Metabolic Bone Disease – Biochemistry Flashcards
What is metabolic bone disease?
A group of disease that cause a change in bone density and bone 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 main components of bone strength?
Mass
Material
Microarchitecture
Macroarchitectue
When is peak bone mass reached?
Around 25 years
When does bone mass begin to decline?
Around 40 years
NOTE: in women, the decline in bone mass accelerates after menopause
How are microfractures repaired?
Bone remodelling
Briefly describe the bone remodelling cycle.
A microcrack crosses the canaliculi and severs the osteocyte processes, inducing osteocyte apoptosis
This signals to the surface lining cells, which release factors to recruit cells from the blood and marrow to the remodelling compartment
Osteoclasts are generated locally and resorb the matrix and the mitrocrack
Then osteoblasts deposit new lamellar bone
Osteoblasts that become trapped in the matrix become osteocytes
What is the normal range for serum calcium concentration?
2.15-2.56 mmol/L
Describe the distribution of calcium.
46% plasma protein bound (albumin)
47% free calcium
7% complexes (with phosphate or citrate)
What is the ‘corrected’ calcium level?
- considers the calcium bound to albumin
Corrected calcium = [Ca2+] + 0.02(45-[albumin])
Describe the effect of metabolic alkalosis on calcium distribution.
It makes more calcium bind to plasma proteins thus reducing the free calcium levels
NOTE: 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
a. Bone
Acute- release of available calcium (not stored in hydroxyapatite crystal form)
Chronic, increased osteoclast activity- catabolic
b. Kidneys Increased calcium reabsorption Increased phosphate excretion Bone resorption via RANK Increased stimulation of 1-alpha hydroxylase (thus increasing calcitriol production)
Where does the PTH-mediated increase in calcium reabsorption take place in the nephron?
DISTAL convoluted tubule via TRPV5/6
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?
Magnesium
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
NOTE: even at high Ca conc, 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 biochemical results are diagnostic of primary hyperparathyroidism?
Elevated total/ionised calcium
With PTH levels frankly elevated or in the upper half of the normal range (negative feedback should drop PTH if there is hypercalcaemia)
What are the clinical features of primary hyperparathyroidism?
Stones, Bones, Abdominal Groans and Psychic Moans
- Stones – renal colic, nephrocalcinosis, CRF
- Bones – osteitis fibrosa cystica
- Abdominal moans – dyspepsia (indigestion), pancreatitis, constipation
- Psychic groans – depression, impaired concentration
NOTE: patients may also suffer fractures secondary to the bone resorption
IMPORTANT NOTE: hypercalcaemia also causes diuresis (polyuria and polydipsia)
What is the main site of action of calcitriol and what effect does it have?
Small intestine – increases calcium and phosphate absorption
Describe the effects of calcitriol on bone and in the kidneys.
Facilitates PTH effect on the DCT in the kidneys (increased calcium reabsorption)
Synergises with PTH in the bone to increase osteoclast activation/maturation
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?
no absolute value?
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 some signs and symptoms of Rickets.
Symptoms: 1. Lack of play 2. Bone pain and tenderness (axial) 3. Muscle weakness (proximal) Sign: 1. Age dependent deformity 2. Myopathy 3. Hypotonia 4. Short stature 5. Tenderness on percussion plus CHVOSTEK and TROSSEAU signs
State some Vitamin D related causes of Rickets/Osteomalacia.
Dietary deficiency Malabsorptoin (GI) 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 ornormal in the serum of a Rickets patient:
a. Calcium
b. Phosphate
c. Alkaline Phosphatase
d. 25-OH cholecalciferol
e. PTH
f. URINE phosphate
a. Calcium
Normal or Low
b. Phosphate
Normal or Low
c. Alkaline Phosphatase
High
d.25-OH cholecalciferol (Calcifediol)
Low
e. PTH
High
f. URINE phosphate
High
Other than PTH, what else can cause increased phosphate excretion?
FGF23 (inhibits phosphate/Na co transporter)
What effect does the FGF23 factor have that is unlike PTH?
It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production (which is how it leads to osteomalacia)
Which cells produce FGF23 factor?
Osteoblast lineage cells
Other than Vitamin D deficiency, what else can cause Rickets/Osteomalacia?
Phosphate deficiency (so Vit D and Ca are normal but not enough phosphate causes)
State some phosphate-related conditions that cause Rickets/Osteomalacia.
- Isolated phosphataemia:
1. X-linked Hypophosphataemic Rickets (mutation in Phex which breaks down FGF23 so get high levels of FGF23)
- Autosomal Dominant Hypophosphataemia Rickets
(cleavage site of FG23 mutated so get high levels) - Oncogenic Osteomalacia (mesenchymal tumours can produce FGF23)
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 number of bone remodelling units
2. It causes an imbalance in bone remodelling with increased bone resorption compared to bone formation
Describe the biochemistry of someone with osteoporosis.
Everything should be normal if the cause is primary
- this should exclude all other causes
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
- Commonest fracture
- Good measure of cancellous bone
- It is a highly metabolically active bone so it is quick to respond to treatment
Hip – second commonest fracture
NOTE: 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)
- in production of collagen extension peptide are cleaved which can be measured
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 used to measure bone resorption
After how long do bone resorption markers fall?
4-6 weeks
What are the 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 ALP 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
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 after the age of 50)
What biochemical changes occur in renal osteodystrophy?
Increased serum phosphate
Reduction in calcitriol
Describe the sequelae of renal osteodystrophy.
Secondary hyperparathyroidism
This is unsuccessful and hypocalcaemia develops
This leads to excessive stimulation of the parathyroid glands, leading to parathyroid hyperplasia
The parathyroid cells begin to reduce expression of calcium-sensing receptors (CSR) and Vitamin D receptors (VDR) and become autonomous (tertiary)
This causes hypercalcaemia
Describe the sexual dimorphism in bone growth
Men have appositional bone growth whilst women form new bone on the inside of the bone marrow
In BMD, what does a 1 SD reduction imply?
2.5X increase in fracture risk
In BMD, how is a T-score calculated?
measured BMD - young adult mean BMD
all divided by young adult SD
What are the two types of rare hereditary rickets and what are their causes?
- Type 1 VitD-dependant rickets
- deficiency of 1-alpha hydroxylase - Type 2 VitD-dependant rickets
- defcetive VitD- recpetor for calcitriol
