Endocrine and Metabolic Bone Disorders Flashcards
(39 cards)
1
Q
What proportion of the body’s calcium does bone store?
A
> 95%
and is also a reservoir of phosphate
2
Q
Composition of bone
A
- 35% bone mass organic (type 1collagen fibers)
- 65% bone mass inorganic mineral component (calcium hydroxyapatite crystals filling the space in-between collagen fibrils)
3
Q
What are the cell types in bone?
A
Osteoblasts
-> synthesise osteoid and participate in mineralisation/calcification of osteoid(bone formation)
Osteoclasts
-> release lysosomal enzymes which break down bone(bone resorption)
- osteocytes
4
Q
Bone resorption
A
- osteoclasts release lysosomal enzymes which break down bone (bone resorption)
5
Q
Bone remodelling
A
- DYNAMIC process involving bone resorption and bone formation
6
Q
Osteoclast differentiation
A
- involves osteoblasts
- RANKL expressed on osteoblast surface
- RANKL binds to RANK-R to stimulate osteoclast formation and activity
- Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) –> regulate balance between bone formation & resorption
7
Q
What are the structural types of bone?
A
- Cortical (hard) bone
- Trabecular (spongy or trabecular) bone; meshwork of bony bars (trabeculae)
- Both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong
- Woven bone – disorganised collagen fibrils, weaker (woven bone is immature)
8
Q
What are the effects of vitamin D deficiency on bone?
A
- Inadequate mineralisation of newly formed bone matrix (osteoid)
- Vitamin D is needed to mineralise newly formed bone
- Children – RICKETS
- > affects cartilage of epiphysial growth plates and bone
- > skeletal abnormalities and pain, growth retardation, increased fracture risk. There is a lot of deformity and also short stature in rickets.
- Adults – OSTEOMALACIA
- > after epiphyseal closure, affects bone
- > skeletal pain, increased fracture risk, proximal myopathy
- > Adults don’t have rickets because they don’t grow anymore, the growth plates have closed.
9
Q
What might you observe in vitamin D deficiency?
A
- Normal stresses on abnormal bone cause insufficiency fractures - Looser zones
- Waddling gait - typical
10
Q
Looser zones
A
- stress fractures / insufficiency fractures
- pseudo structures
- caused by normal stress on abnormal bone
- bone is weak
11
Q
What are the effects of hyperparathyroidism on bone?
A
- check!!!!!!
12
Q
What are the 3 types of hyperparathyroidism?
A
- 1° HPT: PT-gland adenoma producing PTH (not regulated PTH secretion leads to high PTH and consequently high serum calcium.
- 2° HPT: increased PTH secondary to renal disease or vitamin D deficiency causing low calcium. PTH is high as a physiological response. The calcium is low or normal.
- 3° HPT: The PT-glands become autonomous and increase in size as a result of chronic hypocalcaemia due to renal disease. They secrete lots of PTH but this isn’t capable of increasing calcium much because of kidney disease.
13
Q
Renal failure and bone disease
A
- Renal function leads to:
a) decrease in calcitriol -> decreased calcium absorption
b) decreased PO43- excretion -> high serum PO43- AND increase in vascular calcification Phosphate rises in CKD which also binds to calcium and calcium drops in the blood) - this leads to hypocalcaemia -> leads to:
a) decreased bone demineralisation -> osteitis fibrosa cystica
b) increase in PTH -> increased bone resorption -> osteitis fibrosa cystica
Decreased bone mineralisation, increased PTH, can lead to tertiary, phosphate causes calcification in e.g. blood vessels, cysts in bone called brown tumours due to extremely high PTH.
14
Q
Brown Tumours
A
- radiolucent bone lesions
- also known as osteitis fibrosa cystica and rarely as osteoclastoma
- one of the manifestations of hyperparathyroisim
- reparative cellular process, rather than a neoplastic process
- Well-defined, purely lytic lesions that provoke little reactive bone. The cortex may be thinned and expanded, but will not be penetrated.
