29 Bone/Mineral Homeostasis Flashcards
What are the two main ions in bone mineral homeostasis?
- Calcium (Ca2+)
- main ion we’re considered about in terms of bone regulation
- Phosphate (PO43-)
Bone is the principle reservoir for ______ and ______
Bone is the principle reservoir for calcium and phosphate
- ~98% Ca2+
- ~85 % PO43-
Remainder is in intracellular fluid, circulation
Three reasons why it’s important to regulate calcium and phosphate:
- Health/strength of bones
- Osteoporosis, osteopenia (reduced density), osteopetrosis (increased density - susceptible to fractures) - long-term/chronic effects
- 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)
- Ca2+ is an essential intracellular signal that can regulate expression of many genes
What are three “control sites” for plasma calcium and phosphate?
- Gut
- uptake (input), excretion
- Bone
- Main Reservoir (storage)
- Remodeling
- 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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How is vitamin D3 a key player in regulating plasma calcium and phosphate?
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- In the Gut
- Vit D promotes reabsorption of Ca2+ and PO43-
- increases plasma concentrations
- Vit D promotes reabsorption of Ca2+ and PO43-
- 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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Bone is a dynamic tissue, what does this mean?
Bone is constantly regenerated and resorbed
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What is an Osteoblast?
Bone cell responsible for the deposition of bone (formation)
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What are osteoclasts?
Bone cells responsible for the resorption of bone (breaking down)
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What are two major regulators of bone remodeling?
- Vitamin D metabolites
- Parathyroid hormone
Both stimulate bone resorption (stimulate osteoclasts -> breakdown of bone -> mobilization of Ca2+)
How are osteoclasts activated?
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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Parathyroid hormone is a _____ hormone
Parathyroid hormone is a peptide hormone
What are two main actions of the parathyroid hormone, where do these actions take place?
- In Bone:
- promote bone resorption (indirect activation of osteoclasts via RANKL from osteoblasts)
- Increases Ca2+ and PO43-
- In Kidney
- promotes Ca2+ absorption, promotes PO43- excretion
- Increase Ca2+
- Decrease PO43-
- promotes Ca2+ absorption, promotes PO43- excretion
- 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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Synthetic parathyroid hormone (PTH 1-34 - teriperatide) is marketed as a therapeutic for ______
Synthetic parathyroid hormone (PTH 1-34) is marketed as a therapeutic for osteoporosis
What stimulates the release of PTH from the parathyroid gland?
Decreased circulating Calcium
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By promoting metabolism of vitamin D in the kidney, what happens in the gut?
Vitamin D promotes calcium and phosphate reabsorption in the gut
Vitamin D is synthesized spontaneously from _______ in our skin
Vitamin D is synthesized spontaneously from cholesterol in our skin
- exposure to sunlight accelerates the synthesis of vitamin d from cholesterol
Vitamin D3 is inactive, what is its active form called?
1,25-hydroxy-D3
1,25-OH-D3
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Why would Vitamin D be considered a steroid (secosteroid) hormone?
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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What happens to vitamin D in the liver?
What is it called following this modification?
Vitamin D is metabolized first in the liver with the addition of a hydroxyl group
Now called: 25-OH-D3
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What happens to vitamin D (now 25-OH-D3 following liver modification) in the kidney?
What is it called following this modification?
Two different scenarios:
- PTH is present (low Ca2+)
- kidney promotes processing to the active form
- addition of a second OH at C-1
- 1,25-OH-D3
- kidney promotes processing to the active form
- 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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Actions of 1,25-OH-D3?
Kidney
Bone
Gut
Net
see image
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What senses Calcium levels?
Calcium receptors in the parathyroid (PTH levels are regulated accordingly)
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PTH exerts effects on ________ in the ____ and ______
PTH exerts effects on PTH receptors in the kidney and osteoblasts
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What are four secondary regulators of bone mineral homeostasis?
- FGF23
- Calcitonin
- Glucocorticoids
- Estrogens
*Interest only for this class*
What is Hypocalcemia?
Circulating free calcium is too low
What provides short term relief from hypocalcemia?
Hypocalcemia = calcium too low
- take calcium (oral, IV, IM)
- take active D3 metabolite
Hypocalcemia causes:
- hyperexcitability of cells
- early symptom is Trousseau’s sign
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Unresolved hypocalcemia can lead to:
seizures, muscle tetany/spasms
Long term danger of Hypocalcemia?
Development of secondary hyperparathyroidism
What is Secondary Hyperparathyroidism?
- 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
How would you treat hypoparathyroidism?
Intrinsic defect of parathyroid:
Treat with Vit D supplementation, Ca2+ supplementation
Two possible long-term causes of Hypocalcemia?
- Hypoparathyroidism
- Vitamin D deficiency
Those with hypocalcemia caused by vitamin D deficiency could be treated with:
ingestion of active Vit D3 metabolites (calcitriol)
sunshine
dietary correction
Removal of the parathyroid gland could result in what condition?
Hypocalcemia
What is Hypercalcemia?
Too much circulating calcium
What are effects of hypercalcemia?
Loss of cellular excitability
Lethargy, coma
Pain in bones due to excessive PTH
What is a common cause of Hypercalcemia?
Primary hyperparathyroidism
What is primary hyperparathyroidism?
How might you treat it?
- 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)
What is osteoporosis?
Abnormal bone loss -> fractures
- long-term, gradual disorder
- loss of balance between formation and resorption of bone
- porous bones
- loss of balance between formation and resorption of bone
What are 2 common causes of osteoporosis?
Long-term glucocorticoid administration
Hyperparathyroidism
In what demographic is osteoporosis most common?
Aging females
Decreased levels of estrogen in aging women can cause osteoporosis, what are two ways this could be combatted?
- hormone replacement (serious adverse effects - cancers)
- estrogen mimics
- SERMS (Synthetic Estrogen receptor modulators; eg raloxifene)
- meant to reduce the adverse effects
What is Teriparatide?
Drug (biological) - recombinant, fully active PTH fragment (1-34) (first 34 amino acids of PTH)
How would Teriparatide, a recombinant fragment (first 34 aa) of fully active PTH be used to treat Osteoporosis when PTH stimulates bone resorption?
- 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
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What are bisphosphonates?
Class of drugs used to treat osteoporosis by inhibiting resorption of bone by osteoclasts
eg Alendronate
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
- 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??)
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What is the structural similarity of ALL Bisphosphonates?
Bisphosphonates all have two phosphonate groups
(inc etidronate, Pamidronate, alendronate)
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Bisphosphates are all derivatives of _________
Bisphosphates are all derivatives of inorganic pyrophosphoric acid (AKA pyrophosphate)
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Phosphonate groups (such as those in bisphosphonates (alendronate)) have a high affinity for ______, and therefore accumulate in _____
Phosphonate groups (such as those in bisphosphonates) have a high affinity for Calcium
- therefore these drugs accumulate in bone
Which of the bisphosphonates is most commonly used?
Alendronate
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What effect does the accumulation of Bisphosphonates (alendronate) in bone have?
Promotes apoptosis of osteoclasts
- targetted to osteoclasts during bone resorption where they have a variety of toxic effects = prevent bone resorption
What is Osteoprotegerin?
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)
How does osteoprotegerin inhibit bone resorption?
(shown in the image as the crescent moon)
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Osteoprotegerin inhibits bone resorption by preventing RANKL binding to and activation of osteoclasts
What is Denosumab?
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
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