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PMCOL 200 > 29 Bone/Mineral Homeostasis > Flashcards

29 Bone/Mineral Homeostasis Flashcards

1
Q

What are the two main ions in bone mineral homeostasis?

A
  • Calcium (Ca2+)
    • main ion we’re considered about in terms of bone regulation
  • Phosphate (PO43-)
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2
Q

Bone is the principle reservoir for ______ and ______

A

Bone is the principle reservoir for calcium and phosphate

  • ​~98% Ca2+
  • ~85 % PO43-

Remainder is in intracellular fluid, circulation

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3
Q

Three reasons why it’s important to regulate calcium and phosphate:

A
  1. Health/strength of bones
    • Osteoporosis, osteopenia (reduced density), osteopetrosis (increased density - susceptible to fractures) - long-term/chronic effects
  2. Ca2+ balance has significant effects on electrical excitability of cells
    • by binding to membrane glycoproteins (can lead to acute crises when Ca2+ levels are abnormal)
  3. Ca2+ is an essential intracellular signal that can regulate expression of many genes
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4
Q

What are three “control sites” for plasma calcium and phosphate?

A
  1. Gut
    • uptake (input), excretion
  2. Bone
    • Main Reservoir (storage)
    • Remodeling
  3. Kidney
    • uptake (input), excretion

Legend for the diagram:

  • D(+) = Vitamin D3 - active
  • CT = Calcitonin
  • PTH = Parathyroid hormone
  • FGF = Fibroblast growth factor
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5
Q

How is vitamin D3 a key player in regulating plasma calcium and phosphate?

A
  • In the Gut
    • Vit D promotes reabsorption of Ca2+ and PO43-
      • increases plasma concentrations
  • In the kidney
    • Vitamin D (and parathyroid hormone) lead to controlled overexcretion of Ca2+ and PO43-
    • by either reducing excretion and promoting reabsorption = affect plasma concentrations
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6
Q

Bone is a dynamic tissue, what does this mean?

A

Bone is constantly regenerated and resorbed

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7
Q

What is an Osteoblast?

A

Bone cell responsible for the deposition of bone (formation)

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8
Q

What are osteoclasts?

A

Bone cells responsible for the resorption of bone (breaking down)

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9
Q

What are two major regulators of bone remodeling?

A
  1. Vitamin D metabolites
  2. Parathyroid hormone

Both stimulate bone resorption (stimulate osteoclasts -> breakdown of bone -> mobilization of Ca2+)

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10
Q

How are osteoclasts activated?

A

Activation of osteoclasts is indirect

  • hormones activate osteoblasts
  • Secretion of RANK ligand (RANKL) from osteoblasts - act on pre-fusion osteoclasts -> promote maturation to osteoclasts
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11
Q

Parathyroid hormone is a _____ hormone

A

Parathyroid hormone is a peptide hormone

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12
Q

What are two main actions of the parathyroid hormone, where do these actions take place?

A
  1. In Bone:
    • promote bone resorption (indirect activation of osteoclasts via RANKL from osteoblasts)
    • Increases Ca2+ and PO43-
  2. In Kidney
    • promotes Ca2+ absorption, promotes PO43- excretion
      • Increase Ca2+
      • Decrease PO43-
  • NET EFFECT:
    • Increase circulating Calcium
    • slight increase or neutral effect on circulating phosphate

*Calcium and phosphate form a precipitate and we don’t want that*

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13
Q

Synthetic parathyroid hormone (PTH 1-34 - teriperatide) is marketed as a therapeutic for ______

A

Synthetic parathyroid hormone (PTH 1-34) is marketed as a therapeutic for osteoporosis

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14
Q

What stimulates the release of PTH from the parathyroid gland?

A

Decreased circulating Calcium

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15
Q

By promoting metabolism of vitamin D in the kidney, what happens in the gut?

