29 Bone/Mineral Homeostasis Flashcards by Echo Quinton

What are the two main ions in bone mineral homeostasis?

Calcium (Ca2+)
- main ion we’re considered about in terms of bone regulation
Phosphate (PO₄^3-)

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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

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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

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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?

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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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+)

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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

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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-

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

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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

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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

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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
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)

PTH exerts effects on ________ in the ____ and ______

PTH exerts effects on PTH receptors in the kidney and osteoblasts

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_

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

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

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??)

What is the structural similarity of ALL Bisphosphonates?

Bisphosphonates all have two phosphonate groups (inc **etidronate**, **Pamidronate**, **alendronate**)

Bisphosphates are all derivatives of \_\_\_\_\_\_\_\_\_

Bisphosphates are all derivatives of _inorganic pyrophosphoric acid (AKA **pyrophosphate**)_

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

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)

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