The Skeleton and Metabolism Flashcards
What are the hormones with skeletal effects?
- Oestrogen that is important for maintaining bone health
- Androgens that are important for maintaining bone health
- Cortisol affects bone and can be detrimental at excessive levels.
- Parathyroid hormone (PTH) is involved in bone maintenance and regulation of extracellular calcium and phosphate.
- Vitamin D (Calcitriol) is involved in bone maintenance and regulation of extracellular calcium and phosphate
- Calcitonin
What hormones are secreted from the skeleton?
FGF-23 (fibroblast growth factor 23)
Where is the majority of calcium in the body?
There is a large amount of calcium in the body but a large amount of it is locked away in bone.
Where is the minority of calcium in the body?
Extracellular free calcium - in plasma and interstitial fluid.
What is extracellular free calcium important for and what does this mean for its regulation?
It is important for many physiological processes such as electrical signalling. It needs to be tightly regulated around 2.2 - 2.6 mmol per litres
Why does calcium intake and outake needed to be balanced?
To mantain calcium homeostasis
What happens to most of the calcium intake?
80% is lost from the gut
2% is excreted by the kidney
What is the recommended daily intake of calcium?
1000-1200 mg (25-30 mmol)
What is calcium bound to?
It is half protein bound mainly to albumin
What is the major function of bone?
Bone as a metabolic organ. Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with:
- PTH
- Vitamin D
- Calcitonin
- FGF-23
What synthesises PTH and where are these cells found?
PTH is synthesised by parathyroid glands with parathyroid chief cells. These are usually 4 small glands located on the posterior surface of the thyroid gland. There is some variability of number and location between individuals.
How many chief cells do the parathyroid glands contain?
Contain about 80,000 chief cells
What do the chief cells do?
They mointor the extracellular calcium and adjust their secretion.
How many amino acids is PTH secreted as?
84 amino acids
What is PTH like in circulation?
It has a short half-life in circulation
What is the major role of PTH?
Defence against hypocalcaemia
How does PTH maintain plasma Ca?
As calcium moves towards the lower end of the range, then PTH is secreted near maximal and equally as calcium levels rise above the maximal level it is suppressed to minimal levels. This is negative feedback - homeostatic relationship.
What senses the free calcium?
It is sensed by GPCR on chief cells - calcium sensing receptor. Activation of this sensor by free Ca in the extracellular fluid regulates PTH synthesis and secretion in an inverse manner. As extracellular calcium rises, PTH secretion falls.
What happens when Ca binds to the GPCR on the chief cells?
It supresses PTH release.
What is calcitriol?
Otherwise known as Vitamin D, it is a steriod hormone, not a vitamin.
What does the calcitriol nuclear receptor do?
It activates different transcription of target genes, or less commonly can repress transcription of some genes.
When is calcitriol synthesised?
It is synthesised in skin in response to exposure to UV (‘sunshine vitamin’).
How is vitamin D activated?
By 2 metabolic steps:
- The initial product is hydroxylated in the liver to form 25OH D3, a major circulating metabolite. This is the prohormone.
- The final activation step: 1-alpha hydroxylation of 25OH D3 in kidney produces (catalyses) 1,25(OH)2 D3, or calcitriol, the active hormone.
What is measured in the blood to test vitamin D levels?
The prohormone, not yet activated, if serum measurements of vitamin D is needed as it indicates the amount of vitamin D activated form the body has.
What controls the levels of calcitriol?
1-alpha hydroxylase in the kidneys. This determines the active pool of calcitriol.
What increases the activity of 1-alpha hydroxylase?
PTH
Low phosphate - decreasing phosphate in the plasma can lead to increased activation of vitamin D
What are the actions of Calcitriol?
- Increase absorption of Ca and Pi from the GI tract; there is little absorbance in absence
- Inhibits PTH secretion by decreasing level of transcription in the parathyroid gland
- Complex effects on bone, generally in synergy with PTH so vitamin D is vital for normal mineralisation of bone
What are the actions of PTH?
- Promotes release of Ca from bone which prevents hypokalaemia to maintain calcium levels in bone
- Increases renal Ca reabsorption by activating specific renal tissue transporters
- Increases renal Pi excretion by action on specific renal tissue transporters
- Upregulates 1-alpha hydroxylase activity activates vitamin D
Where is calcium found in the body?
- 99% of bone calcium
- 1% is mainly intracellular
- Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance
What is the effect of PTH on bone in regards to Calcium?
It increases calcium turnover by releasing calcium from bone. It directly increases the reabsorption, so the fraction of calcium being excreted will be decreased - increasing extracellular calcium.
What is the effect of PTH on bone in regards to phosphate?
It increases the excretion of phosphate, if the extracellular calcium drops, reabsorption can be increased to counteract that drop. However, phosphate needs to drop to maintain the homeostasis of minerals.
Summarise the effect of PTH on bone
Increases reabsorption of calcium and increases excretion of phosphate to maintain homeostasis of minerals.
