Metabolic bone disease: biochemistry

Question 1

what is metabolic bone disease?

Answer 1

A group of diseases that cause a change in 
bone density			bone strength
by 
1. INCREASING bone resorption
2.   DECREASING bone formation
3.   Altering bone structure

And may be associated with disturbances in mineral metabolism

Question 2

What are the 5 common metabolic bone disorders?

Answer 2

Primary hyperparathyroidism

Rickets/ Osteomalacia

Osteoporosis

Paget’s Disease

Renal osteodystrophy

Question 3

symptoms in these disease:

• metabolic
• specific to bone

Answer 3

Metabolic

• Hypocalacaemia
• Hypercalcaemia
• Hypo/Hyperphosphataemia

Specific to bone

• Bone Pain
• Deformity
• Fractures

Question 4

what does the bone calcium do?

Answer 4

-hydroxyapatite
-cancellous bone metabolically active
remodelling
continuous exchange of ECF with bone fluid reserve

Question 5

What makes a bone strong?

-the 4 Ms

Answer 5

Mass

Material properties (matrix and mineral)

• collagen
• woven versus lamellar
• mineralisation
• microcracks

microarchitecture

• trabecular thickness
• trabecular connectivity
• cortical porosity

microarchitecture

• hip axis length
• diameter

Question 6

what might be used to assess bone structure and function?

Answer 6

Bone histology
Biochemical tests
Bone mineral densitometry, e.g. osteoporosis
Radiology

Question 7

what is the age related changes in bone mass like?

Answer 7

Men have greater bone mass than women
bone mass increases, no increase from 27 to 42 (called consolidation), then decreases. For women there is a sharp drop in bone mass during menopause

Question 8

how can growth and exercise change peak bone mass?

Answer 8

change in bone dimensions
change in bone shape
change in trabecular volumetric BMD

Question 9

what is bone remodelling

Answer 9

bone has a structure designed to absorb energy
irreversible PLASTIC deformation does occur resulting in microfractures, which dissipate the excess energy, generally limited to the interstitial bone between osteons . If these accumulate bone strength will be compromised.

Bone remodeling is the process by which these areas are repaired, each osteon essentially represents a previous remodelling event.

Question 10

describe the bone remodelling cycle

Answer 10

Bone remodelling occurs in the basic multicellular unit, seen here.

Activation occurs
A microcrack crosses canaliculi, so severing osteocyte processes causing osteocytic apoptosis. This is thought to act as a signal to the connected surface lining cells (which are osteoblast lineage), which along with the osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment. For the resorption phase to start osteoclasts are generated locally and resorb matrix and the offending microcrack, then successive teams of osteoblasts deposit new lamellar bone. Osteoblasts that are trapped in the matrix become osteocytes; others die or form new, flattened osteoblast lining cells.

Question 11

what are the biochemical investigations that can be used in bone disease?

Answer 11

Serum
Bone profile		
-calcium
- corrected calcium (albumin
-phosphate
-alkaline phosphatase

Renal function

• creatinine
• parathyroid hormone
• 25-hydroxy vitamin D

Urine

• Calcium/ Phosphate
• NTX

Question 12

biochemical changes table

Answer 12

see ppt

Question 13

calcium balance systems

Answer 13

Calcium is most abundant mineral in body; 1kg

Mainly in BONE
Huge fluxws in /out of bone; it is not a metabolicaaly inert tissue
Cancellous bone has a huge blood supply; respiratory physiologists tell you the alveolar surface area for gas exchange is TENNIS court; bone is many times greater.

Thinking about calcium is easy

GUT whats comig in; 1g day recommended intake

Kidney whats going out

BONE flux; your compensatory mechanism

Question 14

how do serum calcium measurements need correction?

Answer 14

We measure in serum is a TOTAL calcium
free; the active form
complexed; to P and citraate
protein-bound to ALBUMIN

So the corrected calcium a lab gives you compensates for the protein level; if protein levels are HIGH they  compensate down; o.o2 for each g/l of albumin

PROBLEMS occur in acid-base disturbance

If HYPERVENTILATE; get alkalosis which causes more ca to bind to prtotein so that free levels drop; all experienced this;tingling

venous stasis may falsely elevate LEVELS

Question 15

How does PTH regulate serum calcium levels?

