Bone Biology Flashcards
State the roles of calcium
Bone and teeth rigidity
Muscle contraction
Membrane potential stability
Neurotransmitter release
secretory processes
blood clotting
intracellular 2nd messenger
enzyme regulation
What does a decrease in free ECF Ca2+ concn (severe hypocalcaemia) cause?
An increase in Na+ permeability, depolarisation of membrane potential closer to threshold which results in muscle spasm
What does an increase in cytosolic Ca2+ cause?
Contraction. Whereas an increase in free ECF Ca2+ decreases neuromuscular excitability
What does an increase in free ECF Ca2+ cause?
A decrease in neuromuscular excitability and therefore a decreased likelihood of contraction
What is the plasma Ca2+ concentration?
2.2-2.6mmol/L
What is the intracellular Ca2+ concentration?
around 0.1micromol/L
What are two important roles of phosphate?
Component of ATP
Crucial in activation and deactivation of enzymes (kinases and phosphatases)
How are calcium and phosphate linked?
Both are components of hydroxyapatite crystals in bone
Both are regulated by the same three hormones
What three hormones regulate calcium and phosphate?
Parathyroid hormone (PTH)
1,25-dihydroxyvitamin D (calcitriol)
Calcitonin
How many parathyroid glands do humans have?
4
Where are the parathyroid glands located?
2 on the posterior surface of the left lobe of the thyroid gland and two more on the right lobe
What are the parathyroid glands composed of?
Chief cells which synthesise and secrete PTH
What do parathyroid glands secrete?
Parathyroid hormone (PTH)
What is the main regulator of PTH?
Plasma calcium concentration
What stimulates release of PTH?
a decrease in plasma calcium concentration (hypocalcaemia)
What kind of hormone is PTH?
a peptide hormone
What is the significance of PTH being a peptide hormone?
It circulates freely in the plasma and is rapidly metabolised
What are the net effects of PTH on the kidney and bone?
To increase plasma calcium concentration and to lower plasma phosphate concentration
Describe the effect of hypocalcaemia
hypocalcaemia stimulates secretion of PTH from chief cells. PTH then acts on the kidney and bone resulting in an increase in plasma calcium and a simultaneous decrease in plasma phosphate
What do the kidneys form when they filter plasma?
Tubular fluid
At what point is tubular fluid referred to as urine?
the fluid that leaves the collecting duct at the end of the nephron is referred to as urine and excreted from the body
How much of the calcium ion filtered by the kidneys is reabsorbed and where?
around 65% is reabsorbed in the proximal convoluted tubule (PCT) and around 25% in the thick ascending limb.
another 5-10% is absorbed in the distal nephron
What percentage of filtered calcium ions are excreted from the body in the urine?
around 0.5%
How does PTH increase plasma calcium concentration?
PTH stimulates the reabsorption of calcium in the distal nephron, reducing the amount excreted in the urine and therefore raising plasma concentration
Why does PTH modify transepithelial transport?
1) stimulate reabsorption of calcium ions in the distal nephron of the kidney
2) inhibit renal phosphate absorption in the proximal convoluted tubule
Where does the synthesis of 1,25-dihydroxyvitamin D occur?
mitochondria of cells in the proximal convoluted tubule
What are the 3 actions of 1,25-dihydroxyvitamin D?
1) enhance renal calcium reabsorption
2) enhance calcium reabsorption by the small intestine
3) modulate movement of calcium and phosphate in and out of bones
What is the net effect of a persistent increase in plasma parathyroid hormone concentration?
Stimulation of bone resorption
What impact does PTH have on osteoclasts?
PTH indirectly increases both the number and activity of osteoclasts
What is the net effect of an intermittent increase in plasma parathyroid hormone concentration?
Stimulation of bone deposition
What impact does the intermittent increase in PTH have on osteoblasts?
Promotes osteoblast differentiation and inhibition of osteoblast apoptosis
In what two forms does vitamin D exist in in the body?
Vitamin D3
Vitamin D2
How is vitamin D3 synthesised?
synthesised by the skin if sufficient UV light is absorbed
How is vitamin D2 obtained?
only obtained from the diet - vegetables
How do vitamin D2 and D3 differ?
