Theme 5: Bone and New Markers Flashcards
What is the purpose of bone?
- structural support
- protects vital organs
- bank for calcium, phosphate etc
- home for bone marrow
What is cortical bone?
- the hard outer layer
- a.ka compact bone
- gives bone its smooth, white and solid appearance
- accounts for 80% of total bone mass in adult skeleton
What is an osteon?
individual microscopic columns that together all make up cortical bone
functional unit of cortical bone
What is one osteon made up of?
multiple layers of osetoblasts and osteocytes around a central canal called the haversian canal
What connects individual osteons together?
Volkmann’s canals
What is the outer surface of cortical bone covered by?
periosteum
What is the inner surface of cortical bone covered by?
endosteum
What is the endosteum?
the boundary between the cortical bone and the inner trabecular bone
What is trabecular bone?
- spongy inner layer
- open cell porous network
- thin formations of osteoblasts covered in endosteum create an irregular network of spaces
- bone marrow and RBCs within these spaces
Where is bone marrow found?
trabecular bone
Which are the bone forming cells?
osteoblasts –> they create and repair new bone
Which are bone resorbing cells?
osteoclasts
Which are bone co ordinating cells?
osteocytes (which are trapped/buried osteoblasts)
what is the organic matrix of bone made up of?
mainly collagen (osteoid) and ground substance
What is the inorganic component of bone made up of?
hydroxyapatite (calcium and phosphate) and minerals (magnesium, sodium and potassium)
What are the 5 functions of osteoblasts?
- Make osteoid
- Mineralise organic matrix
- Communicates with other bone cells
- Makes hormones
- Become osteocytes
What do osteoclasts do?
- breakdown old bone
- produce enzymes such as TRAP to breakdown extracellular matrix
- Help enhance blood calcium levels
Which hormones regulate osteoclasts?
PTH, calcitonin and IL-6
What do osteocytes do?
- Give bone mechanosensory properties e.g how the bones know its being used
- Co-ordinate regulation of bone turnover - osteocytes tell the bones what to do and when to do it
Explain the bone cycle/ remodelling
- normal bone is in constant state of turnover caused by resorption by osteoclasts and formation of osteoblasts
- Osteoclasts reabsorb and break down bone
- signals to osteoblasts
- The nutrients are reabsorbed, and osteoblasts lay down new osteoid
What is the relationship between bone mass and age?
- bone mass increases with age until peak at 30 in females and 45 in males
- then bone mass decreases with age
- with increasing age, osteoblastic activity falls and osteoclastic activity increases
Why do women loose bone mass more rapidly than men?
oestrogen helps maintain bone health so there is faster bone loss due to menopause
Which biochemical markers can we measure when looking at bone formation (i.e production of active osteoblasts) ?
- alkaline phosphatase
- osteocalcin
- P1NP (procollagen type 1N propeptides)
Which biochemical markers can we measure when looking at bone resorption (i.e what is released when bone is broken down) ?
- hydroxyproline
- pyridinium crosslinks
- cross linked telopeptides of type 1 collage (NTX, CTX)
Why is bone alkaline phosphatase useful to measure?
- released by osteoblasts
- release stimulated by increased bone remodelling/ when bone turnover changes
- can show fractures, hyperparathyroidism, pagets disease and pubertal growth spurts
What is P1NP and why do we measure it?
- precursor molecule of type 1 collagen
- synthesised by osteoblasts
- increased with osteoblast activity
- decreased by reduced osteoblast activity
Why do we measure collagen cross links? (NTX, CTX)
- Cross linking molecules which are released with bone resorption, correlate highly with bone resorption
- increased in periods of high bone turnover - hyperthyroidism, adolescents and menopause
What is DEXA imaging?
- measures bone mass (bone density X-ray)
- measured in T-scores
What is a T-score?
number of standard deviations away from the mean compared to a young healthy person of the same sex on a DEXA scan
- 1 and above = normal bone density
- 1 and -2.5 = low bone mass –> osteopenia
- 2.5 and below –> osteoporosis
What is osteoporosis?
a systemic skeletal disease characterised by LOW bone mass and deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture
-decrease bone mass –> failure of structural integrity
What is a fragility fraction?
- fracture that occurs as a result of minimal trauma, such as falling from a standing height or less, or no identifiable trauma
- a fracture caused by injury that would be insufficient to fracture a healthy bone
What are the common sites for fracture?
- spine
- neck of femur
- wrist
What are the risk factors for fracture?
- age
- sex - F>M
- recent fragility fracture
- smoking
- alcohol
- falls
- drugs
- inflammatory conditions
- malabsorption
- T1 DM
- family history
- BMI
How can we predict the risk of a fracture for a patient with osteoporosis?
FRAX
What are the secondary causes of osteoporosis?
- early menopause
- hyperthyroidism
- cushings
- any cause of malabsorption
- RA
- COPD
- cystic fibrosis
- glucocorticoids
- immobility
- CKD
What are the different ways of investigating the secondary causes of osteoporosis?
