Endocrine and Metabolic Bone Disorders (with calc reg) Flashcards
(77 cards)
1
Q
What is the major store of calcium?
A
bone (>95%)
2
Q
what are the main types of stores of calcium?
A
inorganic minerals- calcium hydroxyapatite (65%
organic components- Type I collagen (35%)
3
Q
what cells build up bones?
A
osteo[b]lasts
synthesise osteoid, mineralise and calcify osteoid
4
Q
what receptors do osteoblasts express?
A
PTH and calcitriol receptors
5
Q
what cells break down bone?
A
Osteoclasts - C for crush
resorb bone via lysosomal enzymes
6
Q
what stimulates osteoclast formation and activity?
A
osteoBLAST activity:
RANKL released by osteoblasts binds to RANK receptor of the osteoclast
7
Q
what endogenous substance acts to reduce the activity of the osteoclast?
how does it inhibit osteoclasts?
A
OPG- osteoprotegrin
its acts as a competitive inhibitor of RANKL binding site i.e. the RANK receptor
nb RANKL produced by osteoblasts
8
Q
what is the initial precursor to calcitriol?
where does it go?
A
vitamin D (from diet and skin) goes into the liver to become calcidiol (25(OH)vitD)
(eventually ends up in kidney)
9
Q
what is the product created by the liver after vitamin D uptake?
A
calcidiol (25-OH-D)
inactivate form of vitamin D
10
Q
where does calcidiol go next?
A
kidney
11
Q
what is formed in the kidney from calcidiol?
A
calcitriol (1,25(OH)2D)
active form of vitamin D
12
Q
where does calcitriol have its effects?
A
bone
small intestine
13
Q
What is the effect of calcitriol in the bone?
A
increase release of calcium and phosphates
done by PTH also
14
Q
what is the effect of PTH on the kidney?
A
increase in calcitriol synthesis
decrease calcium excretion in urine (aim to retain calcium)
15
Q
what is the effect of calcitriol in the gut?
A
increase absorption of dietary calcium
16
Q
what is the effect of hypercalcaemia in terms of membrane excitability?
A
decreases excitability due to blockage of Na+
17
Q
what is the effect of hypocalcaemia in terms of membrane excitability?
A
greater influx of Na+ possible so excitability increases
18
Q
what are the symptoms of hypocalcaemia?
A
all due to increase Na+ influx: o Parathesia. o Convulsions. o Arrhythmias. o Tetany. o Signs: Chovstek and Trousseau
19
Q
what are the signs displayed in hypocalcaemia?
A
Chvostek’s sign – tap facial nerve below zygomatic arch, face twitch.
Trousseau’s sign – inflate BP cuff for minutes induces carpopedal spasm.
20
Q
what are the causes of hypocalcaemia?
A
o Vitamin D deficiency – low calcitriol.
o Renal failure – impaired 1alpha-hydroxylase activity therefore low calcitriol.
o Low PTH levels – hypoparathyroidism from neck surgery or autoimmune.
o PTH resistance – Pseudohypoparathyroidism.
21
Q
symptoms of hypercalcaemia acronym
A
Stones
Bones
Gastric moans
Psychic groans
slowing down
22
Q
“stones” symptoms
A
hypercalcaemia causes renal stones and therefore:
- polyuria
- thirst
- Nephrocalcinosis
- renal colic
- chronic renal failure.
23
Q
“abdominal moans” symptoms of hypercalcaemia
A
GI effects include:
- anorexia
- nausea
- dyspepsia
- constipation
- pancreatitis.
24
Q
“psychic groans” symptoms of hypercalcaemia
A
CNS effects include:
- fatigue
- depression
- impaired concentration
- altered mentation
- coma.
