25. Calcium & Phosphate Metabolism Flashcards
Bone turnover serves as homeostasis of serum calcium and phosphate, in conjunctions with what other controls?
- Parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
Briefly, describe calcium homeostasis
- 99% of body calcium is in bone
- 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 homeostasis
- 85% of body phosphorus is in bone
- Remainder is mainly intracellular
- Extracellular: H2PO4-, HPO42-, 2.5-4.5 mg dL-1 (0.75-1.45 mmol L-1)
- May fluctuate more than Ca
List some clinical features of hypercalcaemia
- 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 hypercalcaemia.
COMMON:
- In ambulatory patients: primary hyperparathyroidism
- In hospitalized patients: malignancy
LESS COMMON:
- 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 hypercalaemia of malignancy.
Most common cause of hypercalcaemia in hospitalized patients
- Humoral, e.g., lung carcinoma secreting PTHrP
- Metastatic
Haematological
- myeloma
List some causes of hypocalcaemia
COMMON CAUSE:
- Vitamin D deficiency
- Renal failure
LESS COMMON CAUSES:
- Hypoparathyroidism
What is the difference between rickets and osteomalacia?
- 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
- Secondary hyperparathyroidism
What is the difference between osteoporosis and osteomalacia?
Osteoporosis: loss of bone mass:
- Endocrine
- Malignancy
- Drug-induced
- Renal disease
- Nutritional
Osteomalacia: loss of bone mineralization
How would you diagnose osteoporosis?
Measurement of bone mineral density (BMD). Dual-energy X-ray absorptiometry (DEXA or DXA scan)
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 – 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 vit 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 remodeling cycle
Microdamage or mechanical stress stiulates the recruitment, differentiation adn activation of osteoclasts that resorb the damaged bone.
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.
=> PGE2, NO, and ATP act to activate Wnt signaling
=> sclerostin (SOST), DKK1, and SFRP1 all inhibit Wnt signaling and subsequent osteoblast activity.
Describe the osteocyte regulation of bone remodeling (using the signalling pathways and ligands, etc.)
Osteocyte regulation of bone remodeling. 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.
