The Skeleton and Metabolism

Question 1

List the hormones that display skeletal effects?

Answer 1

• Oestrogen = maintains bone health
• Androgens = maintains bone health
• Cortisol = detrimental in excess
• Parathyroid hormone (PTH) = bone maintenance + regulation of extracellular Ca2+ + phosphate
• Vitamin D (calcitriol) = bone maintenance and regulation of extracellular Ca2+ + phosphate
• Calcitonin

Question 2

What hormone is secreted from the skeleton?

Answer 2

FGF-23 (fibroblast growth factor 23)

Question 3

What is extracellular free calcium important for and what does it mean for its regulation?

Answer 3

Important for physiological processes e.g electrical signalling

Question 4

Why does Ca2+ intake and outtake need to be balanced?

Answer 4

Maintains Ca2+ homeostasis

Question 5

What molecule is calcium often bound to?

Answer 5

• Half of the calcium present is free [Ca2+] (physiologically active)
• Half is protein bound (mainly albumin)

Question 6

How is bone a metabolic organ?

Answer 6

Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with

• Parathyroid hormone (PTH)
• Vitamin D (1,25-dihydroxy D3)
• Calcitonin
• FGF-23

Question 7

What synthesises PTH?

Answer 7

PTH is synthesised by parathyroid chief cells on the parathyroid gland

• Chief cells monitor extracellular calcium and adjust their function

Question 8

What is the main role of PTH?

Answer 8

Major role is defence against hypocalcaemia

• As free Ca2+ levels are low serum PTH levels rise, as free Ca2+ levels are high serum PTH levels decrease.
• Linear region = negative feedback homeostatic function

Question 9

What happens when Ca binds to GPCR on the chief cells?

Answer 9

Supresses PTH release

Question 10

What is calcitriol?

Answer 10

Known as vitamin D, is a steroid hormone not a vitamin

Question 11

What does the calcitriol nuclear receptor do?

Answer 11

Synthesised in the skin in response to exposure to UV (‘sunshine vitamin’)

Activated by 2 metabolic steps

• 25 hydroxylation in the liver to form 25OH D3, which is the major circulating metabolite (not activated form essentially a prohormone)
• 1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone

Steroid hormone therefore binds to a nuclear receptor activating the transcription of target genes

Question 12

What is vitamin D increased by?

Answer 12

• PTH
• Low phosphate in plasma

Question 13

What are the actions of vitamin D?

Answer 13

• Increase absorption of Ca and Pi from GI tract
  
  • Little absorption in absence
• Inhibits PTH secretion (transcription)
  
  • In a negative feedback mechanism
• Complex effects on bone, generally in synergy with PTH

Question 14

What are the actions of PTH?

Answer 14

• Promotes release of Ca from bone (as PTH is the main defence against hypocalcaemia)
• Increases renal Ca reabsorption
• Increases renal Pi excretion
• Upregulates 1α hydroxylase activity which activates vitamin D

Question 15

What is the action of PTH on bone?

Answer 15

• PTH receptors are present osteoblasts and osteoclasts
• Promotes bone formation
• Activates osteoclasts via RANKL
• Promotes bone remodelling

Question 16

What is the effect of PTH on bone in regards to calcium

Answer 16

Promotes release of Ca from bone (as PTH is the main defence against hypocalcaemia)

Question 17

What is the effect of PTH on bone in regards to phosphate?

Answer 17

Increases excretion of phosphate, if extracellular Ca2+ drops, reabsorption can be increased to counteract the drop

However, phosphate needs to drop to maintain the homeostasis of minerals

Question 18

Summarise the effect of PTH on bone?

Answer 18

• Increases reabsorption of Ca2+ and increased excretion of phosphate
  
  • Maintains homeostasis of minerals
• More calcium = less phosphate

Question 19

How does PTH increase the absorption of calcium and phosphate from the GI tract?

Answer 19

• Increases the expression of the 1-alphahydroxylase enzyme in the kidney which increases levels of calcitriol.
• Calcitriol increases absorption of calcium and phosphate from the GI tract

Question 20

What does the effect of PTH partly depend on?

Answer 20

Concentration dynamic

• Intermittent low doses anabolic - promotes remodelling
• Persistent high concentration leads to excess resorption over formation leading to bone loss

Question 21

What is calcitonin?

Answer 21

• Secreted by C cells of thyroid
• Stimulus for secretion is high [Ca2+]

Question 22

What is the effect of calcitonin?

Answer 22

• Opposite effect of PTH
• The net effect is to decrease extracellular calcium

Question 23

How does calcitonin work?

Answer 23

• Decreases extracellular calcium via renal transporters
• Inhibits osteoclasts to inhibit calcium release from bone

Question 24

Target organs for calcitonin

Answer 24

Kidney - decreases calcium and phosphate

Bone - decreases bone resorption by inhibiting osteoclast activity

Question 25

What can synthetic calcitonin be used for?

Answer 25

Treatment of paget’s disease of bone and severe osteoporosis

Calcitonin inhibits osteoclasy activity = reduction in bone reabsorption = weakening of bones

Question 26

What is the lacunar-canalicular network?

Answer 26

Allows for the communication between osteocytes and from osteocytes to surface cells and systemic circulation

Question 27

What are the lacunae?

Answer 27

Small cell sized holes where osteocytes live when they intune themselves into bone after terminal differentiation

Question 28

What secretes FGF-23?

Answer 28

Hormone secreted by osteocytes

Question 29

Where does FGF-23 act?

Answer 29

• Expressed and secreted by osteocytes
• Increased by calcitriol and Pi
• Inhibits calcitriol synthesis
• Increases renal Pi excretion

Question 30

What is hypophosphatemic rickets?

Answer 30

Hypophosphatemic rickets: rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)

Question 31

What is vitamin D resistant ricketts and give an example?

Answer 31

Normally ricketts would be treated by vitamin D but in rare cases is resistant

One example is hypophosphatemic rickets

Question 32

How does the rise in extracellular Pi stimulate FGF-23?

Answer 32

Rise stimulates secretion of FGF-23 from osteoclasts that promote phosphate excretion via kidney

FGF-23 interacts with other loops, it inhibits alpha-1 hydroxylase decreasing calcitriol

Question 33

What is hypocalcaemia?

Answer 33

Below normal range of 2.2 - 2.6 mM

Question 34

What is hypercalcaemia?

Answer 34

Above normal range of 2.2-2.6 mM

Question 35

What are the clinical features of hypercalcaemia?

Answer 35

• Depression
• Fatigue
• Anorexia
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Renal calcification
• Bone pain

Mnemonic = ‘painful bones, renal stones, abdominal groans and psychic moans’

Question 36

What is a severe features of hypercalcaemia?

Answer 36

• Cardiac arrhythmias
• Cardiac arrest

Question 37

What are common causes of hypercalcaemia?

Answer 37

Ambulatory patients = primary hyperparathyroidism

Hospitalized patients = malignancy (secondary release of PTH from tumour cells)

Question 38

Less common causes of hypercalcaemia?

Answer 38

Hyperthyroidism

Excessive intake of vitamin D

Question 39

Describe primary hyperparathyroidism

Answer 39

• Excessive secretion of PTH
• Due to benign adenoma in one or more of the parathyroid glands

Question 40

How is primary hyperparathyroidism resolved?

Answer 40

Through surgical removal of affected glands

Question 41

What is hypercalcaemia of malignancy?

Answer 41

• Common problem of advanced malignancy
• Tumour secretes PTH related peptide activating the PTH receptor
  
  • Mimics the effects of excessive PTH
    
    • Leads to bone disease, cancer and hypercalcaemia