Module 2 lecture 3 Flashcards
1
Q
Difference between osteoblasts and osteoclasts
A
Osteoblasts put calcium back into the bone
osteoclasts dig calcium out of bone
2
Q
What does Osteocyte do
A
Decides whether osteoblasts are stimulated or osteoclasts
3
Q
What percent of phosphate is in the bone
A
86%
4
Q
The form of calcium that is in the bone is called______
It is composed of _______, ________ and ______-
A
hydroxyapatite
It is composed of calcium, PO4 and H20
5
Q
T/F When we resorb calcium from bone via osteoclastic activity, we also bring phosphate out of the bone with calcium
A
True
6
Q
Osteoclasts release
A
calcium and phosphate
7
Q
how are osteocytes stimulated
A
Mechanical force detected by cell, which extends to canaliculli
8
Q
Name two important factors that decrease BMD
A
Sclerostin and RANKL
9
Q
Neutralizing what two factors is a strategy to combat post menopausal osteoporosis
A
sclerostin and RANKL
10
Q
What is the main driver for elevating calcium levels if they get too low
A
PTH
11
Q
Where is PTH secreted from
A
Parathyroid gland
12
Q
How does PTH affect the extracellular Ca levels
A
Increases it
13
Q
How does PTH increase the Ca levels
A
Stimulates osteoclastic activity
14
Q
PTH effect on calcium reabsorption in kidneys
A
PTH stimulates calcium reabsorption from kidneys
15
Q
How does PTH stimulate calcium reabsorption from kidneys
A
upregulates calcium channels ECac/ TrPV5
16
Q
PTH effect on PO4 loss in urine
A
Increases PO4 loss in urine
17
Q
PTH effect on vit D production in kidney
A
Increases vitamin D production in kidney
18
Q
PTH secretion is triggered by
A
low serum Ca 2+ levels
19
Q
What is CaSR
A
Gq linked GPCR that secretes PTH when not bound by Ca2+.
20
Q
When Ca2+ is bound to CaSR it will stimulate
A
PLC
21
Q
What kind of effect does PLC have on PTH secretion
A
Negative
22
Q
One of the main activities of PTH is regulation of production of
A
1, 25 (OH)2-D3
23
Q
first step of vitamin D synthesis
A
7- dehydrocholesterol–UV Irradiation——->cholecalciferol (vitamin D3)
24
Q
Second step of vitamin D synthesis
A
Vitamin D3 (cholecalciferol) transported to liver via vitamin D binding protein and hydrolyzed to 25-hydroxy vitamin D3 by 25-hydroxylase
25
Third step of vitamin D synthesis
25 hydroxy vitamin D3 is transported to kidney and is catalyzed by 1-a-hydroxylase to form 1, 25 dihydroxy vitamin D3
(A more active form in terms of absorbing calcium from intestine)
26
Alternate third step for vitamin D synthesis
25- hydroxy vitamin D3 goes to the kidney and is catalyzed by 24-hydroxylase to form 24,25 dihydroxy vitamin D3 (less active interms of absorbing calcium)
27
______________ has activities in intestine in terms of calcium regulation
1,25 dihydroxy vitamin
28
Actions of vitamin D3 on Ca and PO4 absorption
Increases Ca and PO4 absorption
29
What is the rapid (direct) effect of vitamin D3
stimulates translocation of another calcium channel (TrPV6)
30
What happens to the TrPV6 channel in rapid (direct) effect of vitamin D3? How does this affect Ca.
Rapidly transported to luminal side of intestinal mucosal cells. This allows for the flow of Ca into mucosal cells
31
What does calbindin D9K do?
It acts as a transporter of Ca within the cell to pump out the calcium. Prevents calcium sequestration within enterocyte.
