Metabolic Bone Disease: Biochemistry Flashcards
1
Q
What is metabolic bone disease?
A group of diseases that cause a change in… (2)
by… (3)
A
- Bone density
- Bone strength
by
- INCREASING bone resorption
- DECREASING bone formation
- Altering bone structure
2
Q
5 common metabolic bone disorders?
A
- Primary hyperparathyroidism
- Rickets/ Osteomalacia
- Osteoporosis
- Paget’s Disease
- Renal osteodystrophy
3
Q
Metabolic symptoms of common metabolic bone disorders? (4, 2 really:/)
A
- Hypocalcaemia
- Hypercalcaemia
- Hypo/ Hyperphosphataemia
4
Q
Bone symptoms of common metabolic bone disorders? (3)
A
- Bone pain
- Deformity
- Fractures
5
Q
Bone stores calcium as…
A
inorganic hydroxyapatite
6
Q
Some types of bone are very metabolically active, e.g. …
A
cancellous bone (particularly in vertebrae)
7
Q
Bone remodelling requires a continuous exchange of …
A
ECF with bone fluid reserve.
8
Q
What organs are involved in calcium homeostasis
A
Bone, small intestine, kidney
9
Q
What % of calcium is free, bound (to what: carrier protein and the other 1)
A
- 47% free ionised (active) Ca unbound
- 46% protein bound to albumin
- 7% complexed to PO4 + citrate
10
Q
how does hyperventilating change serum calcium
A
get an alkalosis which causes more Ca to bind to the protein so that the free levels drop.
11
Q
What calcium level promotes PTH
A
Low
12
Q
PTH acts where? (2)
A
Bone, kidney
13
Q
Effect of PTH on bone? (2 and also acute and then chronic)
A
helps to release Ca and PO4 from bone. There is an acute release of available Ca (not hydroxyapatite crystals). More chronically, there is increased osteoclast activity to resorb bone, releasing Ca and PO4.
14
Q
Effect of PTH on kidney? (3)
A
increases absorption of Ca from the distal tubule in the kidney and increases PO4 excretion
also increases the production of Calcitriol in the kidneys via the stimulation of 1-hydroxylase, which will increase Ca absorption in the gut (this is the main effect of Vitamin D)
If there is an increase in PO4 from the bone and gut, this will need to excreted which is why PTH causes an increase in Ca and simultaneously causes PO4 to be excreted from the kidneys. PTH inhibits the Na/PO4 co-transporter in the PCT which allows the PO4 to be excreted.
15
Q
Changes to serum phosphates and alkaline phosphatase in most metabolic bone disorders?
A
Increases, only doesn’t in osteomalacia where P goes down (Alk P is up)
and primary HPT where P goes down (Alk P is up)
And osteoporosis where its normal
16
Q
Alkalosis changes serum calcium how?
A
More becomes bound to albumin
17
Q
What ion is PTH dependent on?
A
Mg
18
Q
Low Mg can impair which hormone leading to bone diseases?
A
PTH
19
Q
how can a small cell carcinoma cause hypercalcaemia?
A
?PTHrP is produced by some tumours which activates PTH receptor and so hypercalcaemia
20
Q
What else can activate the PTH receptor apart from PTH
A
PTHrP
21
Q
What is the curve of PTH secretion to Ca level?
A
Sigmoidal
22
Q
If there is super high Ca levels, what is the PTH level
A
There is always a baseline secretion
23
Q
What is the SET-POINT in the curve of PTH secretion to Ca level?
A
Steepest point of the curve, 1/2 the maximal suppression
24
Q
Where in the kidney does PTH act
A
Distal tubule
25
How does PTH absorb Ca in the distal tubule?
PTH binds to receptors which causes the activation of a transport protein for Ca to bind to to enter the cell (TPRV5)
26
Once Ca has entered the cell how does it get into the blood from the DCT cell? (2 ways)
Ca then binds to an intracellular protein, and is transported through the cell and is either excreted via CaATPase (by AT) or by the Na/Ca exchanger.
27
How does PTH causes activated osteoclasts (3 stages)
PTH acts on osteoblasts to signal to produce more osteoclasts.
More activated osteoclasts are produced through the RANK and RANKL pathway.
Osteoclast progenitors have a RANK receptor which binds to RANKL on the osteoblasts/ stromal cells to then produce activated osteoclasts.
28
How do osteoclast progenitors become osteoclasts
Osteoclast progenitors have a RANK receptor which binds to RANKL on the osteoblasts/ stromal cells to then produce activated osteoclasts.
