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?
This compensates for changes in protein level (if proteins are high, itcompensates down)
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)
More chronically, increased osteoclast activity
b. Kidneys
Increased calcium reabsorption
Increased phosphate excretion
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
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: 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
Bones – osteitis fibrosa cystica
Abdominal moans – dyspepsia, 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?
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: Lack of play Bone pain and tenderness (axial) Muscle weakness (proximal) Sign: Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion
State some 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 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 Low e. PTH High f. URINE phosphate High
Other than PTH, what else can cause increased phosphate excretion?
FGF23
What effect does this factor have that is unlike PTH?
It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production
Which cells produce this factor?
Osteoblast lineage cells
Other than Vitamin D deficiency, what else can cause Rickets/Osteomalacia?
Phosphate deficiency
State some 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)
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
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
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 – 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 tocollagen production?
Procollagen type 1 N-terminal propeptide (P1NP)
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
These can be measured
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 it 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
