T2 L12 Physiology of bone repair Flashcards
What are the functions of the skeleton?
Maintaining bone structure Locomotion Haematopoiesis Ca2+ / mineral homeostasis Protection of inner organs
What is the consequence of too much bone resorption?
Osteoporosis
Osteopenia
Rickets
What is the consequence of too little formation?
Osteopetrosis
What is the definition of bone resorption?
Solid bone dissolved by physiological processes
Why is bone resorption important?
Repair of broken bones
Remodelling of bones as person grows
Remodelling of bone for specific stresses
What is the definition of demineralisation?
Breaking down bone by making hydroxyapatite soluble
What is osteopenia?
Condition were bone mineral density is lower than normal
What are the uses of measuring bone mineral density?
Identify osteoporosis
Determine risk for fractures
Measure response to osteoporosis treatment
What is osteopetrosis?
One of several diseases where bones harden in excess
Bone becomes hard, lacks flexibility, easily fractures
Autosomal recessive disease
What is rickets?
Disease of bone development usually due to malnutrition
What does rickets result in?
Bone deformities
Increased tendencies for fractures
Spinal deformity
How is bone classified on macroscopic level?
Cortical bone Cancellous bone (spongy)
What is cortical bone?
Thick bone organised in osteons
Associated with or connected to outer surface of bone
High turnover to remodel according to stress across bone
Spicules
Trabeculae
What is cancellous bone?
Bony structs organised into loose network with blood / bone marrow between struts
30-90% is porous and contains bone marrow
What happens to cancellous bone in osteoporosis?
Increased porosity
Less strong, less ridge, more elastic
How is bone organised microscopically?
Lamellar
Woven
Describe lamellar organisation of bone?
Secondary bone which is created by remodelling woven bone
Organised and stress oriented
Stronger and less flexible than woven bone
Osteons
Describe woven organisation of bone
Immature
Disorganised
Not stress orientated
More osteocytes, higher rate turnover, weaker and more flexible than lamellar bone
What are the 3 principle cell types in bone?
Osteoblasts
Osteocytes
Osteoclasts
Describe osteoblasts
Form new bone and release signalling substances
Produce protein components of acellular matrix which regulates bone growth and degradation
Located on developing bone surfaces
Post-mitotic - most will undergo apoptosis
What are osteoblasts derived from?
From mesenchyme
Precursor cells in bone marrow storm
Describe the histology of osteoblasts
20-25 microns
Round and regular shape
Mononucleate
Describe osteocytes
Quiescent mature cells embedded in bone matrix
Function is maintenance and detection of environmental and ageing stresses
Within osteoid
What are osteocytes derived from?
Osteoblasts
Describe the histology of osteocytes
Long and thin
Extensive branches that travel through canaliculi
Main cell body inside lacunae is 20x5microns
Mononucleate
Describe osteoclasts
Function is bone degradation and remodelling bone
Can proliferate
What are osteoclasts derived from?
Same precursor as monocytes (haematopoietic stem cells)
Describe the histology of osteoclasts
40-100micrometre diameter
15-20 closely packed oval-shaped nuclei
Regular, cube-like shape with ruffled border
What does the ruffled border on osteoclasts do?
Has integrins to surround region of resorption
Prevents dilution of acid
Prevents loss of proteases
What is an osteoid?
Unmineralised, organic portion of bone matrix that forms prior to maturation of bone tissue
What are the organic components that make up the matrix?
Proteins e.g. collagen and elastin
Polysaccharides
Glycosaminoglycans
What are the inorganic components that make up the matrix?
Ca2+
Phosphate
Hydroxyapatite
Magnesium
Wha types of components are found in the matrix?
Organic components
Inorganic components
Growth factors
Describe glycosaminoglycans
Long unbranched polysaccharides
Highly negative
Resist compression
Abundant in cartilage
Describe the role of growth factors
Revealed by osteoclast action which stimulates and attracts osteoblasts leading to proliferation and mineralisation
Bone remodelling leading to bone turnover and activation-resorption-formation sequence
What is the Haversian system?