29
Primary HPT is more common in men or women
Women
30
Causes of hyperparathyroidism?
Parathyroid adenoma 80%
Parathyroid hyperplasia 20%
Parathyroid CA <1%
Familial Syndromes
MEN 1 2%
MEN 2A rare
HPT-JT rare
31
Defining Diagnosis of Primary HPT?
an elevated total/ ionised Calcium with PTH levels frankly elevated or in the upper half of the normal range
32
If the Ca= high, PTH= should be....
suppressed to the very end of the normal range
33
Clinical features of primary HPT? (pneumonic, at least 5)
BONES, STONES, ABDOMINAL MOANS AND PSYCHIC GROANS.
- Renal stones, nephrocalcinosis, (high Ca trying to excrete so get kidney stones- increased incidence to renal impairment)
- Dyspepsia, pancreatitis (dyspepsia= increased acid secretions)
- Constipation, nausea, anorexia (affects the gut- appetite is gone)
- Depression, impaired concentration
- Drowsy, coma (in elderly people, causes mental problems.
34
What do patients present and complain about when coming in with PHPT?
Get: thirst, polyuria, tiredness, fatigue, muscle weakness
35
How does high serum Ca cause diuresis
Na/K/Cl transporter in the Loop of Henle (ascending limb) shuts if down serum Ca is high so no reabsorption of Na/K/Cl, causing diuresis.
36
Why does the Na/K/Cl triple transporter in the ALOH shut down with high serum Ca
In order to maintain the potential difference (+ve lumen, -ve blood)
37
what does the drug frusemide do and what does it cause?
Loop diuretic, shuts down triple transporter in ALOH, causes diuresis
38
acute/ pulsed increase in PTH effect on bone?
it has an anabolic effect and helps to build bone.
39
chronically elevated PTH effect on bone? What can this lead to?
catabolic effect which affects the cortical bone. This leads to a fracture increase due to thin cortices.
40
Long term hypercalcaemia causes what in the vasculature?
calcification of the arteries and will develop to hypertension and an increased vascular risk in the long term.
41
Primary HPT Biochemical Findings for:
```
Serum Ca
Serum PO4
Serum PTH
Urine Ca
Cr
```
- Increased serum Ca by absorption from bone/ gut
- Decreased serum PO4
- PTH in the upper half of the normal range or elevated renal excretion in PCT
- Increased urine Ca excretion
- Cr may be elevated
42
Describe how UV light results in vitD
UV light converts 7-dehydrocholesterol -> to cholecalciferol and then to 25-hydroxycholecalciferol in the liver -> 25OH form is activated in the kidney to -> 1,25 dihydroxy
43
1,25 dihydroxycholecalcifderol/calcitriol effects?
increases gut absorption of Ca and PO4.
kidneys, Ca is reabsorbed through Vitamin D facilitating PTH in distal tubule and phosphate excretion in PCT
In bone, increases PTH function producing osteoclasts and releasing Ca and PO4
44
What receptor protein and molecule is involved in absorbing Ca in the kidney
- TPRV5 and Calbindin
45
What receptor protein and molecule is involved in absorbing Ca in the gut
- TPRV6 and Calbindin
46
Vit D effect in the gut? What receptor and protein?
- Vitamin D activates Ca and PO4 absorption in the duodenum via TRPV6 and Calbindin
47
Calcitriol effect of PTH secretion?
Reduces it
48
How is Ca absorbed in the gut, active or passive?
There is passive transport- paracellularly
| There is active transport- up to 40% saturable and this will occur in the duodenum, usually via the action of Vitamin D.
49
What is measured when testing for Vit D deficiency?
the 25-OHcholecalciferol bound to Vitamin D binding protein (DBP)
50
Symptoms of rickets? (3)
- Bone pain and tenderness (axial)
- Muscle weakness (proximal)
- Lack of play
51
Signs of rickets/osteomalacia? (5)
- Age dependent deformity
- Myopathy
- Hypotonia
- Short stature
- Tenderness on percussion
52
Rickets/osteomalacia causes? (including 4 GI causes)
```
o Lack of sunlight
o Decreased production with age
- Dietary- GI
o Small bowel malabsorption/ bypass
o Pancreatic insufficiency
o Liver/ biliary disturbance
o Drugs, phenytoin, phenobarbitone increased CYP450 activity that inactivates Vit D
- Renal
o Chronic renal failure
- Rare hereditary
o Vitamin D dependent rickets Type 1: deficiency of 1-hydroxylase
```
53
Hypocalcaemia effects on muscle?
muscle spasm and paresthesia. Can be at risk of seizures too.
