Metabolic Bone Disease – Biochemistry Flashcards
What is metabolic bone disease?
A group of diseases that cause a change in bone density + strength by increasing bone resorption, decreasing bone formation or altering bone structure
What are the five main metabolic bone disorders?
Primary Hyperparathyroidism Osteomalacia/ Rickets Osteporosis Renal Osteodystrophy Paget’s Disease
What are the 4 main components of bone strength?
Mass
Material properties (collagen, lamellar, mineralisation)
Microarchitecture (trabecular thickness + connectivity)
Macroarchitectue (Diameter)
When is peak bone mass reached?
~25 years
When does bone mass begin to decline?
~ 40 years
in women, decline in bone mass accelerates after menopause
How are microfractures repaired?
Bone remodelling
Briefly describe the bone remodelling cycle.
- Microcrack crosses canaliculi + severs osteocyte processes, inducing osteocyte apoptosis
- This signals to surface lining cells, which release factors to recruit cells from blood + marrow to the remodelling compartment
- Osteoclasts are generated locally + resorb the matrix + the microcrack
- Osteoblasts deposit new lamellar bone
- Osteoblasts that become trapped in the matrix become osteocytes
What is the normal range for serum total calcium?
2.15-2.56 mmol/L
Describe the distribution of calcium.
46% PPB (albumin)
47% free calcium
7% complexes (with phosphate or citrate)
What is the ‘corrected’ calcium level?
Compensates for changes in protein level (if proteins are high, it compensates down)
Describe the effect of metabolic alkalosis on calcium distribution. What effect does venous stasis have on free calcium levels?
Alkalosis: Makes more calcium bind to plasma proteins thus reducing free calcium levels
Venous stasis may elevate free calcium
What are the two main targets of PTH?
Kidneys
Bone
Describe the effects of PTH in:
a. Bone
b. Kidneys
Bone
Acute release of available calcium (not stored in hydroxyapatite crystal form)
More chronically, increased osteoclast activity
Kidneys
Increased calcium reabsorption at DCT
Increased phosphate excretion at PCT
Increased stimulation of 1-alpha hydroxylase (thus increasing calcitriol production leading to increased gut absorption of Ca)
Where does the PTH-mediated increase in calcium reabsorption take place in the nephron?
DISTAL convoluted tubule
Where does the PTH-mediated increase in phosphate excretion take place in the nephron?
PROXIMAL convoluted tubule
How many amino acids make up PTH and which part of this is active?
84
Active: N1-34
What is PTH dependent on? In what patient group could this cause low PTH?
Magnesium
Hypomagnesemia in alcoholics = low PTH + low Ca
What is the half-life of PTH?
8 mins
What else can the PTH receptor be activated by other than PTH?
PTHrP (PTH related protein)
This is produced by some tumours
What does the parathyroid gland use to monitor serum calcium?
Calcium-sensing receptors
Describe the relationship between PTH level and calcium in vivo.
Steep inverse sigmoid function
There is a minimum level of PTH release (it can’t get below this even in the case of hypercalcaemia)
What are the causes of primary hyperparathyroidism?
Parathyroid adenoma (80%)
Parathyroid hyperplasia (20%)
Parathyroid cancer
Familial syndromes
What 4 biochemical results are diagnostic of primary hyperparathyroidism?
HIGH total/ ionised calcium
PTH HIGH or in upper half of normal range (negative feedback should drop PTH if there is hypercalcaemia)
Increased urine calcium excretion
Cr may be high
What are the clinical features of primary hyperparathyroidism?
Stones: renal colic, nephrocalcinosis
Bones: osteitis fibrosa cystica
Abdominal moans: dyspepsia, pancreatitis, constipation, anorexia
Psychic groans: depression, impaired concentration
Fractures secondary to bone resorption
Diuresis (polyuria + polydipsia)
What is the main site of action of calcitriol and what effect does it have?
Small intestine: increases calcium + phosphate absorption
Describe the effects of calcitriol on bone, kidneys and gut
Facilitates PTH effect on the DCT in the kidneys (increased calcium reabsorption)
Synergises with PTH in the bone to increase osteoclast activation
Intestines: Activates Calcium + phosphate absorption
Which receptors/proteins are involved in mediating the effects of calcitriol on the intestines?
TRPV6
Calbindin
What parameter is used to determine whether a patient is vitamin D deficient?
Deficient < 20 ng/M (50 nmol/L)
Normal > 30 ng/M (75 nmol/L)
What is Rickets?
Inadequate vitamin D activity leads to defective mineralisation of the cartilaginous growth plate (before a low calcium)
State 8 signs and symptoms of Rickets.
Symptoms: Lack of play Bone pain and tenderness (axial) Muscle weakness (proximal) Sign: Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion
State 5 Vitamin D related causes of Rickets/Osteomalacia.
Dietary deficiency Malabsorptoin Drugs e.g. enzyme inducers such as phenytoin Chronic renal failure Rare hereditary
For each of the following state whether it would be high, low or normal in the serum of a Rickets patient:
a. Calcium
b. Phosphate
c. Alkaline Phosphatase
d. 25-OH cholecalciferol
e. PTH
f. URINE phosphate
Calcium: Normal or Low Phosphate: Normal or Low Alkaline Phosphatase: High 25-OH cholecalciferol: Low PTH: High (compensatory) URINE phosphate: High
Other than PTH, what else can cause increased phosphate excretion?
