Biochem - Fracture and Dislocation Flashcards
Types of bone
Compact/ cortical bone
Cancellous, spongy or trabecular bone
Cortical bone
High proportion of bone w/ few spaces
Trabecular bone
Low proportion of bones and a lot of space. Composed of a network of rods and plates called trabeculae
Bone matrix component
Type I collagen, bone proteoglycan, osteocalcin
Hydroxyapatite
Hydroxypapatite
A complex calcium phosphate salt helps mineralise the bone and bind the calcium into the bone
Patterns in which collagen can be laid down in
Woven bone
Lamellar bone
Woven bone
An immature form w/ random fibre orientation
Laid down during rapid growth and fracture repair
Lamellar bone
Composed of successive layers of collagen fibres w/ distinct orientation
Gives a strong structure
Long bones are composed of
Diaphysis
Epiphyses
Diaphysis
Cyclindical shaft
Epiphyses
Expanded ends of the bones
Sometimes called growth plate
When can bone growth occur
As long as the growth plate hasn’t fused
Bone cells
Osteoblasts
Osteocytes
Osteoclasts
Lining cells
Osteoblasts principal function
Bone formation, synthesising bone matrix and priming it for subsequent mineralisation
Osteoblasts characteristics
Plump cuboidal cells w/ abundant organelles for synthesis and secretion of proteins
Single nucleated
Form an epithelial layer on the bone surface
Lining cells
Osteoblasts which have completed phase of synthetic activity
Can be reactivated
Important function in bone remodelling
Possibly co-operate w/ osteocytes (communication) in regulating calcium exchange from bone
Osteocytes
Osteoblasts engulfed in bone matrix during appposition and eventually entombed within
Apposition
Laying down lamellar structure on the outer aspect of the bone
Most abundant cells in bone
Osteocytes
What do osteocytes rely on canaliculi for
Maintain junctions w/ other entombed cells and w/ bone surface therefore requires vascular supply
Main function of osteocytes
Regulation of calcium homeostasis and last act as strain gauge to monitor and record the extent of physical loading
Osteoclasts
Large multinucleate cells responsible for resorption of bone
Distinctive appearance and contains unique organelles
Unique organelles in osteoclasts
Ruffled border
Clear zone
Why are women bones more fragile and prone too cortical fracture
More endosteal resorption as opposed to periosteal apposition - men
How does trabecular bone change w/ age
Tends to diminish
How does cortical bone change w/ age
Thins
How is the capacity for longitudinal growth maintained
Persistence of epiphyseal growth cartilages
Cartilage undergoes interstitial growth and is replaced by (not transformed into) bone
How is the bone exposed
IL-6 is detected by receptors on lining cells and causes retraction
What happens when osteoblasts receive the signal from cytokines
They produce RANK ligands
RANK ligands stimulate surface receptors to produce more osteoclasts
As more are produced, osteoclasts get bigger and bigger and start resorption
Increased RANK ligand/ OPG ratio
Promotes bone loss
OPG production
Produced by osteoblasts which prevents osteoclast activation
Needs to balance w/ RANK ligand
Osteomalacia
Occurs when the bone doesn’t mineralise correctly due to vit D deficiency
Less mineralisation –> reduction in rigidity and propensity for bone to fracture
Defining osteoclast cell function
Acid phosphatase Glucoronidase Collagenase Metalloproteinase Cathepsins
Defining osteoblast cell function
Alkaline phosphatase Osteocalcin Pro-collagen peptides Cytokines PTHrP
Body calcium
1 Kg is stored in the bone - broken down if body in dire need
Extracellular fluid stores 10mg/l
Storage form of bone
Calcium is stored in bone as hydroxyapatite
Phosphate is also bound in bone w/ Ca and will released when bone is broken down
Calcium in blood
Measure total calcium in blood because its cheaper
Calcium is bound to proteins in the blood
But only ionised calcium is physiologically important
Total [Ca]
2.2 -2.6 mmol/L
Total [Ca 2+]
1.1 - 1.3 mmol/L
Adjusted Ca =
Total Ca + 0.02(40-[Albumin])