Only differ on the side chain of ring D
Why can vitamin D also be considered a hormone?
because it is endogenously synthesised
How is vitamin D activated?
the addition of 2 hydroxyl groups to form 1,25dihydroxyvitamin D
What is the activated form of vitamin D and what does it have a role in?
1,25-dihydroxyvitamin D
Role in calcium balance
What is the action of 1,25-dihydroxyvitamin D?
to raise the plasma concentrations of both calcium and phosphate
What sites does 1,25-dihydroxyvitamin D impact on?
the small intestine (duodenum) and kidney to raise plasma calcium
What impact does 1,25-dihydroxyvitamin D have on the small intestine?
up-regulates the reabsorption of calcium by increasing expression of epithelial calcium channels, pumps and binding proteins
also stimulates synthesis of a NaPi cotransporter to increase phosphate absorption
What impact does 1,25-dihydroxyvitamin D have on the kidney?
acts synergistically with PTH to enhance calcium reabsorption in the distal tubule and promotes phosphate reabsorption.
Less dramatic effects than PTH
What medical condition can be caused in children with vitamin D deficiency and why?
Rickets
Vitamin D deficiency leads to impaired intestinal absorption of calcium and therefore hypocalcaemia.
Hypocalcaemia causes increase in PTH secretion, PTH leads to increased bone resorption so bones soften and deform.
What is the equivalent of rickets in adults?
Osteomalacia
What kind of hormone is calcitonin?
Peptide hormone
What cell produces calcitonin?
C cells (aka clear or parafollicular cells) of the thyroid gland
What triggers calcitonin secretion?
an increase in the extracellular calcium concentration above normal (hypercalcaemia)
What is the main action of calcitonin?
To lower plasma calcium concentration
What impact does calcitonin have on osteoclasts?
calcitonin inhibits the resorptive activity of osteoclasts, slowing the rate of bone turnover
Is the action of calcitonin hyper or hypocalcaemic?
HYPOcalcaemic
How does calcitonin cause phosphaturia?
It results in mild phosphaturia by inhibiting phosphate transport in the proximal convoluted tubule
Which of the three regulatory hormones has the smallest role in calcium ion homeostasis?
Calcitonin
What sites does PTH act on?
Kidney, bone and small intestine
What site does 1,25-dihydroxyvitamin D act on?
Kidney and small intestine
What site does calcitonin act on?
kidney and bone
What is the composition of bone?
60% mineral (largely hydroxyapatite)
25% organic (90% type 1 collagen, 10% non-fibrous extracellular matrix)
15% water
In the microscopic bone structure, where are circumferential lamellae?
outside of most cortical bone
In the microscopic bone structure, where are concentric lamellae organised?
organised in Haversian systems/osteons
In the microscopic bone structure, what are interstitial lamellae?
remnants of old lamellae
What are the three stages of endochondral ossification?
cartilage
calcified cartilage
bone
What is intramembranous ossification?
bone develops directly from sheets of mesenchymal connective tissue
What are osteoblasts derived from?
Mesenchymal or ectomesenchymal derived
What do osteoblasts produce?
Osteoid matrix
Where are osteoblasts found?
On bone surface - periosteum, endosteum
What are osteocytes?
trapped osteoblasts, linked by gap junctions
Are osteocytes vital?
Yes
What are osteoclasts derived from?
Haemopoietic source - macrophage/monocyte line
Where are osteoclasts found?
Howships lacunae
What do osteoclasts do?
dissolve bone mineral - acid
breakdown organic matrix - enzymes
What weight of calcium is present in the body?
1kg
How is calcium regulated QUICKLY?
rapid exchanges between bone and ECF
How is calcium regulated SLOWLY?
intestinal absorption and renal excretion
How does PTH increase plasma calcium concentration?
Withdraws calcium from the bone bank
What are the five phases involved in bone remodelling?
1) activation
2) osteoclast recruitment and resorption
3) reversal
4) osteoblast recruitment and bone formation
5) termination - quiescence
What is osteogenesis imperfecta?
defective collagen formation, effects whole skeleton
What is osteopetrosis?
defective osteoclastic bone resorption
Name three metabolic bone diseases
Hyperparathyroidism
Pagets disease
Fibrous dysplasia
What happens to bone following an extraction?
