Recap:
Major functions of bone
Types of bone
Cells involved in bone remodelling
Osteoid composition
What else do osteoblasts secrete?
How is bone remodelling regulated?
- Function of bone à support, movement, Ca2+ and phosphate homeostasis, protection
- Types of bone –> first woven, then lamellar bone (mature bone), two types of lamellar bone –> cortical and trabecular
- Cells involved in bone remodelling –> osteoblasts and osteoclasts
- Osteoid –> Type 1 collagen, proteoglycans, glycoproteins
- Osteoblasts secrete –> alkaline phosphatase, RANK ligand, Osteoprotegrin, osteocalcin (Binds Ca2+)
Regulation –> balance of OPG to RANKL, hormones PTH and oestrogen, interleukins, cytokines and age.
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Bone structure and function:
Describe main functions of bone as a metabolic tissue
Describe main functions of bone as a protective load bearing tissue
Metabolic tissue:
- Acts as a mineral buffer, largest stores of Ca2+
- Needs to be able to repair microfractures that occur throughout life to maintain quality of bone
- Coordination of bone cells (osteoclasts vs blasts) vital
Protective, load bearing:
- Cortical vs trabecular (weight vs strength)
- Rigidity and resilience (hydroxyapatite: Collagen)
What pathological changes can there be to bone?
- Change in the quantity of bone:
- too little –> osteoporosis, common
- too much –> osteopetrosis, uncommon, very bright on an xray
- Change in quality of bone:
- defective/ loss of mineralisation –> rickets/ osteomalacia/ hyperparathyroidism
- Change in the structure of bone:
- osteogenesis imperfecta --> collagen defect, loss of flexibility bones v brittle
- Paget’s disease –> rapid turnover due to osteoclasts, poor quality woven bone
- Tumours
What clinical tests are there to assess bone structure?
- Blood tests:
- PTH, Ca2+, Vitamin D
- Routine –> Alkaline phosphatase, albumin (nutritional status links to bone density)
- Imaging:
- plain X-ray
- Radionuclide scans –> inject radioactive substance which targets overactive cell (osteoblast/clasts)
- MRI/ CT/ Ultrasound
- Bone biopsy –> tumour
- Bone density –> DEXA scan (dual energy X-ray Absorptiometry)
What is osteoporosis?
What bones are most commonly fractured?
Osteoporosis = complex skeletal disease characterised by low bone density and microarchitectural defects in bone tissue, resulting in increased bone fragility and susceptibility to fracture.
Common, affects 3,000,000 people in the UK, european and asian populations
Risk of fracture increases with Age, 1/2 for women, 1/5 for men, most common in post menopausal women
Bones most commonly fractured = neck of femur, vertebra and wrist
What damage can occur to the vertebral column with osteoporosis?
- Crush fracture e.g. left picture L4 is crushed
- Natural kyphosis of the thoracic vertebrae, with osteoporosis these vertebrae can become crushed, exaggerating the kyphosis giving a hunched over appearance
- Intervertebral foramina get smaller too, can lead to nerve impingement
What is the pathology shown?
- Left: Radial fracture and loss of ulnar styloid process, due to fall on outstretched hand
- Right: Left intracapsular femur neck fracture, risk of cut off blood supply and avascular necrosis
What are the wider implications of osteoporosis?
- Osteoporosis often picked up due to a fall and subsequent fracture
- Leads to a loss of confidence –> less exercise, lower bone density, slower reflexes and poor balance
- –> increased risk falls and fractures
- Pain
- Decreased QOL, permanent disability, lost independence
- Long term admission –> catch secondary infection/ AKI from surgery
- High mortality
What are some of the risk factors for osteoporosis?
Unmodifiable:
- Age/ postmenopausal woman
- Sex
- Ethnicity (european or asian)
- Family Hx
Modifiable:
- Immobility (wolffs law)
- smoking/ alcohol
- steroids
- vitamin D/ Ca2+ deficiency
- Low BMI
Describe the pathophysiology of osteoporosis
Peak bone density is achieved after reaching bone maturity, after which is declines with age. PBD influenced by genetics, nutrition and physical activity.
