Bone Homoestasis Dr. Pond Flashcards

EXAM 2

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1
Q

Risk factors for Osteoporosis in females

A

Age: over 50 -> menopause
lower body weight and muscle mass

early menopause: low estrogen
no pregnancy: low estrogen

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2
Q

Risk factors for Osteoporosis in males

A

-age: over 50
-short statue, thin build
-weak hip muscles
-low tesosterone

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3
Q

Other risk factors

A

caffeine
depression
low vitamin D and calcium
certain meds

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4
Q

Which medication increases the risk for osteoprosis?

A

Corticosteroids

-decreases organic matter in bones
-decreases calcium and phosphates in bones

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5
Q

What is the organic matrix in the bone?

A

Osteoid (95% collagen, 5% ground substance - mixture of proteoglycans)

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6
Q

What is the inorganic matrix in the bone?

A

-Hydroxyapatite
-other minerals

build on top of organic matrix

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7
Q

Function of Osteoblasts

A

synthesize Osteoids
-> Hydroxyapatite get deposited on it

Osteoblasts get trapped together with hydroxyapatite in the bone they are forming

->no longer active in bone production -> they become the resident bone cells (osteocytes)

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8
Q

Function of Osteoclasts

A

Bone resorption

secretes proteases -> breaking down the osteoids
secretes acids dissolves hydroxyapatite

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9
Q

How does PTH affect Ca2+, PO4(3-)?

A

-increases Ca2+
-decreases PO4(3-)

stimulates the production of active Vitamin D ->
Vitamin D has to be formed into the active form

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10
Q

How does Vitamin D affect Ca2+, PO4(3-)?

A

-increases Ca2+
-increases PO4(3-)

inhibits the production of PTH -> negative feedback loop to PTH
stimulates FGF-23

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11
Q

How does Fibroblast growth factor 23 affect Ca2+, PO4(3-)?

A

only decreases PO4(3-)

inhibits production of active Vitamin D -> negative feedback loop to Vitamin D

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12
Q

What is the role of calcitonin?

A

-decreases Ca2+ in the plasma
-decreases PO4(3-) in the plasma
-> works on osteoclasts -> stimulates resorption and keeps Ca and PO4(-3) in the bone (levels go down in the serum)

other secondary regulators are:
prolactin, growth hormone, insulin, thyroid hormone, glucocorticoids, sex steroids

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13
Q

On which organ does PTH work?

A

Kidney

increases reabsorption of Ca2+
decreases reabsorption of PO3(-4) -> more excretion

also works in the bones

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14
Q

What is PTH’s effect on the bone?

A

increasing resorption (bone breakdown) -> it is going to free up Ca and PO (Ca levels go up, PO4(3-) will be exerted)

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15
Q

On which organ does Viramin D work?

A

The gut

increases absorption of Ca2+
increases absorption of PO3(-4)
through upregulation of their transporters

Kidney:
Vitamin D can also inhibit the urine output of Ca2+ and PO3(-4) –> but that’s a weaker effect

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16
Q

On which organ does FGF-23 work?

A

in the kidneys:
decreases reabsorption of PO3(-4)

some activity in the bones

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17
Q

On which organ does Calcitonin work?

A

mainly in the bone
decreases bone resorption -> more Ca2+ and PO3(-4) stays in the bone -> less coming out of the bone into the serum -> decrease Ca2+ and PO3(-4) serum levels

some activity in the kidneys
-> more elimination of Ca2+ and PO4(3-)

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18
Q

How do Ca2+ levels regulate PTH?

A

high levels of Ca2+ –> decreases PTH

as Ca2+ goes up it actives the Ca-sensitive protease
-> the protease cleaves PTH (peptide hormone) into fragments

as Ca2+ goes up it binds to CaR -> decreases PTH release from the parathyroid gland

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19
Q

How does PO4(-3) regulate PTH?

A

high Phosphate levels stimulate PTH production

as PO4(-3) goes up it binds to Ca2+ and forms calcium phosphate -> which will reduce free calcium -> there is less calcium binding CaR on the parathyroid gland
-> which will stimulate PTH production

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20
Q

What is the mechanism of PTH’s effect on the bone?

A

PTH induces RANKL (ligand) from osteoblasts
-> RANKL binds on RANK (receptor) on osteoclast precursor -> activation of osteoclasts -> RESORPTION (bone breakdown)
-> increase in free Ca and PO4(-3)

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21
Q

How does low PTH level affect bone metabolism?

A

low PTH induces IGF-1 (insulin growth factor)
-> activating osteoblast and bone formation

so PTH can cause bone breakdown - at chronic high dose with RANKL
and thought to cause bone formation - at chronic low dose

22
Q

Which drug uses PTH’s effect of bone formation?

A

Teriparatide
-recombinant PTH for osteoporosis
increases bone formation
(mimics low dose of PTH -> stimulates osteoblasts)
-given SC (since it is a peptide)
-approved for use for only 2 yrs (osteosarcoma in rats)

23
Q

ADE of Teriparatide

A

joint pain, arthritis, nausea

24
Q

How does Cinacalcet work?

