANKL expression on osteoblasts
increases it--> therefore increases osteoclast maturation
115
what are the National Osteoporosis Foundation's recommendations regarding pharmacological therapy for postmenopausal women with a hx of hip or vertebral fracture or with osteoporosis based on BMD measurement of
1. for the tx of HIGH RISK postmenopausal women with T score between -1 and -2.5, suggest pharmacological tx
- -> for postmenopausal women with osteopenia (score between -1 and -2.5) treatment is cost effective when 10 year probability of hip fracture reaches 3% or the 10 year probability of major osteoporotic fractures combined is >20%
2. postmenopausal women and men aged 50 and older presenting with the following should be considered for tx:
A. a hip or vertebral (clinical or morphometric) fracture
B. T score 20%
116
what is generally considered first line therapy for osteoporosis in postmenopausal women
bisphosphates
117
what is the MOA of bisphosphates in the tx of osteoporosis
bisphosphates have an affinity for hydroxyapatite--> they adhere to bone surface via hydroxyapatite binding sites
as osteoclasts come along to resorb bone, the bisphosphates are endocytosed by osetoclasts and cause apoptosis--> overall REDUCE BONE RESORPTION
different mechanisms for inhibition (within the cell) depending on whether they contain nitrogen
1. N-biphosphate inhibits FARNESYL PYROPHOSPHATE SYNTHASE enzymes--> key enzyme in cholesterol synthesis (mevolonic acid) pathway
2. non-N-bisphosphates get incorporated into ATP--> non-hydrolyzable ATP--> cannot be used for ATP-dependent cell process
**the dose of NON-nitrogen containing bisphosphates needed to inhibit mineralization is very similar to the dose needed to inhibit bone resorption//the dose of nitrogen-containing bisphosphates needed to inhibit mineralization in 1000X greater than the dose needed to inhibit bone resorption
118
list the non-nitrogen containing bisphosphates
etidronate
clodronate
tiludronate
119
list the nitrogen containing bisphosphates
```
pamidronate
alendronate
neridronate
ibandronate
risedronate
ZA
```
120
why are nitrogen containing bisphosphates preferentially used
the dose of NON-nitrogen containing bisphosphates needed to inhibit mineralization is very similar to the dose needed to inhibit bone resorption
the dose of nitrogen-containing bisphosphates needed to inhibit mineralization in 1000X greater than the dose needed to inhibit bone resorption
121
why do bisphosphates have the potential to inhibit bone mineralization
because they have a structure that is chemically similar to inorganic pyrophosphate (PPi)
PPi also has a high affinity for the bone surface and is an inhibitor of bone mineralization--normally degraded by alkaline phosphate to allow bone mineralization
bisphosphates are chemically similar to PPi but cannot be cleaved by alkaline phosphate
122
what are some side effects of bisphosphates
1. atypical femoral fractures with prolonged bisphosphate use
(not typical osteoporotic fractures... clear, transverse, starts medial, proceeds inwards, cortex is thick... similar to STRESS fractures)
2. GI--> nausea, dyspepsia
3. esophagitis or esophageal erosion--> most commonly seen with N-aminobisphosphonates (patients are advised to avoid reclining for 30 minutes after taking bisphosphates)
4. osteonecrosis of the jaw--> typically only seen at high doses
123
what is Zoledronic Acid?
"ZA"
nitrogen containing bisphosphate
most potent bisphosphate and longest duration of action (given ONCE by IV per year)
124
what particular side effects are of concern with zoledronic acid?
1. concern of post-infusion syndrome--> significant flu-like symptoms for three days following infusion (mild fever, muscle and joint aches, short lived)
2. slight propensity for increased serum Cr following infusion so its important to check renal function before infusion
3. increased incidence of Afib but not well understood why--> could be a chance finding
125
list the drugs used in osteoporosis therapy
1. bisphosphates
2. estrogen
3. selective estrogen receptor modulators
4. RANKL-monocloncal antibody
5. PTH analog
126
why is estrogen not widely used for osteoporosis therapy
due to increased risks of uterine cancer, breast cancer, DVT, stroke
127
for whom would estrogen be first line therapy for osteoporosis
for postmenopausal women with vasomotor symptoms
128
is testosterone replacement therapy recommended as tx for osteoporosis in men?