Women decline faster than men
What are the main screening tools used in osteoporosis?
What is secondary prevention?
- FRAX = evaluates the fracture risk of patients by taking into account their risk factors and past fractures which gives you a score
- Score may indicate a DEXA scan or may DEXA as a screen
- Secondary prevention may be indicated –> prevent further falls with mobiloty aids, supported living situation
What is DEXA?
What are possible DEXA scores?
- DEXA (Dual energy Xray absorptiometry)
- Gives two Scores Z score and T score (focus on T score)
- T scores relate to the mean bone density of a young adult:
- BMD of less than 1 SD from young adult mean (T score ≥-1) = Normal
- BMD 1-2.5 SD below young adult mean (T score less than -1 but above -2.5) = osteopenia (may occur after fracture and immobility in healthy adult).
- BMD more than 2.5 SD below the young adult mean (T score less than -2.5) indicates osteoporosis.
How would you manage osteoporosis?
- Diet
- exercise
- supplements - vitamin D and calcium
- Fall prevention
- Pharmacy:
- oral bisphosphates
- SERMs
- PTH
- Denosumab
What pharmacological treatments can be used to treat osteoporosis?
- Bisphosphates –> alendronic acid
- SERM –> selective oestrogen receptor modulator –> Raloxifiene
- PTH
- Monoclonal antibodies: Denosumab –> bind RANKL
Name a bisphosphate and its administration
What is their mechanism of action
What diseases are they useful in treating?
What are their side effects
- Alendronic acid
- Must be on empty stomach, 1 glass water, remain upright for half an hour –>prevent erosion of oesophagus
- MOA:
- Absorbed onto the hydroxyapatite crystals which slows down rate of bone remodelling
- Taken up by osteoclasts interferes with ruffled border attachment to bone
- Osteoclasts unable to attach to bone, less enzymes released and less bone resorption
- Slows rate of bone remodelling
- Uses: Osteoporosis and Pagets disease, Hypercalcaemia of malignancy
- Side effects:
- asymptomatic hypocalcaemia
- general GI disturbance
- oesophageal reactions
- osteonecrosis of the jaw–> rare but be aware of dentition before treatment, in larger doses or zolendronic acid.
- possible long term effects –> atypical femoral fractures
Absorption and elimination:
- Poorly absorbed; absorption ¯ if taken with Ca2+
- Not metabolised, excreted unchanged in urine (caution in CKD)
Name the SERM used in osteoporosis treatment
What is its MOA? why is it useful?
SERM = selective estrogen receptor modulator = Raloxifine
MOA: has mixed agonist/ antagonist function at the ER
Useful as hormone replacement therapy used to stimulate all estrogen receptors so women were at risk of developing breast and uterine cancers. SERM Raloxifine stimulates ER in bone, anatogonises ER in breast/ uterine tissue.
Use: osteoporosis
What hormone can be used in osteoporosis treatment?
What is its action
How is it administered
What are the SE’s?
- Parathyroid hormone
- Promotes bone production
- Administration:
- via subcutaneous injection
- Intermittent PTH stimulates production of trabecular bone –> inc. osteoblast diff and activity and decrease apoptosis
- Continous PTH causes bone loss
- Side effects: hypercalcaemia, muscle cramp, nausea and vomiting
What antibody treatment can be used in osteoporosis?
What is its MOA
Administration
SE’s
- Denosumab = monoclonal antibody directed against RANKL
- Mimics the natural decoy receptor osteoprotegerin and binds to RANKL, inhibiting RANKL stimulation of osteoclasts prevent bone resorption
- Administration : SC injection
- SE’s: hypocalcaemia, diarrhoea, dysponea and constipation
Name two disorders that affect mineralisation of bone
Which groups do these disorders primarily affect?