32
What prevents calcium sequestration in enterocytes
Calbindin D9K
33
What prevents phosphate accumulation prevention
Fibroblast GF 23 (FGF23)
34
What is FGF 23 secreted by
Osteoblasts and osteocytes
35
FGF 23 is released in response to
elevated serum phosphate
36
FGF 23 effect on kidney
Stimulates phosphate secretion in kidney
37
How does FGF 23 stimulate phosphate excretion in kidney
by suppressing phosphate transporters that would reabsorb phosphate from renal filtrate
38
FGF 23 effect on PTH secretion
Inhibits PTH secretion
39
FGF 23 effect on vitamin D
inhibits synthesis
40
FGF 23 effect on bone mineralization
inhibits it
41
Does FGF 23 have autocrine or paracrine effects
Both autocrine and paracrine
42
what is the mutant version of FGF 23 called
protease resistant mutant of FGF 23
43
What does protease resistant mutant of FGF 23 cause
autosomal dominant hypophosphatemic rickets
44
What is autosomal dominant hypophosphatemic rickets
Lack of bone mineralization due to lack of phosphate
45
What are 3 factors that regulate PTH secretion from Parathyroid gland
CaSR
1, 25-(OH)2 vit D3
FGF 23
46
How does CaSR regulate PTH secretion
calcium increase inhibits PTH
calcium decrease stimulates PTH
47
How does 1, 25-(OH) vit D3 regulate PTH secretion
feedback inhibition of PTH secretion (PTH stimulates vit D3 production in the kidneys
48
How does FGF 23 affect PTH secretion
Inhibits PTH secretion
49
Calcitonin is secreted by
C cells in thyroid gland
50
How does calcitonin affect serum Ca2+
It is a negative regulator of serum
51
How does calcitonin affect osteoclastic activity
Inhibits osteoclastic bone resorption
52
effect of calcitonin on calcium and PO4
Increase
53
calcitonin is stimulated by
high serum calcium levels
54
Calcitonin can be used to suppress
hypercalcemia
55
What is pagets disease
It is characterized by uncontrolled osteoclastic bone resorption and secondary bone formation.
56
Symptoms of pagets disease
bone pain
bone deformities
loss of hearing (hypercalcemia)
may be caused by virus
57
postmenopausal osteoporosis causes
decrease in estrogen levels causes a decrease in bone mass
more osteoclasts. This causes shift towards bone remodeling towards resorption.
58
Aging osteoporosis causes
age related dcerease in osteoblasts
59
risk factors for osteoporosis
age, physical activity levels, low Ca2+ intake in early years, long term glucocorticoid therapy
60
hypercalcemia is caused by
hyperthyroidism and malignant tumors
61
how does hyperparathyroidism cause hypercalcemia
PTH causes increased bone resorption
62
hypocalcemia is caused by
Hypoparathyroidism
Vitamin D deficiencies
63
3 different vitamin 3 preparations
Cholecalciferol vit D3
Calcidiol
calcitrol
64
people with compromised liver function will not be able to convert Vit D3 to
25-hydroxy
65
People with compromised kidney function will not be able to convert ________to _______
25 hydroxy to 25 dihydroxy
66
mechanism of action of vit D3
Increase calcium and PO4 absorption from gut and renal tubules
67
vit D can be used for
Hypocalcemia, hypoparathyroidism
68
First line of therapy for osteoporosis
Bissphosphonates
69
What do bisphosphonates do?
Inhibit bone resorption
70
What is it that allows bisphosphonates to accumulate in hydroxyapatite in bone
bisphosphonates are structural analogs of pyrophosphates.
71
How do bisphosphonates treat osteoporosis (mechanism)
50% of absorbed dose goes to the bones and ends up bound in hydroxy apatite
It is taken up by osteoclasts
They have INHIBITORY effects on osteoclasts.
72
Bisphosphonates get into bone and inhibit what enzyme
Farensyl PP synthase
73
How does bisphosphonates affect osteoclasts
causes apoptosis
74
Bisphosphonates effect on BMD and osteoclastic activity
increase BMD and decrease osteoclastic activity
75
dosing precautions for bisphosphonates
Take before breakfast
stay upright for 30 mins
76
Why do you want patient to be upright for 30 minutes after taking bisphosphonates
So it does not end up in esophagus and cause gastric irritation of esophagus
77
all drug names for bisphosphonates end with
-Nate
78
Which two bisphosphonate drugs are only approved for pagets and cancer and not osteoporosis
Pamidronate
etidronate
79
What are isoprenoids
basic units used to build cholesterol
80
FPP abbreviation
Farensyl pyrophosphate
81
how is FPP formed
isopentene pyrophosphate (IPP) + dimethyl allopyrophosphate (DMAPP) = GPP
GPP+IPP gives FPP
82
What can FPP be used for
To prenylate GTP binding proteins such as RAC and RAS
83
Why do RAC and RAS need to be prenylated with FPP
farensyl groups are attached to the GTP binding proteins RAS and RAC, that is what inserts into membrane and localizes proteins to membrane
84
What happens when Ras and Rac signaling is interrupted?
leads to a decrease in osteoclat survival and numbers
85
How is Rac and Ras signalling interrupted?
By bisphosphonates when they inhibit production of farensyl pyrophosphate synthase
86
What are 2 PTH drugs for osteoporosis
Teriparatide (forteo)
Abaloparatide (tymlos)
87
How do the PTH drugs Forteo and tymlos work
they preferentially stimulate osteoblast activity
88
How does teriparatide increase bone mass
preferentially stimulate osteoblast activity
89
Explain the interaction of teriparatide with PTH 1 receptors
Continuous supply- leads to increase in osteoclast number and no change in osteoblast number.
