Endocrinology and Disease of Bone Flashcards
How is vitamin D formed?
25-OH-D synthesized in skin from 7-dehydrocholesterol + UVB
(D3 Cholecalciferol and D2 Ergocalciferol from diet)
Calcidiol (25-OH-D) stored in liver
25-OH-D further hydroxylated in kidney forming
1,25(OH)2D (Active Vitamin D, Calcitriol)
Enzyme = 1 alpha hydroxylase
What can stimulate 1-alpha hydroxylase in the kidneys?
PTH (Parathyroid hormone)
What is the principle effect of calcitriol?
Increase calcium, magnesium and phosphate absorption in the small intestines
What are the other effects of calcitriol?
Increased reabsorption of calcium and decreased phosphate reabsorption in the kidneys (via FGF23)
Stimulates osteoclast formation from precursors
Stimulates osteoblasts to make osteoclast-activating factors (OAFs e.g. RANKL)
Inhibit PTH
What does vitamin D deficiency cause? State some symptoms.
Lack of bone mineralisation
Softening of bone (can lead to bowing of the legs) Bone deformities
Bone pain
Severe proximal myopathy
(Rickets in children, osteomalacia in adults)
State some causes of vitamin D deficiency.
Inadequate dietary intake Lack of sunlight Receptor defects (rare - autosomal recessive resistant to vitamin D treatment) Liver or Renal failure Gastrointestinal malabsorptive states
What is usually measured to gauge the level of calcitriol? What condition must be fulfilled for this to be a good measure of calcitriol?
25-hydroxycholecalciferol
This is only a good measure in the case of normal renal function
Describe how you would diagnose vitamin D deficiency.
Plasma Calcium = LOW
Plasma 25-hydroxycholecalciferol = LOW
Plasma PTH = HIGH (secondary hyperparathyroidism stimulated by the hypocalcaemia)
Plasma Phosphate = LOW
Radiological findings e.g. widened osteoid seams
What would you expect the plasma phosphate level to be in someone with renal failure and why?
HIGH – because there is a decrease in plasma excretion via the kidneys
What would you expect the plasma calcium level to be in someone with renal failure and why?
LOW – because they are not producing as much calcitriol (due to renalfailure interfering with 1-alpha hydroxylase) so there is less calcium absorption in the small intestines
What are the consequences of hypocalcaemia caused by renal failure?
There is a decrease in bone mineralisation and an increase in bone resorption (because of an increase in PTH) leading to osteitis fibrosa cystica The imbalance in calcium and phosphate can also lead to the formation of salts that can be deposited in extra-skeletal tissue causing extra-skeletal calcification
What can vitamin D excess lead to?
Hypercalcaemia and hypercalciuria (due to increased intestinal absorption of calcium)
What can vitamin D excess result from?
Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure Granulomatous disease – granulomatous tissue has 1-hydroxylase so it can be a source of ectopic calcitriol
What is the action of PTH?
Increase Ca2+ reabsorption from kidney
Increase Ca2+ reabsorption from bone
Increase Calcitriol formation (Regulate 1alpha hydroxylase)
How is PTH regulated?
Ca2+ sensing receptor on parathyroid cells inhibits PTH when bound. (Calcium provides negative feedback)
How is phosphate regulated?
PCT cell has Na+/PO4 3- co-transporter (absorbs PO43-) PTH inhibits this - increases excretion
FGF23 - Fibroblast growth factor 23 (from osteocytes) also promotes excretion
Calcitriol inhibited by FGF23 to reduce PO43- absorption from gut
What are the (broad) effects of hyper and hypo calcaemia?
Hypercalcaemia (>2.6 mmol/L) blocks Na+ influx - less excitability
Hypocalcaemia (<2.2mmol/L) enhances Na+ influx - More excitability
What are some consequences of HYPOcalcaemia
CATs go numb: Convulsions, Arrythmias, Tetany, Parathesia
Chvostek’s sign - tap facial nerve below zygomatic arch, positive response = facial muscle twitching positive response indicates neuromuscular irritability
Trousseau’s sign - elevate BP through cuff - positive sign = carpopedal spasm clawed hand
What are some causes of hypercalcaemia?
