Meatabolic bone disease: biochemistry

Question 1

What makes a bone strong?

Answer 1

4 M’s
Mass
Material properties (matrix and mineral)-cross links etc
Microarchitecture-trabecular thickness, connection
Macroarchitecture-shape of bones/diameter

Question 2

How does bone mass change with age?

Answer 2

Rise up you your mid 20’s-then stable till mid 40s
Then reduce at stable rate
menopause makes it drop lot-

As you grow-bone density increases-grows outwards-but also in direction of bone-makes them fitter
Makes them grow over the periosteum-testrosterone makes that happen more
Women make the bone thicker but not grow out as much

Question 3

What are the biochemcical investigations you need for bone?

Answer 3

Ca / P / AlkP / bone formation and bone resorption

but do corrected calcium-because a lot is protein bound to albumin- (46%) -need to take acount of that
47% FREE ionised is a good target to aim for

Alkalosis-makes ionized free to albumin bound

Question 4

What are the effects of PTH?

Answer 4

Minute to minute regulation-if Ca low
then immediatly resorb bone -release Ca and P
Also acts on Kidney to excrete P, absorb Ca, and create more activr Vit D3

Remember-PTH is Mg dependent (if that low Ca is low)
And PTH receptor, PTHrP can also activate it

PTH increases the Ca entry channels from kidney-where it activates Calmodulin in cell AND being able to put in blood via sodium exchanger or ATPase

Question 5

how is PTH regulated?

Answer 5

PTH is Mg dependent (if that low Ca is low)
And PTH receptor, PTHrelated P can also activate it

But based on free ionised Ca
But minimum PTH is hard to achieve-even at v high Ca levels

Question 6

how does PTH cause bone resorption?

Answer 6

through the osteoblasts to produce RANKL-causing more Osteoclast differentiation

Question 7

How dangerous is Primary hyperparathyroidism?

Answer 7

Its actually comon and usually benign
80% -benign adenoma
hyperplasia
CA

RARER-familial syndromes

Question 8

What are the biochemical signs of primary HPT? and symptoms?

Answer 8

High Ca-corrected over 2.6 and high to upper normal range of PTH
low Serum phosphate
urine calcium excretion
Cr elevated

still bones, stones, abdominal moans and psychic groans

abdo: dyspepsia/pancreatitis, constipation, nausea, anorexia
Stones; increase chances before you even know its there-and nearly normal after treatment
Bones: more and more cortical bone-less cancellous-more white on imaging => increase fracture risk

Question 9

How dangerous is high serum calcium?

Answer 9

Very dangerous-causes diuresis at very high doses
Around 3mmol-its like taking a full diuretic (like furosemide)-
high Ca shuts down the triple transporter in loop of henle-cause AKI-death etc

Question 10

When do you operate to treat HPT?

Answer 10

serum calcium> 0.25mmol
If urine calcium above 10mmol or stones
if creatining <60
if Tscore low
IF THEY ARE YOUNG---

Question 11

What are the main effects of Vitamin D?

Answer 11

Well can be made to calcitriol-which us synergistic with PTH-resorb bone and take more in kidney
also increase active uptake of calcium from the gut (passive intake is very bad)-if not making any Vit D-lose 200mg a day naturally-so offset by taking some
Without Vit D-need all passive-need to eat 3g of Ca-impossible

Question 12

How do you decide how much Vit D you should have?

Answer 12

Until you reach a certain point-PTH rises to try and increase Ca-so the right level is when PTH stops rising-around 70ng

Question 13

What is rickets? what are the signs of Hypocalceamia?

