Lecture 30: Bone Minerals Flashcards
What is the principal reservoir for calcium and phosphate?
Bone
Why is regulation of Calcium and Phosphate important?
- Health/strength of bones
- Ca balance has effects on electrical excitability of cells
- Ca is an essential intracellular signal
What are the major targets of Ca2+ and PO43- control?
The Gut, Kidney and Bone
What is resorption?
The breakdown of bone which allows calcium to go into the bloodstream
what do Osteoblasts cause?
Deposition of bone
What do osteoclasts cause?
Resorption of bone
What are the major regulators of bone remodelling?
Vitamin D metabolites and PTH
How can Osteoclasts be activated?
Osteoclasts must be activated by osteoblasts that release the Rank Ligand which binds to osteoclasts and binds to the Rank receptor on osteoclasts
What are Parathyroid Hormones effects on the bone?
It promotes bone resorption indirectly through RANKL so it increases Ca and PO4 levels
What are Parathyroid Hormones effects on the Kidney?
It promotes Ca absorption and promotes PO4 excretion
What is the net effect of Parathyroid hormone?
It increases calcium and PO4 in the blood
Where is parathyroid hormone released from?
The parathyroid gland
What is PTH made is response to?
Reduced levels of circulating calcium
Why does PTH promote phosphate excretion in the kidneys?
So it doesn’t form precipitates, crystals and stones
How does PTH affect vitamin D in the kidneys?
It promotes the processing of vitamin D to its active form
What causes PTH to be released?
Decreased levels of circulating calcium
How does the parathyroid gland sense the level of circulating calcium?
It has calcium-sensitive receptors
What kind of Hormone is Vitamin D?
A steroid hormone
What is vitamin D metabolized in the liver to form?
- Calcitriol (1,25-hydroxy vitamin D3)
* Calciferol (24,25-hydroxy D3)
What is the active form of the Vitamin D metabolites?
Calcitriol (1,25-hydroxy vitamin D3)
How is vitamin D metabolized?
First the liver converts vitamin D3 to 25-OH-D3 and then the kidney converts this to Calcitriol and Secalciferol
What causes Secalciferol (24,25-hydroxy D3) to be produced?
High circulating levels of calcium or high levels of the calcitriol form
What does Vitamin D do?
Promotes the resorption of calcium to increase levels in the blood
What promotes the kidneys to produce Calcitriol (1,25-hydroxy vitamin D3)
High levels of PTH and low levels of circulating calcium
How does Vitamin D3 affect the kidney?
It increases calcium reabsorption from bones and promotes phosphate excretion
How does vitamin D3 affect the bone?
It promotes bone resorption and increases calcium and phosphate levels in the blood
How does vitamin D3 affect the gut?
It promotes the uptake of calcium and phosphate from the gut to increase circulating levels
What is the net effect of the active form of vitamin D3?
It increases circulating calcium and phosphate
Where does PTH exert it effects?
In kidneys and osteoblasts
What does PTH stimulation of vitamin D do?
It leads to vitamin D effects in gut, kidney and bone
What are the normal circulating levels of calcium?
2.2 mM total calcium, 1mM free caclcium
How can hypocalcemia be resolved short term?
The patient can be given calcium or an active D3 metabolite that will increase blood calcium levels
What can Hypocalcemia cause?
Hyperactivity of cells
What is an early symptom of Hypocalcemia?
Trousseau’s sign
what is a longer-term danger of Hypocalcemia?
Secondary hyperparathyroidism
What is secondary hyperparathyroidism?
A hyperactive parathyroid due to low plasma calcium due to kidney failure that stops reabsorption of Ca2+. So the parathyroid wants to increase circulating hormone by releasing PTH but there is no calcium being absorbed so its consistently being released
What does secondary hyperparathyroidism lead to?
The breakdown and weakening of bones
What usually causes long term Hypocalcemia?
- Hypoparathyroidism
* Vitamin D deficiency
How does Hypoparathyroidism cause Hypocalcemia?
A defect in the parathyroid gland that doesn’t allow it to produce parathyroid hormone
How is secondary hypoparathyroidism caused by hypocalcemia treated?
With vitamin D and calcium supplementation
How can Vitamin D deficiency cause Hypocalcemia?
The inability to generate vitamin D metabolites
How can hypocalcemia caused by vitamin D deficiency be resolved?
By dietary correction or ingestion of active Vit D3 metabolites (calcitriol), sunshine
What is Hypercalcemia?
Too much circulating calcium
What does acute hypercalcemia cause?
Loss of cellular excitability, lethargy, coma, pain in bones due to excessive PTH
What causes Hypercalcemia long-term?
Primary hyperparathyroidism
What can primary hyperparathyroidism be due to?
A tumor
What is treatment form primary hyperparathyroidism?
- Resection of the gland
- Bisphosphonates, calcitonin, inhibitors of bone resorption
- Calcimimetics
What are Calcimimetics?
Drugs that mimic the effects of calcium on the calcium receptors causing negative feedback and decrease the amount of parathyroid hormone released
What is Osteoporosis?
A loss in bone density
Why is osteoporosis seen in post-menopausal women?
because estrogen promotes bone deposition
What is one of the ways the osteoporosis can be treated and what are their downsides?
Hormone replacement - but they have serious adverse effects like cancers
What are other common causes of osteoporosis aside from hormones?
- Glucocorticoid administration
* Hyperparathyroidism
What is Teripide used to treat?
Osteoporosis
How does Teriparatide work?
It acts on osteoblasts to activate them but because it doesn’t give enough for them to activate osteoclasts causing deposition
What are Bisphosphonates used to treat?
Osteoporosis
How do Bisphosphonates work?
They inhibit osteoclast resorption of bone through inhibiting glucocorticoids. They also have a toxic effect on osteoclasts
How do glucocorticoids affect the deposition of bone?
They tend to promote the activity of osteoclasts which cause resorption of bones and suppress the activity of osteoblasts
Why do bisphosphonates have a toxic effect on osteoclasts?
The phosphonate groups of the bisphosphonates have a high affinity for Ca2+ so they accumulate in bone allowing osteoclasts to target them
What is Osteoprotegerin used to treat?
Osteoporosis
How does Osteoprotegerin work?
It competes with RANK by binding to RANKL and inhibiting activation which inhibits bone resorption by osteoclasts
What is Denosumab used to treat?
Osteoporosis
How does Denosumab work?
It is an antibody against RANKL, and mimics osteoprotegerin