25
causes of hypercalcaemia
o Primary hyperparathyroidism
– benign adenoma of parathyroid.
o Malignancy
– tumours often secrete a PTH-RP (PTH-Related Peptide).
o Paget’s disease
– condition with a high bone turnover (bone remodelling disease)
o Vitamin D Toxicosis (excess calcitriol production)
26
mechanism in primary hyperparathyroidism causing hypercalcaemia
PTH = high
calcium = high
(no –ve feedback as autonomous)
27
mechanism in tumours secreting PTHr in hypercalcaemia
```
PTH = low
PTHr = high
calcium = high.
```
28
principle effects of calcitriol
- intestinal absorption of Ca2+, Mg2+, PO43-
- regulation of osteoblast differentiation
- Ca2+ reabsorption increased, Phosphate reabsorption decreased in kidney
Magnesium needed to make PTH
29
what hormone enables decreased reabsorption of phosphate?
where does it target? mechanism of action
what effect does it have on calcium?
FGF23 - Fibroblast Growth Factor 23
(produced by osteocytes)
- main regulator of phosphate
- acts on kidneys (PCT)
- reducing expression of sodium/phosphate co-transporter that usually helps reabsorb phosphate at the PCT
- reduces calcium absorption by suppressing 1 alpha hydroxylase so reduced Vit D activation
30
what are the effects of Vit D deficiency ?
```
softening of the bone
bone deformities
bone pain
severe proximal myopathy
increased risk of fractures
```
--> osteomalacia
31
what are the results of Vitamin D def in adults and children (conditions)?
adults- osteomalacia (post closing of growth plates)
children- rickets (cartilage growth of epiphyseal growth plates retarded)
32
how is vitamin D3 (cholecalciferol) created by the body
using 7-dehydrocholesterol in the skin and UVB light
33
what are the causes of vitamin D deficiency?
o Block in UVB light catalysation.
o Malabsorption or bad diet – e.g. Crohn’s.
o Liver disease –lack of hydroxylation.
o Renal disease – lack of second hydroxylation.
o Receptor defects – autosomal recessive/rare.
34
what hormone does PTH stimulate in the kidneys?
1 alpha hydroxylase
35
what is the cause of primary hyperparathyroidism?
adenoma causing autonomous PTH production
(no feedback mechanism therefore causes a hypercalcaemia)
treat with removal of the parathyroids
36
why does secondary hyperparathyroidism cause a LOWER calcium level?
more PTH is secreted in response to low calcium:
Secondary arises due to Vit D def or CKD
- defective kidney can't make calcitriol anymore leading to a lower Ca2+ (secondary event)
- the parathyroid responds by then releasing EXCESS PTH to make up for the low calcium
no hypercalcaemia follows (calcium normal or low as problem is not the gland)
37
biochemical diagnosis of vit D def
1) high PTH (to compensate--> hyperparathyroidism)
| 2) low Ca2+, calcitriol
38
what radiological findings indicate vitamin D deficiency?
widened osteoid seams
| "brown tumour" are bone lesions showing excessive osteoclastic bone resorption
39
what is the treatment for Vit D def with normal renal function?
give synthetic vitamin D so kidney hydroxylates by itself
- Ergocalciferol (25-hydroxyvitamin D2)
- Cholecalciferol (25-hydroxyvitamin D3)
normal kidney means enzymes are present to hydroxylate as normal
40
what is the treatment for Vit D def with impaired renal function?
Alfacalcidol (1-alpha-hydroxycholecalciferol)
- calcitriol analogue
- give ready-hydroxylated vitamin as 1 alpha hydroxylase is lacking in impaired kidney
41
how can impaired kidney function lead to extra-skeletal depositions?
decreased calcitriol and phosphate excretion therefore they increase in the serum
this binds to calcium and causes depositions
binding to calcium also reduces free calcium
42
what conditions are a result of decreased bone mineralisation
osteitis fibrosa cystica
| osteomalacia
43
consequences of Vit D toxicosis
- hypercalcaemia (excess calcitriol production)
- hypercalciuria (more calcium excretion)
due to increase intestinal calcium reabsorption
44
what are the causes of Vit D toxicosis?
o Excessive treatment of vitamin D deficiency – e.g. too much Alfacalcidol.
o Granulomatous disease
– e.g. sarcoidosis – macrophages in granuloma produce 1-alpha-hydroxylase which overproduces vitamin D.