- calcium and bone profile
- U&Es
- TFTs
- FBC
- VitD
- PTH
- coeliac screen
- FSH, LH, oestradiol, prolactin
What is antiresorptive treatment?
- for prevention of osteoporotic fractures
- stops bone breakdown by acting on osteoclasts
- commenest drugs are bisphosphonates
What is anabolic treatment?
works on osteoblasts in preventing osteoporotic fractures
What is the mechanism of action of bisphosphonates?
- inhibit osteoclast formation, migration and osteolytic activity, promote apoptosis
- modulate signalling from osteoclasts to osteoblasts
- concentrated in newly mineralising bone and under osteoclasts
What is denosumab?
- a RANK ligant inhibitor (as RANK ligand causes osteoclasts to mature and develop)
- highly effective injection
- inhibits osteoclast formation, function and survival
- increase in spine bone density
Where can osteolytic bone mets occur?
- breast/lung
- kidney/thyroid
- destroys normal bone (osteoclasts) –> can lead to hypercalcaemia
Where can sclerotic/osteoblastic bone mets occur?
- prostate
- lymphoma
- breat/lung
Where are the usual sites of spread of bone metastases?
spine pelvis femur humerus skull
What are the presenting features of bone mets?
- Pain – often worse at nights and initially gets better with movement, usually becomes constant
- Broken bones
- Numbness, paralysis, trouble urinating – spinal cord compression from bone metastases
- Loss of appetite, nausea, thirst, confusion, fatigue – symptoms of hypercalcaemia
- Anaemia – disruption of bone marrow
What are the symptoms of mild and severe hypercalcaemia
Mild:
- polyuria, polydypsia
- mood disturbance
- anorexia
- nausea, fatigue
- constipation
Severe:
- abdo pain
- vomiting
- coma
- pancreatitis
- dehydration
- cardiac arrhythmias
What is the next blood test you could do in anyone with a high calcium level?
parathyroid hormone - the predominant control for calcium levels
How does PTH control calcium levels?
• When blood calcium becomes low, the calcium sensing receptors on parathyroid gland detect this and release parathyroid hormone
• This leads to restoration of calcium levels
• Once calcium has gone back to normal we have negative feedback mechanisms to reduce PTH levels
-Mg and VitD also affect PTH
What are the non-PTH mediated causes of hypercalcaemia? (so PTH will be low)
- malignancy
- vitD intoxication
- medications
- immobilisation
- endocrine disorders - hyperthyroidism, acromegaly, phaeochromocytoma
What are the PTH mediated causes of hypercalcaemia? (so PTH will be high)
primary hyperparathyroidism
What is primary hyperparathyroidism?
- parathyroid glands malfunction and make too much PTH and don’t sense calcium properly so calcium raises as well
- also will have low phosphate and high alk phos
What is secondary hyperparathyroidism?
- parathyroid working fine
- low calcium is detected so we raise PTH
- this is not a problem
- causes are usually CKD or VitD deficiency
What is the association between adenomas and PHPT?
- adenoma
- single adenoma accounts for 85% of cases of PHPT - Glandular hyperplasia
- all 4 glands enlarged - Ectopic adenomas
- Parathyroid carcinoma
How would we treat patients with symptomatic hypercalcaemia?
surgery - removing parathyroid - is best option
Which drugs can we use to treat PHPT?
Calcimimetics:
- activate CaSR in the parathyroid gland
- therefore leads to reduced PTH secretion
What is Paget’s disease of bone?
- rapid bone turnover and formation
- leading to abnormal bone remodelling
- mainly 50+ yo , M>F
- polyostotic (affecting many bones) or monostotic (affecting one bone)
- elevated alkaline phosphatase reflecting increased bone turnover
- FH in 10-15% of cases
What are the clinical features of Paget’s disease?
- bone pain
- bone deformation
- fractures
- arthritis
- cranial nerve defects if skull affected - hearing and vision loss
- risk of osteosarcoma
- most commonly affects pelvis, femur and lower lumbar vertebrae
What investigations of Pagets can we perform?
lab assessment
plain x-RAYS
Nuclear medicine bone scan
What is the best treatment for Pagets?
bisphosphates - give bisphosphates to slow down bone turnover - same treatment as osteoporosis
What is osteomalacia?
- adult rickets
- lack of mineralisation of bone - not enough calcium, phosphate
What is the difference between childhood rickets and osteomalacia in adults?
adult form - widened osteoid seams with lack of mineralisation
rickets - widened epiphyses and poor skeletal growth
What are the causes of osteomalacia?
- Insufficient calcium absorption from intestine - due to lack of dietary calcium or vitD deficiency/resistance
- Excessive renal phosphate excretion
What are the clinical features of osteomalacia?
- diffuse bone pain - usually symmetrical
- muscle weakness
- bone weakness
- high alk phos, low vitD, possibly low calcium and high PTH (secondary hyperparathyroidism)
- malabsorption