Answer 15

If plasma calcium drops within seconds have secretion of PTH from pre-formed stores

Acts on 2 systems

1.Bone acute release of available calcium; not in hydroxyapatite crystals
more chronically INCREASED osteoclast activiyty to re-absorb bone

2. Kidney Increased ca re-absorption in the distal conv tubule; the only site where ca re-absorption is under active hormonal controlStimulation of 1alpha Ohase activity , so increasing actiavated vit D production, which leads to increased gut re-abs of ca;
   Decreases 24 oh ase activityIncreases p excretion by inhibiting the NAP cotransporter in the proximal tubule

Question 16

clinically relevant points about PTH

Answer 16

1. 84 amino acid peptide
   but N1-34 active
2. Mg dependent
3. T 1/2 8 min
4. PTH receptor is activated
   also by PTHrP

Question 17

how does the parathyroid gland monitor serum Ca through the calcium-sensing receptor?

Answer 17

A steep inverse sigmoidal function
relates PTH levels and Cao2+ in vivo.

MINIMUM: even at high calcium levels
there is base-line PTH secretion

SET-POINT: point of half maximal
suppression of PTH; steep part of slope;
Small perturbation causes large change PTH

**MINIMUM This is important in diagnosis.
Even in Hyperacalcaemia of malig PTH will be detectable; lower half normal rangs

Question 18

PTH drives active calcium absorption in

Answer 18

the distal tubule of the kidney

Question 19

how does PTH cause bone resorption?

Answer 19

RANK system

Question 20

how is primary HPT diagnosed?

Answer 20

Primary hyperparathyroidism is diagnosed by

‘an elevated total/ionised calcium with PTH levels frankly elevated
or in the upper half of the normal range’

(ie. Corrected Calcium > 2.60 mmol/l with PTH > 3.9 pmol/l (nr 1.0 - 6.8))

Subjects with hypercalcaemia and a PTH in the upper half of the normal range are physiologically not normal

It is important to note that such ‘non-suppressed’ concentrations are entirely compatible with the diagnosis of Primary HPT

Question 21

clinical features of primary HPT

Answer 21

Thirst, polyuria
Tiredness, fatigue, muscle weakness

“Stones, abdominal moans and psychic groans”

	Renal colic, nephrocalcinosis, CRF

	Dyspepsia, pancreatitis
	Constipation, nausea, anorexia

	Depression, impaired concentration
	Drowsy, coma

Patients may also suffer fractures secondary to bone resorption

Question 22

high serum calcium causes a diuresis

Answer 22

frusemide

diuresis results in hypercalciuruia

Question 23

Chronically elevated PTH causes:

Answer 23

Chronically elevated PTH causes increased cortical bone resorption

Increased bone turnover

Acute/ pulsed PTH : anabolic

Chronic: catabolic

Cortical > cancellous

Question 24

biochemical findings in primary HPT

Answer 24

1. Increased serum calcium by absorption from bone/gut
   
   2. Decreased serum phosphate renal excretion in proximal tubule
   3. PTH in the upper half of the normal range or elevated
2. Increased urine calcium excretion
3. Cr may be elevated

Question 25

how is VIT D metabolised?

Answer 25

Discuss metabolism Action INTESTINE 1,25(OH)2Vitamin D activates Ca and P absorption; Bone synergises with PTH to increase osteoclastic osteolysis differentiation agent for osteoclast precursors Kidney facilitates PTH action in distal t. to increase Ca reabsorption Excess 1oh ase occurs in granulomatoud disesae ie sarcoid, TB

Question 26

Vit D binding protein half life

Answer 26

Vit D binding protein (DBP): t 1/2 3 days, filtered by kidney

Question 27

activated Vitamin D increases ?

