WEEK 7 Flashcards
What are the three hormones involved in bone and calcium homeostasis?
Steroid hormone (Bone)
Calcitonin (Bone turnover)
PTH/Vit D/FGF23 (Soluble calcium)
What are the three major functions of bones?
1) Protection of vital organs
2) Support of muscles
3) Reservoir of calcium
What are the two major functions of soluble calcium?
1) Excitation of muscles/nerves
2) Cell adhesion
What is the normal range of serum calcium for calcium homeostasis?
2.1-2.6mmol/L
What is the normal ratio between free (ionised) calcium and calcium bound to albumin?
50:50
Where are the three areas calcium homeostasis occurs and how is this done?
1) GI tract-uses Vit D to regulate the amount taken in from diet
2) Kidneys-uses PTH/Vit D/FGF23 for reabsorption
3) Bones-uses PTH/Vit D to sequest Ca2+
What is the role of the parathyroid glands?
Regulation of calcium and phosphate levels
What hormone does the parathyroid gland secrete?
Parathyroid hormone (PTH)
What are the four actions of PTH?
1) Increases calcium reabsorption in renal distal tubule
2) Increases intestinal calcium absorption (via Vit D activation)
3) Increases calcium release from bone
4) Decreases phosphate reabsorption (stimulates osteoclast activity)
When is PTH secretion increased from the parathyroid glands?
Low calcium (hypocalcaemia) or High phosphate (Hyperphosphatemia)
Describe the feedback loop due to hypocalcaemia
Increased PTH secretion from the parathyroid glands, PTH acts on bone causing increased bone resorption (due to decreased PO4 reabsorption)/kidney causing increased urinary PO4, decreased urinary Ca2+ and increased 1,25D3 production (active Vit D)/intestine causing increased Ca2+ and PO4 absorption (due to increased 1,25D3 production), resulting in increased serum Ca2+, inhibition of PTH secretion via 1,25D3 and serum Ca2+
Describe the parathyroid hormone
84 AA peptide but only first 34 AA biologically active (PTH 1-34) which binds to GPCRs mainly in the kidneys and osteoblasts
What is the normal adult reference range for PTH?
1.6-6.9pmol/L
What is the role of PTH in the kidney?
Increases distal tubule reabsorption of Ca2+ and inhibits PO4 reabsorption
Stimulates production of 1,25D3 (active Vit D)
What is the role of PTH on bones?
Increases bone resorption by stimulation of osteoblasts, therefore osteoclasts
How is PTH transcription inhibited?
By 1,25D3
How is PTH translation inhibited?
By serum Ca2+
What is the precursor to active Vitamin D?
25D3 (25-hydroxyvitamin D3)
What is the active form of Vitamin D?
1,25D3 (1,25-dihydroxyvitamin D3)
What are the two ways to obtain Vit D naturally?
UV radiation (most) Diet-fish and eggs
How is the active form of Vitamin D formed due to UV radiation?
7-dehydrocholesterol to Vit D3 in the skin, Vit D3 undergoes 1st hydroxylation in the liver to 25D3, 25D3 undergoes 2nd hydroxylation in the kidney which is induced by PTH to form 1,25D3 (active Vit D)
What is used more commonly to measure Vit D sufficiency, the active or inactive form?
Inactive form
What is the effect of Vit D?
Increased intestinal Ca2+ and PO4 absorption
Where is calcitonin produced?
Parafollicular (C) cells of the thyroid gland
What is the effect of calcitonin release due to hypercalcaemia?
Inhibition of bone resorption by direct effect on osteoclasts
What is FGF23?
Fibroblast Growth Factor 23
Where is FGF23 produced?
Bone cells (osteocytes and maybe osteoblasts)
What stimulates FGF23 release?
High serum PO4 (hyperphosphatemia)
What is the effect of FGF23?
Increased renal excretion of PO4 and suppression of renal synthesis of active Vit D
What is the main inducer of FGF23?
1,25D3
What is the relationship between calcium and phosphate levels?
Inverse (reciprocal)
Describe the feedback loop for hypercalcaemia
Decreased PTH secretion from the parathyroid glands, causing decreased bone resorption (due to increased PO4 reabsorption and increased calcitonin)/decreased urinary PO4, increased urinary Ca2+ and decreased 1,25D3 production (active Vit D)/decreased Ca2+ and PO4 absorption (due to decreased 1,25D3 production), resulting in decreased serum Ca2+
Describe the feedback loop for hyperphosphatemia
Increased PTH secretion from the parathyroid glands, PTH acts on bone causing increased FGF23 (increasing urinary PO4 and decreasing 1,25D3 production)/kidney causing increased urinary PO4, decreased urinary Ca2+ and decreased 1,25D3 production, resulting in decreased serum PO4
What is bone?
Specialised connective tissue-ECM which is able to calcify
What is bone made of?
Collagen fibres (Type 1) with preferential orientation Non-collagenous proteins essential to bone function (osteocalcin, osteonectin, osteopontin) Several types of cells (osteocytes, osteoblasts, osteoclasts)
Describe the organisation of tissue from molecule to bone
Collagen molecules with bone crystals (hydroxyapatite-cause strength)➜collagen fibril➜collagen fibre➜lamella➜osteon➜bone
What is an osteocyte?
