Bone Metabolism Flashcards
What are the normal types of bone?
Lamellar - cortical/compact and cancellous/trabecular/ spongy
Woven
When is woven bone seen? (3)
In children
Healing from a fracture
Pathology
How much of total bone mass of an adult is compact bone?
80%
How does the surface area of trabecular bone compare to compact bone?
10x greater
Describe the organisation of woven bone.
Why is this beneficial? What is the disadvantage?
Random collagen organisation
Forms quickly but it is mechanically weak
What are the three broad components of bone matrix?
35-40% organic
60% inorganic
5% water
What makes up the organic part of bone matrix? (3)
Type 1 collagen (triple helix = 10nm)
Proteoglycans
Growth factors/cytokines/osteoid
What is the purpose of the collagen?
What about the proteoglycans?
Tensile strength
Compressive strength
What makes up the organic part of bone matrix?
Calcium hydroxyapatite (Ca10(PO4)6(OH)2) (crystal = 500nm)
What cells are found in bone? (4)
Osteoprogenitor cell
Osteoblast
Osteocyte
Osteoclast
What are the reasons for remodelling?
1) renews bone before deterioration
2) redistributes bone matrix along mechanical stress lines.
When bone is remodelled, why is it initially trabecular bone?
3-10 times quicker than cortical bone
Larger surface area
Responds to stresses on bone quicker
What cells sense mechanical stress of bone?
What does the death of these cells signal?
Osteocytes
Remodelling
What secretes sclerostin (glycoprotein) and what does this do?
Osteocytes
Inhibits bone formation by osteoblasts.
PTH and mechanical stress
What inhibits sclerostin? (2)
What increases it?
Inhibited by PTH and mechanical stress
Increased by calcitonin
What is the antibody to sclerostin currently in clinical trials called? What does it do?
Romosozumab
Increase bone density
What is EphrinB2?
Where is EphrinB4 receptor expressed?
What does this do?
Ligand expressed by osteoclasts
On osteoblasts
Generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals. Inhibits osteoclast precursor differentiation and enhances osteoblast differentation.
What increased ephrinB2 expression?
PTH
What are the processes of bone remodelling? (6)
- Osteoclast attaches to bone forming leak proof seal
- Protein-digesting enzymes breakdown collagen fibres
- Acid dissolves bone minerals
- Bone proteins and minerals (mainly Ca2+) cross osteoclast to exit into interstitial fluid.
- Osteoblasts fill lacuna with osteoid.
- Osteoid is mineralised approx. 1 week later
Outline the process of bone remodelling. How long doest the process take?
The osteocytes stimulate the osteoclast precursors to differentiate into osteoclasts. These are activated and then they resorb the bone. The osteoblasts then fill these lacuna with osteoid, which is then mineralised.
3-4 months
What cells FORM bone?
What cells RESORB bone?
Osteoblasts
Osteoclasts
How much of the calcium in the body is in the skeleton?
99.9%
What does the maintenance of normal serum calcium depends on? (3)
Intestinal absorption
Renal excretion
Skeletal mobilisation
What does the serum calcium level have to be regulated between?
2.2 - 2.6mmol L (8.5-10.5 mg/dL)
What is the recommended daily intake of calcium?
500-1300mg
How much calcium do the kidneys excrete a day?
200mg
How much calcium is excreted in the stools a day?
600-800mg
How much calcium is absorbed from the gut a day?
How much calcium is secreted into the gut?
400mg
150mg
What is the normal plasma concentration of phosphate?
0.8 -1.5mmol/L
What is most important in regulating phosphate metabolism?
PTH
What does low plasma calcium stimulate?
Parathryroid hormone secretion
What does PTH promote? (4)
Ca2+ uptake from kidney and intestines
Ca2+ reabsorption from bone (increases number and activity of osteoclasts)
PO4 excretion from kidney
Synthesis of 1,25-dihydroxyvitamin D (1,25 (OH)2 vitamin D3)
How does PTH stimulate osteoclasts?
Osteoblasts have receptor for PTH, osteoblasts produce RANKL, osteoclasts and their precursors have RANK receptor.
What does vitamin D3 increase?
Ca2+ absorption from the gut
What is RANKL?
What cells produce it?
Receptor activator of nuclear factor kappa-B ligand
Osteoblasts and stromal cells
What is M-CSF?
What cells produce it?
Macrophage colony-stimulating factor
Osteoblasts and stromal cells
What is OPG?
Osteoprotegrin (decoy receptor for RANKL)
What induces RANKL? (10)
Vitamin D PTH TNF-alpha Glucocorticoids IL-1, IL-11 T4/T3 PGE2 Histamine IGF-1 Low gravity
What inhibits RANKL? (2)
Oestrogen
TGF-beta
What is the effect of RANKL and M-CSF?
Osteoclast formation
When there is a high plasma Ca2+ level, what is released (and where from)?
What plasma level does this occur at?
Calcitonin (from thyroid)
When serum Ca2+ >2.25mmol/L
What does calcitonin do? (4)
Inhibits bone resorption by inhibiting osteoclast differentiation and activity
Increases Ca2+ excretion from kidney
Inhibits Ca2+ absorption by intestines
Stimulates calcium deposition in bones
How can vitamin D be obtained? (2)
Diet
UV light on precursors in skin
What is the normal daily requirement of vitamin D?
400 IU/day
Where is 1,25(OH)2 vitamin D3 made?
In the kidney
What is the effect of vitamin D3?
Stimulates Ca2+ absorption from gut
Stimulates bone resorption in same way as PTH
Where is the vitamin D receptor present?
What does it affect?
In osteoblasts
Gene expression and differentiation
What is 1,25 (OH)2 vitamin D3 involved in?
Preparing ECM for mineralisation via production of pro-collagen type 1 and production of alkaline phosphatase matrix vesicles
What other factors affect bone metabolism? (3)
Oestrogen
Glucocorticoids
Progesterone
What does oestrogen do? (2)
Increases Ca2+ absorption in gut
Decreases re-absorption (inhibit osteoclasts) in bone
What do glucocorticoids do? (2)
What is an effect of prolonged corticosteroid treatment?
Decrease Ca2+ absorption in gut
Increased re-absorption/decreased formation in bone
Osteoporosis
What might progesterone be used to treat osteoporosis?
Adding progesterone cream to osteoporosis therapy increased bone density by around 10% in 1st 6 months to rate of 3-5% annually (stabilises at levels of 35 year old). May be key to reversing osteoporosis.
What stimulates osteoblasts? (9)
Oestrogen, progesterone, testosterone
PTH, T4, vitamin D
IGF, TGF-beta, PDGF
What inhibits osteoblasts? (1)
Cortisol
What stimulates osteoclasts? (8)
PTH, T4, vitamin D
IL-6, IL-1, IL-11, RANKL, M-CSF
What inhibits osteoclasts? (8)
OPG, oestrogen, progesterone,
prostaglandins, cortisol, IL-4,
IL-18, IFN-gamma
What is the net effect of PTH?
Increased serum calcium and decreased serum phosphate
What is the net effect of 1,25-D3?
Increased serum phosphate
What is the net effect of calcitonin?
Decreased serum calcium
What inhibits the production of vitamin D3? (3)
Decreased PTH
Elevated serum calcium
Elevated serum phosphate
What inhibits the production of PTH?
Elevated serum calcium
Elevated 1,25(OH)2D in kidney