no not generally
129
when is estrogen prescribed for osteoporosis
only in women if experiencing symptoms of menopause but stopped within 5-10 years
130
name two selective estrogen receptor modulators used in the tx of osteoporosis
tamoxifen and raloxifene
131
MOA of selective estrogen receptor modulators (tamoxifen and raloxifene)
competitively inhibit estrogen receptors
have both pro- and anti-estrogen effects in various tissues
estrogen agonist in bone
estrogen antagonist in breast (used as adjunct breast cancer therapy)
systemically act against estrogen which can promote hot flashes
132
what is a side effect difference between tamoxifen and raloxifene
tamoxifen induces endometrial hyperplasia whereas raloxifene does not
133
how do selective estrogen receptor modulators compare to other therapies for osteoporosis
improvement with the drugs are not as robust as with other agents
efficacy in decreasing vertebral compression fractures
with raloxifene, only reduction of ankle fractures was statistically significant
still used in osteoporosis tx but not as efficacious as bisphosphates
134
name a RANKL monoclonal antibody used in the tx of osteoporosis
denosumab
decoy RANKL
very long half life (admin only once every 6 months SC)
135
MOA of RANKL monoclonal antibodies (denosumab)
1. prevents binding of RANKL to RANK receptor of osteoclast precursor--> prevents formation of osteoclast precursor
2. prevents binding of RANKL to RANK receptors of mature osteoclasts--> reduces function and survival
**3 years of denosumab therapy increased BMD by 9% at the lumbar spine and 6% at total hip
136
what is the relative risk reduction associated with denosumab therapy for osteoporosis
70% for vertebral fractures
40% for hip fractures
20% for other fractures
137
side effects of denosumab
eczema
138
name a PTH analog used in the tx of osteoporosis
teriparatide
139
what is the biological role of normal PTH
maintain normal serum calcium
140
what is the result of intermittent PTH exposure (i.e with tx with a PTH analog like teriparatide)
promotes osteoblast activation (anabolic effect)
preliminary rise is most significant in the lumbar spine
141
contraindications for therapy with PTH analog (for osteoporosis)
children/young adults
ACTIVE PAGETs disease
skeletal metastases
skeletal malignant condition
pregnancy
142
side effects of PTH analogs in the tx of osteoporosis (i.e teriparatide)
1. possible bone cancer (only found in animal models, reason why its only used for 1.5-2 years)
2. hypercalcemia
3. leg cramps
4. nausea
5. orthostatic hypotension
143
why are there issues with duration of therapy for osteoporosis
some risks with long term therapy
consider drug holidays
144
list 3 types of medications associated with bone loss/increased fracture risk
1. glucocorticoids
2. aromatase inhibitor therapy
3. androgen ablation therapy
145
how can glucocorticoids cause increased bone loss/increased fracture risk?
1. exert direct anti-apoptotic effect on mature osteoclasts
2. increase RANKL and decrease OPG from osteoblasts therefore increasing osteoclast resorptive ability
3. suppressive effect on osteoblast formation, activity and survival
146
how can aromatase inhibitor therapy cause increased bone loss/increased fracture risk?
1. AIs block the synthesis of estrogen--> lowers levels of estradiol, estrone and estrone sulcate
2. side effect is reduced bone density and increased fractures (mimics perimenopausal symptoms)--> bone protection measures should be taken
147
how can androgen ablation therapy cause increased bone loss/increased fracture risk?
