Bone Biology Flashcards
What is the principle hormone for regulation of plasma, sodium and potassium ion concentrations?
Aldosterone
What are the three hormones involved in regulating plasma calcium ion concentration and plasma phosphate levels?
- Parathyroid hormone (PTH)
- Calcitonin
- 1,25-dihydroxyvitamin D
What type of calcium ions are biologically active and subject to regulation?
Free calcium ions (not plasma bound calcium ions)
What form is calcium found in within the bone?
Precipitated calcium phosphate
Give an example of an enzyme that is regulated in response to intra-cellular calcium concentration.
Calmodulin-dependant kinase II (CaMK-II)
Give 10 roles that free calcium ions play in essential activities around the body.
- Bone and teeth rigidity
- Muscle contraction
- Maintenance of membrane potential stability
- Neurotransmitter release
- Secretory processes
- Blood clotting
- Intracellular 2nd messenger
- Enzyme regulation
- Membrane stability
- Excitation-contraction coupling of cardiac and smooth muscle cells
What causes hypocalcaemia?
When levels of calcium in your blood are too low
What serious side effect of severe hypocalcaemia can lead to asphyxiation?
Over-excitability/contraction of skeletal muscles
Define asphyxiation
The state or process of being deprived of oxygen
In skeletal muscles, what initiates contraction?
Calcium ions released from intra-cellular stores in response to an action potential
In muscles, what happens when there is an increase in systolic calcium ions?
Contraction
In muscles, what happens when there is an increase in free extra-cellular fluid calcium ions?
Decreases neuromuscular excitably and therefore likelihood of contraction
Where is calcium ion concentration higher, outside or inside the cell?
Outside
What controls the intestinal absorption of calcium?
Hormones
What are the functions of kinases?
- add phosphate groups to specific amino acid residues on target proteins , that in turn alter the functional activity of that target protein.
- They play an important role in intra-cellular signalling.
What is the function of phosphotases?
Remove phosphate from residues on target proteins
What is the careful regulated range of calcium concentration in plasma?
2.2-2.6mmol/L
What is the careful regulated intracellular range of calcium concentration?
Approx 0.1micro moles/L
Unlike calcium, why is the plasma phosphate concentration not strictly regulated?
Because phosphate levels tend to fluctuate throughout the day, especially after meals.
In what two ways are calcium and phosphate balance linked?
- both are the principal components of hydroxyapatite crystals in bone
- Both are regulated by the same three hormones
What three bodily systems do the hormones PTH, 1,25-dihydroxyvitamin D, and calcitonin act on?
- Bone
- Kidneys
- GI tract
How many parathyroid glands do humans have?
4
Where are the 4 parathyroid glands situated?
2 are located on the posterior surface of the left lobe of the thyroid gland, and 2 on the right.
What cells compose the parathyroid glands?
Chief cells
What do chief cells synthesis and secrete?
PTH
What is the main regulator of PTH?
Plasma calcium ions
In regards to PTH secretion, what does a decrease in plasma calcium ion concentration (hypocalcaemia) stimulate?
PTH secretion
What type of hormone is PTH?
A peptide hormone
What are the net effects of PTH on kidney and bone?
To increase plasma calcium ion concentration and to lower plasma phosphate concentration
How does PTH reduce the amount of calcium ions secreted in the urine?
By stimulating renal reabsorption of calcium ions in the distal nephron
In the kidneys, where are PTH receptors located?
On the lateral membranes of tubular epithelial cells
What two events occur due to PTH modifying transepithelial transport?
- Stimulates renal calcium ion reabsorption
- Inhibits renal phosphate reabsorption
What is the outcome of PTH inhibiting renal phosphate reabsorption?
Increased excretion of phosphate in the urine, helping to avoid any precipitation of free calcium ions. (This would be counter-productive if an increase in free calcium ions was necessary)
Where does stimulation of 1,25-dihydroxyvitamin D occur?
In the mitochondria of cells in the proximal convolluted tubule
What are the 3 actions of 1,25-dihydroxyvitamin D?
- Enhance renal calcium ion reabsorption
- Enhance calcium ion absorption by the small intestine
- Modulate movement of calcium ions and phosphate in and out of bone
What is the function of osteoblasts?
Build bone cells and play a role in deposition of bone
What is the function of osteoclasts?
Release enzymes to resorb bone, through this process calcium and phosphate ions are released.
What effect does a persistent increase in PTH concentration have on osteoclast number and activity?
Increases them
What effect does an intermittent increase in PTH concentration have on osteoblasts?
