Skeleton and metabolism Flashcards
Hormones with skeletal effects
- Oestrogen
- Androgens
- Cortisol
- Parathyroid hormone (PTH)
- Vitamin D (calcitriol)
- Calcitonin
Hormones secreted from the skeleton
• FGF-23 (fibroblast growth factor 23)
Bone as 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
Daily calcium turnover
Daily intake recommended 1000-1200mg (25-30 mmol)
Extracellular: plasma Ca 2.2-2.6 mmol L-1
About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin)
AW Ca = 40, 40 mg = 1 mmol. 900/40 = 22.5 mmol in ECF.
Parathyroid glands
- PTH synthesised by parathyroid chief cells
- Secreted as 84 AA polypeptide
- Short half-life in circulation (<5 min)
- Parathyriod. 80K cells continuously monitoring blood Ca, and increasing or decreasing PTH secretion accordingly.
Parathyroid hormone (PTH)
- Major role is defence against hypocalcaemia
- Plasma Ca is maintained 2.2 – 2.6 mM (free, ionized Ca2+ is approximately half)
- Free Ca sensed by GPCR on chief cells
- Ca binding supresses PTH release
Vitamin D
- Calcitriol (really a steroid hormone, not a vitamin!)
- Synthesised in skin in response to exposure to UV (‘sunshine vitamin’)
- Activated by 2 metabolic steps
Actions of PTH
Site of regulation is chief cells of PT gland
• Secretion increases as plasma [Ca2+] decreases
Actions:
• Promotes release of Ca from bone
• Increases renal Ca reabsorption
• Increases renal Pi excretion
• Upregulates 1α hydroxylase activity
Actions of calcitriol
Site of regulation is control of 1α hydroxylase in kidney
Increased by
• PTH
• Low phosphate
Actions:
• Increase absorption of Ca and Pi from GI tract
Little absorption in absence
• Inhibits PTH secretion (transcription)
• Complex effects on bone, generally in synergy with PTH
• The only way to increase the body’s Ca reservoir is via absorption from the gut, and little takes place in the absence of vitamin D.
Calcium homeostasis
- 99% of body calcium is in bone
- Remaining 1% is mainly intracellular
- Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance
Actions of PTH on bone
• PTH receptors on osteoblasts and osteoclasts
• Promotes bone formation
• Activates osteoclasts via RANKL
• Promotes bone remodelling
Effect depends on concentration dynamics
• Intermittent low doses are anabolic
• Persistent high concentration leads to excess resorption over formation – bone loss
Lacunar-Canalicular network
• Allows communication between osteocytes and from osteocytes to surface cells and systemic circulation
FGF-23: a hormone secreted by osteocytes
- Hypophosphatemic rickets: rare phosphate-wasting conditions leading to bone mineralization defects (osteomalacia)
- Consortium investigating autosomal-dominant HR (ADHR) traced mutation in gene that turned out to be FGF-23
Actions of FGF-23
- Expressed and secreted by osteocytes
- Increases renal Pi excretion (by reducing Na-Pi reabsorption from proximal tubule)
- Increased by calcitriol and Pi
- Inhibits calcitriol synthesis
Disorders of calcium
- Normal range 2.2 – 2.6 mM
- Hypocalcaemia
- Hypercalcaemia
Clinical features of hypercalcemia
- Depression, fatigue, anorexia, nausea, vomiting,
- Abdominal pain, constipation
- Renal calcification (kidney stones)
- Bone pain
- Severe: cardiac arrhythmias, cardiac arrest
- The deleterious effects are partly due to the fact that ionic Ca is near saturation and rises can lead to precipitation (calcification). There may also be direct neurological effects.
Hypercalcemia saying
“painful bones, renal stones, abdominal groans, and psychic moans,”
Causes of hypercalcaemia
Most common causes: • In ambulatory patients: primary hyperparathyroidism • In hospitalized patients: malignancy Less common causes include: • Hyperthyroidism • Excessive intake of vitamin D
Primary hyperparathyroidism
- Usually due to a benign adenoma in one or more PT glands
- Often detected on screening – many patients asymptomatic
- ~10% of patients present with clinical evidence of bone disease
- 10 - 20% of patients present with kidney stones
- Resolved by surgical removal of affected gland(s)
Hypercalcaemia of malignancy
- Common problem of advanced malignancy
* Tumour may secrete PTH-related peptide, binds and activates PTH receptor
Site of regulation of PT gland
Is Chief cells
• Secretion increases as plasma [Ca2+] decreases