Physiological osteoclastic bone resorption
Following extraction, in what dimension is there the largest bone resorption?
greatest amount of bone loss in the horizontal dimension mainly on the buccal aspect of the ridge
What is the net effect of resorption following extraction on the ridge?
results in a narrower and shorter ridge and also the relocation of the ridge to a more palatal/lingual position
How long does the bone remodelling process take?
6 months
What types of drugs can impact on bone remodelling? (Name 4 types)
Bisphosphonates
Denosumab and anti-angiogenics
steroids
NSAIDs
What are bisphosphonates?
Non-metabolised analogues of pyrophosphate
What is the function of bisphosphonates?
They are capable of localising to bone and inhibiting osteoclastic function
What do bisphosphonates bind avidly to?
exposed bone mineral around resorbing osteoclasts so therefore there can be a high level of bisphosphonate in the resorption lacunae
What does the fact that bisphosphonates are not metabolised mean?
high concentrations are therefore maintained in bone for long periods of time
Are bisphosophonates anti-angiogenic?
Yes
What are the two classes of bisphosphonate?
non-nitrogen containing
nitrogen containing
Name a non-nitrogen containing bisphosphonate
Clodronate
Name a nitrogen containing bisphosphonate
Alendronate
How do non-nitrogen containing bisphosphonates function?
resemble pyrophosphate so are incorporated into phosphate chain of ATP rendering it unusable for energy production in osteoclasts
How do nitrogen-containing bisphosphonates function?
preventing formation of key lipids in osteoclasts which anchor proteins to the cell membrane.
Without these cell death occurs
Name four conditions treated with bisphosphonates
osteoporosis
multiple myeloma
prostate cancer
breast cancer
What bisphosphonate patients are considered low risk?
not yet started taking them
taking them for prevention or management of osteoporosis
What bisphosphonate patients are considered high risk?
previous diagnosis of MRONJ
Taking as management of malignant condition
for other non-malignant condition of the bone eg. Paget’s disease
under care of specialist for rare condition eg. osteogenesis imperfecta
concurrent use of corticosteroids or immunosuppressants
radiotherapy, chemotherapy, coagulotherapy
What is the SDCEP management advised for low risk patients?
if unavoidable then atraumatic extractions, raising flaps, achieve good haemostasis, review at 4 weeks.
If not healing at 4-6 weeks refer to oral/maxfax surgeon
What is the SDCEP management advised for high risk patients?
contact oral/maxfax surgeon for advice on primary care or referral
What are the three criteria for MRONJ?
1) Current or previous bisphosphonates, anti-angiogenic drugs or RANKL inhibitors
2) exposed bone or bone that can be probed that has persisted for more than 8 weeks
3) no history of radiation therapy to jaws
What are the signs and symptoms of MRONJ?
area of exposed necrotic bone
internal or external discharging fistulas
painful generally
loose mobile teeth
bony sequestrae
paraesthesia
usually mandible (60-70% cases)
How do you treat established MRONJ lesions?
no definitive guidelines.
Conservative management, irrigation, antibiotics, do not curette, remove small/loose sequestrae, stop bisphosphonate if safe to do so
What is denosumab (prolia)?
Human monoclonal antibody that inhibits osteoclastic function
What is the timescale of denosumab effect?
osteoclast function inhibited within 6 hours of SC injection and function returns 6 months later
How does denosumab work?
inhibits receptor activator of nuclear factor kappa B ligand (RANKL), a protein which acts as primary signal for bone removal
What is everolimus and what is its action?
a serine-threonine kinase, inhibits mammalian target of rapamycin resulting in reduced growth of cells, angiogenesis and survival of cells
What is the impact of corticosteroids administered systemically and in strong doses?
Delay healing
What drugs can affect absorption of calcium from the stomach?
Anti-seizure drugs eg. carbamazepine, phenytoin and long term proton pump inhibitors
What drugs increase the renal excretion of calcium?
Diuretics
What drugs reduce androgen and oestrogen levels?
drugs for treatment of breast and prostate cancer
