The Skeleton and Metabolism Flashcards
List some hormones that have affects on the skeleton
- Oestrogen
- Androgens
- Cortisol
- Parathyroid hormone (PTH)
- Vitamin D (calcitriol)
Calcitonin
What is our daily calcium turnover?
Daily calcium intake is recommended to be at 1000-1200mg (25-30 mmol).
Extracellular calcium levels are kept at 2.2-2.6 mmol/L.
About half is free [Ca2+] (physiologically active), and the other half is protein bound (mainly to albumin).
How does bone function as a metabolic organ?
Bone turnover serves the homeostasis of serum calcium and phosphate.
These are the hormones involved:
- parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
Describe the parathyroid hormone (PTH)
PTH is synthesised by parathyroid chief cells, which is secreted as an 84 amino acid polypeptide. It has a short half-life in the circulation of <5 minutes.
It has a major role in defence against hypocalcaemia.
Free calcium is sensed by GPCR on chief cells. Calcium binding to them suppresses PTH release.
What is vitamin D?
A steroid hormone called calcitriol that is synthesised in the skin in response to exposure to UV
How is vitamin D activated?
It is activated by 2 metabolic steps:
1) The initial product is hydroxylated in the liver, and forms 25OH D3, major circulating metabolite. You can think of it as a prohormone, and this is what we use for serum measurements of vitamin D because it indicates the amount of activated form.
2) The final activation step: a 1a hydroxylase enzyme located in kidney cells then catalyses 25 OH D3 into 1,25(OH)2, or calcitriol, which is the active hormone, active form of vitamin D
What are the actions of calcitriol?
- increase absorption of calcium and phosphate from the GI tract
- inhibits PTH secretion (transcription)
- complex effects on bone, generally in synergy with PTH
What are the actions of PTH?
- promotes release of calcium from the bone
- increases renal calcium reabsorption
- increases renal phosphate secretion
- up-regulates 1α hydroxylase activity
What are the actions of PTH on bone?
(since there are PTH receptors on oestoblasts and osteocytes)
- promotes bone formation
- activates osteoclasts via RANKL
- promotes bone remodelling
The effect depends on the concentration dynamics:
- intermittent low doses are anabolic
- persistent high concentration leads to excess resorption over formation - bone loss
What is calcitonin?
Another hormone secreted by the thyroid gland, involved in calcium homeostasis in the opposite direction to PTH, its net effect is to decrease extracellular calcium
It does this via:
- Renal transporters. It decreases the reabsorption of calcium and phosphate
- It inhibits osteoclast activity, decreasing bone reabsorption
Synthetic calcitonin has been used as a treatment in particular types of bone diseases, like Paget’s disease and severe osteoporosis
What is the purpose of the Lacunar-Canalicular network?
it allows for the communication between osteocytes, and from osteocytes to surface cells and the systemic circulation
Describe fibroblast growth factor 23 (FGF-23)
It was discovered in 2000.
Hypophosphatemic rickets is a rare phosphate-wasting condition leading to bone mineralisation effects (osteomalacia). Consortium investigating autosomal-dominant hypophosphatemic rickets (ADHR) traced a mutation in a gene that turned out to be FGF-23.
Thus, we know it has a central role in phosphate homeostasis.
What are the actions of FGF-23?
- expressed and secreted by osteocytes
- increased by calcitriol and phosphate
- inhibits calcitriol synthesis
- increases renal phosphate excretion (by reducing Na-Pi reabsorption from the proximal tubule)
What are the symptoms of hypercalcaemia?
Symptoms are vague, which make it difficult to diagnose
- Depression
- Fatigue
- Anorexia
- Nausea
- Vomiting
- Abdominal pain
- Constipation
- Renal calcification (kidney stones)
- Bone pain
SEVERE:
- Cardiac arrhythmias
- Cardiac arrest
What are some causes of hypercalcaemia?
The most common causes:
- in ambulatory patients: primary hyperparathyroidism
- in hospitalised patients: malignancy
Less common causes include:
- hyperthyroidism
- excessive intake of Vitamin D