Effect on calcium binding to proteins
Acidosis decreases binding, more CaPr
Alkalosis increased binding, more Ca 2+
Regulation of plasma calcium
Parathyroid hormone - most important
Binding to proteins/ PO4
Vit D
Calcitonin
PTH action - medium term
Acts on bone to stimulate osteoclast resorption
PTH action - rapidly
Acts on kidneys to promote Ca being reabsorbed via the tubules so Ca re-enters the bloodstream
PTH action - long term
Acts on kidney to reduce active form of vitamin D, vit D125 —> acts on intestines to improve calcium absorption in the blood
What happens when levels of calcitonin drops
Removes inhibitory effect on osteoclasts allowing PTH stimulation to result
Calcium sensing receptor modulation
Ca binds to Trans-membrane receptor
Acts as an antagonist decreasing PTH release
When Ca low in the presence of normal intracellular Mg PTH released from vesicles fusing w/ csm
Calcium sensing receptor defects
Genetic defects can occur where the calcium sensing receptor ‘resets’ the prevailing circulating ionised (adjusted) calcium
The commonest and most important of these is where the circulating calcium is elevated in the condition Familial Benign Hypercalcaemic Hypercalciuria (FBHH) but have low Ca in urine
The importance of RANKL
Tumour necrosis family
Decoy receptors osteoprotegrin
Regulates skeletal remodelling and immune function
MCSF + RANKL = osteoclastogenesis
Roles of RANKL and OPG
PTH stimulates osteoblasts to produce RANKL –> stimulating osteoclasts
Oestrogen stimulates the osteoblasts to produce OPG, decreasing activity of osteoclasts
Symptoms of hypercalcaemia
Aca > 2.6 mmol/L
Nausea Peptic ulcers Constipation Renal calculi (kidney stones) Polyuria Renal failure Deposition of Ca in aorta, skin etc
Causes of hypercalcemia
Hyperparathyroidism Hypercalcemia of Malignancy Toxicosis Sarcoid Vit A excess Addisons' disease
Symptoms of hypocalcaemia
Aca < 2.6 mol/L
Paresthesia Muscle spasms Tetany Cataracts Neurotransmission at neuromuscular junction disrupted Chvostek's and Trousseau's sign
Causes of hypocalcemia
Hyoparathyroidism
Vit D deficiency
Treatment of primary hyperparathyroidism
Surgery - only definitive treatment
Causes of Hypercalcaemia of Malignancy (HCM)
Tumours produce a factor that acts like PTH but is slightly diff, Parathyroid hormone related protein, PTHrP
More potent –> more severe hypercalcaemia
Causes of hypothyroidism
Post-op (parathyroid, thyroid, cancer) - removed by accident
Idiopathic
Why do we use Adjusted Ca
Of particular value in chronic disease states e.g. cancer where the decrease in albumin may mask hypercalcaemia
Endosteum
Site of formation for new bone and contains osteogenic precursor cells
Medullary cavity
Space within diaphysis that contains red and yellow bone marrow
Red bone marrow
Produces RBC’s and WBC’s
Yellow bone marrow
Contains adipose and connective tissue
Produces some WBC’s
Metaphysis
Spongy bone in between epiphysis and diaphysis
Periosteum
Composed of an inner layer of osteogenic cells and an outer fibrous layer
Function of periosteum
Helps protect the bone
Assists in fracture repair
Helps nourish the bone tissue
Attachment point for tendons and ligaments
Bone growth in length
Zone 1 - resting cartilage
Zone 2 - proliferating cartilage
Zone 3 - hypertrophic cartilage
Zone 4 - calcified cartilage
Zone 1 - resting cartilage
Closest to epiphysis and made up of relatively quiescent cells
Anchors epiphyseal growth plate to the bone of the epiphysis
High matrix:cell volume allows diffusion of nutrients —> maintains chondrocytes in deeper layers
Zone 2 - proliferating cartilage
Slightly larger chondrocytes – dividing and replacing ones dying at diaphyseal side of epiphyseal growth plate
Produce matrix and are responsible for longitudinal growth of the bone
Zone 3 - hypertrophic cartilage
Contains 3 zones:
Maturation
Degeneration
Provisional calcification
Maturation zone
Chondrocytes increase in size
Accumulate calcium within Mt
Degeneration zone
Deteriorate and die
Ca is released from vesicles impregnating matrix w/ Ca salt
Provisional calcification zone
