Calcium and phosphate metabolism Flashcards
Why is bone turnover important?
for homeostasis of serum calcium and phosphate
What affects homeostasis of serum calcium and phosphate?
Parathyroid hormone (PTH)
Vitamin D (1,25-dihydroxy D3)
Calcitonin
FGF-23
Distribution of body calcium
99% in bone
1% intracellular
<0.1% extracellular (2.2-2.6mmol/L)
FGF-23
hormone promoting renal phosphate excretion by reducing Na-Pi absorption from proximal tubule
synthesised and secreted by osteocytes
lifespan of FGF-23
FGF-23 has a short half-life and this half-life is regulated by enzymatic cleavage of the peptide into two inactive fragments.
How does FGF-23 cause hypophosphataemic rickets?
The cleavage recognition site in hypophosphataemic rickets has a single amino acid substitution (mutation) that makes it unrecognisable and the peptide isn’t cleaved, remaining active and promoting excessive phosphate loss. This leads to impaired bone mineralisation and rickets.
FGF-23 disorders
Oncogenic osteomalacia (tumour secreting FGF-23) X-linked hypophophataemic rickets Autosomal dominant hypopho-phataemic rickets (gain of function mutation)
Causes of Hypercalcaemia in hospitals
Most common cause of hypercalcaemia in HOSPITALISED patients:
- humoral e.g. lung carcinoma secreting PTHrP (PTH-related peptide)
- metastatic
- haematological (e.g. myeloma)
Most common causes of hypocalcaemia
Less common causes of hypocalcaemia
Vitamin D deficiency
Renal failure
Hypoparathyroidsim
What is the most common cause of osteomalacia?
Vitamin D deficiency
-usually due to combination of low dietary intake and lack of exposure to sunlight
Who is at risk of Vitamin D deficiency?
Elderly- if in nursing home and not taking supplements
Breast-fed babies kept out of sunlight
What can vitamin D deficiency result in?
Rickets (in children)
-failure of bone mineralisation and disordered cartilage formation
Osteomalacia (in adults)
-impaired bone mineralisation (soft bones)
Vitamin D-dependent rickets type I
Disease caused by a mutation of 1a-hydroxylase enzyme:
- normal levels of vitamin D precursor
- but low levels of active calcitriol
- calcium and phosphate will be low
- PTH will be high
Vitamin D-dependent rickets type II
Disease caused by a mutation of vitamin D receptor:
- precursor levels will be normal
- calcitriol levels will be high, however not effective because it is not adequately activating its receptor
- calcium and phosphate will be low
- PTH will be high
Hypophosphataemic rickets
rare phosphate-wasting (excessive phosphate excretion) condition leading to bone mineralisation defects (osteomalacia)
Cause of hypophosphataemic rickets
- Mutation leading to excess FGF-23 activity
- Ectopic FGF secretion (benign tumour)
clinical features of osteomalacia
· Diffuse bone pain
· Waddling gait, muscle weakness
· On X-ray, stress fractures
Osteoporosis
loss of bone mass/density due to the thinning of both cortical bone and the trabecular mesh
Serum biochemistry of osteomalacia
- Low/normal calcium
- Hypophosphataemia
- Raised alkaline phosphatase
- Secondary hyperparathyroidism (the low calcium would stimulate PTH release)
Causes of osteoporosis
· Endocrine · Malignancy · Drug-induced · Renal disease · Nutritional · Age
Osteoporosis vs Osteomalacia
Osteoporosis:
-loss of bone mass/density
Osteomalacia:
-loss of bone mineralisation
First sign of osteoporosis
sustaining a fracture, usually:
- wrist
- neck of the femur (hip)
- intervertebral
Diagnosing Osteoporosis
Dual Energy X-Ray Absorptiometry Scan (DEXA or DXA)
-measures bone mineral density
How does DEXA work?
Bone mineral density peak = 25 years old, thereafter it slowly declines. With DEXA, we achieve a T score by taking the average bone mineral density score for a young adult and then comparing it measured bone mineral density score.
The T score = the number of standard deviations below the average bone mineral density for a young adult at peak bone density (~25 yo):
- If you are 1 standard deviation below the average →osteopenia. This is nevertheless still a loss of bone density and does tend to occur with age
- If you are 2.5 standard deviations below the average →osteoporosis
Endocrine causes of osteoporosis
· Hypogonadism- notably any cause of oestrogen deficiency
· Excess glucocorticoids- endogenous or exogenous
· Hyperparathyroidism
· Hyperthyroidism
Significance of oestrogen levels in osteoporosis
Significant for women because oestrogen production terminates at menopause. The remaining oestrogen will depend on the peripheral conversion of adrenal androgens via aromatase.
after menopause, there is a slight acceleration in the decline of bone density. Typically their bone mineral density may decrease to the level within the osteopenia category.
The curve for a male would be pretty similar, although without the slight acceleration due to menopause. But, essentially males also become more prone to osteoporosis with age, and will certainly get osteopenia.
Treatments for Osteoporosis
Postmenopausal:
· Hormone Replacement Therapy- safety of long-term treatment has been questioned
Bisphosphonates
· Inhibit function of osteoclasts (e.g. risedronate, alendronate)
PTH Analogues
· Intermittent doses of PTH promote good bone remodelling (raised prolonged doses of PTH tend to favour osteoclast activity for bone reabsorption)
Denosumab
· Antibody against RANK ligand
Romosozumab
· Antibody against sclerostin protein (which usually inhibits osteoblast differentiation)
Ensure adequate calcium and vitamin D intake, appropriate exercise
Effect of renal disease failure on bone
Decreased renal function:
- Decreased activation of calcitriol
- Decreased absorption of Ca
- Increased PTH (secondary hyperparathyroidsim) which causes an excess of reabsorption over formation→bone erosion
Increased PTH is probably doing more harm than good because its pathways for increasing Ca i.e. reabsorption from kidney tubule and activation of vitamin D are just not as effective.
reduced H+ excretion, causing metabolic acidosis which causes bone erosion.
As renal failure progresses it may lead to renal osteodystrophy.
