week 1 - bone and the skeleton Flashcards
(92 cards)
1
Q
describe osteoblasts
A
involved in bone formation
remain as resting osteocytes at the end of the bone remodelling cycle
2
Q
describe osteocytes
A
dormant
sensitive to stimuli and communicate to osteoblasts
3
Q
describe osteoclasts
A
involved in bone resorption
derived from monocyte precursors in marrow
4
Q
what is bone remodelling
A
coordinated osteoclastic resorption and osteoblastic proliferation
5
Q
six steps of bone remodelling
A
activation resorption osteoblast recruitment osteoid formation mineralization quiescence
6
Q
two types of bone growth
A
endochondral ossification - longitudinal
subperiosteal apposition - width
7
Q
rate of bone remodelling depends on…
A
growth
hormones and growth / biochemical factors
mechanical stress
8
Q
RANKL/RANK/OPG pathway
A
osteoblasts produce RANKL which binds to RANK on osteoclasts and activates them
OPG inhibits RANKL
absence of OPG causes long bone fragility fractures
9
Q
composition of bone
A
inorganic - calcium hydroxyapatite
organic - type 1 collagen, proteoglycans, osteocalcin, cytokines/IL
10
Q
result of loss of mineralization
A
osteomalacia / rickets
11
Q
result of low bone mass
A
osteoporosis, osteogenesis imperfecta
12
Q
disease resulting from high bone mass
A
osteopetrosis
13
Q
disease resulting from high bone turnover
A
pagets, hyperparathyroidism, thyrotoxicosis
14
Q
disease resulting from low bone turnover
A
adynamic disease, hypophosphatasia
15
Q
describe osteoporosis
A
reduced total bone mass
adequate mineralisation of present osteoid
relatively increased bone resorption
16
Q
menopausal osteoporosis
A
reduced bone mineral mass
estrogen deficiency
17
Q
corticosteroid induced osteoporosis
A
steroids increase osteoclastic activity, decrease osteoblastic activity, impair collagen formation and cause increased bone turnover and poor bone formation and healing
corticosteroids increase bone resorption rate and depth and can block osteoblast action
18
Q
relationship between PTH and ionised Ca
A
increases while the other decreases
19
Q
causes of low Ca and high PTH
A
secondary hyperparathyroidism causes:
renal impairment
vitamin D deficiency
20
Q
causes of low Ca and low PTH (hypoparathyroidism)
A
destruction of parathyroid glands idiopathic/autoimmune surgical removal radiotherapy severe magnesium deficiency
21
Q
causes of high Ca and high PTH
A
adenoma - in parathyroid glands - uncontrolled PTH causes increased calcium
hyperplasia also causes
22
Q
causes of high Ca and low PTH
A
malignancy excess intake granulomatous disorders sarcoid medications
23
Q
primary hyperparathyroidism
A
unregulated PTH secretion
hypercalcaemia
markedly increased bone turnover
may retain bone mass
24
Q
clinical features
A
boney cavities
kidney stones
abdominal pain, vomiting
depression
25
signs of hyperparathyroidism on an x-ray
subperiosteal bone resorption
generalized decrease in bone density
brown tumour
chondrocalcinosis - knee, wrist and shoulder
26
describe pagets disease
rapid bone turnover
bone resorption and formation are increased
disorganised structure
reduced bone strength
risk of fracture
linked to osteosarcoma tumour suppressor gene
27
describe osteopetrosis
failure of osteoclastic and chondroclastic resorption
failure of remodelling
genetic disorder
28
describe fluorosis
abnormal matrix mineralization
| fluoride replaces calcium in the matrix
29
describe osteogenesis imperfecta
genetic
collagen one deficiency
low muscle tone
30
space age bone disease
reduced numbers of osteoblasts
minimal mechanical stress on bone
normal osteoclast numbers
31
types of calcium in serum
free (unbound) - 47%
bound to albumin - 47%
complexed - 6%
32
organs involved in calcium homeostasis
kidney, gut, bone, parathyroid glands
33
describe calcium homeostasis
absorbed mainly in duodenum and jejunum - Ca goes into blood
reabsorbed in kidney
resorption in bone
34
role of PTH in calcium homeostasis
stimulates renal tubular calcium reabsorption
promotes bone resorption
stimulates formation of calcitriol in kidney which enhances calcium absorption fom gut
35
calcitriol role in calcium homeostasis
role in promoting calcium and phosphate absorption from gut
| increase bone resorption = calcium released
36
two pathways of calcium absorption
a cell mediated active transport pathway - controlled b calcitriol
passive diffusion - depends on luminal Ca concentration and is unaffected by calcitriol
37
where in the kidney is calcium reabsorbed
65% in proximal tubule
20% in thick ascending loop of henle
