Parathyroid Hormone, Calcium and Bone Flashcards
What are the target serum calcium levels?
2.1-2.6mM/L
What can calcium be bound to in circulation?
Albumin
What percentages of calcium are free and bound to albumin?
50% each
What is the half life of PTH?
8mins
What type of receptor does PTH bind to?
GPCR
What effect does hypocalcaemia have on PTH secretion?
Increases it
What effect does increased PTH secretion have on bone (and what is caused)?
- Increased bone resorption
- Increased serum calcium
What effect does increased PTH secretion have on kidney (and what is caused)?
- Increased urinary phosphate (inc. bone resorption –> inc. serum calcium)
- Decreased urinary calcium (inc. serum calcium)
- Increased 1,25D3 production (inc. calcium + phosphate absorption in intestine –> inc. serum calcium + phosphate)
What is the active form of vitamin D?
1,25-dihydroxyvitamin D3 (1,25D3)
How is 1,25D3 produced?
- Either vitamin D3 made from 7-dehydrocholesterol when UV light hits skin or obtained from source (eg. fish, eggs)
- Liver converts vitamin D3 into 25-hydroxyvitamin D3 (25D3)
- Kidney (with PTH) converts 25D3 to 1,25D3 using 1α-hydroxylase
Where is calcitonin produced?
Thyroid c-cells (parafollicular cells)
What stimulates calcitonin release?
Hypercalcaemia
What is the effect of calcitonin?
Inhibit bone resorption
What effect does hypercalcaemia have on PTH secretion?
Decreases it
What effect does decreased PTH secretion have on bone (and what is caused)?
Decreased bone resorption (dec. serum calcium)
What effect does decreased PTH secretion have on kidney (and what is caused)?
- Decreased urinary phosphate (dec. bone resorption –> dec. serum calcium)
- Increased urinary calcium (dec. serum calcium)
- Decreased 1,25D3 production (dec. calcium + phosphate absorption in intestine –> dec. serum calcium + phosphate)
Where is fibroblast growth factor 23 (FGF23) produced?
Osteocytes
What effects does increased FGF23 have?
- Increased urinary phosphate
- Decreased urinary calcium
- Suppresses renal synthesis of 1,25D3
What effect does hyperphosphataemia have on PTH secretion?
Increases it
By action of what substances is serum phosphate reduced in hyperphosphataemia?
- Mainly FGF23
- Some PTH
What is primary hyperparathyroidism?
Raised serum PTH due to a parathyroid tumour
What does primary hyperparathyroidism cause?
- Hypercalcaemia
- Low serum phosphate
- Loss of negative feedback from hypercalcaemia
Symptoms of primary hyperparathyroidism
- Lethargy/confusion
- Thirst/polyuria
- Renal stones
- Constipation
- Pancreatitis
- Joint pain
- Fracture
- Depression
- Hypertension
How is primary hyperparathyroidism treated?
Surgery
Difference between rickets and osteomalacia
- Rickets affects growing skeleton (children)
- Osteomalacia affects adult skeleton
What is rickets/osteomalacia?
Deficiency of vitamin D (and/or calcium)
What causes rickets/osteomalacia?
- Lack of mineralisation of osteoid
- Failure to absorb sufficient calcium from GIT
What is osteoid?
Collagen component of bone
Symptoms of rickets
- Bow legs
- Swollen joints
Symptoms of osteomalacia
- Bone pain
- Pseudofractures
How is rickets/osteomalacia treated?
Vitamin D replacement (dietary or through sunlight)
What is secondary hyperparathyroidism?
Raised serum PTH secondary to renal disease
Mechanism of how secondary hyperparathyroidism occurs
- Abnormal kidney function (disease)
> Dec. urinary phosphate
> Inc. urinary calcium
> Dec. 1,25D3 production - Bones sense raised serum phosphate levels and produce lots of FGF23
> Further dec. 1,25D3 production - Intestine absorbs less calcium + phosphate
- Hypocalcaemia feedback to parathyroid
> Inc. PTH secretion
How is secondary hyperparathyroidism treated?
- Phosphate binders
- Vitamin D analogues
Symptoms of chronic kidney disease-mineral and bone disorder (CKD-MBD) and what causes them?
- Osteomalacia-type symptoms
> Dec. calcium and 1,25D3 after kidney disease (same as lead-up to secondary hyperparathyroidism) - Bone disease and increased fracture risk
> Secondary hyperparathyroidism causes drastically increased PTH
> Causes lots of bone resorption
What is oncogenous osteomalacia (cause + result)
- Caused by benign tumour secreting FGF23
- Means high serum FGF23 and low serum 1,25D3
What is X-linked hypophosphaemic rickets?
Mutations in PHEX gene lead to elevated FGF23 and suppressed 1,25D3
What is osteoporosis?
Loss of bone mass/density (mineral and non-mineral bone decreased)
Types of osteoporosis (description of each)
- Osteoporosis of aging = gradual decline in bone density from early adult peak
- Postmenopausal osteoporosis = rapid decline in female bone density following decline in estrogen at menopause
- Steroid-induced osteoporosis = decline in bone density associated with use of steroids as therapy for inflammatory diseases
Treatment options for osteoporosis
- Hormone replacement therapy
> Estrogen - Inhibition of osteoclast development
> Denosumab is a RANK ligand antibody
> Blocks RANK ligand on osteoblasts from interacting with RANK on osteoclasts
> Decreased differentiation of pre-osteoclasts - Inhibition of osteoclast activity
> Bisphosphonates disrupt intracellular enzymes required for osteoclast activity - Stimulation of osteoblast activity
> Teriparatide is the first 34 AAs of PTH
> Is anabolic stimulator of bone formation
How can osteoporosis be prevented?
- Exercise
- Vitamin D and calcium
- Avoid smoking
- Avoid high alcohol intake
Cell types in bone
- Osteocytes
- Osteoblasts
- Osteoclasts
Where are osteocytes found specifically?
Embedded in calcified bone matrix
What do osteoblasts do?
Bone forming cells:
- Produce matrix constituents
- Aid calcification
What do osteoclasts do?
Bone resorbing cells:
- Produce acid (resorbs mineral) and enzymes (resorb matrix)
How are osteoclasts matured?
- Originally osteoclast precursor
- RANK ligand on osteoblast binds RANK on precursor
- Makes mature osteoclast