Answer 27

activated Vitamin D increases gut calcium absorption

Question 28

VIT D actions on: - intestine - bone - kidney - feedback

Answer 28

INTESTINE 1,25(OH)2Vitamin D activates Ca and P absorption duodenum (TRPV6, calbindin) Vit D increases active calcium transport in gut Bone Synergises with PTH, acting on osteoblasts to increase formation of osteoclasts through RANKL Increases osteoblast differentiation and bone formation Kidney facilitates PTH action to increase Ca reabsorption in distal tubule (inducing TRPV5, calbindin) Feedback: parathyroid directly to reduce PTH secretion bone to increase FGF-23 production

Question 29

Rickets: - define - symptoms - signs

Answer 29

“inadequate Vitamin D activity leads to defective mineralisation of the cartilagenous growth plate (before a low calcium)” Symptoms Bone pain and tenderness (axial) Muscle weakness (proximal) Lack of play ``` Signs Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion ```

Question 30

causes of rickets/osteomalacia:

Answer 30

``` Vitamin D related Dietary Gastrointestinal Small bowel malabsorption/ bypass Pancreatic insufficiency Liver/biliary disturbance Drugs- phenytoin, phenobarbitone ``` Renal Chronic renal failure Rare hereditary Vitamin D dependent rickets: type I deficiency of 1 α hydroxylase type II defective VDR for calcitriol Dietary Factors lack of sunlight decreased production with age not added to foods xcept USA GI v common in gastrectomies now coeliac , DRUGS increase p450 cytochrome activity that inactivates vitD

Question 31

FGF-23 cause what?

Answer 31

FGF-23 cause PCT phosphate loss, aswell as PTH FGF-23 32KD protein Produced by osteoblast lineage cells, long bones LIKE PTH causes P loss UNLIKE PTH inhibits activation of Vit D by 1 α OH ase

Question 32

PTH action on phosphate generated in Ca resorption is?

Answer 32

PTH action on phosphate generated in Ca resorption is backed up by FGF-23

Question 33

even when calcium and vit D levels are normal, osteomalacia and phosphate can also get:

Answer 33

can also get with renal phosphate loss, when calcium and Vitamin D levels are usually normal’ Kidney forced to lose phosphate ‘isolated’ hypophosphataemia X-linked hypophosphataemic Rickets 1;20,000 mutations in PHEX; high levels of FGF-23 toddlers with leg deformity, enthesopathy, dentin anomalies Autosomal dominant hypophosphataemic rickets (ADRR) variable age of onset; may improve cleavage site for FGF-23 mutated, so high FGF-2 oncogenic osteomalacia mesenchymal tumours produce FGF-23, causes phosphaturia and stops 1α OHase

Question 34

FGF-23 excess can cause

Answer 34

FGF-23 excess can cause rickets/osteomalacia

Question 35

Kidney proximal tubule damaged causes

Answer 35

Kidney proximal tubule damaged causes phosphaturia and stops 1α hydroxylation of Vit D

Question 36

Fanconi Syndrome | leads to

Answer 36

``` Fanconi Syndrome multiple myeloma heavy metal poisoning: lead, mercury drugs: tenofovir, gentamycin congenital disease: Wilsons, glycogen storage diseases ```

Question 37

osteoporosis is due to:

Answer 37

low bone density

Question 38

osteoporosis causes

Answer 38

high turnover- increased bone resorption greater than bone formation low turnover- decreased bone formation more pronounced than decreased bone resorption increased bone resorption and decreased bone formation

Question 39

what does estrogen deficiency do to bone?

Answer 39

Increases the number of remodelling units Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%) Enhanced osteoclast survival and activity Remodelling errors. Deeper and more resorption pits lead to Trabecular perforation Cortical excess excavation Decreased osteocyte sensing

Question 40

biochemistry in osteoporosis is used to exclude other causes

Answer 40

Serum biochemistry should all be normal if primary Check for Vit D deficiency Check for secondary endocrine causes Primary hyperparathyroidism PTH high Primary hyperthyroidism free T3 high TSH suppressed Hypogonadism Testosterone low 3. Exclude multiple myeloma 4. May have high urine calcium

Question 41

what is the main tool to assess osteoporosis

Answer 41

Bone Density (BMD) is the main tool to assess for osteoporosis Dual energy X-ray absorptiometry- current method Measures transmission through the body of X-rays of two different photon energies Enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue

Question 42

define osteoporosis based on BMD:

Answer 42

T-score = (measured BMD – young adult mean BMD) / young adult standard deviation T-score = -2.5 OSTEOPOROSIS -1 to -2.5 OSTEOPAENIA > -1 NORMAL

Question 43

why central measurements?