FGF23
What effect does FGF23 have that is unlike PTH?
It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production
Which cells produce this FGF23?
Osteoblast lineage cells
Other than Vitamin D deficiency, what else can cause Rickets/Osteomalacia?
Phosphate deficiency
State 5 phosphate-related conditions that cause Rickets/Osteomalacia.
X-linked Hypophosphataemic Rickets (mutation in Phex (this cleaves FGF23))
Autosomal Dominant Hypophosphataemia Rickets
Oncogenic Osteomalacia (mesenchymal tumours can produce FGF23)
PCT damage causes phosphaturia + stops 1a-hydroxylation of Vit D
Fanconi syndrome
What can cause osteoporosis due to increased bone resorption and decreased bone formation?
Glucocorticoids
How does oestrogen deficiency lead to a decrease in bone mineral density?
It increases the no. of bone remodelling units
Causes an imbalance in bone remodelling with increased bone resorption compared to bone formation
Causes remodelling errors
Causes decreased osteocyte sensing
Describe the biochemistry of someone with osteoporosis.
Everything should be normal if the cause is primary
What is the single best predictor of fracture risk?
BMD
What is used to measure BMD?
DEXA scans
Which bones are used when measuring BMD and why?
Vertebral bodies
Commonest fracture
Good measure of cancellous bone
It is a highly metabolically active bone so it is quick to respond to treatment
Hip: 2nd commonest fracture
fracture risk assessment tool (FRAX) uses hip BMD
Which chains make up type 1 collagen?
2 x alpha 1
1 x alpha 2
What can be used as a marker of bone formation that is linked to collagen production?
Procollagen type 1 N-terminal propeptide (P1NP)
an extension peptide that is cut off + can be measured in the blood
What can be used as a measure of bone resorption that is linked to collagen production?
C-terminal telopeptide (CTX): serum
N-terminal telopeptide (NTX): urine
3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage which can be measured
After how long do bone resorption markers fall?
4-6 weeks
What are the 4 problems with cross-linking collagen, with regards to measurement of bone markers?
Reproducibility
Positive association with age
Need to correct for creatinine
Diurnal variation in urine markers
What bone formation marker is commonly in use?
Alkaline Phosphatase
What is Alkaline phosphatase as a bone formation marker used in the diagnosis and monitoring of?
Osteomalacia
Paget’s
Bone Metastases
What is P1NP being used for now?
Used as a predictor of response to anabolic treatments
What are the two forms of alkaline phosphatase?
Liver
Bone
Which bone diseases will cause a rise in ALP?
Osteomalacia
Bone metastases
Paget’s disease
Also hyperparathyroidism and hyperthyroidism
How does alkaline phosphatase change with age?
Increases markedly during puberty reaching its highest levels
Remains relatively constant following puberty (potential small rise > age 50)
What biochemical changes occur in renal osteodystrophy?
Increased serum phosphate
Reduction in calcitriol
Describe the sequelae of renal osteodystrophy.
- Secondary hyperparathyroidism (compensatory)
- This is unsuccessful + hypocalcaemia develops
- This leads to excess stimulation of the parathyroid glands, leading to parathyroid hyperplasia
- Parathyroid cells begin to reduce expression of calcium-sensing receptors (CSR) + Vitamin D receptors (VDR) + become autonomous (tertiary)
- This causes hypercalcaemia
What symptoms are common in metabolic bone disease?
Hypo/Hypercalcaemia
Hypo/Hyperphosphataemia
Bone pain (fractures + deformity)
What can effect peak bone mass?
Growth
Exercise
What is the lifespan of osteoclasts and osteoblasts?
Osteoclasts ~ 2 weeks
Osteoblasts ~ 3 months
What are the 3 main systems involved in calcium balance?
GUT: Ingested Ca
Kidney: Excreted Ca
Bone: Flux (compensatory mechanism)
What is the set-point on a PTH/ Ca2+ graph?
Point of 1/2 max. suppression of PTH, steep part of slope.
Small shift in Ca2+ causes large change in PTH
How does PTH cause bone resorption?
Through acting on receptors on osteoblasts
Osteoblasts release RANKL
RANKL binds RANK on osteoclast precursors, causing proliferation + differentiation
Why can high serum calcium be a medical emergency?
It causes a diuresis
High Ca sensed on basolateral membrane shuts down Na+/ K+ recycling
Less Na+ reabsorbed, thus less water reabsorbed
Increases dehydration, Ca keeps increasing
How do acute and chronically raised PTH differ in effect?
Acute: Anabolic
Chronic: Catabolic, increases cortical bone resorption
What are the feedback actions of Calcitriol?
Negative feedback to parathyroid directly to reduce PTH secretion
Positive feedback to bone to increase FGF23
What 5 consequences can arise from hypocalcaemia that may develop in osteomalacia?
Paresthesias Bronchospasm's Seizures Laryngospasms Heart failure
How is PTH stimulated phosphate absorption in the gut compensated for?
FGF23 causes phosphate excretion in PCT
How do skeletal remodelling disorders caused by CKD contribute to mortality rates?
CKD impairs skeletal anabolism, decreasing osteoblast function + bone formation rates
CKD contributes to heterotopic calcification (vascular= strokes)
