CEP - Parathyroid Hormone, Calcium and Bone (Lecture 13)

bad to the bone

What are the functions of bones?

• Protection of vital organs.

• Support and attachment of muscles.

• Act as a reservoir for calcium.

What are the two general layers of bones? Describe these layers.

• Cortical bone – Dense, hard outer layer. Makes up most of bone mass.

• Trabecular bone – Porous inner layer where blood cells are produced. 

Which layer of bone is synthesised and resorbed at a higher rate?

Trabecular Bone

What is the bone mainly made up of?

The bone is made mainly of calcium-phosphate salt crystals such as hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂).

What other things does the bone contain?

It also contains an organic matrix of collagen fibres, proteoglycans, and cells. The bones also contain free Ca²⁺ as well as the salt-bound form. 

What is bone remodelling? (simple definition)

Bone remodelling is the dynamic renewal of bone tissue as a result of activity of osteoclasts and osteoblasts.

What events occur in bone remodelling?

1. Osteoblasts activate osteoclasts through the release of bone cell cytokines.

2. Osteoclasts act to break down part of the bone, by release of H⁺ ions and proteases (RANKL) onto the bone surface.

3. This releases Ca²⁺ and PO₄^3- and other components of the bone, forming pits called Howship’s Lacunae. Also released are growth factors that increase osteoblast production and decrease osteoclast activity. Osteoclasts can also be inhibited by oestrogen.

4. Osteoblasts then reform the bone, using extracellular Ca²⁺. Osteoblast activity can be promoted by IGF-1.

5. During bone formation, initially collagen and proteoglycans are secreted by osteoblasts in layers before the calcium salts are added. The uncalcified collagen structure is known as the osteoid.

What things does serum calcium concentration depend on?

• absorption of calcium from food

• excretion in urine and faeces

• calcification/decalcification of bone

What are the components of the body’s calcium and how much of each component is there?

• 0.1% is extracellular

• 98.9% is stored in bones

• 1.0% is stored in other cells apart from cells in bones

What forms can calcium take in the blood and how much calcium takes each form?

• free and ionised in the blood as Ca²⁺

• protein bound, or unionised as part of another molecule

• around 50% of the calcium is in the free ionised form, the rest is either protein-bound or unionised.

How much of ingested calcium is excreted and how are they excreted?

• Around 65% of ingested calcium is excreted in the faeces, and a further 10% is excreted in urine.

• The rest is present in the blood and may be used for bone calcification.

What are the functions of calcium?

• Formation of bone.

• Involved in action potential transmission at synapses.

• Involved in muscular contraction.

• Involved in cellular communication.

• Involved in cell adhesion.

• Regulates excitability of muscles.

How is Vitamin 1,25D3 produced?

1. Acetate and 7-dehydrocholesterol are converted to previtamin D in the skin, using UV radiation. 

2. Previtamin D is converted to vitamin D₃ in the skin.

3. Vitamin D₃ then undergoes hydroxylation by the liver to form 25-hydroxyvitamin D₃.

4. 25-hydroxyvitamin D₃ is hydroxylated by the kidneys to 1,25-Dihydroxyvitamin D₃, stimulated by PTH.

Can Vitamin D3 be ingested?

Yes, around 10% of vitamin D3 is directly absorbed through diet (fish, egg, fortification of food) or medication.

What is PTH?

• Parathyroid hormone, which is a peptide hormone with 84 amino acids that is produced by the parathyroid glands to increase calcium levels in the blood.

• Only the first 34 amino acids have biological activity.

What are the normal serum PTH levels?

range from 1.6-6.9pmol/l

Which sort of receptors does PTH bind to?

PTH binds to G-protein coupled receptors, mainly on kidney cells and osteoblasts. 

What are the four main mechanisms of action of PTH?

1. Stimulates reabsorption of Ca²⁺ by renal tubules, reducing Ca²⁺ excretion in urine.

2. Decreases phosphate (PO₄^3-) reabsorption by renal tubules, leading to more PO₄^3- excreted in urine, which increases serum Ca²⁺ levels.

3. Stimulates hydroxylation of 25-hydroxyvitamin D₃ in kidneys, to form 1,25-Dihydroxyvitamin D₃ (1,25D3).

4. Stimulates bone resorption, this is where Ca²⁺ from the bones is reabsorbed into the blood. It does this by stimulating osteoclast activity.

What is the difference between fast and slow responses to PTH?

• The fast response is an immediate release of Ca²⁺ by activation of existing osteoclasts.

• The slow response takes days, and results from the proliferation of more osteoclasts.

What are the mechanisms of Vitamin 1,25D3 in increasing calcium levels?

1. Stimulates Ca²⁺ and PO₄^3- absorption by the gut. It increases calcium absorption by increasing the concentration of Ca²⁺-binding protein which increases intestinal absorption of Ca²⁺.

2. Stimulates osteoclast activity.

3. Decreases renal excretion of Ca²⁺.

What is calcitonin?

