Calcium and phosphate metabolism Flashcards
What is osteoporosis and its causes
Loss of bone mass (mineral and organic matrix)
Causes:
- endocrine
- malignancy
- drug induced
- renal disease
- nutritional
- age
How is osteoporosis diagnosed?
Measurement of bone mineral density (BMD)
Measurement made by dual energy X-ray absorptiometry (DEXA or DXA) scan, uses two x-ray machine, compare results
In healthy person bone density peaks at 25-35
0 SD mean you have the same bone mass as a young adult based on population averages. Expected rate with age drops
T score
- Number of SDs below average for young adult at peak bone density
Z score
- Matched to age and/or group
Normal T score: of –1 or above
Osteopenia: T-score lower than –1 and greater than –2.5
Osteoporosis: T-score of –2.5 or lower
Severe Osteoporosis: T-score of –2.5 or lower and presence of at least one fragility fracture.
What are the endocrine causes of osteoporosis?
Hypogonadism – cause of oestrogen deficiency - in males or females. More common in females that are post-menopausal because oestrogen levels drop and incidence of osteoporosis increases
Excess glucocorticoids – endogenous or exogenous e.g due to Cushing’s which if untreated can cause osteoporosis or glucocorticoid therapy maintained for too long
Hyperparathyroidism – elevated levels of parathyroid hormone leads to excess resorption over bone formation
Hyperthyroidism – increases bone metabolism and can also if untreated be a risk factor for osteoporosis.
What are the risk factors for accelerating the rate of bone loss?
- A los peak in the peak bone mass during growth and development, don’t achieve healthy average. Bone loss continues, starting from lower peak.
- Early menopause, before 45, results in increased rate of bone loss, possibly leading onto osteoporosis
- Following normal menopause some women lose bone mass at faster rate than others - greater risk of osteoporosis
What are the treatments for osteoporosis?
Ensure adequate calcium and vitamin D intake
Postmenopausal HRT
Bisphosphonates - risedronate, alendronate
PTH analogues
Denosumab - human monoclonal antibody against Rank Ligand
Romosozumab - human monoclonal antibody against sclerostin
How does bisphosphonates treat osteoporosis?
Inhibits function of osteoclasts
Reduces rate of bone turnover / osteoclast involement in bone resportion
issue - bone remodelling is supposed to happen, so concerns about prolonged use could still lead to boen changes due to lack of remodelling
first line of treatment
How do PTH analogues treat osteoporosis?
PTH usually icnreases bone remodelling, but depends on levels
Moderate levels promote bone remodelling, increase in bone resorption and formation
Prolonged high PTH leads to increased resorption, resorption part predominates over formation
How does romosozuman treat osteoporosis?
A human monoclonal antibody against sclerostin, protien which puts break on WNT signalling, therefore stops osteoblast differentiation.
Antagonising this proteins redcues available levels of protein, takes break off
promotes bone formation
anabolic
What is osteomalacia?
Loss of bone mineralisation (rickets in children) - makes bones soft and malleable
Less common than osteoporosis - which is loss of bone mineralisation and bone matrix.
What are the signs and symptoms of osteomalacia?
Permanent deformities in bone growth (rickets) if left untreated
Diffuse aches and pains
Weak bones , difficulty in walking in adults
Low plasma Ca, Pi
Elevated alkaline phosphatase, an enzyme that is a marker of bone turnover.
PTH may be elevated, secondary to low calcium.
What are the causes of osteomalacia?
Vitamin D deficiency (most common), lack of sunlight and supplementation is common cause in kids, also in elderly adults that don’t go out as much
Mutations leading to errors in vitamin D metabolism (Rare)
Hypophosphatemia
Treatment most commonly involves ensuring adequate vitamin D and Ca
Why is hypocalcaemia a hallmark of conditions involing vitamin D deficiency?
Because vitamin D promotes calcium and phosphate absorption from the gut.
In lab results of osteomalacia you would expect:
- Hypocalcaemia
- With some degree of hypophosphataemia
- Mediate precursor of 1,25(OH)2D3 low so vit D low
Where is the main circulating precursor of vitamin D3 catalysed?
What increases and decreases the reaction?
25 OH D3 catalysed in kidneys by alpha hydroxylase enzyme, product is active form. - Calcitriol 1,25(Oh)2D3
Reaction is increased by
- PTH
- Low plasma Ca
- Low plasma Pi
Decreased by / downregulated by
- FGF-23 from osteocytes
- High plasma Ca
- High plasma pi
Why is there high PTH in osteomalacia and hypocalcaemia?
Secondary hyperparathyroidism due to the low calcium.
Vitamin D deficiency elevated PTH, secondary to the low calcium because the low calcium is what stimulates PTH production, which is how PTH is controlled in negative feedback loop with plasma Ca conc.
What are the two rare mutations that cause vitamin D dependent rickets?
Type 1 - 1 alpha hydroxylase mutation
1a hydroxylase mutation imapcts calcitriol production, active form is not being made/at low levels
- low calcium and phosphate
- high PTH levels in response to high calcium
Type 2- vitamin D receptor mutation , makes it less sensitive to vitamin D binding
- Vit D precursor levels normal
- Calcitriol high - low ca and pi stimulates calcitriol production as a normal response
- calcitriol ineffective due to receptor mutation
- PTH high - secondary hyperparathyroidism
What are three examples of rare conditions that lead to low calcium, phosphate and osteomalacia?
X-linked hypophosphatemia rickets
Autosomal domiannt hypophosphatemia rickets
- both genetic, caused by single gene mutations
Oncogenic osteomalacia via benign tumour
in common:
- FGF-23 is elevated, high in all of them
- Leading to low phosphate
- Excess FGF-23 either due to a mutation or in oncogenic osteomalacia it is ectopic FGF-23 secretion through a benign tumour.
- calcium and calcitriol can be normal or low
- FGF-23 is inhibiting calcitriol but low phosphate os stimulating factor for calcitriol,hence may be normal levels
- low calcium promotes PTH producion -but calcitriol may not be signicantly reduced and PTH may be normal
What are the levels of calcium and phosphate in bone disease and renal failure?
Low calcium
Low Pi
Nomral precursor 25 OH D3
low calcitriol
high PTH