Promotes osteoblasts differentiation and inhibition of osteoblast apoptosis
What two forms does vitamin D exist in the body?
- Vitamin D3
- Vitamin D2
How is vitamin D3 synthesised?
From skin if sufficient UV light is absorbed
How do you obtain vitamin D2?
Only from the diet (vegetables)
In their chemical structure, what is the only difference between vitamin D3 and D2?
Differ in the side chains of ring D. (The side chain of D3 is characteristic of cholesterol, whereas the side chain of D2 is characteristic of plant steroids)
What is the action of 1,25-dihydroxyvitamin D?
It acts on the small intestine and kidney to raise plasma calcium ion concentration
What are the two roles of the small intestine (duodenum) in regards to calcium and phosphate?
- Up-regulates trans cellular reabsorption of calcium ions by increasing expression for epithelial calcium ion channels, pumps and binding proteins
- Stimulates the syneresis of a NaPi co-transporter to increase phosphate absorption
What are the two roles of the kidneys in regards to calcium and phosphate?
- Acts synergistically with PTH to enhance calcium ion reabsorption in the distal tubule
- promotes phosphate reabsorption
What activated vitamin D?
Addition of two hydroxyl groups
Two hydroxyl groups activate vitamin D. Where is the first hydroxyl group added?
In the liver
Two hydroxyl groups activate vitamin D. Where is the second hydroxyl group added?
In the renal proximal tubule under regulation by PTH
What is the consequence of vitamin D deficiency?
Impaired intestinal absorption of calcium ions , resulting in hypocalcaemia, which then leads to an increase in PTH secretion, which increases bone resorption- softening and deforming bones. (Rickets or osteomalacia)
What is the consequence of vitamin D deficiency?
Impaired intestinal absorption of calcium ions , resulting in hypocalcaemia, which then leads to an increase in PTH secretion, which increases bone resorption- softening and deforming bones. (Rickets or osteomalacia)
In children, what disease occurs as a consequence of vitamin D deficiency, and how does it present?
Rickets, it has a characteristic bow leg appearance
In adults, what disease occurs as a consequence of vitamin D deficiency, and what does this mean for the patient?
Osteomalacia, means that the patient is much more prone to developing fractures
What cells synthesise calcitonin?
C cells (clear or parafollicular cells) of the thyroid gland
What triggers the release of calcitonin?
An increase in extracellular calcium ion concentration above normal (hypercalcaemia)
What is the action of calcitonin?
To lower plasma calcium ion concentration
What cells express calcitonin receptors?
Osteoclasts
What effect does calcitonin have on osteoclasts?
Inhibits the resorptive activity of osteoclasts, slowing the rate of bone turnover
What are the 4 skeletal functions of bone?
- protects organs
- provides rigidity
- allows attachment of muscles and teeth
- movements
What is the composition of bone?
- 60% mineral (largely hydroxyapatite)
- 25% organic (90% type 1 collagen, 10% non-fibrous extracellular matrix)
- 15% water
What is the purpose of alveolar bone?
To support the tooth
What is the purpose of the basal bone?
Forms the structure of jaw bone (mandible or maxilla)
What type of bone disappears gradually after extraction of a tooth?
Alveolar bone
What is the bone called that surrounds the tooth socket?
Cortical bone
The alveolar bone structure consists of two types of bone, what are they?
- Cortical
- Trabecular
What bone, within alveolar bone, is loose, spongy and cancellous?
Trabecular bone
When using intraligamentary anaesthetic, how does the LA reach the apex of the tooth?
When injecting under pressure into the PDL, the LA diffuses through the porous lining of the socket, through the trabecular bone and reaches the apex.
When looking at microscopic lamellar bone structure, what three types of lamellae bone can be visualised?
- Circumferential
- Concentric
- Interstitial
What type of ossification forms cartilage?
Endochondral ossification
What bone cells are mesenchymal/ectomesenchymal derived, live on bone surfaces and produce osteonecrosis matrix?
Osteoblasts
What bone cells are essentially trapped osteoblasts in the bone?
Osteocytes
What bone cells are derived from haemopoietic sources (macrophage/mopnocyte line) and dissolve hydroxyapatite out of bone in the process of bone turnover?
Osteoclasts
In the body, how often is bone completely replaced?
Every 10 years
What are the benefits of complete bone turnover in the body?
- keeps skeleton effectively engineered for its use
- helps maintain plasma calcium ion levels
What cells lay down new bone?
Osteoblasts
What is tetany?
“ a symptom that involves involuntary muscle contractions and overly stimulated peripheral nerves”
What causes tetany?