A hormone released by parafollicular cells in the thyroid gland which can decrease serum Ca²⁺ levels.

How does calcitonin decrease calcium levels?

Inhibition of osteoclast activity, therefore inhibiting bone resorption. 

Can an individual survive without calcitonin?

Yes, as the effect of calcitonin is quite weak.

What is FGF23?

Fibroblast growth factor 23, which is produced by osteocytes and osteoblasts and acts to reduce serum PO₄^3- levels by inhibiting its renal reabsorption.

Give an example of how the secretion of FGF23 can be stimulated?

Secretion of FGF23 can be stimulated by 1,25D3.

What does hyperphosphatemia mean?

High levels of PO₄^3- in the blood

What symptoms does hyperphosphatemia cause?

• muscle weakness

• reduced cardiac contractility

• diaphragm muscle weakness

• confusion

• hallucinations

What is hypophosphatemia?

Low levels of PO₄^3- in the blood

How can hypophosphatemia be caused?

Can be caused by high levels of FGF23 in the blood. This could be due to:

• Tumour induced osteomalacia (TIO): Excessive production of FGF23 by osteocytes due to tumour.

• X-linked dominant hypophosphatemic rickets (XLR): Mutation in PHEX protease which breaks down FGF23. As it cannot function properly, FGF23 levels remain elevated.

• Autosomal dominant hypophosphatemic rickets (ADHR): Mutation in the FGF23 itself makes it immune to PHEX proteolysis, so levels remain elevated.

What is primary hyperparathyroidism?

• As a result of a parathyroid tumour/adenoma, or an overactive parathyroid gland, there is an increased secretion of PTH. 

• This leads to hypercalcaemia (high serum calcium levels) as well as hypophosphatemia.

What are the symptoms of hyperparathyroidism?

Symptoms include lethargy, confusion, thirst, polyuria, renal stones, joint pains, fractures, depression, and hypertension.

How can primary hyperparathyroidism be treated?

Treated by surgery to remove the tumour or surgery to remove a parathyroid gland.

What is secondary hyperparathyroidism?

• Elevated serum PTH levels as a result of renal disease, or another disease which lowers blood calcium.

• In case of renal disease, the kidneys might not be able to convert vitamin D₃ to Vitamin 1,25D3 as efficiently.

• Low vitamin 1,25D3 levels in the blood lead to reduced calcium levels, which leads to hyperparathyroidism as the body tries to recover the calcium levels.

• Could also be caused by calcium or vitamin D deficiency.

How can secondary hyperparathyroidism be treated?

Treated by phosphate binders or vitamin D supplements.

What occurs in those with rickets/osteomalacia and why does this occur?

• Lack of calcium mineralization of the osteoid (collagenous) component of the bone.

• This is because of failure to absorb sufficient calcium in the GI tract.

• This leads to soft bones.

How can rickets/osteomalacia be caused?

• This could be caused by vitamin D deficiency, either due to poor diet or lack of sunlight.

• There could also be a genetic component to the disease, such as XLR (X-linked dominant hypophosphatemic rickets) mentioned in the phosphate disorders. 

What is the difference between rickets and osteomalacia?

• Rickets: If the disorder occurs while the skeleton is growing, in developing children. Symptoms include bow legs and swollen joints.

• Osteomalacia: If the disorder occurs in an adult skeleton. Symptoms include bone pains and pseudofractures.

How can rickets and osteomalacia be treated?

Vitamin D replacement therapy

What is osteoporosis?

Loss of bone density due to a reduction in both mineral and non-mineral components of the bones. 

What can osteoporosis lead to?

Increased risk of fractures, particularly in more vulnerable bones such as the wrists, spine and hips.

How can osteoporosis occur?

• This occurs naturally during ageing, and in women it occurs drastically post menopause.

• Osteoporosis can also occur because of steroid use, for example glucocorticoid medications.

How does post-menopausal osteoporosis occur?

As a result of decline in oestrogen levels, which normally inhibit osteoclasts.

How can post-menopausal osteoporosis be countered?

Oestrogen replacement therapy

What can spinal osteoporosis lead to?

The accumulation of spinal fractures, which damage the integrity of the vertebral column and impact posture.

Give some examples of treatments for osteoporosis.

• Oestrogen replacement therapy.

• Denosumab – inhibits osteoclast development by blocking RANK ligands on osteoblasts, which would normally interact with RANK on osteoclasts to promote differentiation of pre-osteoclasts to osteoclasts.

• Bisphosphonates – inhibit osteoclast activity by disruption of intracellular enzymes.

• Teriparatide – first 34 amino acids of PTH. Stimulates osteoblast activity to stimulate bone formation.

How can we prevent osteoporosis?

• Risk for osteoporosis can be reduced by exercise which enhances osteoblast activity through bone stress.

• Also, risk can be reduced by vitamin D and calcium supplementation and a good diet to avoid deficiency, as well as avoiding smoking and avoiding excessive alcohol consumption.