What are the most common causes of these disorders?
- Rickets and osteomalacia both characterised by inadequate mineralisation of bone -> different manifestations of the same pathological process
- Rickets: Affects children
- growth plate still present –> defective mineralisation of the growth plate
- Normally hypertrophic chondrocyte zone, these should apoptose and bone matrix should be deposited
- In rickets it is not mineralised, cartilage tissue remains that can become deformed with use ( valgus and varus)
- Cells can become splayed outwards and widening of growth plate
- Osteomalacia:
- Affects both adults and children
- defective mineralisation of osteoid
- Most common causes are: Vitamin D deficiency, resultin in low calcium and low phosphate levels
What are three key pathological features with rickets?
- Growth retardation
- bony deformities
- imaging shows widening/ splaying of the epiphyseal growth plate/ metaphysis
what are some of the key presentation features of osteomalacia?
What blood tests would you do? What results would you expect?
How can we treat osteomalacia?
- may be asymptomatic
- may have muscle weakness proximally
- bone pain
- fractures
Blood tests:
- Calcium and phosphate would be low
- Alk P would be high
- Low vitamin D
Usually treated with education, diet and supplements
What different types of bone cancer can be seen?
- Primary vs secondary bone cancers:
- primary bone cancer is when the cancer has arisen from within bone tissue
- this is very rare
- secondary cancer is more common and is where another cancer has metastasised to the bone
- often prostate, breast and lung cancers
- Benign vs malignant:
- benign bone cancer –> osteoma or chondroma
- malignant bone cancer –> osteosarcoma or chondrosarcoma
- Lytic vs sclerotic:
- When bone is invaded by metastatic cells it often causes two types of lesions depending on the primary cancer
- In breast and lung –> often see lytic lesions, where bone is broken down and replaced with cancer tissue, often see hypercalcaemia
- In prostate cancer –> tends to stimulate bone growth that is unstructured woven bone. This becomes mineralised and forms a sclerotic lesion.
- Often affects surrounding tissues.
What is Paget’s disease?
what is the pathophysiology and what type of lesions can be seen?
What bones may it affect?
What is its occurence?
- Pagets disease is characterised by increased bone turnover with overactive osteoclasts which resorb bone very quickly –> lytic lesions
- Osteoblasts react by laying down unstructured poor quality woven bone that does not get remodelled –> sclerotic lesions
- woven bone is weak
- results in overgrowth, bowing, pain, fractures and deformity
- May be focal or multifocal
- It can affect the skull and its foramina, may present with cranial nerve palsy, e.g. visual disturbance or hearing loss
- Estimated to occur in 1-3% of people over 55 yrs
What investigations would be done in suspected Paget’s disease?
What results would you expect?
- Bloods:
- Ca2+ (normal) , PTH (?) Alk P (high)
- Xray
- Radionuclide bone scan – > see overactive osteoclasts
- Bone biopsy if malignant change is suspected –> cells working at much faster rate and therefore more susceptible to mutations and cancer, patient needs to be reviewed, suspect malignancy if rapid growth and erythema.
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Tolerance and Autoimmunity37
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Bone Structure, Formation, Growth35
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Muscle Structure and Pathologies21
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Bone and Joint Infection17
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Forearm and Elbow34
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Skin and Soft Tissue Infections10
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Gluteal Region, Hip and Thigh Anatomy50
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Disability7
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Calcium and phosphate homeostasis36
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Breaking Bad News5
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Limits of personal, professional and legal responsibilities10
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Respect for autonomy and best interests of adults4
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Pectoral Girdle and Upper Limb51
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Lower Limb: Proximal Neurovasculature42
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Lower Limb: Distal Neurovasculature42
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Wrist and Hand34
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Antibiotics: Mechanism of Action22
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Bone structure/formation/growth/ repair38
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Bone abnormalities27
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Wound Healing38