A cell embedded in calcified bone matrix with long processes which contact other osteocytes and osteoblasts for cell communication
What is an osteoblast?
A bone forming cell which produces matrix constituents and aids calcification
Where do osteoblasts originate from?
Mesenchymal stem cells (bone marrow stems cells or connective tissue mesenchymal cells)
What are two classical markers of osteoblasts?
Alkaline phosphatase and osteocalcin (increased levels=increased bone turnover)
What is an osteoclast?
A bone resorbing cell usually found in contact with calcified bone surface in lacunae (pits)
Where do osteoclasts originate from?
Bone marrow lineage
What do osteoclasts produce?
Acid (to resorb mineral) and enzymes (to resorb matrix)
How are osteoclasts attached to bones?
Integrins
What are some classical markers of osteoclasts?
Carbonic anhydrase, tartrate-resistant acid phosphatase (TRAP), RANK and calcitonin receptor
Look at images of basic structure of bones and histology of bone cells in notes
4 images
Describe the process of osteoclast development
Osteoblast and osteoclast precursor interact via RANK ligand (RANKL) on osteoblast to form mature osteoclast
Which molecules stimulate the RANK receptor on the osteoclast precursor?
Vit D and PTH
Which molecules inhibit the RANK receptor on the osteoclast precursor?
Oestrogen, TGF-beta and IL-4
Describe the bone remodelling cycle
Resting surface➜Bone resorption via osteoclast➜Reversal phase (cement line/resorption pit formation)➜Bone formation via osteoblast (osteoid)➜Bone formation (osteoid-mineralisation front)➜Resting surface (new packet)
What is hyperparathyroidism (HPT)?
Overactivity of the parathyroid glands (raised serum PTH)
What is the cause of primary hyperparathyroidism (HPT)?
Parathyroid tumour (usually benign adenoma) resulting in loss of negative feedback from hypercalcaemia
What is the result of primary HPT?
Hypercalcaemia and hypophosphatemia
What are the clinical features due to primary HPT?
neuro: lethargy/confusion
renal: thirst/polyuria, renal stones
GI: constipation, pancreatitis
rheumatic: joint pain, fracture
neuropsychiatric: depression
cardiac: hypertension
What is the treatment for primary HPT?
Surgery
What is the cause of secondary hyperparathyroidism (HPT)?
Renal disease resulting in increased phosphate and decreased active Vit D
Describe the changes to kidney function due to secondary HPT
decreased urinary phosphate causes hyperphosphatemia+increased urinary calcium causing hypocalcaemia+decreased 1,25D3 production (resulting in osteomalacia)=increased PTH secretion
What is the effect of renal disease on FGF23 levels?
Increases FGF23 levels
Describe effects of increasing circulating FGF23
Increasing levels:
Hypophosphatemic rickets/tumour-induced osteomalacia➜Chronic kidney disease (CKD)➜DIALYSIS
What is the cause of oncogenous osteomalacia?
Benign tumour secreting FGF23 causes increased serum FGF23 and decreased serum 1,25D3
What is the cause of X-linked hypophosphatemic rickets?
PHEX mutation causing elevated FGF23 and suppressed 1,25D3
What is the difference between rickets and osteomalacia?
Rickets affects growing skeleton, osteomalacia affects adult skeleton
What is the cause of rickets/osteomalacia?
Vitamin D (and/or calcium) deficiency due to diet/lack of sunlight
What is the process causing rickets/osteomalacia?
Lack of mineralisation of collagen component of bone (osteoid) due to failure to absorb calcium from GI tract causing bone to be softer
What is osteoid?
Bone matrix (collagen) yet to be mineralised
What are two classic symptoms of rickets?
Bow legs due to osteoid at the growth plate being weak
Swollen joints due to growth plate expansion to compensate
What are two classic symptoms of osteoporosis?
Bone pain and pseudofractures
What is the treatment for rickets/osteoporosis?
Vitamin D replacement (dietary/sunlight)
What is osteoporosis?
A loss of bone mass/density due to both mineral and osteoid decrease as a result of increased bone resorption=normal bone but less of it
What is the result of osteoporosis?
Increased fracture risk (wrist, spine, hip)
What are prevention options for osteoporosis?
Exercise=enhanced osteocyte activity via bone stress
Vit D and Calcium
How does aging relate to osteoporosis?
M+F show gradual decline in bone density from early adult peak (mid 20s)
What is postmenopausal osteoporosis?
The rapid decline in female bone density following oestrogen decline at menopause
What is steroid-induced osteoporosis?
A decline in bone density associated with steroid use as therapy for inflammatory diseases
What can spinal osteoporosis lead to?
A Kyphotic spine (greater S-shaping) due to compression fractures
What is the fracture threshold relating to osteoporosis?
The bone mass threshold below which fractures are much more likely to occur
What are the four therapeutic options for osteoporosis?
1) Hormone replacement therapy (oestrogen replacement)
2) Inhibition of osteoclast development (denosumab-RANKL antibody)
3) Inhibition of osteoclast activity (bisphosphonates)
4) Stimulation of osteoblast activity (intermittent PTH use, stimulating osteoblasts/bone formation-Teriparatide)