Vitamin D deficient
Low PTH - Surgical, AI (rare) Mg deficiency
PTH resistance - pseudohypoparathyroidism
Renal failure - 1 alpha hydroxylase impairment
What are some consequences of HYPERcalcaemia?
Stones, abdo moans and psychic groans
S
Polyuria and thirst
Nephrocalcinosis, renal colic, Chronic renal failure
AM
Anorexia, nausea, dyspesia, constipation, pancreatitis
PG
Fatigue, depression, impaired concentration, altered mentation
Levels above 3mmol/L can cause coma
What are some causes of HYPERcalcaemia?
Parathyroid tumour - hyperparathyroidism
Malignant tumour - Ectopic PTH-like peptide
Conditions causing high bone turnover - Hyperthyroidism, Paget’s
Vitamin D intoxication
What are some differential diagnoses of hypercalcaemia?
1’ - High Ca2+, High PTH, Low Phosphate
Malignancy - High Ca2+, Low PTH, Low Phosphate
How is vitamin D deficiency treated?
Normal renal function - Give 25(OH)D for patient to convert Either as D2 (Ergocalciferol) or D3 (Cholecalciferol)
Impaired renal function - give Vitamin D preparations as no 1 alpha hydroxylase E.g Alfacalcidol - 1alpha hyrdoxycholecalciferol
How does dynamic formation of bone occur?
Osteoblasts - make osteoid
Osteoclasts - resorb bone
Osteblasts express RANKL, binds to precursor osteoclast RANK-R leads to differention into mature osteoclasts..
What is the arrangement of healthy bone?
Cortical - hard
Trabecular - spongy
Lamellar arrangement - alternates layers
What are the consequences of excess phosphate?
Osteitis fibrosa cystica - bone cysts ‘Brown tumours’
Treatment - low phosphate diet, phosphate binders, Alphacalcidol
Parathyroidectomy in 3’
Vascular calcification - phosphate binds to Ca2+
What is Osteoporosis and what can cause it?
Osteoporosis - reduced bony trabeculae, higher risk fractures >2.5 SD below average value for healthy at age (T score) DEXA femoral neck and lumbar spine
Hypogonadism
Endocrine - cushings, hyperthyroid
Iatrogenic - glucocorticoids, heparin
MENOPAUSE
What are some Osteoporosis treatments?
HRT - Oestrogen (increases endometrial/breast cancer risk) give progestrogen
Venous thromboembolus risk increases
Bisphosponates - bind to hydroxyapatite, injected by osteoclasts impairs their function decreases prognetor maturation, may kill osteoclasts good for osteoporosis, malignancy, paget’s, severe hypercalcaemia
Cause GI disruption, don’t eat or take drugs around time
OSTEONECROSIS OF THE JAW - risk in cancer patient
May oversupress bone balance - cause atypical
fractures
Denosumab - human monoclonal antibody binds RANKL (once every few month SC)
Teriparatide - recombinant PTH fragment (more effective for formation than resorption)
Daily SC, 3rd line treatment SUPER FUCKING EXPENSIVE
What is paget’s disease?
Chaotic bone formation, excessive osteoclast activity, excessive osteoblast compensation
woven bone formed - disorganised and mechanically weaker than lamellar bone
Bone hypertrophy, deformity and weakness
NO ONE KNOWS WHY? Tends to happen over 50
Increased vascularity, deafness, radiculopathy
MOST COMMON PLACES - skull, thoracolumbar spine, pelvis, femur, tibia
Plasma Ca2+ normal, plasma alkaline phosphatase increased [BONE]
lytic lesions, radionuclide bone scan demonstates skeletal extent