One type of microscopic organisation of bone tissue
Communication system between cells is immobilised in bone matrix
What is the Haversian canal?
Longitudinal canal within bone tissue
Runs parallel to surface and along long-axis of bone
Surrounded by lamellae to form Haversian system
What are canaliculi?
Microscopic canals between lacunae of ossified bone
Radiating processes of osteocytes projects into these canals
What is compressive strength?
Ability to resist compression without collapsing or expanding to point of failure
What provides compressive strength in bone?
Hydroxyapatite
What is tensile strength?
Ability to resist stretching without breaking
What provides tensile strength?
Collagen
Where do osteoclasts resorb bone?
In Howship’s lacunae
What is Howship’s lacunae?
Space on edge of bony spicule which has been made by and contains osteoclast
What controls activation-resorption-remineralisation sequence?
Surface osteoblasts
Detect mechanical factors (stresses on that bone) and hormonal factors that initially trigger bone remodelling
What are the 2 ways bone can form?
Intramembranous
Endochondral
What is intramembranous bone formation?
Bone formation without cartilage model
Describe the mechanism of intramembranous bone formation
Osteoblasts lay down osteoid and bone mineralisation
Form tiny bony spicules
Join with nearby spicules
Form trabeculae (woven bone)
What is endochrondral bone formation?
Bone formation based on cartilage model. Cartilaginous template made from mesenchyme
Describe the mechanism of endochondral bone formation
Chondrocytes proliferate and secrete extracellular matrix and proteoglycans
Osteoblasts arrive
Osteoid laid down
Mineralisation begins
What factors govern bone remodelling?
Recurrent mechanical stress
Calcium homeostasis
What happens to bone trabeculae under recurrent mechanical stress?
Becomes dense and prominent to strengthen bone
How does recurrent mechanical stress govern remodelling?
Surface osteoblasts and osteocyte network detect stresses
Inhibits bone resorption and promotes deposition
What are bisphosphonates used for?
Osteoporosis to diminish bone resorption by osteoclasts
Give an example of a bisphosphonae
Alendronate
What is the mechanism of bisphosphonates?
Inhibit osteoclast-mediated bone resorption
Related to inorganic pyrophosphate
- pyrophosphate is endogenous regulator of bone turnover
- accumulates on bone as it binds to calcium, ingested by osteoclasts which interferes with osteoclast metabolism
Give an example of a drug that encourages osteoblast formation of bone
Teriparatide
What drug prevents osteoclast maturation?
Denosumab
What is densoumab?
Monoclonal antibody that targets RANK ligand
- mimics action of OPG to prevent activation and differentiation of osteoclasts
What is RANK ligand?
Member of TNF cytokine family
Functions as key factor for osteoclast differentiation and activation
What is the molecular mechanisms in osteopetrosis?
Osteoclasts can’t remodel bone
Defective vacuolar proton pump which can’t make Howship’s lacuna acidic so bone isn’t resorbed
Defective chloride channel
What are the consequences of osteopetrosis?
Fatal within 10 years Brittle (dense) bones Blindness Deafness Severe anaemia
What is the treatment for osteopetrosis?
Bone marrow transplant - only partially effective
How long does fracture healing take in adults?
2 to 3 weeks in upper body
At least 4 weeks in lower body
What are the 4 phases of fracture healing?
1) Reactive phase - haematoma and inflammation
2) Soft callus formation
3) Hard callus formation
4) Remodelling
Describe the reactive phase of fracture healing
Blood cells enter wound and haematoma forms
Inflammatory cells invade to form granulation
Bone precursor cells arrive from periosteum
Describe the soft callus formation stage of fracture healing
Woven bone (or hyaline cartilage) joints pieces of broken bone
- woven bone is near blood vessels
- fibrocartilage is further away
Fast process
Describe the hard callus formation stage of fracture healing
Lamellar bone replaces woven bone
Slow process resulting in stronger bones
Describe the remodelling phase of fracture healing
Endochondral (lamellar) bone is replaced by trabecular bone
Trabecular bone is remodelled into original bone shape
Where is calcium stored?