15% in distal convoluted tubule
last two are increased by effects of PTH
38
where is PTH produced
parathyroid glands
39
describe the secretion of PTH
regulated by free calcium and is sensed by calcium sensing receptors
as calcium levels fall, PTH rises
40
what are calcium sensing receptors
g-coupled receptors on parathyroid cells and renal tubules
41
major role of vitamin D
maintaining serum calcium within normal limits
42
what does calcitriol do when dietary calcium is inadequate
calcitriol will increase bone resorption via vitamin D receptors on osteoblasts
43
relationship between PTH and calcitriol
calcium sensing receptor detects fall in ionised calcium
this increases PTH production which is a major stimulus for calcitriol production
PTH production is suppressed directly and indirectly by increasing iCa
44
hypocalcaemia causes
not enough PTH which could be due to:
neck surgery, autoimmune destruction of parathyroid glands or magnesium deficiency
could be due to a lack of vitamin D - malabsorption, little exposure to sunlight or renal disease (kidneys fail to make active form)
45
hypercalcaemia causes
inappropriate production of too much PTH due to adenoma of parathyroid gland
inappropriate dosage of vitamin D
malignancy - lung cancer, breast cancer, multiple myeloma
46
role of phosphate in the body
critical in skeletal development, bone mineralisation
47
where is phosphate found
85% is in the mineralised matrix of bone
rest is mostly intracellular and bound to lipids and proteins - cell membranes, nucleic acids, enzyme cofactors, glycolytic intermediates and ATP
1% in extracellular fluids
48
main hormones in phosphate homeostasis
PTH
fibroblast growth factor 23 (FGF 23)
calcitriol
49
role of PTH and FGF23 in phosphate homeostasis
they inhibit the reabsorption of phosphate by acting on the renal tubule
50
response to an increase in serum phosphate
PTH and FGF23 production increases - they then act on renal tubule to increase secretion of phosphate by reducing its reabsorption
51
two types of bone
cortical bone and trabecular bone
52
functions of osteoblasts
deposition of collagen and noncollagenous proteins
transport of mineral salts
secretes: cytokines/growth factors, enzymes and proteins
53
some of the factors that stimulate osteoblast expression of RANK ligand
PTH, vitamin D, glucocorticoids, interleukins, TNF-alpha
54
OPG function
it is a decoy receptor that prevents RANKL binding to RANK
| inhibits osteoclast formation, function and survival
55
what is sclerostin
a protein secreted by osteocytes
| it inhibits Wnt signalling in cells
56
fracture healing process
osteocytes near crack undergo apoptosis
lining cells pull away from bone matrix and form a canopy which merges with the blood vessels
stromal cells are released from sclerostin inhibition and/or exposed to other factors eg. IL-1 and they generate pre-osteoblasts - SCs also secrete M-CSF to help generate pre-osteoclasts
pre-osteoblasts proliferate and secrete other factors - also start to express RANKL
pre-osteoclasts to mature osteoclasts
osteoclasts bind to bone matrix with integrins and secrete acid and cathepsin K to resorb bone
bone-derived GFs IGF and TGF-beta are released
osteoclast undergos apoptosis - regulated by estrogen
pre-osteoblasts mature and secrete OPG instead of RANKL - OBs also secrete osteoid and mineralise it to fill the cavity
some OBs turn into osteocytes, some into lining cells and the rest undergo apoptosis
meanwhile osteoclasts have been re-establishing a network with each other and the lining cells
new matrix will accumulate mineral and increase in density for about 3 years
57
how do long bones change as we age to an adult
increased length and diameter
58
how does the spine change as we age to an adult
increased size and trabecular thickness
59
factors affecting peak bone mass
```
gender
calcium intake
growth hormone IGF axis
steroid metabolism
alcohol
gonadal status
physical activity
smoking
```
60
effects of estrogen on bone acquisition
little effect on proliferating chondrocytes
| major effect on terminally differentiating chondrocytes and mineralising bone
61
function of estrogen on bone remodelling
decreased estrogen leads to increased RANKL
62
risk factors for osteoporotic fractures
```
age >65
vertebral compression fracture
malabsorption syndrome
primary hyperparathyroidism
hypogonadism
early menopause
rheumatoid arthritis
smoker
low dietary calcium intake
```
63
determinants of fracture risk
bone strength
| extraskeletal conditions - propensity to fall and fall conditions
64