A

Calcimimetic - mimics Ca2+ -> binds to CaR
-> inhibits PTH production
-used in hyperparathyroidism

ADE: diarrhea, N/V, hypocalcemia

25
Q

How is Vitamin D3 called?

A

CholeCalCiferol (3x C in the name)

-from diet and skin

26
Q

How is Vitamin D2 called?

A

ErgoCalCiferol (2x C in the name)
-from plants, yeats, and milk

27
Q

How is Vitamin D3 produced from our skin?

A

7-Dehydrocholesterol is stored in our skin
-through UV light converted to Pre-D3
-trough heat converted to CholeCalCiferol

28
Q

How is Vitamin (D3 and D2) activated?

A

in the liver converted to 25(OD)D3 (through 25-hydroxylase

then in the kidney to Calcitriol (1,25(OH)2D3) by the 1-alpha-hydroxylase

29
Q

Which patient population should be supplemented with active Vitamin D instead of Vitamin D3

A

elderly
renal impaired patients
hepatic impaired patients
-> since it is converted in the liver and kidney

30
Q

Which enzyme produces the active form of vitamin D?

A

1-alpha-hydroxylase in the kidney

31
Q

Molecules that stimulate the production of active Vitamin D

A

-low Ca2+ and PO4(-3)
-high PTH
-low FGF-23

32
Q

What are common ADEs of active vitamin D?

A

-edema
-N/V
-hypercalcemia –> since it increases absorption of Ca and PO4(-3) in the gut

33
Q

Where is FGF-23 produced?

A

in the bones by osteocytes and osteoblasts
-> FGF-23 binds to FGF-1 and FGF-IIIc receptors in the presence of Klotho (accessory receptor)

34
Q

Which organ is involved in the PO4(-3) regulation by FGF-23

A

Kidney

decreases reabsorption of PO4(-3) -> excreted in the urine
-> Phosphaturia

35
Q

How does FGF-23 regulate Vitamin D?

A

inhibitng 1-alpha-hydroxylase in the kidney

36
Q

What stimulates FGF-23 production

A

-active vitamin D3 (1,25(OH)2D3)

-low serum phospahte

37
Q

Where does Calcitonin work?

A

in the bones and kidneys: decreases Ca and PO4(-3)

-> inhibits bone resorption (osteoclasts)
-> prevents the mobilization of Ca and PO4(-3) so it doesn’t get back into the serum

weak action in the kidney: reduces reabsorption of Ca and PO

38
Q

Why is resorption actually beneficial to the bones?

A

Because it is required for bone formation

39
Q

How do Glucocorticoids contribute to osteoporosis?

A

-in the bones: block bone formation (uses protein (collagen of the bone) to form glucose
-in the gut: antagonizes Vitamin D-stimulated calcium absorption
-in the kidney: increases Ca2+ excretion
decreases Ca and PO4(-3)

40
Q

What is the effect of estrogen on the bone?

A

thougt to reduce bone-resorbing action of PTH,
also dirctly anti-resorptive to the bone

41
Q

What is the MOA of Bisphosphonates?

A

-decreases osteoclast bone resorption
inhibits osteoclast activity
inhibits osteoclast survival: alendronate, risedronate
increase osteoclast apoptosis

-bind hydroxyapatite -> protect them from dissolution by acids (from osteoclasts)

-treatment of osteoporosis, hypercalcemia (caused by bone resorption and transfer of released Ca to the bloodstream), cancer (high dose)

42
Q

How should Bisphosphonates be taken?

A

-in the morning on an empty stomach, and take a full glass of water - since less than 10% absorbed orally

-remain upright for 30 min (ibandronate - 60 min)

43
Q

How are Bisphosphonates metabolized?

A

No metabolism

50% accumulates in the bone: duration of action is not predictive -> remainder excreted unchanged in the urine

44
Q

What are the ADEs for Bisphosphonates?

A

GI: diarrhea, nausea, abdominal pain
-esophageal ulcers
-osteonecrosis of the jaw
-potential for esophageal cancer

45
Q

Contraindicated population

A

-decreased renal function
-esophageeal disorder (IV formulation works)
-peptic ulcer disease (IV formulation works)

46
Q

What is the MOA for Denosumab?

A

RANKL inhibitor -> decreases osteoclasts
-> reduction in resorption

ADE: hypocalcemia, hypophosphatemia (since we inhibit the release of free Ca and PO4(-3)
-serious infections
-osteonecrosis of the jaw
-N/V, diarrhea
-fatigue, backache, headache, pain in limbs
-nasopharyngitis

47
Q

What is the MOA for Romosozumab?

A

Sclerostin inhibitor

-increases bone formation
-decreases bone resorption (to a lesser extent)

-short-term use (12 months or less)

48
Q

What is the role of Sclerostin?

A

inhibits the precursor of osteoblasts and osteoblasts
-stimulates apoptosis of osteoblasts

49
Q

What are the serious side effects of Romosozumab?

A

-MI
-stroke
-cardiovascualr death

-hypocalcemia (some decrease in resorption in free Ca release)
-osteonecrosis of the jaw

50
Q

The increase of which molecule causes Phosphatuira?

A

FGF-23