The Skeleton and Metabolism Flashcards
List the hormones that display skeletal effects?
- 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
What hormone is secreted from the skeleton?
FGF-23 (fibroblast growth factor 23)
What is extracellular free calcium important for and what does it mean for its regulation?
Important for physiological processes e.g electrical signalling
Why does Ca2+ intake and outtake need to be balanced?
Maintains Ca2+ homeostasis
What molecule is calcium often bound to?
- Half of the calcium present is free [Ca2+] (physiologically active)
- Half is protein bound (mainly albumin)
How is bone a metabolic organ?
Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with
- Parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
What synthesises PTH?
PTH is synthesised by parathyroid chief cells on the parathyroid gland
- Chief cells monitor extracellular calcium and adjust their function
What is the main role of PTH?
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
What happens when Ca binds to GPCR on the chief cells?
Supresses PTH release
What is calcitriol?
Known as vitamin D, is a steroid hormone not a vitamin
What does the calcitriol nuclear receptor do?
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
What is vitamin D increased by?
- PTH
- Low phosphate in plasma
What are the actions of vitamin D?
- 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
What are the actions of PTH?
- 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
What is the action of PTH on bone?
- PTH receptors are present osteoblasts and osteoclasts
- Promotes bone formation
- Activates osteoclasts via RANKL
- Promotes bone remodelling
What is the effect of PTH on bone in regards to calcium
Promotes release of Ca from bone (as PTH is the main defence against hypocalcaemia)
What is the effect of PTH on bone in regards to phosphate?
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
Summarise the effect of PTH on bone?
- Increases reabsorption of Ca2+ and increased excretion of phosphate
- Maintains homeostasis of minerals
- More calcium = less phosphate
How does PTH increase the absorption of calcium and phosphate from the GI tract?
- 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
What does the effect of PTH partly depend on?
Concentration dynamic
- Intermittent low doses anabolic - promotes remodelling
- Persistent high concentration leads to excess resorption over formation leading to bone loss
What is calcitonin?
- Secreted by C cells of thyroid
- Stimulus for secretion is high [Ca2+]
What is the effect of calcitonin?
- Opposite effect of PTH
- The net effect is to decrease extracellular calcium
How does calcitonin work?
- Decreases extracellular calcium via renal transporters
- Inhibits osteoclasts to inhibit calcium release from bone
Target organs for calcitonin
Kidney - decreases calcium and phosphate
Bone - decreases bone resorption by inhibiting osteoclast activity
What can synthetic calcitonin be used for?
Treatment of paget’s disease of bone and severe osteoporosis
Calcitonin inhibits osteoclasy activity = reduction in bone reabsorption = weakening of bones
What is the lacunar-canalicular network?
Allows for the communication between osteocytes and from osteocytes to surface cells and systemic circulation
What are the lacunae?
Small cell sized holes where osteocytes live when they intune themselves into bone after terminal differentiation
What secretes FGF-23?
Hormone secreted by osteocytes
Where does FGF-23 act?
- Expressed and secreted by osteocytes
- Increased by calcitriol and Pi
- Inhibits calcitriol synthesis
- Increases renal Pi excretion
What is hypophosphatemic rickets?
Hypophosphatemic rickets: rare phosphate-wasting conditions leading to bone mineralization 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 rickets
How does the rise in extracellular Pi stimulate FGF-23?
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
What is hypocalcaemia?
Below normal range of 2.2 - 2.6 mM
What is hypercalcaemia?
Above normal range of 2.2-2.6 mM
What are the clinical features of hypercalcaemia?
- Depression
- Fatigue
- Anorexia
- Nausea
- Vomiting
- Abdominal pain
- Constipation
- Renal calcification
- Bone pain
Mnemonic = ‘painful bones, renal stones, abdominal groans and psychic moans’
What is a severe features of hypercalcaemia?
- Cardiac arrhythmias
- Cardiac arrest
What are common causes of hypercalcaemia?
Ambulatory patients = primary hyperparathyroidism
Hospitalized patients = malignancy (secondary release of PTH from tumour cells)
Less common causes of hypercalcaemia?
Hyperthyroidism
Excessive intake of vitamin D
Describe primary hyperparathyroidism
- Excessive secretion of PTH
- Due to benign adenoma in one or more of the parathyroid glands
How is primary hyperparathyroidism resolved?
Through surgical removal of affected glands
What is hypercalcaemia of malignancy?
- 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
- Mimics the effects of excessive PTH