54
Vit D solubility?
Fat soluble
55
Primary HPT Biochemical Findings for:
Serum Ca
Serum PO4
Serum PTH
serum alkaline phosphatase
Low PO4
Low Ca
High PTH
High alkaline phosphatase
56
FGF 23 is secreted by what, in response to what and what is its functions
Secreted by osteocytes in response to elevated phosphate
decreases the reabsorption and increases excretion of phosphate. FGF23 may also suppress 1-alpha-hydroxylase, reducing its ability to activate vitamin D and subsequently impairing calcium absorption
57
How does PTH effect phosphate absorption in the kidneys
There are PO4 transporters to coabsorb the PO4 and Na in the PCT, PTH removes these
58
How does FGF23 effect phosphate absorption in the kidneys
Shuts down the PO4 Na cotransporter
59
how does FGF23 and PTH prevent hypocalcaemia and avoid hyperphosphataemia
Low Ca -> PTH secretion -> Ca absorbed in gut with PO4 -> Ca switches off PTH so PO4 isn't excreted -> bone senses excess PO4 -> produces FGF23 -> switches off PO4 absorption in the gut -> stops vit D production too
60
What abnormally functioning hormone causes excess phosphate loss
FGF-23, the PO4 would be continuously lost.
61
explain X-linked hypophosphataemic Rickets
- Most common form of rickets in the USA- can’t break down FGF-23 so have high levels of it. Its due to mutations in PHEX.
62
explain Autosomal Dominant Hypophosphataemic Rickets
is an autosomal dominant problem can’t cleave FGF-23 thus have high levels of it
63
Explain oncogenic osteomalacia
Benign Mesenchymal tumors
| - Produce FGF-23, causes phosphaturia and stops 1-OHlase.
64
WHAT IS Fanconi syndrome
damage to the proximal tubule. This leads to leakage of PO4, glucose and there will be acid-base disturbance. This is because the proximal part is where the alkali is supposed to be reclaimed.
In urine- there will be abnormalities.
65
CAUSES OF FANCONI SYNDROME? (4)
Multiple myeloma
Heavy metal poisoning: lead, mercury
-Drugs: tenofovir, gentamycin
Congenital disease: Wilson’s, glycogen storage diseases
66
Main CAUSE OF FANCONI SYNDROME?
Gentamycin in gram -ve infections
67
Osteoporosis is essentially ...
LOW BONE DENSITY
68
Osteoporosis shows loss of connections between XXX
the trabecular network.
69
Causes of high turnover osteoporosis? (5)
```
o Oestrogen deficiency- primarily in postmenopausal women
o Hyperparathyroidism
o Hyperthyroidism
o Hypogonadism in young women and men
o Cyclosporine (?)
o Heparin treatment
```
70
Causes of low turnover osteoporosis? (3)
o Liver disease- primarily primary biliary cirrhosis (reduces the rate of new bone formation)
o Heparin
o Age above 50yrs
71
What type of bone is highly metabolically active
Cancellous
72
How often do we get a new skeleton
Every 5-7 years
73
What makes bone strong? (4)
Mass
Material properties
Microarchitecture
Macroarchitecture
74
How does material properties make a bone strong? (3)
- Collagen fibrils which cross link.
Woven versus lamellar
mineralisation
75
How does Microarchitecture make a bone strong? (3)
Trabecular thickness
Trabecular connectivity
Cortical porosity
76
How does Macroarchitecture make a bone strong? (2)
Hip axis length
| Diameter of bone
77
4 ways Bone structure and function may be assessed ?
- Bone histology
- Biochemical tests
- Bone mineral densitometry e.g. osteoporosis
- Radiology
78
when is peak bone mass reached and how long is it maintained, difference between men and women loss of bone mass?
The peak bone mass is around the mid 20’s. It is stable until around 40.
Men have a slow loss of mass. Women have a fast, early loss in early menopause
79
How does oestrogen affect bone growth in puberty
oestrogen, lose the capacity to lay down bone outwards
| Women put bone on the endocortical surface so bone remains a similar diameter.