If we give 1 h/day infusion, osteoblast numbers increase with no increase in osteoclasts.
90
Why is there a dual effect seen during PTH exposure and osteoblasts
Osteoblasts have the ability to secrete factors that drive osteoclast differentiation (RANK L).
Continuous PTH exposure by osteoblasts, they secrete a high quantity RANK L. This activates the RANK receptor on surface of osteoclasts precursors, driving differentiation into osteoclasts.
91
What does continuous RANK exposure do to osteoclast numbers
Increases it.
92
What do osteoblasts secrete that neutralize RANKL
Osteoprotegorins
93
How does continuous PTH (teriparatide) secretion affect osteoblast and osteoclasts
Increased RANKL
decreased OPG (osteoprotegorin)
Increased osteoclast differentiation
increased bone resorption
increased serum calcium
94
How does intermittent PTH (Teriparatide) secretion affect osteoblasts and osteoclasts
Decreased osteoblast apoptosis
increased core binding factor (Cbfa1) (pre-osteoblasts)
Increased osteoblast number
increased bone mass and strength
95
What do we use to rapidly increase BMD between bisphosphonates and teriparatide (PTH)
PTH rapidly increases BMD
96
Comparison of teriparatide to bisphosphonates (pros)
May be more effective at preventing fractures than bisphosphonates. Builds bone mass at higher rate than bisphosphonates.
97
Comparison of teriparatides to bisphosphonates (CONS)
injected daily
not recommended beyond 2 yrs
black box warning for risk of bone cancer
98
What is prolia (denosumab) binding to?
Binds to RANKL
99
What does denosumab binding to RANKL do?
prevents activation of RANK on osteoclast precursors, preventing differentiation of osteoclasts
100
What is a step that needs to be taken before administering denosumab
get hypercalcemia under controlM
101
Difference between romosozumab and denosumab
Denosumab targets RANKL, romosozumab targets sclerostin
102
How and when is sclerostin secreted
sclerostin is secreted from osteocytes in absence of load.
103
What does sclerostin do
Increases osteoclasts and decreases osteoblasts (decreases BMD)
104
Contraindication of romosozumab
Not used in patients with MI or stroke
105
Romosozumab mechanism
Binds sclerostin and neutralizes it. This prevents it from decreasing osteoblasts and increasing osteoclasts
106
how does sclerostin interact with LRP 5/6 and WNT
Sclerostin binds LRP 5/6 and inhibits WnT signalling
107
What is more effective at preventing fractures between raloxifene and estradiol
Estradiol is more effective
108
What is the advantage that raloxifene has over estradiol
It is selective for bones, does not increase risk for breast cancer or uterine cancer.
109
Mechanism of calcitonin
Decreases osteoclast activity and blocks renal absorption of PO4 and Ca2+
110
Calcitonin is most commonly used to treat
Hypercalcemia
111
what does cinacalcet treat
Hyperparathyroidism
112
What happens to Ca sensing receptor in CKD patients
It can become less responsive to Ca2+
113
Why does hyperparathyroidism happen in patients with CKD
Kidneys do not make 1,25 (OH) vit D in response to PTH (1,25 vit D is an important feedback inhibitor for PTH secretion.
114
How does cinacalcet enhance the response of the CaR to elevated Ca levels
Binds CaR and inhibits the release of PTH
115
How does cinacalcet affect PTH and calcium levels
decreases both PTH and calcium levels
116
cinacalcet is a PAM of CaR T/F
True
117
etelcalcetide effects on PTH and serum Ca
decreases both PTH and Ca2+
118
mechanism of etelcalcetide
Similar to cinacalcet (given after dialysis to activate the CaR by acting as a PAM. Makes calcium more effective at that receptor.
119
Name two analogs of vitamin D
Zempar and Hectorol
120
Which one is the prodrug hectorol or zemplar
Hectorol
121
Mechanism of zemplar and hectorol? how do they differ from cinacalcite and etelcalcetide
Zemplar and hectorol bind to the Parathyroid gland and inhibit PTH production. Cinacalcite and etelcalcitide bind to CaR to reduce PTH secretion
122
CKD patients lose their ability to excrete phosphate in response to
PTH and FGF 23
123
How can hyperphosphatemia be dangerous
can block blood flow in small blood vessels
124
Name two phosphate binders
Fosenrol (lanthanum carbonate)
Renagel (sevelamer)
125
mechanism of fosenrol
forms insoluble lanthanum salts in GI tract, these salts are not absorbed into the blood stream
126
fosenrol effects on serum PO4 and Ca 2+ levels
Decreases
127
Renagel mechanism of action
Amine containing polymer that binds PO4 in the GI tract
