Calcium and phosphate metabolism Flashcards
What does bone turnover serve and in conjunction with what?
• Bone turnover serves homeostasis of serum calcium and phosphate, in conjunction with:
○ Parathyroid hormone (PTH)
○ Vitamin D (1,25-dihydroxy D3)
○ Calcitonin
○ FGF-23What does FGF-23 lower?
Lowers serum phosphate levels
What does bone remodelling release in the short term?
In the short term, bone remodelling releases minerals, notably calcium, into the circulation
What percentage of body calcium is in bone?
• 99% of body calcium is in bone
Where is 1% of calcium mainly found?
Mainly found intracellularly
What is normal plasma Ca levels?
plasma Ca 2.2-2.6 mmol L-1
How is extracellular calcium found?
• About half of extracellular is free [Ca2+] (physiologically active), half protein bound (mainly albumin)
What does PTH increase?
Increases bone remodelling
How is PTH at low doses?
○ At low doses, PTH is anabolic: promotes formation of new bone
What happens when there is prolonged higher levels of PTH and what does this result in?
Prolonged higher level = excess of resorption over formation
Results in rise in extracellular calcium
What does a persistent raised level of PTH result in and why?
§ Persistent raise
Results in hypercalcaemia because it promotes/increases resorption of Ca from kidney tubule
What does PTH lower?
Lowers phosphate
What does PTH increase expression of what is it responsible for?
○ Increases expression α hydroxylase enzyme that is responsible for converting precursor of vitamin D to 1,25 dihydroxy D3
What percentage of body phosphorous is found in the bone and in what form?
• 85% of body phosphorus is in bone
-Mainly in the form of hydroxyapatite
What is normal levels of phosphate extracellularly?
2.5-4.5 mg dL-1
Why do phosphate levels fluctuate more than calcium levels?
Less tightly controlled
What are clinical features of hypercalcaemia?
• May be asymptomatic for a while
• Depression, fatigue, anorexia, nausea, vomiting,
• Abdominal pain, constipation
• Renal calcification (kidney stones)
• Bone pain
○ “painful bones, renal stones, abdominal groans, and psychic moans”
• Severe: cardiac arrhythmias, cardiac arrest
What is the most common cause of hypercalcaemia in ambulatory patients?
primary hyperparathyroidism
§ Involves benign tumour of one or more of the parathyroid glands
§ parathyroid tumour = excess PTH = excess resorption = high calcium
What is the cause of hypercalcaemia in hospitalised patients?
Malignancy
What are the less common causes of hypercalcaemia?
○ Hyperthyroidism
○ Excessive intake of vitamin D
Serum biochemistry in hypercalcaemia
- Serum calcium - modest to marked increase
- Serum phosphate - low or low normal
- Serum alkaline phosphatase raised in ~ 20% of cases
- Serum creatinine may be elevated in longstanding disease (kidney damage)
- Serum PTH concentration should be interpreted in relation to calcium
What is the most common cause of hypercalcaemia in hospitalised patients?
• Most common cause of hypercalcaemia in hospitalized patients
○ Humoral, e.g., lung carcinoma secreting PTHrP
○ Metastatic
○ Haematological
§ Myeloma
What is the most common cause of hypocalcemia?
- Vitamin D deficiency
- Renal failure
What are the less common causes of hypocalcemia?
Hypoparathyroidism
What does vitamin D promote and what does a lack of it cause?
Promotes calcium uptake so lack of it causes hypocalcemia
What are rickets in children?
Failure of bone mineralisation and disordered cartilage formation
What is osteomalacia in adults?
Impaired bone mineralisation
What are the features of osteomalacia?
- Diffuse bone pain
- Waddling gait, muscle weakness
- On X-ray, stress fractures
What is the serum biochemistry of osteomalacia?
○ Low/normal calcium
○ Hypophosphataemia
○ Raised alkaline phosphatase
○ Secondary hyperparathyroidism
What is osteoporosis?
- loss of bone mass/density
- Increase in bone resorption over formation
What are the causes of osteoporosis?
○ Endocrine ○ Malignancy ○ Drug-induced ○ Renal disease ○ Nutritional ○ Age-related
What is there an increased risk of in osteoporosis?
Increased fracture risk
What is osteomalacia?
loss of bone mineralization
What do we measure for the diagnosis of osteoporosis?
Measurement of bone mineral density (BMD)
What scan do we use in the diagnosis of osteoporosis?
• Dual-energy X-ray absorptiometry (DEXA or DXA scan)
What is the T score?
Number of SDs below average for young adult at peak bone density
What is the Z score?
A Z-score compares your bone density to the average values for a person of your same age and gender.
What are the endocrine causes of osteoporosis?
• Hypogonadism – notably any cause of oestrogen deficiency
○ Oestrogen is essential for bone health
○ Needed in males as well
○ inactivation of aromatase enzyme in men leads to failure of oestrogen production = osteoporosis
• Excess glucocorticoids – endogenous or exogenous
• Hyperparathyroidism
• Hyperthyroidism
What are the different treatments for osteoporosis?
- HRT
- Bisphosphonates
- PTH analogues
- Denosumab
What do bisphosphonates do?
inhibit function of osteoclasts leading to inhibition of bone resorption
What is Denosumab?
An antibody against RANK ligand
What is RANK and what does it stimulate?
○ Surface receptor on pre-osteoclasts
○ Stimulates osteoclast differentiation
What are RANK ligands produced by?
○ Produced by pre-osteoblasts, osteoblasts and osteocytes
What do RANK ligands do?
○ Bind to RANK and stimulates osteoclast differentiation
What is OPG and what is it produced by?
○ Decoy receptor produced by osteocytes
How do OPG works?
Binds to RANK-L, preventing activation of RANK
What determines osteoclast differentiation rate?
Ratio of RANK-L to OPG is what determines osteoclast differentiation rate
What is wnt signalling pathway required for?
• Required for osteoblast differentiation
What is the wnt signalling pathway negatively regulated by and how?
Negatively regulated by DKK (dickkopf) and sclerostin (SOST)
-Interact with LRP5 receptor preventing interaction
Steps involved in WNT signalling pathway
- WNT has GPCR
○ Frizzled
○ Requires co-receptor – LRP5/6
○ Both of these interact to activate WNT signaling - Effector: beta-catenin
○ Locked in a network of interacting proteins until WNT binds - Binding causes complex set of events freeing β-catenin
4.Beta-catenin accumulates in cytoplasm and translocates to nucleus where it initiates transcription
What is sclerostin highly expressed in?
Sclerostin (SOST) is highly expressed in osteocytes
How does sclerostin work?
○ Secreted, makes its way to surface
○ Prevents osteoblast differentiation
What must be downregulated for bone formation?
○ Must downregulate RANK-l secretion and SOST to allow osteoblast differentiation
What must be upregulated to resorb bone?
○ Upregulate RANK-l and SOST to prevent osteoblast differentiation