80
How does exercise change bone growth in puberty
More layers of bone put on the outside if this bone is stressed
81
How does exercise change bone growth post puberty
Later in life, can only change things on the inside of the bone
82
what process repairs microfratcures
Bone remodeling is the process by which these areas are repaired
83
What represents a remodelling event of a microfracture
Each osteon
84
Describe the remodelling cycle starting with a micro fracture
If a little crack occurs, this is picked up by osteocytes sitting in bone via their mechanoreceptors.
They send signals and so macrophages are activated and signal to make osteoclasts resorb the bone.
A constant stimulus for this is needed. After the bad bit of bone is taken out, the osteoblasts come and form bone marrow mesenchymal stem cells. If these osteoblasts get stuck in the middle, they form osteocytes
85
What cell dies in bone as you get older
osteocytes
86
Effect of oestrogen and how it causes menopausal bone loss
: Oestrogen increases the action of OPG, thus causing inhibition of the RANK pathway (usually activates osteoclasts).
Menopausal changes include a decrease in oestrogen reduced inhibition of the RANK pathway- increased osteoclast action.
Causes remodelling errors and
Trabecular perforation
Cortical excess excavation
87
How does an osteocyte signal that a microcrack has occurred
A microcrack crosses canaliculi, so severing osteocyte processes causing osteocytic apoptosis.
88
MoA of oestrogen to avoid osteoporosis?
Oestrogen increases the action of OPG, thus causing inhibition of the RANK pathway (usually activates osteoclasts)
89
Which bone is rapidly lost in the first few years of menopause
Cancellous
90
Biochemistry in Osteoporosis: serum levels of all things in normal osteoporosis?
Should be normal
91
What biochemical tests do you do for osteoporosis? (4)
1) Check for Vitamin D deficiency
2) Check for Secondary endocrine causes.
3) Exclude multiple myeloma
4) May have high urine Ca
92
What secondary endocrine causes do you test for in osteoporosis? (3)
Primary hyperparathyroidism PTH is high
Primary hyperthyroidism free T3 is high and TSH is suppressed.
Hypogonadism testosterone is low.
93
What tests do you do to confirm osteoporosis? (4)
Dual Energy X-Ray Absorpiometry (DEXA)
94
What areas are BD measured to check for osteoporosis
Vertebral measurements
| Hip measurements
95
What can be measured in serum to indicate collagen synthesis in bone formation
P1NP= Procollagen Type 1 N-terminal Propeptide.
96
What can be measured to indicate collagen breakdown in bone resorption
measuring urine hydroxyproline or urine collagen cross-links
97
measuring urine hydroxyproline or urine collagen cross-links gives us an idea of what...
osteoclast activity
98
procollagen becomes -->
tropocollagen
99
examples of bone markers: (3)
```
urine hydroxyproline
urine collagen cross-links.
P1NP= Procollagen Type 1 N-terminal Propeptide.
Alkaline phosphatase
Osteocalcin
```
100
Akaline Phosphatase purpose?
essential for mineralization of bone
| - Regulates concentrations of phosphocompounds
101
Osteocalcin purpose?
involved in limiting mineralization, it’s incorporated into bone so that fragments are released on resorption
102
Alkaline phosphatase is increased in which diseases: (5)
- Paget’s disease
- Osteomalacia
- Bone metastases
- Hyperparathyroidism
- Hyperthyroidism
103
What is osteoid
osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue
104
Renal osteodytrophy levels of:
Serum PO4
VitD
PO4 increased
| Vit D decreased
105
Renal osteodystrophy causes the development of XX to compensate which leads to Y which causes Z
After a while this causes ƒ which leads to Ω
Secondary hyperparathyroidism
hypocalcaemia
hyperphosphataemia
tertiary hyperparathyroidism
hypercalcaemia
106
Parathyroid hyperplasia develops in tandem with the progressive XXXX
decline in renal function.
107
How does parathyroid hyperplasia occur
Initially, the parathyroid glands respond by increasing the proportion of secretory (chief) cells within the gland and then by increasing the total number of cells, resulting in diffuse hyperplasia of the gland.
In diffuse hyperplasia, cell growth is polyclonal, but is accompanied by down-regulation of the Ca receptor and VDR.
As CKD progresses to Stage 5 (end-stage renal disease), the parathyroid hyperplasia evolves even further; monoclonal abnormalities lead to nodular hyperplasia of the glands. These grossly enlarged parathyroid glands are associated significantly with reduced expression of Ca receptors and VDRs.
Parathyroid glands with nodular hyperplasia, thus become less responsive to serum Ca levels and resistant to the medial treatment of Secondary HPT.
108
What leads to metastatic calcification
hyperphophataemia
