Year 2: Metabolic bone disorders Flashcards
What are the two components of bone?
- Osteoid: unmineralised bone (organic component)
- 35%
- Mainly Type I collagen fibres
- Inorganic minergal component
- 65%
- Calcium hydroxyapatite crystals (that fill the space between the collagen fibres)
What is the function of the osteoblasts?
They built boneby synthesising collagen fibres and help in osteoid mineralisation
What is the function of osteoclasts?
They resorb bone and thereby free calcium and phosphate via the release of lysomal enzymes
How do osteoclasts get activated?
They differentiatiate in response to RANKL-Receptor stimmulation of surface
The RANKL is expressed on osteoblasts surfaces–> osteoclasts get activated by osteoblasts!
How to osteoblasts get activated?
Resond to PTH & calcitriol (1,25 (OH)2 vit D)
–> regulate bone formation and absorbtion
What is the cortical part of the bone?
The hard shell of the bone
What is the Trabecular part of bone?
spongy, inner part of bone
What is meant by the term “woven” bone
disorganised collagen fibrils, weaker
–> loss of lamellar sturcture
How do you call a bone that is weaker due to unoranised collagen fibres?
Woven bone
What is the normal structure of a bone called?
Lamellar pattern of bone :
collagen fibrils laid down in alternating orientations that makes it mechanically strong
What are the direct effects of Vitamine D deficiency on bone?
Inadequate mineralisation of newly formed bone matrix (osteoid)
How does Vitamin D deficiency present in children?
Rickets
- skeletal abnormalities and pain, growth retardation, increased fracture risk
- also affects cartilage and epiphysal growth
What does Vit D deficiency cause in adults?
OSTEOMALACIA
- affects the bone (not the epiphysal)
- skeletal pain, increased fracture risk, proxmyopathy
–> might lead to wabbeling gait and looser zones (in severe deficiency)
What is a looser zone in bone?
Fractures from inadequadly mineralised bone due to normal weight
Explain primary, secondary and tertiary Hyperparathyroidism
How does renal failure lead to vascular calcification?
Because there is reduced excretion of PO4 3-, therefore highter phosphate levels that form insoluble Calcium phosphate plaques
What does renal failure in terms of bone health lead to?
It leads to
- more bone resorbtion (to kepp calcium levels because of VitD deficiency, no Ca2+ can be absorbed)
- Leading to osteitis fibrosa cystica –> hyperparathyroid bone disease
What is osteitis fibrosa cystica?
Hyperparathyroid bone disease
leading to “Brown tumors”– >radiolucent bone lesions due to hight osteoclast activity stimmulated by high PTH to get Ca2+ up
rare now
How do you treat osteitis fibrosa cystica?
Two main issues
- High Phosphate levels
- low phosphate diet
- Phosphate binders – reduce GI phosphate absorption
- Alphacalcitriol
- to restore Vit D levels, decrease bone resorbiton due to low Ca2+
- Parathyroidectomy in 3. hyperparathyroidism
- in hypercalcaemia + hyperparathyroid bone disease
What exactly is osteoporosis?
Loss of bony trabeculae and reduced bone mass leading to weaker bone –> increase risk of fractures
What is BMD?
What does it tell you?
BMD= Bone mineral density
Can be diagnostic of osteoporosis (T-score) if it is = 2.5 below average –>
How is bone mineral density normally measured?
Via and DEXA (Dual Energy X-ray Absorptiometry ) of the femoral neck and lumbar spine
It measures the bone calcium content–> rthe more calcium, the higher the bone mineral density
What are the factors that predispone you to osteoporosis?
- Post-menopausal hormone deficiency (oestrogen is protective)
- Age-related changes in bone homeostasis (osteoclast senescence)
- Hypogonadism in young women and in men
- Different endocrine conditons
- Latrogenic
- heparin
- prolonged glucosteriods
What are latrogenic conditions?
Diseases that are caused by medical care
Which endocrine disorders can cause Osteoporosis?
oCushing’s syndrome
oHyperthyroidism
oPrimary hyperparathyroidism
What are the possible treatments for osteoporosis?
- •Oestrogen/Selective Oestrogen Receptor Modulators
- •Bisphosphonates
- •Denosumab (antibody)
- •Teriparatide
Explain the use of oestrogen in osteoporosis
- Post menopausal
- replace E2 to reduce bone resorbtion
- also give progesterone if uterus is intact –> to cause period and prevent endometrial CA
- Main Risks are
- Breast Cancer
- Venous thromboembolism
What is the MOA of Bisphosphonates?
They impair the osteoclasts and induce apoptosis –> redue bone reabsorbtion
Happens by Bind avidly to hydroxyapatite (that is digested by osteoclasts –> leads to disruption of intracellular enzymatic activity in osteoclast)
What is the clinical use of bisphosphonates?
It is used in
- Osteoporosis –> reduce bone turnover
- Malgnancy
- Associated hypercalcaemia
- Reduce bone pain from metastases
- Paget’s disease – reduce bony pain
- After rehydration in severe hypercalcaemia emergency
What are the main side effects of bisphospobates?
Unpleasent to take, need to take on empty stomach
- Oesophagitis
- may require switch from oral to iv preparatåion
- Osteonecrosis of the jaw
- greatest risk in cancer patients receiving iv bisphosphonates
- Atypical fractures
- may reflect over-suppression of bone remodelling in prolonged bisphosphonate use
What is Denosumab?
When and how is it used?
It is a human antibody binding to RANKL
–> inhibits osteoclast activation –> reduces bone resporbtion
- SC injection 6/12ly
- 2nd line to bisphosphonates
What is Teriparatide?
What and how is is used for?
•Recombinant PTH fragment
- Increases bone formation and bone resorption, but formation outweighs resorption
- 3rd line treatment for osteoporosis
- Daily s.c. injection
- £££
What would be your fist, secound and third line treatment in OSteoporosis?
- Bisphosphonates
- Denosumab (RANKL antibody)
- Teriparatide (PTH fragement stimmulating bone formation)
What is pagets disease of bone?
(Cause and consequence)
•Accelerated, localised but disorganised bone remodelling –> leading to WOVEN bone
MOA: Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)
Leading to
- hypertrophy with increased fragility and deformity
- Characterised by abnormal, large osteoclasts – excessive in number
What is the cause of pagets disease of bone?
It is not knonw
- Genetic cause?
- viral origin?
- But most commonly seen in
- Highest in UK, N America, Australia and NZ, Lowest in Asian and Scandinavia
- No sex difference
- appears over age of 50
What are the clinical features of someone with pagets diseae?
- Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
- Arthritis
- Fracture
- Pain
- Bone deformity
- Increased vascularity (warmth over affected bone)
- Deafness – cochlear involvement
- Radiculopathy – due to nerve compression
How would you diagnose someonw with pagets disease of bone?
Normal Plasma Ca2+
Increased plasma alkaline phosphatase
Plain X-Rays:
- Lytic lesions (early), thickened, enlarged, deformed bones (later)
- Radionuclide bone scan demonstrates extent of skeletal involvement
How would you treat pagets disease of bone?
- Bisphosphonates – very helpful for reducing bony pain and disease activity
- Simple analgesia
