Metabolic Bone Disease - Biochemical (13.01.2020) Flashcards
What are the 5 common metabolic bone disorders?
- Primary hyperparathyroidism
- Rickets/ Osteomalacia
- Osteoporosis
- Paget’s Disease
- Renal osteodystrophy
Symptoms of these diseases
Metabolic
- Hypocalacaemia
- Hypercalcaemia
- Hypo/Hyperphosphataemia
Specific to bone
- Bone Pain
- Deformity
- Fractures
What makes bone strong?
4 M’s:
- mass
- material properties
- microarchitecture
- microarchitecture
Ways to asses structure and function of bone?
- Bone histology
- Biochemical tests
- Bone mineral densitometry, e.g. osteoporosis
- Radiology
Exercise and bone
- can increase bone mass
- can increase bone density
- in young age
- changes shape and bone dimensions depending in where strength is needed
- change in trabecular volumetric BMD
Sexual dimorphism in bone growth
- Men: bigger bones under the influence of testosterone
- Women: lower bone mass than men
- steroids and IGF-1 play a role here.
life spans of osteoclasts and osteoblasts
c: weeks
b: months
Biochemical investigations in bone disease
- Serum
Bone profile
- calcium
- corrected calcium (albumin)
- phosphate
- alkaline phosphatase
Renal function
- creatinine
- parathyroid hormone
- 25-hydroxy vitamin D
- Urine
- Calcium/ Phosphate
- NTX
Alkalosis and calcium levels
alkalosis makes more calcium bind to albumin
Clinical feature of 1* HPT
- Thirst, polyuria (hypercalcaemia causes diuresis)
- 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 (Chronically elevated PTH causes increased cortical bone resorption cortical>cancellous)
- Acute/ pulsed PTH : anabolic
- Chronic: catabolic
Biochemical findings in PHT
- Increased serum calcium by absorption from bone/gut
- Decreased serum phosphate renal excretion in proximal tubule
- PTH in the upper half of the normal range or elevated
- Increased urine calcium excretion
- Cr may be elevated
Where in the gut is calcium reabsorbed under the actions of vitamin D3?
20-60% in duodenum, jejunum and colon
Passive: Paracellular
linear
Active: up to 40%
saturable
duodenum
1,25 Vit D
Dangers of rickets becoming severe
- bronchospasm
seizures
echopic calcification in basal gangla -> PD - dementia
- cataracts
- muscle twithcing
- NM irritability (e.g. chvosteks sign, trousseaus sign -> spasm after BP cuff put on for a few minutes)
What are the causes of Ricktes/osteomalacia?
- dietary
- GI
- Small bowel malabsorption/ bypass (very common in gastrectomies; coeliac)
- Pancreatic insufficiency
- Liver/biliary disturbance
- Drugs- phenytoin, phenobarbitone
- Renal (chronic renal failure)
- Rare hereditary
- vitamin D dependant rickets
- T1: deficiency of 1 alpha hydroxylase
- T2: defective VDR for calcitriol
- vitamin D dependant rickets
Lack of sunlight!
Not added to foods except in USA.
Decreased production with age.
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
-> decreases levels of P043-
Can cause rickets or osteomalacia
What are phosphate wasting hormones?
PTH and FGF-23
Fanconi syndrome - causes
- multiple myeloma
heavy metal poisoning: lead, mercury
drugs: tenofovir, gentamycin
congenital disease: Wilsons, glycogen storage diseases
Commonest causes of phosphate related osteomalacia
Kidney proximal tubule damaged -> causes phosphaturia and stops 1α hydroxylation of Vit D
Osteoporosis - causes
High Turnover
- oestrogen deficiency
- hyperthyroidism
- HPT
- Heparin
- cyclosporine?
- hypogonadism in young women and in men
Low turnover
- liver disease - primarily primary biliary cirrhosis
- heparin
- age above 50
Increased bone resorption and decreased bone formation:
- glucocorticoids
How much bone is lost in menopause?
30% of trabecular bone
50% of women have a post-menopausal fracture
Oestrogen deficiency:
- 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
BMD in osteoporosis
- Single best predictor of fracture risk
- BMD represents 70% of total risk
- T-score: how many SDs are you away from a 25 year old
- Z-score is in the same age group
Correlation of fracture risk with BMD
1 SD reduction = 2.5 increase in risk of fracture
Bone markers
- not widely used
- divided into markers of FORMATION and markers of RESORPTION
- as you are forming bone molecules are released because you are cutting ends off of Procollagen
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
BSAP
- increased in anything causing increased bone turnover
- very high when you are growing
= bone specific alkaline phosphatase
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
Heterotopic calcification
- calcification of BVs
- doe of a vascular event
Renal osteodystrophy
GFR below 60 ->
- increases serum phospahte
- decrease in calcitriol
so: 2* HPT to compensate
BUT: unsuccessful and hypocalcameia develops
Later: autonomous PTG and this causes 3* HPT
PTH enlargement, nodular parathyroids
What is metabolic bone disease?