Answer 43

``` Vertebral Commonest fracture Increasing incidence after aged 60 Measure of cancellous bone Metabolic bone; quickest response to treatment ``` Hip 2nd commonest #, > 70, costs and mortality Fracture Risk Assessment Tool (FRAX) uses hip BMD

Question 44

why are bone markers useful

Answer 44

Markers of bone formation and resorption give us insight into activity Unlike BMD they are DYNAMIC Divided into markers of FORMATION RESORPTION

Question 45

describe collagen synthesis 1

Answer 45

2 ‘Alpha 1’ and 1 ‘Alpha 2’ chain of type I collagen produced by the osteoblast join Extension peptides cut off these propeptides can be measured in blood P1NP = Procollagen type 1 N-terminal Propeptide

Question 46

describe collagen synthesis 2

Answer 46

3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a PYRIDINIUM ring linkage These can be used to measure bone resorption; serum CTX, urine NTX

Question 47

Bone resorption markers are used in monitoring osteoporosis treatment- HOW

Answer 47

Monitoring of response to treatment with anti- resorptive drugs (BMD change 18mnths) bone resorption markers fall in 4-6 weeks expect a 50% drop of urine NTx by 3 months

Question 48

what are the problems with cross links?

Answer 48

1. Reproducibility: CV 20% 2. Positive association with age 3. Need to correct for Cr 4. Diurnal variation in urine markers

Question 49

what is the clinical use of bone formation markers

Answer 49

Only one in common usage is ALKALINE PHOSPHATASE Use in diagnosis and monitoring of Pagets Osteomalacia Boney metastases (prostate with PSA) NOW P1NP is being use as a predictor of response to ANABOLIC treatments PTH treatment rises to peak in 3 months; predicts response

Question 50

BSAP - types - role - uses

Answer 50

``` Types tissue-specific form; liver vs bone intestine, germ cell, placental forms Role essential for mineralisation regulates concentrations of phosphocompounds Uses Consistent within an individual; t ½ 40 hours ``` ``` Increased in Paget’s disease Osteomalacia Bone metastases Hyperparathyroidism Hyperthyroidism ```

Question 51

what is Chronic Kidney Disease Mineral Bone Disorder

Answer 51

Skeletal remodeling disorders caused by CKD contribute directly to to heterotopic calcification , especially vascular The disorders in mineral metabolism that accompany CKD are key factors in the excess mortality caused by CKD ``` CKD impairs skeletal anabolism, decreasing osteoblast function and bone formation rates ```

Question 52

renal osteodystrophy: - biochemistry - so what occurs?

Answer 52

Biochemistry Increasing serum phosphate Reduction in 1,25 Vit D (calcitriol) SO Secondary Hyperparathyroidism develops to compensate BUT unsuccessful and HYPOCALCAEMIA develops LATER Parathyroids AUTONOMOUS (tertiary) causing HYPERCALCAEMIA

Question 53

progression of secondary HPT

Answer 53

Parathyroid hyperplasia develops in tandem with the progressive decline in renal function. The constantly increasing functional demand on parathyroid glands (mainly as a result of hypocalcaemia) drives cell proliferation. 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.1 In diffuse hyperplasia, cell growth is polyclonal, but is accompanied by down-regulation of the CaR and VDR.1 As CKD progresses to stage 5 (end-stage renal disease [ESRD]), parathyroid hyperplasia evolves even further; monoclonal abnormalities lead to nodular hyperplasia of the glands.2,3 These grossly enlarged parathyroid glands are associated with significantly reduced expression of CaRs and VDRs.4,5 Parathyroid glands with nodular hyperplasia therefore become less responsive to serum calcium levels6,7 and resistant to the medical treatment of SHPT.6,8