A

Vitamin D promotes calcium and phosphate reabsorption in the gut

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16
Q

Vitamin D is synthesized spontaneously from _______ in our skin

A

Vitamin D is synthesized spontaneously from cholesterol in our skin

  • exposure to sunlight accelerates the synthesis of vitamin d from cholesterol
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17
Q

Vitamin D3 is inactive, what is its active form called?

A

1,25-hydroxy-D3

1,25-OH-D3

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18
Q

Why would Vitamin D be considered a steroid (secosteroid) hormone?

A

It’s derived from cholesterol

  • Actually called a ‘secosteroid’ because it is missing one of the rings that you would find in cholesterol
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19
Q

What happens to vitamin D in the liver?

What is it called following this modification?

A

Vitamin D is metabolized first in the liver with the addition of a hydroxyl group

Now called: 25-OH-D3

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20
Q

What happens to vitamin D (now 25-OH-D3 following liver modification) in the kidney?

What is it called following this modification?

A

Two different scenarios:

  1. PTH is present (low Ca2+)
    • kidney promotes processing to the active form
      • addition of a second OH at C-1
      • 1,25-OH-D3
  2. High Ca2+ and high 1,25-OH-D3
    • addition of a second OH at Carbon 24
    • Inactive form
    • 24,25-OH-D3
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21
Q

Actions of 1,25-OH-D3?

Kidney

Bone

Gut

Net

A

see image

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22
Q

What senses Calcium levels?

A

Calcium receptors in the parathyroid (PTH levels are regulated accordingly)

23
Q

PTH exerts effects on ________ in the ____ and ______

A

PTH exerts effects on PTH receptors in the kidney and osteoblasts

24
Q

What are four secondary regulators of bone mineral homeostasis?

A
  1. FGF23
  2. Calcitonin
  3. Glucocorticoids
  4. Estrogens

*Interest only for this class*

25
Q

What is Hypocalcemia?

A

Circulating free calcium is too low

26
Q

What provides short term relief from hypocalcemia?

A

Hypocalcemia = calcium too low

  • take calcium (oral, IV, IM)
  • take active D3 metabolite
27
Q

Hypocalcemia causes:

A
  • hyperexcitability of cells
    • early symptom is Trousseau’s sign
28
Q

Unresolved hypocalcemia can lead to:

A

seizures, muscle tetany/spasms

29
Q

Long term danger of Hypocalcemia?

A

Development of secondary hyperparathyroidism

30
Q

What is Secondary Hyperparathyroidism?

A
  • Hyperactive parathyroid activity due to chronic low plasma Ca2+ (normally result of kidney failure or poor renal reabsorption of Ca2+)
  • Secondary hyperparathyroidism will lead to breakdown and weakening of bone
    • because constant release of PTH
31
Q

How would you treat hypoparathyroidism?

A

Intrinsic defect of parathyroid:

Treat with Vit D supplementation, Ca2+ supplementation

32
Q

Two possible long-term causes of Hypocalcemia?

A
  • Hypoparathyroidism
  • Vitamin D deficiency
33
Q

Those with hypocalcemia caused by vitamin D deficiency could be treated with:

A

ingestion of active Vit D3 metabolites (calcitriol)

sunshine

dietary correction

34
Q

Removal of the parathyroid gland could result in what condition?

A

Hypocalcemia

35
Q

What is Hypercalcemia?

A

Too much circulating calcium

36
Q

What are effects of hypercalcemia?

A

Loss of cellular excitability

Lethargy, coma

Pain in bones due to excessive PTH

37
Q

What is a common cause of Hypercalcemia?

A

Primary hyperparathyroidism

38
Q

What is primary hyperparathyroidism?

How might you treat it?

A
  • Overactivity of the parathyroid - typically due to tumor
  • Therapy: resection of the gland
  • Therapeutics might be used to ‘protect bone’ (biphosphonates, calcitonin, inhibitors of bone resorption)
  • Second possible therapy is calcimimetics (mimics calcium effects on CaR, negative feedback regulation of parathyroid)
39
Q

What is osteoporosis?