45
structures of bone
- cortical (hard)
- trabecular (spongy)
- woven (disorganised collagen fibres--> dysfunctional and weaker bone)
46
what are looser zones?
fractures in areas of normal stresses as a result of vitamin D def
47
how does primary hyperparathyroidism differ to chronic low plasma calcium?
- primary hyperparathyroidism have normal kidney function
- while chronic low plasma calcium is caused by impaired renal function
calcitriol is not made so PTH increase and so does calcium
no feedback loop
48
what is osteoporosis?
condition of reduced bone mass and a distortion of bone microarchitecture (trabeculae) which predisposes to fracture after minimal trauma.
49
parameter to determine osteoporosis using BMD
BMD is greater than 2.5 SD below the normal
or the T score is less than -2.5
50
how is BMD measured?
using DEXA scan
(Dual Energy X-ray Absorptiometry) of femoral head and lumbar spine
measuring calcium content
51
what are the risk factors of osteoporosis?
o Post-menopausal oestrogen deficiency.
o Age-related deficiency in bone homeostasis.
o Hypogonadism in young people.
o Endocrine conditions – Cushing’s, hyperthyroidism, primary hyperparathyroidism.
o Iatrogenic – prolonged glucocorticoids, heparin.
52
differences between osteomalacia and osteoporosis
malacia: due to vit D def leading to defective MINERALISATION , shows abnormal biochemistry
porosis: MISMATCH in bone remodelling processes leading to reduced BONE MASS and shows normal biochemistry
53
what are the treatment options of osteoporosis?
- oestrogen receptor modulators (SERMs e.g. raloxifene)
- bisphosphonates e.g. alendronate
- denosumab (RANKL analogue)
- teriparatide (PTH fragments increases bone formation)
teriparatide has a paradoxical effect as PTH would normally increase bone resorption by increasing RANKL expression on osteoblasts. Here the recombinant fragment stimulate bone FORMATION
54
what are the treatment options of osteitis fibrosa cystica?
Osteitis Fibrosa Cystica is due to increased PTH, increased bone resorption and decreased mineralisation (seen in renal failure) therefore:
1) alfacalcidiol (renal failure means as they can't form active Vit D)
2) treat the hyperphosphatemia (prevent is binding to calcium)
- low diet P
- reduce absorption in the gut
3) parathryoidectomy (in tertiary disease)
55
what are the oestrogen receptor modulators used in osteoporosis treatment?
- oestrogen HRT
| - SERMS (selective oestrogen receptor modulators)
56
oestrogen HRT :effect of oestrogen?
| what is the requirement of progestogens?
Oestrogen has anti-absorptive effects on the skeleton (prevents bone loss by inhibiting osteoclasts).
Women with an intact uterus need progestogens to prevent endometrial hyperplasia/cancer.
Use is limited due to concerns with breast cancer and VTE.
57
SERMS agonists and antagonists
1) Tissue-selective ER antagonists – e.g. Tamoxifen
- antagonises ERs in breast (good)
- oestrogenic activity in bone (good)
- oestrogenic effects on endometrium persist. (bad)
2) Tissue-selective ER agonists – e.g. Raloxifene
- oestrogenic activity in bone (good)
- anti-oestrogenic activity on the breast AND uterus (GOOOOD)
Still has VTE and stroke risks.
58
which SERM is better to use in patient with uterine hyperplasia
Selective Oestrogen Receptor Modulators:
Raloxifene over tamoxifen
-->due to anti-oestrogenic effects in breast and uterus
NB both have oestrogenic effects on the bone so they are efficacious for bone disease
59
what are the 2 SERM drugs and their oestrogenic properties?