Low calcium ion levels resulting in spontaneous action potentials
What cells does fast Ca2+ efflux (due to PTH) in bone involve?
Osteocytes
What cells does slow Ca2+ efflux (due to PTH) in bone involve?
Osteoclasts
What are the three actions of calcitonin on bone cells?
- Reduce osteocyte activity
- Reduce osteoblast activity
- Reduce osteoclast numbers
What is the main action of vitamin D in regards to calcium levels?
Increases calcium ion absorption in the intestine
What are the 5 phases in bone remodelling?
- Activation
- Osteoclast recruitment and resorption
- Reversal
- Osteoblast recruitment and bone formation
- Termination- quiescence
Give two examples of genetic abnormalities of bone?
- osteogenesis imperfecta
- osteoperosis
What is osteogenesis Imperfecta?
Is a defect in collagen formation, resulting in fragile bones that break easily
What is osteoperosis?
A condition characterised by reduction of overall bone density
What medication, when used in long-term, is well known for inducing osteoperosis?
Glucocorticoids
What is hyperparathyroidism?
A condition where excess PTH is synthesised due to over activity of the parathyroid glands.
Name two metabolic bone diseases
- Paget’s disease
- Fibrous Dysplasia
What is Paget’s disease?
A disease that involves disruption of the normal cycle of bone renewal and repair, which causes bones to be weakened and become deformed.
What is fibrous dysplasia?
A condition where scar-like tissue develops in place of normal bone.
What is meant by a sequestrum?
A piece of necrotic bone detached from the healthy tissue, usually secondary to trauma
What is the clinical relevance of bone remodelling and what further treatments could be effected by this process post extraction?
- provision and design of bridges
- the need for immediate dentures
- the timing of dental implant placement
What 4 drugs affect bone remodelling?
- Bisphosphonates
- Denosumab and anti-angiogenic drugs
- Steroids
- NSAID’s
Define, non-metabolised analogues of pyrophosphate that are capable of localising to bone and inhibiting osteoclastic function.
Bisphosphonates
What is the half life of bisphosphonates and what does this mean?
Half life is approx 10 years, therefore high concentrations are maintained within bone for long periods of time.
What other characteristic do Bisphosphonates have that helps to inhibit bone remodelling?
Anti-angiogenic
What are the two classes of Bisphosphonates? Give examples.
- Non-nitrogen containing bisphosphonate (e.g. clodronate)
- Nitrogen containing bisphosphonates (e.g. alendronate)
What class of bisphosphonates is more common?
Nitrogen containing Bisphosphonates (e.g. alendronate)
Why is it necessary to swallow bisphosphonate tablets sitting upright?
Because they are acidic, so you don’t want them getting stuck in the oesophagus as they may burn the mucosa
What are the conditions normally treated with bisphosphonates?
- multiple myeloma (44%)
- breast cancer (32%)
- osteoperosis (13%)
- prostate cancer (5%)
Why is it important to distinguish whether a patient takes oral bisphosphonates or IV bisphosphonates?
Oral intake puts patient at low risk complications, whereas IV intake puts patient at high risk of complications.
According to the SDCEP guidlines 2011 and 2017, what patients are categorised as low risk for complications?
- patients not yet started taking bisphosphonates
- patients taking bisphosphonates for the prevention of osteoporosis
According to the SDCEP guidlines 2011 and 2017, give examples of patients that are categorised as high risk for complications?
- previous diagnosis of MRONJ
- taking bisphosphonates as part pf cancer treatment
- if they have another non-malignant condition of the bone (e.g. Paget’s disease)
- concurrent use of systemic corticosteroids or other immunosuppressants
- radiotherapy treatment
Etc.
Why would someone treated with radiotherapy be at higher risk for MRONJ?
This procedure damages the vasculature to the bones and compromises their ability to heal, making them more likely to get necrosis.
Why is the mandible more predisposed to MRONJ/necrosis than the maxilla?
Because the maxilla has a better vascular supply
What is denosumab?
A human mono-clonal antibody that inhibits osteoclast function, by inhibiting the receptor activator of nuclear factor kappa B ligand (RANKL).
What is the function of RANKL?
Acts as the primary signal for bone removal
Name three newer drugs that have been developed to treat MRONJ.
- Everolimus
- Raloxifene
- Teriparatide
Give two reasons as to why corticosteroids delay healing?
- Due to anti-inflammatory action
- Due to Inhibiting action on fibroblastic proliferation, collagen synthesis and epithelialization
What group of medication should be avoided following bone augmentation surgery for dental implants and why?
NSAID’s, as they have been found to interfere with production of prostaglandins.