A

Abnormal bone loss -> fractures

  • long-term, gradual disorder
    • loss of balance between formation and resorption of bone
      • porous bones
40
Q

What are 2 common causes of osteoporosis?

A

Long-term glucocorticoid administration

Hyperparathyroidism

41
Q

In what demographic is osteoporosis most common?

A

Aging females

42
Q

Decreased levels of estrogen in aging women can cause osteoporosis, what are two ways this could be combatted?

A
  • hormone replacement (serious adverse effects - cancers)
  • estrogen mimics
    • SERMS (Synthetic Estrogen receptor modulators; eg raloxifene)
    • meant to reduce the adverse effects
43
Q

What is Teriparatide?

A

Drug (biological) - recombinant, fully active PTH fragment (1-34) (first 34 amino acids of PTH)

44
Q

How would Teriparatide, a recombinant fragment (first 34 aa) of fully active PTH be used to treat Osteoporosis when PTH stimulates bone resorption?

A
  • PTH acts primarily as a stimulus on osteoblasts, and acts via RANKL to activate osteoclasts
    • acts on PTH receptors on osteoblasts
  • Mechanism of action requires proper timing of dosage (injected once daily - pulsatile delivery)
  • Thought to ‘tip the balance’ towards osteoblast activity because only activated for a brief amount of time
    • promotes bone building
45
Q

What are bisphosphonates?

A

Class of drugs used to treat osteoporosis by inhibiting resorption of bone by osteoclasts

eg Alendronate

46
Q

What is the mechanism of action of Bisphosphonates (Alendronate)?

  • Inhibition of ____________
    • Specific target is ___\_
    • recent concern about side effects: _______\_
    • Speculation that these may also act to inhibit _______\_
    • Trials have combined bisphosphates with _______\_, but effects are inconclusive
A
  • Inhibition of osteoclast resorption of bone
    • Specific target is unclear
    • recent concern about side effects: cancers, abnormal fractures
    • Speculation that these may also act to inhibit glucocorticoid effects
    • Trials have combined bisphosphates with teriparatide, but effects are inconclusive

(teraparatide??)

47
Q

What is the structural similarity of ALL Bisphosphonates?

A

Bisphosphonates all have two phosphonate groups

(inc etidronate, Pamidronate, alendronate)

48
Q

Bisphosphates are all derivatives of _________

A

Bisphosphates are all derivatives of inorganic pyrophosphoric acid (AKA pyrophosphate)

49
Q

Phosphonate groups (such as those in bisphosphonates (alendronate)) have a high affinity for ______, and therefore accumulate in _____

A

Phosphonate groups (such as those in bisphosphonates) have a high affinity for Calcium

  • therefore these drugs accumulate in bone
50
Q

Which of the bisphosphonates is most commonly used?

A

Alendronate

51
Q

What effect does the accumulation of Bisphosphonates (alendronate) in bone have?

A

Promotes apoptosis of osteoclasts

  • targetted to osteoclasts during bone resorption where they have a variety of toxic effects = prevent bone resorption
52
Q

What is Osteoprotegerin?

A

Protein

  • endogenous inhibitor of the RANK/RANKL system
    • naturally occurring ‘scavenger’
    • Can prevent RANKL binding and activating osteoclasts, and this inhibits bone resorption
      • (decoy receptor for RANKL)
53
Q

How does osteoprotegerin inhibit bone resorption?

(shown in the image as the crescent moon)

A

Osteoprotegerin inhibits bone resorption by preventing RANKL binding to and activation of osteoclasts

54
Q

What is Denosumab?

A

Osteoprotegerin mimic used to treat osteoporosis (synthetic osteoprotegerin)

  • Monoclonal antibody directed against RANKL
  • Same mechanism as endogenous osteoprotegerin protein:
    • Inhibits bone resorption by preventing RANKL binding to RANK and activating osteoclasts

PMCOL 200 (30 decks)

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