Answer 13

Inadequate Vit D activity leading to defective minerailsation
stymptoms: Bone pain, weakness, muscle weakness, lack of play,
age dependent myopathy, low muscle tone, tender bones
Causes-Malabsorpion-pancrease issues, liver issues, drugs, CKD, Rare hereditary-VitD dependent rickets (type I (no 1a hydroxylase)/II (no vitD receptor)

But only really have hypocalceamia quite late in
Mostly-tetany -neuromuscular irritability
Cardiac-increased QT interval
Chronic-exctopic calcification of basal ganglia-young parkinsons
dementia

Remember-Chvostek signs (face reaction when touching) and trousseaus signs (if blow cuff around arm, wrist cranes)

Question 14

What are the biochemical signs of Rickets?

Answer 14

Calcium LOW
phosphate Low
Alk Phos high
Vit D- low
PTH-high (secondary)

urine-phosphate (due to PTH, FGF23 stimulation-internalising of Phosphate intake channels-
FGF comes because when VitD makes you take in PO4-then Ca shuts the PTH down, so FGF ensures you get rid of PO4)

Question 15

What is the relation beteween osteomalacia and phosphates

Answer 15

P also makes up bones-so can cause rickets
usually causes by kidney forced to lose P

isolated hypophosateamia-X linked rickets-genetic high FGF
AD hypophpshposdia rickeys-cant cleave FGF23 -active longer
oncogenic causes

But a lot more common-Kidney Proximal tubule DAMAGED. the tubule if where glucose and other are taken in-so all released in urine
Fanconi syndrome-Multiple myeloma, heavy metal poisoning, more

Question 16

What is fanconi syndrome?

Answer 16

Fanconi syndrome-Multiple myeloma, heavy metal poisoning
cause damage in Proxmial tubule-But a lot more common-Kidney Proximal tubule DAMAGED. the tubule if where glucose and other are taken in-so all released in urine

Question 17

What is osteoporosis? Main types? causes of each?

Answer 17

Low bone density
Can be high turnover (can be estrogen def, or HPTH, HTH, hypogonadism, drugs) or low (liver disease, Heparin, age)
Glucocroiticoids-increase bone resorption and formation

Estrogen def-very big difference-increase of resorbtion-remodelling errors leading trabecular perforation, cortical excess-decrease of osteocyte
men-just normal low linear loss
=> increase fracture rates (50% women post menopause)

Question 18

What are the biochemical signs of Osteoporosis?

Answer 18

Should all be normal-
check for VitD defi, check secondary endocrine cause,
Check HPTH, HTH
check for multiple myeloma
check urine Ca (may be high)

DEXA–BMD t-score under 2.5SD of 25 y/o (t sscore -2.5)
Osteopenia- (-1 - -2.5 =normal but low)

Question 19

What are bone markers?

Answer 19

When u make collagen-procollagen has extra cleaved chains- these peptide can be measures and tell you how much collagen is being made-
P1NP
can also measure-urine NTX-molecules that form cross links with collagen-and then can be found and measured
not used that much because hard to reproduce-need to correct for Cr, vary in day (high in morn), positive association with age
All that measures the treatment of osteoporosis-because bisphophonates are very very unreliable

ONLY one actually in use-Alkaline phosphatase
Can be use to measure bone formation rate from pagets, osteomalacia, Boney metastasis
P1NP also sorta used (rise after treatment)

Question 20

What is alkaline phosphatase and what does it tell you?

Answer 20

Liver form, Bone form and intestine form

Essential for mineralisation-long half life-regulation coencetrations

Alk P is increased in any disease with high bone turnover-or if people are growing

Question 21

How does CKD mineral bone disorder cause bone metabolic disease?

Answer 21

Skeletal remodelling caused by CKD contribute to vascular calcification-widespread

Its because GFR drops-phosphates levels rise (cant excrete fast enough), reduce Vit D production
=> causes secondary hyperparathyroidism to compensate-unsuccessful-hypocalceamia develops
THEN nodular PTH autonomous (tertirary)-causes cause high calcium

overall-get acidosis-demineralise
reduce Vit D-osteomalactio
P retention + Vit -cause secondary PTH-> increase bone resorb
in circulation, P and Ca bin causing metastatic calcification (and die early cause of that)