More Calcium = Less phosphate
How does PTH increase the absorption of calcium and phosphate from the GI tract?
It increases the express of 1-alphahydroxylase enzyme in the kidney which will increase the levels of active Calcitriol. Calcitriol increases the absorption of calcium and phosphate from the GI tract.
Where does PTH act on bone?
- Acts on PTH receptors on osteoblasts and osteoclasts.
- Promotes bone formation by osteoblasts
- Activates osteoclasts via RANKL; indirectly and directly
- Promotes bone remodelling
What does the effect of PTH partly depend on?
It partly depends on concentration dynamics. Intermittent low doses are anabolic. Persistant high concentration leads to excess resorption over formation leading to bone loss.
What can PTH treatment be used for?
It can be used as a therapy of diseases of bone mineralisation particularly osteoporosis. If PTH rises and stays, then it will have the net effect of releasing calcium from bone.
What is calcitonin?
32 amino acid peptide
What secretes calcitonin and what is the stimulus for secretion?
It is secreted by C cells of thyroid. The stimulus for secretion is high calcium concentration.
What is the affect of calcitonin?
It has the opposite effect to PTH. The net effect is to decrease extracellular calcium.
How does calcitonin work?
It decreases extracellular calcium via the renal transporters. It inhibits osteoclasts to inhibit calcium release from bone.
What is the use of calcitionin in humans?
There is little evidence that it has a significant role in calcium homeostasis. Calcium homeostasis works well without it. This was discovered in cases where the thyroid was removed and there was no C cells. It didn’t disrupt the calcium balance.
What is the target organs for calcitonin?
Kidney: decreases calcium and phosphate
Bone: decreases bone resorption by inhibiting osteoclast activity
What can synthetic calcitonin be used for?
Synthetic calcitonin used in treatment of Paget’s disease of bone and severe osteoporosis
What is the lacunar-canalicular network used for?
It allows communication between osteocytes and from osteocytes to surface cells and systemic circulation.
What is the lacunae?
They are small cell sized holes where the osteocytes live when they intune themselves into bone after terminal differentiation.
What is the canaliculi?
It is a fine network of tubes running between lacunae and from lacunae to the surface o f the bone in both directions.
What secretes FGF-23?
A hormone secreted by osteocytes
Where does FGF-23 act?
It is synthesised and released by osteocytes and acts on receptors in the kidney.
What happens to FGF-23 usually?
It is normally enzymatically cleaved and degraded, limiting its half-life
What is hypophosphatemic ricketts?
Rare-phosphate wasting (excess phosphate excretion) condition leading to bone mineralisation defects (osteomalacia).
What is vitamin D resistant ricketts and give an example
Normally ricketts would be treated by vitamin D but in rare cases is resistant. One example is hypophosphatemic ricketts.
What is the role of FGF-23 and how was it discovered?
The central role is in phosphate homeostasis. This was found when genetic analysis found that they identified mutations involving a substitution in the cleavage recognition sequence which means that the FGF-23 peptide wasn’t cleaved, meaning the molecule remained active and thus excessive phosphate loss.
Describe the action of FGF-23 briefly
- Expressed and secreted by osteocytes
- Increased by calcitriol and Pi
- Inhibits calcitriol synthesis
- Increases renal Pi excretion (by reducing Na-Pi reabsorption from proximal tubule).
How does the rise in extracellular Pi stimulate FGF-23?
If there is a rise, this stimulates the secretion of FGF-23 from the osteoclasts that in turn promotes phosphate excretion via the kidney. In addition, FGF-23 interacts with other loops. It inhibits alpha-1 hydroxylase activity thereby decreasing calcitriol levels.
What is the normal range of calcium?
2.2 - 2.6 mM
Hypocalcaemia
below the normal range
Hypercalcaemia
above the normal range
Clinical features of hypercalcaemia
- Depression
- Fatigue
- Anorexia
- Nausea
- Vomiting
- Abdominal pain
- Constipation
- Renal calcification (kidney stones) - Calcification (precipitation) which causes kidney stones
- Bone pain
What are the severe features of hypercalcaemia?
- Cardiac arrhythmias
- Cardiac arrest
What are the most common causes of hypercalcaemia?
Ambulatory causes: primary hyperparathyroidism
Hospitalised patients: malignancy
What are the less common causes of hypercalcaemia?
- Hyperthyroidism
- Excessive intake of vitamin D
What is primary hyperparathyroidism?
- Excess secretion of PTH
- usually due to a benign adenoma in one or more of the PT glands.
What percentage of patients present with bone disease and kidney stones?
10% present with clinical evidence of bone disease
10-20% present with kidney stones
How is primary hyperparathyroidism resolved?
Resolved by surgical removal of affected gland(s)
What is hypercalcaemia of malignancy?
Common problem of advanced malignancy.
Tumour may secrete PTH-related peptide which binds and activates PTH receptor. This will mimic the effects of excessive PTH. This can lead to bone disease, cancer and hypercalcaemia.