- XR: dark areas in bone
15
Q
Osteitis fibrosa cystica
A
- hyperparathyroid bone disease
- rare
- excess osteoclastic bone resorption secondary to high PTH
16
Q
TREATMENT OF OSTEITIS FIBROSA CYSTICA (HYPERPARATHYROID BONE DISEASE)
A
Hyperphosphataemia
- Low phosphate diet
- Phosphate binders – reduce GI phosphate absorption
Alphacalcidol – ie calcitriol analogues (They cannot hydroxylase vit D so you have to give them the active form)
Parathyroidectomy in tertiary hyperparathyroidism
- Indicated for hypercalcaemia &/or hyperparathyroid bone disease
17
Q
Osteoporosis
A
- Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
- With age, everyone has a reduction in bone mass.
- In women, there is a fast drop in bone mass in menopause if not on HRT (can even be 30%)
- increased risk of fractures
18
Q
What is the structural feature of bone in osteoporosis? What is the visible defect?
A
- fewer trabeculae
- also thinner?
19
Q
Diagnosis definition of osteoporosis
A
- Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower)
- BMD predicts future fracture risk
- FRAX tool is also useful
20
Q
How do you measure bone density?
A
- Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine
- Mineral (calcium) content of bone measured, the more mineral, the greater the bone density (bone mass)
- Involves radiation
- Measure two areas (femoral neck and lumbar spine)
- Machine measures calcium density in bone
- Plot the patients T-score on the graph.
21
Q
What is a T-score? What is a z-score?
A
- T-score compares to the bone of a 20/25 year old
- z-score is a comparison for the age matched normal
22
Q
What are the similarities and differences in osteoporosis and osteomalacia?
A
- Both predispose to fracture!!
OSTEOMALACIA
- Vitamin D deficiency (adults) causing inadequately mineralised bone
- Serum biochemistry ABNORMAL (low 25(OH) vit D, low/low N Ca2+, high PTH (2o hyperparathyroidism)
OSTEOPOROSIS
- Bone reabsorption exceeds formation
- osteoclasts are more active than osteoblasts, you’re not making enough bone (can be high or low turnover)
- Decreased bone MASS
- Serum biochemistry NORMAL
- Diagnosis via DEXA scan
- no pain in osteoporosis
23
Q
PRE-DISPOSING CONDITIONS FOR OSTEOPOROSIS
A
Postmenopausal oestrogen deficiency
- Oestrogen deficiency leads to a loss of bone matrix
- Subsequent increased risk of fracture
Age-related deficiency in bone homeostasis (men and women) eg osteoblast senescence
- as we age, osteoblasts become more active
Hypogonadism in young women and in men
Endocrine conditions
- Cushing’s syndrome
- Hyperthyroidism
- Primary hyperparathyroidism
Iatrogenic
- Prolonged use of glucocorticoids (Steroids can predispose you to reduction of bone density)
- Heparin
24
Q
What are the consequences of hip fractures?
A
- have a major impact on life
- e.g. permanent disabiilty
- e.g. inability to carry out at least one daily activity
- e.g. unable to walk independently
- e.g. death within 1 year (20%)
25
Treatment options for osteoporosis
- Oestrogen/Selective Oestrogen Receptor Modulators
- Bisphosphonates
- Denosumab
- Teriparatide
- HRT in menopausal women
26
OESTROGEN (HRT) as treatment of osteoporosis
Treatment of post-menopausal women with pharmacological doses of oestrogen
- Anti-resorptive effects on the skeleton
- Prevents bone loss
Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer
Use limited largely due to concerns re:
- Increased risk of breast cancer
- Venous thromboembolism
- not a long term option
- You can give it for a few years but not too long because of increased risk of breast cancer
- Not a long term solution for post-menopausal osteoporosis
27
BISPHOSPHONATES as a treatment of osteoporosis
- Bind avidly to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to reabsorb bone
- Decrease osteoclast progenitor development and recruitment
- Promote osteoclast apoptosis (programmed cell death) -> osteoclasts are paralysed which is good because we want to tip the balance towards bone formation.