1. main therapeutic approach for men with metastatic prostate cancer--> increases bone turnover, decreases bone mineral density and increases risk of clinical fractures
2. loss of bone mineral density can be detected after 6-9 months therefore longer therapy gives higher risk of problems
3. osteoporotic fractures occur in 20% of men within 5 years of starting ADT
148
what is Paget's disease
disorder of increased but disordered and structurally unsound bone mass
usually begins in late adulthood (average age of diagnosis is 70)
relatively common in whites and rare in Native, Asian and Scandinavian
149
what are the 3 phases of Paget's disease
results from loss of control of osteoblast and osteoclast coupling
1. osteolytic stage--> bone resorption with lytic lesions
2. mixed osteoclastic-osteoblastic stage (osteoblastic activity takes over)
3. burned-out quiescent osteosclerotic stage--> decreased bone turnover with skeletal sclerosis
150
what is the pathogenesis of paget's disease
cause remains unclear-> likely combination of genetic and environmental factors
net effect of changes is an increase in NF-kB which increases osteoclast activity--> followed by compensatory increase in bone formation but this is done in a disordered fashion
histologically shows a mosaic pattern of lamellar bone (sclerotic phase)
results in very dense, disordered fragile bone
151
describe the gross anatomy of someone with paget's disease
thick skull
leg-spine fractures
cortical thickening in skull
osteoporosis circumscripta
152
describe the histology seen in someone with Paget's disease
1. large, multinucleated osteoclasts
2. fibrovascular tissue, woven bone, thin trabecular
3. osteosclerotic: osteoblasts, jigsaw puzzle, lamellar
4. osteolytic lesions
5. bone expansion, thick trabeculae
153
what is the clinical course of pagets disease
1. most cases are asymptomatic and are discovered as incidental radiographic findings
2. axial skeleton or proximal femur is involved in 80% of cases
3. pain is localized to the affected bone (common)
4. can have bad side effects---> sarcoma occurs in 1% of those with paget's
154
list 8 other conditions commonly associated with osteoporosis
1. rheumatoid arthritis
2. malabsorptive syndromes
3. sex hormone deficiency
4. primary hyperparathyroidism
5. chronic kidney disease
6. chronic liver disease
7. diabetes
8. hyperparathyroidism
155
why can rheumatoid arthritis be associated with osteoporosis
glucocorticoids and loss of activity/motion can lead to increased bone loss
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why can malabsorptive syndromes be associated with osteoporosis
malabsorption due to bowel diseases can result in reduced calcium and vitamin D intake
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why can sex hormone deficiency be associated with osteoporosis
premature menopause
pituitary disease
chemo
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why can primary hyperparathyroidism be associated with osteoporosis
tumour (usually benign) causes increased PTH production and therefore increased bone turnover
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why can chronic kidney disease be associated with osteoporosis
tx with glucocorticoids and metabolic bone disease --> vitamin D--> deficiency
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why can chronic liver disease be associated with osteoporosis
associated with reduced bone formation, vitamin D deficiency and low sex hormones
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why can diabetes be associated with osteoporosis
type I associated with higher risk for bone fractures
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why can hyperthyroidism be associated with osteoporosis
too much thyroid hormone interferes with the body's ability to absorb calcium into the bones and increases bone turnover
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what is a pathological fracture
a fracture in a bone that is already weakened due to an underlying disease
the force required to break an already compromised bone is less than the force required to break a healthy bone--> experience fractures with minimal or no trauma
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what is a fragility fracture
a kind of pathological fracture that occurs when a person falls from standing height or less
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what is the pathogenesis of osteoporosis
once maximal skeletal mass is obtained, small deficit in bone formation accrues with every resorptive/formation cycle
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what 5 factors can influence the development/pathogenesis of osteoporosis
1. age related changes
2. reduced physical activity
3. genetic factors
4. calcium nutritional state
5. hormonal influence
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how do age related changes affect the pathogenesis of osteoporosis
1. osteoblasts from older individuals have reduced proliferative and biosynthetic potential
2. cellular response to growth factors bound to ECM is attenuated
3. net result is a diminished capacity to make bone
4. this form of osteoporosis is termed SENILE osteoporosis--> low turnover variant
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how does reduces physical activity affect the pathogenesis of osteoporosis
1. due to reduced mechanical forces stimulating bone remodelling
2. athletes generally have higher bone density
3. weight training is much more effective at increasing bone mass than repetitive endurance activities--> requires skeletal loading for effective stimuli
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how do genetic factors affect the pathogenesis of osteoporosis
1. single gene deficits account for only a small fraction of cases
2. polymorphisms within other genes may account for variation of peak bone density within a population
3. top associated genes are RANKL, OPG and RANK
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how does calcium nutritional state affect the pathogenesis of osteoporosis
1. nutritional state contributes to peak bone mass and during peak growth periods a calcium deficit can occur
2. individuals who do not reach a full peak bone mass are at higher risk of osteoporosis
3. calcium deficiency, increased PTH and decreased vitamin D all may have a role in development of senile osteoporosis
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how do hormonal influences affect the pathogenesis of osteoporosis
1. postmenopausal osteoporosis is characterized by an acceleration of bone loss
2. yearly reductions may reach up to 2% or cortical bone and 9% of cancellous bone
3. post-menopausal women suffer more osteoporotic fractures than men of the same age
4. estrogen deficiency--> decreased estrogen increases both bone resorption and formation leading to a high turnover osteoporosis
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list risk factors associated with a decrease in original peak bone mass or an increase in the amount of bone resorption (risk factors for osteoporosis)
1. cigarette smoking
2. female sex
3. caucasian race
4. low body weight
5. genetics
6. inadequate exercise
7. menopause
8. advanced age
9. dementia
10. estrogen deficiency
11. low calcium and vitamin D
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what is gout?