1)Tamoxifen (antagonist)
- good on bone (ag)
- good on breast (ant)
- bad on uterus (ag)
- bad on CVS
therefore endometrial hyperplasia risk aswell as VTE and stroke risk
2) Raloxifene (agonist)
- good on bone (ag) stimulates osteoblasts
- good on breast (anti-OE)
- good on uterus (anti-OE)
- bad on CVS (agonist)
therefore VTE and stroke risk
60
how do bisphosphonates work?
osteoclast apoptosis:
- impair osteoclast ability to resorb by promoting their apoptosis
- binding to hydroxyapatite crystals on bone tissue surface
- reduced osteoclast development and recruitment
61
why is HRT not a good long term plan
| how is the associate risk reduced
increased cancer risk
given with required progestogens
62
uses of bisphosphonates
- osteoporosis (first line)
- malignancy
- Paget’s disease
- severe hypercalcaemic emergencies (IV) to reduce pain and the hypercalcaemia.
63
pharmacokinetics of bisphosphonates
Orally active, poorly absorbed (eat on empty stomach).
| Remains at site of action for YEARS so used mainly in the elderly.
64
side effects of bisphosphonates
Oesophagitis and heart burn (if so switch to IV)
Flu-like symptoms – limited to first dose.
Osteonecrosis of jaw (in cancer patients)
Atypical fractures – could show OVER-suppression of bone remodelling.
65
what is the action of denosumab (human monoclonal antibody)
RANK analogue
o Binds to RANKL and so inhibits osteoclast activation and bone resorption.
o Taken via SC injection bi-yearly and is a 2nd line drug for osteoporosis (cost).
66
what is the action of teriparatide (Recombinant PTH fragments) ?
o Increases bone formation and bone resorption but FORMATION OUTWEIGHS RESORPTION.
o 3rd line treatment, daily SC injections and is very expensive.
PTH can have two types of effect on bone due to short duration or long duration of action on the PTH receptor.
- short acting --> bone formation action
- long acting--> bone resorption
small doses of PTH i.e. in fragment form, will stimulate osteoblast activity and promote bone formation
67
what is the main concept of Paget's disease?
Accelerated, localised and disorganised bone remodelling.
Excessive bone resorption followed by compensatory increase in bone formation leads to formation of woven bone (weaker bone).
68
3 bone characteristics of Paget's
bone: fragility, hypertrophy and deformity
69
Paget's origin and demographics
```
o Genetic; Possible viral origin.
o Affects men and women equally.
o Disease not apparent under 50yo.
o Most patients are asymptomatic.
o Prevalence highest in 1st world countries.
```
Characterised by abnormal, large and numerous osteoclasts.
70
clinical features of Paget's
- most commonly affected areas
- symptoms
most affected areas: skull, thoracolumbar spine, pelvis, femur and tibia
are most asymptomatic
- arthritis,
- fractures
- pain
- bone deformity
- increased vascularity (so warm to touch)
- deafness (cochlea involvement)
- radiculopathy (due to nerve compression).
71
how is Paget's diagnosed biochemically?
```
ALP increase (due to hyperactivity of bones secreting ALP)
Ca2+ is normal
```
remember that Paget's is a disease of bone remodelling and not bone chemistry
72
x-ray diagnosis of Paget's
```
lytic lesions (early)
thickened, enlarged and deformed bones (later)
```
73
treatment of Paget's
o Bisphosphonates – reduce bone pain and disease activity.
| o Analgesia.
74
what is the appropriate vitamin D replacement for those will normal renal function?
Ergocalciferol or cholecalciferol
| indirect Vit D, needs to be produced via enzymatic action
75
what is the appropriate vitamin D replacement for those with impaired renal function?
Alfacalcidol
| direct metabolite therefore conversion not required
76
what can be causing loin pain when presenting with hyperparathyroidism symptoms?
kidney stones due to extra-skeletal calcification
| high calcium levels
77
what is Multiple Endocrine Neoplasia 1?
a hereditary condition associated with tumors of the endocrine (hormone producing) glands.
The most common tumors seen in MEN1 involve the parathyroid gland, islet cells of the pancreas, and pituitary gland.