Net result = reduced bone turnover
28
In what conditions are bisohosphonates used?
- Osteoporosis – first line treatment
- Malignancy
- Associated hypercalcaemia
- Reduce bone pain from metastases
- Helps with pain from bone metastases which are very painful and they can make the calcium levels normal again.
- Paget’s disease – reduce bony pain
- Severe hypercalcaemic emergency – i.v. initially (+++ re-hydration first)
29
Pharmacokinetics of bisphosphonates
- Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally)
- Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years
- > sometimes compliance is not great
- Causes dyspepsia,
- Too effective? Can paralyse osteoclasts for years. In younger patients – what does that do?
30
UNWANTED ACTIONS OF BISPHOSPHONATES
Oesophagitis
- may require switch from oral to iv preparation
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
- Makes bone adynamic
- Small risk of necrosis of bone
- Ask about dental surgery, get that done first before they are started on bisphosphonates
31
DENOSUMAB
- Human monoclonal antibody
- Binds RANKL, inhibiting osteoclast formation and activity
- Hence inhibits osteoclast-mediated bone resorption
- SC injection 6/12ly
- 2nd line to bisphosphonates
32
What is the difference in how denosumab and bisphosphonates work?
- denosumab: inhibits activation of osteoclasts by binding RANKL
- bisphosphonates kills (promotes apoptosis) of osteoclasts
33
TERIPARATIDE as osteoporosis treatment
- Recombinant PTH fragment - amino-terminal 34 amino acids of native PTH
- Increases bone formation and bone resorption, but formation outweighs resorption
- 3rd line treatment for osteoporosis
- Daily s.c. injection
- very expensive!!!
=> balance is tipped in favour of bone formation
34
Paget's disease of bone
- Accelerated, localised but disorganised bone remodelling
- Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)
- New bone formed = WOVEN bone
- structurally disorganised
- mechanically weaker than normal adult lamellar bone
- > BONE FRAILTY
- > BONE HYPERTROPHY & DEFORMITY
- usually affects one bone
- There are some very busy osteoclasts
- Bone looks abnormal and it is mechanically weak (not mechanically strong, cannot withhold stress)
35
Etymology of Paget's disease of bone
- Often positive family history – ? genetic cause
- ?Evidence for viral origin (e.g. measles virus)
- Prevalence
- Highest in UK, N America, Australia and NZ
- Lowest in Asian and Scandinavia
- unequal prevalence in the world
- Men and women affected equally
- Disease usually not apparent under age 50y (in general it is a disease of the elderly)
- Most patients are ASYMPTOMATIC!!!
- Characterised by abnormal, large osteoclasts – excessive in number
36
Clinical features of Paget's disease of bone
- Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
- Arthritis
- Fracture (bone is not mechanically strong)
- Pain
- Bone deformity
- Increased vascularity (warmth over affected bone)
- Deafness – cochlear involvement
- Radiculopathy – due to nerve compression, nerve root (pinched nerve)
37
How do you diagnose Paget's disease of bone?
- normal plasma calcium
- alkaline phosphatase is usually increased
- plain x-rays: Lytic lesions (early), thickened, enlarged, deformed bones (later)
- Radionuclide bone scan demonstrates extent of skeletal involvement
- ALKALINE PHOSPHATASE high bone enzyme, busy in remodelling -> EXAM relevant.
38
Alkaline phosphatase in bone
ALKALINE PHOSPHATASE high bone enzyme, busy in remodelling -> EXAM relevant.
39
What are the treatment options in Paget's disease of bone?
- Bisphosphonates – very helpful for reducing bony pain and disease activity
- Simple analgesia
