Calcium and Phosphate Metabolism Flashcards
Which mechanisms aid Calcium and phosphate balance?
Homeostasis of serum calcium and phosphate maintained via:
- Bone turnover
- Parathyroid hormone (PTH)
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
- FGF-23
How are calcium stores maintained in the short term?
Bone remodelling releases minerals esp. calcium into circulation, therefore can be controlled in short-term in
calcium homeostasis
Where is Ca found in the body?
99% of body calcium is in bone
Remaining 1% is mainly intracellular
Describe the significance of the hormonal control of calcium
Hormonal control of the tiny (<0.1%) extracellular fraction is what maintains Ca balance
Outline the normal extracellular calcium level
Extracellular: plasma Ca 2.2-2.6 mmol L-1
About half is free [Ca2+] (physiologically active), half protein bound (mainly albumin)
Where is phosphate found in the body?
85% of body phosphorus is in bone
Remainder is mainly intracellular
What are the normal extracellular phosphate levels?
Extracellular H2PO4-, HPO42-
- 5-4.5 mg dL-1
(0. 75-1.45 mmol L-1)
May fluctuate more than Ca
What is hypercalcaemia?
Excessive Ca2+
Outline the 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
What are the most common causes of hypercalcaemia?
In ambulatory patients
- primary hyperparathyroidism
In hospitalized patients
- malignancy
What are the less common hypercalcaemia causes?
Hyperthyroidism
Excessive intake of vitamin D
Where is PTH found in the body?
PTH synthesized and secreted by parathyroid glands (4 small glands located behind the thyroid)
What is hyperparathyroidism?
Hyperparathyroidism is typically a benign tumour of one (or more) of the 4 glands, causing increased PTH levels ⇒ increased serum Ca2+
How is the serum biochemistry altered in hypercalcaemia?
Calcium - modest / marked increase
Phosphate - low / low normal
Alkaline phosphatase raised in ~ 20% of cases
Creatinine may be elevated in long standing disease (kidney damage)
[PTH] should be interpreted in relation to calcium - inverse relationship
What is alkaline phosphatase?
Enzyme found in the liver, bone and many other tissues
What causes increased levels of alkaline phosphatase?
In presence of bone disease may be elevated due to increased bone turnover
What is hypercalcaemia of malignancy?
(HCM) - condition in cancer patients defined when serum calcium level (corrected for albumin) is > 2.6 mmol/L
Describe humoral hypercalcaemia of malignancy
Humoral
e.g., lung carcinoma secreting PTHrP
PTHrP secreted by tumor cells and binds to PTHr ⇒ hyperparathyroidism
Can cause bone lesions in hospitalised patients
How does metastatic hypercalcaemia of malignancy occur?
Tumour cells release cytokines promoting osteoclast differentiation = bone resorption
What causes haematological hypercalcaemia of malignancy?
Myeloma of plasma cells secreting osteoclastogenic cytokines e,g, RANKL
What are the most common causes of hypocalcaemia?
Vitamin D deficiency
Renal failure
What are the less common causes of hypocalcaemia?
Hypoparathyroidism
What are rickets / osteomalacia?
Bone disease associated with vitamin D deficiency
What is rickets?
Rickets - in children, failure of bone mineralisation and disordered cartilage formation
What is osteomalacia?
Osteomalacia - in adults, impaired bone mineralisation that lead to bone lesions
loss of bone mineralization - thinning of trabecular mesh and cortical bone
Describe the features of osteomalacia
Diffuse bone pain
Waddling gait, muscle weakness
On X-ray, stress fractures
Describe the serum biochemistry of osteomalacia patients
- Low/normal calcium
- Hypophosphatemia
- Raised alkaline phosphatase
- Secondary hyperparathyroidism: -ve feedback from low Ca2+ causes inc. PTH release
What is osteoporosis?
Metabolic bone disease causing loss of bone mass - asymptomatic
What are the causes of osteoporosis?
Endocrine Malignancy Drug-induced Renal disease Nutritional
What are the signs of osteoporosis?
common presentation of fragility fractures (wrist /hip)
How is osteoporosis diagnosed?
Measurement of bone mineral density (BMD)
Dual-energy X-ray absorptiometry (DEXA or DXA scan)
What does a T score tell us?
Number of SDs below average for young adult at peak bone density
What does a Z score tell us?
Matched to age and/or group
Outline the different T scores for varying stages of bone disorders
Normal
- T score of > -1
Osteopenia
- T score of > 2.5 and < -1
Osteoporosis
- T score of < -2.5
Severe osteoporosis
- T score of < -2.5
- presence of a fragility fracture
What increases the natural risk of developing bone disorders?
Likelihood of developing osteopenia and later osteoporosis increases with age
What are the endocrine causes of osteoporosis?
Hypogonadism – notably any cause of oestrogen deficiency
Excess glucocorticoids – endogenous or exogenous
Hyperparathyroidism
Hyperthyroidism
What is the effect of oestrogen on bones?
Oestrogen inhibits bone resorption
osteoblasts > osteoclasts
favours formation
What is the effect of oestrogen deficiency on bone remodelling?
Osteoclast apoptosis is regulated by oestrogens
With deficiency osteoclasts live longer and able to resorb more bone
How does oestrogen levels change in women at different stages?
Growing follicles are the source of oestrogen
Menopause:
No more follicles; no more oestrogens
Remaining oestrogen levels in women is dependent on peripheral aromatase conversion
What is a common postmenopausal osteoporosis treatment?
HRT – effects well established but safety of long term treatment has been questioned
Give examples of osteoporosis treatments
- HRT
- Bisphosphates
- PTH analogues
- Denosumab
- Romosozumab
- Exercise, VIt. D and Ca
How do bisphosphates work in osteoporosis treatment?
Inhibit osteoclasts function
e.g. risedronate, alendronate
How are PTH analogues administered to counteract osteoporosis?
Intermittent doses at modest level promote ‘good’ bone remodeling (not excess osteoclast > osteoblast)
What is denosumab?
Human monoclonal antibody against RANK ligand
What is Romosozumab?
Antibody against sclerostin protein promoting osteoblast differentiation
How does exercise reduce osteoporosis effects?
Exercise (walking) creates stresses on the skeletal structure detected by osteocytes which regulate bone remodelling (more exercise = osteoblast > osteoclast)
Outline the HRT guidelines
Short-term therapy (3-5 years) for treating vasomotor symptoms
Lowest effective dose to be used
Long term use not recommended
What is the role of osteoblasts in bone remodelling?
Osteoblasts lay down new bone (osteoids) where old bone has been dissolved by osteoclasts
What is RANK?
RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts, stimulates osteoclast differentiation
Where is RANK-L produced?
RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes
What is the role of RANK-L?
Binds to RANK and stimulates osteoclast differentiation
What is OPG?
Osteoprotegerin is a decoy receptor produced by osteocytes
What is the role of OPG?
Binds to RANK-L, preventing activation of RANK
- commonly used against osteoporosis etc.
Which pathway regulates osteoblast differentiation?
Wnt Signalling Pathway
How is the Wnt signalling pathway mediated?
Negatively regulated by DKK (dickkopf) and sclerostin (SOST)
What is Wrt?
Wnt is a family of protein signalling molecules important in development throughout the animal kingdom
What is the Wrt receptor?
The receptor is called frizzled, which requires a co-receptor, Low-density lipoprotein receptor-related protein 5 (LRP5)