Bone Sequestered inside cells / SR Protein bound Complexed with anions Free calcium
Where is PTH made?
By parathyroid chief cells
What does PTH do to calcium?
Increases plasma calcium
Where does PTH act?
Bone
Kidney
Gastrointestinal tract
What effect does PTH have on kidney?
Reduces kidney secretion of calcium and increases secretion of phosphate
What effect does PTH have on bone?
Stimulates bone to mobilise calcium
Detected by osteoblasts and osteocytes –> mobilise sequestered calcium and release cytokines
Increased differentiation and activity e.g. osteoclasts
Where is vitamin D made?
Skin
Liver
Kidney
What effect does vitamin D have on calcium?
Increases plasma Ca2+ for longer time than PTH
Where is calcitonin made?
Thyroid C cells
What effect does calcitonin have on calcium?
Decreases blood calcium as more is taken up by bone
What does OPG (osteoprotegrin) do?
Binds to RANK ligand to prevent RANK binding
Inhibits differentiation of precursor osteoclast into mature osteoclast
Describe the negative feedback of calcium in lactation
Lactation –> low plasma Ca2+
Calcium-sensitive receptor in parathyroid chief cells detect low calcium
Chief cells release PTH
Kidney increases Ca resorption at DCT, enterocytes increase calbindin –> Ca absorption, bone mobilises Ca to plasma
Plasma calcium increases
Describe the steps of vitamin D production and activation
1) Cholecalciferol in skin
2) 25-OH cholecalciferol
3) 1,25-di-OH-cholecalciferol (calcitriol)
4) Increase calbindin in gut enterocytes
5) Increase intestinal absorption of calcium
6) Increase calcium reabsorption in kidney
7) Increase plasma Ca2+
What are the effects of vitamin D?
Increase intestinal calcium absorption - increases calbindin
Stimulates kidneys to reabsorb calcium
Indirectly stimulates osteoclasts
Facilitates bone remodelling
What is calbindin?
Calcium-binding protein that increases intestinal calcium absorption
How is vitamin D production controlled via negative feedback?
25-OH-cholecalciferol feeds back on liver to reduce production of 25-OH-cholecalciferol from cholecalciferol
Calcium feeds back on parathyroid gland to reduce PTH production –> reduces kidney’s activation of 25-OH-cholecalciferol to 1,25-di-OH-cholecalciferol
What are the causes of low plasma calcium?
Pregnancy, lactation Kidney dysfunction Low intake Parathyroid dysfunction Drugs
What drugs can cause low calcium?
Magnesium
Anticonvulsants
What are the consequences of chronic hypocalcaemia?
Skeletal deformities Increased tendency towards bone fractures Impaired growth Short stature Dental deformities
Describe the skeletal deformities in chronic hypocalcaemia
Bowlegs Forward projection breastbone Asymmetrical or odd-shaped skull Soine deformities e.g. scoliosis Pelvic deformities
What are the consequences of acute hypocalcaemia?
Convulsions
Arrhythmias
Tetany
What is Chvostek’s sign?
Latent tetany
Tapping master leads to twitch on same side of face
What is Trousseau’s sign?
Carpopedal spasm with lateral tetany
What is DiGeorge syndrome?
Rare genetic anomaly
Typically has issues with mediastinum that lead to absent thymus and underdeveloped parathyroid glands
Why does hypocalcaemia make membranes less stable?
More excitable
Sodium is more able to leak through
Explains late tetany
Why does hypercalcaemia make membranes more stable?
Reduces excitability
Increases intracellular calcium which inactivates channels to reduce calcium inflow in muscle cells
What are the signs and symptoms of hypercalcaemia?
Can be asymptomatic Reduced excitability - constipation - depression - confusion - kidney stones Abnormal heart rhythms - short QT interval - no ST segment - widened T wave
What are the signs of severe hypercalcaemia?
Coma
Cardiac arrest