marked by transient attacks of acute arthritis initiated by crystallization of monosodium urate within and around joints
gout can be divided into primary and secondary forms--> both share common features of hyperuricemia
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what is the pathogenesis of gout
1. hyperuricemia is necessary but not sufficient for the development of gout
2. elevated uric acid can result from overproduction or reduced excretion or both
3. uric acid is the product of protein metabolism
4. inflammation in gout is triggered by PRECIPITATION OF MONOSODIUM URATE (MSU) crystals into the joints which results in the production of cytokines that recruit leukocytes
5. urate crystals may also activate the complement system leading to chemotactic complement by-products--> these cascades trigger acute arthritis which remits spontaneously in days to weeks
6. repeated attacks of acute arthritis lead eventually to chronic TOPHACEOUS arthritis and formation of TOPHI in the inflamed synovial membranes and periarticular tissue
7. severe damage to the cartilage develops and the function of joints is compromised
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what is the plasma urate level that defines hyperuricemia
about 6.8 mg/dL
176
why is uric acid produced in the body
it is the product of protein metabolism
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describe the clinical presentation of gout
1. acute arthritis--> presents after several years as sudden onset of excruciating joint pain associated with hyperaemia, warmth
2. constitutional symptoms are uncommon except for occasional mild fever
3. most first attacks are MONOARTICULAR and 50% occur in the 1st MTP joint in the foot
4. untreated acute gouty arthritis may last for hours to weeks but gradually there is a complete resolution
5. may be associated with some renal manifestations (uncommon)
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what joint is implicated in 50% of first attacks of gout/acute arthritis
1st MTP joint in the foot
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what type of synovial fluid is associated with gout
type 2 (inflammatory)
cloudy
yellow
contains mostly PNMs
decreased glucose and increased protein
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define Paget's disease
chronic skeletal disorder in which bone resorption and formation are decoupled and turnover occurs faster than normal
new bone is laid down in a disorganized fashion incorrectly coupled to osteoblastic activity
bone is left with an irregular PUZZLE PIECE pattern (mosaic bone) which is vulnerable to fracture
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what occurs in the 1st/lytic stage of Pagets
very active osteoclast activity with cutting cones dissecting through cortical and trabecular bone
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what happens in the 2nd stage of paget's
mixed
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what happens in the 3rd/sclerotic stage of Paget's
final stage of no active osteoblast or osteoclast activity
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what types of laboratory results would you expect in Paget's disease
increased HYDROXYPROLINE in the urine and in and increased ALKALINE PHOSPHATASE in serum both reflect ABNORMAL BONE TURNOVER
185
describe complications associated with Paget's disease
1. secondary osteoarthritis--> abnormal bone and joint morphology leads to abnormal joint stresses, cartilage damage and OA
2. pathological fracture--> the bone may be thick but its architecture is abnormal and it is brittle
3. Narrowing of bony foramina resulting in spinal stenosis or cranial nerve palsy
4. malignant transformation
5. most serious is OSTEOSARCOMA
186
what is the most serious possible complication from Paget's disease
osteosarcoma
187
what is the classic presentation of giant cell arteritis
patients complain of unilateral headache, scalp tenderness and jaw claudication when chewing
--
about 1/2 of patients present with polymyalgia rheumatica due to involvement of arteries supplying the limb girdles--> typically manifesting as neck, shoulder, and hip pain in the mornings
188
how is diagnosis of giant cell arteritis usually made
usually made by clinical suspicion and an increase ESR and CRP
confirmation requires biopsy
189
how should giant cell arteritis be treated
should be treated immediately with high dose corticosteroids to avoid permanent visual damage
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what is seen on biopsy that confirms the clinical suspicion of giant cell arteritis
1. superficial temporal artery demonstrates thickened arterial wall
2. MULTINUCLEATED GIANT CELLS can be seen adjacent to the fragmented internal elastic lamina
3. presence of giant cells indicates inflammation present here is GRANULOMATOUS
4. inflammatory changes and pronounced thickening of the intima lead to narrowing of the arterial lumen