lifestyle changes for prevention of osteoporosis and fractures
```
adequate intake of dietary calcium
regular muscle strengthening exercise
stop smoking
drink alcohol at safe levels
minimise risk of falls
wear a hip protector
```
65
treatment of calcium and vitamin d reduces risk of what type of fracture
non vertebral fracture
66
effects of hormone replacement treatment
prevents bone mineral density decreasing as much with age
| effective on vertebral and non-vertebral fractures
67
effects of selective estrogen receptor moderator
act on estrogen receptors
| effective for vertebral fractures
68
effect of bisphosphonates
increases bone mineral density
reduces fracture risk
effective on vertebral fractures and most biophosphonates are effective on non-vertebral fractures
69
effects of teriparatide
stimulates bone formation
| effective on vertebral and non-vertebral fractures
70
effects of denosumab
binds to RANKL and inhibits osteoclast formation, function and survival
effective on all fractures
71
effects of romosozumab
monoclonal antibody that binds and inhibits sclerostin
| increases formation, decreases resorption
72
formation of vitamin d
formed from 7 dehydrocholesterol - converted by a photolysis reaction and then isomerisation to cholecalciferol in the skin
transported to liver
73
active form of vitamin d
calcitriol
| 1.25-dihydroxycholecalciferol
74
principle actions of vit d
binds to vit d receptor becoming a transcription factor that modulates gene expression of transport proteins which are involved in calcium absorption in the intestine
maintains skeletal calcium balance by promoting intestinal calcium absorption, increases osteoclast numbers causing bone resorption, maintains calcium homeostasis via PTH for bone formation
75
disease from vit d deficiency
rickets/osteomalacia
76
osteomalacia
characterised by impaired mineralisation of bone leading to an accumulation of unmineralised bone matrix (osteoid)
77
rickets
newly formed bone of the growth plate does not mineralise causing growth plate to become thick, wide and irregular
78
clinical features of osteomalacia
initially asymptomatic
bone pain and tenderness
proximal muscle weakness without atrophy
79
causes of vitamin d deficiency
```
lack of sunlight
bizarre diets
partial gastrectomy
small bowel malabsorption
pancreatic disease
chronic renal failure
anticonvulsants
```
80
diagnosing osteomalacia
imaging
isotope bone scan
serum biochemistry
bone biopsy
81
vitamin d can be used to treat..
osteomalacia and vitamin d deficiency
82
causes of rickets
```
vitamin d dependent rickets
hypophosphataemia disorders
fanconi syndrome
renal tubulopathies
hypophosphatasia
fat malabsorption
```
83
types of vitamin d dependent rickets
1A - vitamin d hydroxylation-deficient rickets
1B - vitamin d hydroxylation-deficient rickets
2A - vitamin d-dependent rickets
2B - vitamin d-dependent rickets with normal vitamin d receptor
84
describe type 1A and 2A vitamin d dependent rickets
1A - mutation in the CYP27B1 gene - hydroxylation at alpha 1
2A - with/without alopecia - caused by a defect in the vitamin d receptor gene
most common types of vit d dependent rickets
85
how does FGF23 regulate phosphate homeostasis
blocks phosphate reabsorption and causes excess phosphate loss
86
FGF23 production
formed in osteocytes
| under control of locally bone derived factors that are important for bone mineralisation
87
describe tumoral calcinosis
defective FGF23 or GALNT3 (enzyme required for normal o-glycosylation of FGF23)
increased calcitriol and phosphate
ectopic calcification to remove excess phosphate
88
AD hypophosphatemic rickets
FGF23 resistance to proteolysis
| low calcitriol levels
89
x-linked hypophosphataemic rickets
manifesting during late infancy at onset of walking
bowing long bones, widening metaphyses and rachitic rosary - short stature
low phosphate and low calcitriol and increase in FGF23
mutation in PHEX protein
90
AR hypophosphataemic rickets
affects dentin matrix protein 1 (DMP 1)
involved in osteoblast maturation
exported to extracellular matrix regulating hydroxyapatite
DMP1 inhibits FGF23 expression
leads to bone, cartilage and dentin defects - severe hypophosphataemia and secondary unregulated FGF23
91
hereditary hypophosphataemic rickets with hypercalcuria
defect of NPT2 phosphate transporter in proximal tubule
hypophosphataemia secondary to defects in proximal tubular phosphate transporter
rickets and short stature
92
rickets treatments
additional phosphate
adequate 1.25 diOH vitamin d
avoid calciuria and elevated PTH