A group of diseases that cause a change in
- bone density
- bone strength
by:
- INCREASING bone resorption
- DECREASING bone formation
- Altering bone structure
- And may be associated with disturbances in mineral metabolism
When do we reach peak bone mass? How does it change throughout life?
- in our 20s
- stable until ~40
- Men slow loss
- Women fast loss in early menopause (can lose up to 30% of cancellous bone; there is a slow and fast pahse of post menopausal bone loss)
What is the most abundant mineral in the body?
Calcium (1kg)
constant flux, metabolically active (GIT, kidneys, Bone, soft tissue)
Why do serum calcium levels need correction?
- Total calcium 2.15-2.56 mmol/L
- total calcium contains:
- free calcium (47%)
- calcium bound to albumin (46%)
- complexed calcium (7%) -> to P or citrate
- in alkalosis there is a shift from free to protein bound calcium (e.g. hyperventilation -> alkalosis -> more ca binds to albumin -> less free calcium -> tingling)
- Corrected calcium = [calcium] + 0.02( 45 – [albumin])
- the corrected calcium a lab gives you compensates for the protein level; if protein levels are HIGH they compensate down; 0.02 for each g/l of albumin
- e.g. if they have less albumin, their real calcium amount is actually higher than the free blood result.
=> to account for albumin bound calcium
Facts about PTH
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)
- SET-POINT: point of half maximal
suppression of PTH; steep part of slope;
Small perturbation causes large change PTH - Even at high levels of Ca there is still some baseline PTH
What does hypomagnesemia lead to?
- PTH is Mg dependant
- low Mg will decrease PTH and cause hypocalcemia
In which people is 1* HPT common? What are the common causes?
Age : 50s, female 3:1 male; 2% post menopausal develop
Causes
Parathyroid adenoma 80%
Parathyroid hyperplasia 20% Parathyroid CA <1% Familial Syndromes MEN 1 2% MEN 2A rare HPT-JT rare
Diagnosis of 1* HPT
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
Where does vitamin D feed back to?
- parathyroid directly to reduce PTH secretion
- bone to increase FGF-23 production
What is the definition of vitamin D deficiency?
- no absolute consensus
- many US/EU people are vitamin D deficient
- The preferred level for 25(OH)D is now recommended by many experts to be >30 ng/mL (75nmol/l).
- upper limit questionable as levels can be higher if someone is in the sun a lot.
- On the basis of the literature, it appears that vitamin D intoxication does not occur until blood levels are >150–200 ng/mL (375nmol/l)
What is rickets?
“inadequate Vitamin D activity leads to defective mineralisation of the cartilagenous growth plate (before a low calcium)”
Symptoms
Bone pain and tenderness (axial e.g. on percussion)
Muscle weakness (proximal)
Lack of play (The children don’t play, they want to stay in, they have bone pain)
Signs Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion
Biochemistry of rickets/osteomalacia
Serum Calcium N/low Phosphate N/low Alk phos High 25(OH)Vit D Low PTH High (secondarily to compensate)
Urine
Phosphate High
?Glycosuria, aminoaciduria, high pH, proteinuria
Osteomalacia and phosphate
‘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
=> genetic or oncogenic! also damage to pct
How can FGF cause osteomalacia?
- though low PO43-
- either because it is not deactivated or because tumour cells make too much of it
Biochemistry in osteoporosis
- > used to exclude other causes
1. Serum biochemistry should all be normal if primary Check for Vit D deficiency
- Check for secondary endocrine causes
- Primary HPT: PTH high
- Primary hyperthyroidism: free T3 high; TSH suppressed;
- Hypogonadism: Testosterone low - Exclude multiple myeloma
- May have high urine calcium
Examples of bone markers
Bone formation collagen synthesis:
- 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
Bone formation; collagen synthesis II
- 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
Used to monitor osteoporosis treatment:
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
Problems with cross links:
- Reproducibility: CV 20%
- Positive association with age
- Need to correct for Cr
- Diurnal variation in urine markers
Clinical use of bone formation markers:
- 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
How does alkaline phosphatase change with age?
- Bone alk P represents about 75% of serum levels pre-puberty
- Increases markedly with growth
- Is about 1:1 with liver in adults
- Increases> age 50; esp menopausal women ; levels up by 75%;
- But not used as marker in osteoporosis
- Placental isoform increases during pregnancy
gradually first two trimesters
rapidly last trimester - labs don’t standardly give isoforms
CKD-MBD
CKD mineral bone disorder
- 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
Biochemistry of renal osteodystrophy
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
also: acidosis causes demineralisation
