Calcium and Phosphate Metabolism Flashcards
Bone turnover serves as homeostasis of serum calcium and phosphate, in conjunction with …?
- Parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
Briefly, describe calcium homeostasis.
99% of body calcium is in bone, the remaining 1% is mainly intracellular.
Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance.
Extracellular: plasma Ca 2.2-2.6 mmol L-1
About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin).
Describe phosphate hoemostasis.
85% of body phosphorus is found in bone, the remainder is mainly intracellular.
Extracellular: H2PO4-, HPO42-, 2.5-4.5 mg dL-1 (0.75-1.45 mmol L-1).
Phosphate levels may fluctuate more than Ca.
List some clinical features of hypercalcemia.
- 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
List some causes of hypercalcemia.
MOST COMMON CAUSES
In ambulatory patients: primary hyperparathyroidism
In hospitalized patients: malignancy
LESS COMMON CAUSES:
Hyperthyroidism
Excessive intake of vitamin D
Describe the serum biochemistry of hyperparathyroidism.
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
Describe hypercalcemia of malignancy.
It is the most common cause of hypercalcemia in hospitalised patients. The malignancy can be:
- humoural (e.g. lung carcinoma secreting PTHrP)
- metastatic
It can also have a haemotological cause (myeloma).
List some causes of hypocalcemia.
MOST COMMON CAUSES:
- Vitamin D deficiency
- Renal failure
LESS COMMON CAUSES:
- Hypoparathyroidism
What is the difference between rickets and osteomalacia?
It is a bone disease associated with vitamin D deficiency.
RICKETS - in children, failure of bone mineralisation and disordered cartilage formation
OSTEOMALACIA - in adults, impaired bone mineralisation
What are some features of osteomalacia?
- Diffuse bone pain
- Waddling gait, muscle weakness
- On X-ray, stress fractures
Serum biochemistry:
- Low/normal calcium
- Hypophosphataemia
- Raised alkaline phosphatase
What is the difference between osteoporosis and osteomalacia?
OSTEPOROSIS: loss of bone mass/density due to:
- endocrine
- malignancy
- drug-induced
- renal disease
- nutritional
OSTEOMALACIA: loss of bone mineralization
How would you diagnose osteoporosis?
You would measure bone mineral density (BMD) using dual-energy X-ray absorptiometry (DEXA or DXA scan).
Two beams are used: one to measure thickness of bone and one to measure density.
T SCORE:
- number of SDs below average for young adult at peak bone density
Z SCORE:
- matched to age and/or group
List some endocrine causes of osteoporosis.
- Hypogonadism – notably any cause of oestrogen deficiency
- Excess glucocorticoids – endogenous or exogenous
- Hyperparathyroidism
- Hyperthyroidism
What are some treatments for osteoporosis?
Postmenopausal: HRT (hormone replacement therapy) – effects well established but safety of long term treatment has been questioned
Bisphosphonates – inhibit function of osteoclasts: risedronate, alendronate
PTH analogues
Denosumab – antibody against RANK ligand
Ensure adequate calcium and Vitamin D intake, appropriate exercise
After long research and study, what are the modified HRT guidelines?
- Short-term therapy (3-5 years) for treating vasomotor symptoms
- Lowest effective dose to be used
- Long term use not recommended
What are some clinical features of osteoporosis?
- loss of bone density
- increased fracture risk
- increase in bone resorption over formation
Briefly, describe the bone remodelling cycle.
Microdamage or mechanical stress stimulates the recruitment, differentiation and activation of osteoclasts that resorb the damaged bone.
Osteoclasts die by apoptosis, and osteoblasts migrate to the area of resorbed bone and replace it with unmineralised osteoid, which then becomes mineralised.
What components are important in the induction of osteoclast differentiation by RANK ligand?
RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts, stimulates osteoclast differentiation.
RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes; binds to RANK and stimulates osteoclast differentiation.
OPG (osteoprotogerin): decoy receptor produced by osteocytes; binds to RANK-L, preventing activation of RANK.
Describe the Wnt signalling pathway.
Wnt is a family of protein signalling molecules important in development throughout the animal kingdom. It is complex and highly conserved.
The receptor is called frizzled, which requires a co-receptor, low-density lipoprotein receptor-related protein 5 (LRP5).
In adult animals, Wnt is involved in growth, differentiation and maintenance of many tissues, including bone.
It is required for osteoblast differentiation.
Wnt signalling is under negative control by various proteins, such as DKK (dickkopf) and sclerostin (SOST).
Describe the osteocyte regulation of bone remodelling (using the signalling pathway and ligands, etc.).
Osteocytes express RANKL and macrophage-colony stimulating factor (M-CSF) to promote, and OPG and NO to inhibit, osteoclast formation and activity.
Osteocytes also regulate bone formation via the secretion of modulators of the Wnt signaling pathway.
PGE2, NO, and ATP act to activate Wnt signaling, whereas sclerostin, DKK1, and SFRP1 all inhibit Wnt signaling and subsequent osteoblast activity.
Maintenance of this balance between resorption and formation by the osteocyte is essential for bone homeostasis.