No active cell growth
Necessary for invasion of metaphyseal blood vessels, destruction of cartilage cells, formation of bone along walls of calcified cartilage matrix
Zone 4 - calcified cartilage
Only a few cells thick composed of dead chondrocytes (surrounded by calcified matrix)
Calcified matrix removed by osteoclasts and invaded by osteoblasts laying down new bone matrix —-> diaphyseal border firmly attached to epiphyseal growth plate
HGF
Human Growth Factor
Main stimulus for growth by epiphyseal growth plates
What is ALP a marker of
Bone formation
When to check creatinine kinase levels
Dx of myopathies and myositis
OPG
Osteoprotegrin
Stages of normal fracture healing
- Haematoma formation
- Fibrocartilaginous callus formation
- Bony callus formation
- Bone remodelling
When does haematoma formation occur
Between days 1-5 of the fracture healing
Haematoma formation - fracture healing
Blood vessels are ruptured causing a haematoma, this clots and forms the temporary frame for subsequent healing
Pro-infl cytokines & VEGF are secreted
Fibrocartilaginous callus formation - fracture healing
VEGF → angiogenesis and stem cells are recruited
Chondrogenesis occurs
Osteoprogenitor cells lay down a layer of woven bone
Bony callus formation - fracture healing
RANKL is expressed so the cartilaginous callus is resorbed and begins to calcify
Woven bone continues to be laid down, forming a hard, calcified callus of immature bone
Bone remodelling - fracture healing
Balance between resorption by osteoclasts and new bone formation by osteoblasts
Centre of callus replaced by cortical bone and edges replaced by trabecular bone
When does the fibrocartilaginous callus form
Between days 5-11 of the fracture healing
When does the bony callus form
Between days 11-28 of the fracture healing
When does bone remodelling occur after a fracture
28 days and onwards
Bone remodelling cycle
Activation
Resorption
Reversal
Formation
Bone remodelling - activation
Recruitment and activation of osteoclast precursors (RANKL) and fusion of multiple mononuclear cells to form multinucleated preosteoclasts
Bone remodelling - resorption
Osteoclasts lower the pH in the bone and secrete chemicals to digest the organic matrix resulting in Howships lacunae
Bone remodelling - reversal
Regulator cytokines switch off osteoclasts
Bone remodelling - formation
Osteoblasts move in and produce osteoid
Prerequisites for normal fracture healing
Viability of fragments e.g. intact blood supply
Mechanical rest - either immobilisation or internal fixation
Absence of infection
Examples of abnormal fracture healing
Delayed union
Non-union
Man union
Delayed union
Fracture healing can take 2x as long
Types of non-union
Atrophic
Hypertrophic
Atrophic non-union
Too little callus has formed
Hypertrophic non-union
There is obvious callus but continued instability
Common sites of non-union
Scaphoid
Femoral neck
Tibial shaft
Psuedoarthrosis
When a broken bone fails to heal after a fracture
The fracture structurally resembles a fibrous joint
Common benign tumours
Osteoma
Osteochondroma
Giant cell tumour
Osteoma
Benign ‘overgrowth’ of bone, most typically occurring on the skull
Osteochondroma
Most common benign bone tumour
Cartilage-capped bony projection on the external surface of a bone
Usually in males <20 yrs
Giant cell tumour
Tumour of multinucleated giant cells within a fibrous stroma
Occurs most frequently in the epiphyses of long bones
X-rays show a ‘double bubble’ appearance
Osteosarcoma
Most common primary malignant bone tumour
Seen mainly in children & adolescents
Occurs most frequently in metaphyseal region of long bones prior to epiphyseal closure e.g. femur, tibia, humerus
X-rays show Codman’s triangle & sunburst pattern
Ewing’s sarcoma
Small round blue cell tumour
Seen mainly in children and adolescents
Occurs most frequently in pelvis and long bones - causes severe pain
X-ray shows ‘onion skin’
Chondrosarcoma
Malignant tumour of cartilage
Most commonly affects axial skeleton - palpable mass grows causing pain
More common in middle age
