Metabolic bone disease

Question 1

Where is most of the calcium stored?

Answer 1

• 99% of body calcium is in bone and teeth
• Remainin 1% is mainly IC (in SR)
• hormonal control of the tiny EC fraction (<0.1%) is what maintains Ca balance (what we measure)

Question 2

What is calcium needed for?

Answer 2

Signalling for NT release and muscle contraction

Bone density

Question 3

How is calcium distributed in plasma?

Answer 3

• Half free ions (physiologically active form)

- half protein bound

Question 4

What are osteoblasts?

Answer 4

• Differentiate from mesenchymal stem cells
• Bone forming cells - lay down organic bone matrix (osteoid), promote mineralisation of osteoid
• Life cycle determined by control of differentiation and apoptosis

Question 5

What are osteoclasts?

Answer 5

• Derived from HSCs
• Resorption of bone - secrete acid to dissolve and release mineral content; enzymes to degrade organic matrix
• Life cycle determined by control of differentiation and apoptosis

Question 6

What are osteocytes?

Answer 6

• terminally differentiated, post-mitotic osteoblasts
• Entombed within lacunae in the bone matrix
• Communicate with each other and bone surface via cellular processes (dendrites), which run along canaliculi
• Lacunar-canaliculi network
• may live for decades

Question 7

How is remodelling controlled?

Answer 7

• Favouring resorption - bedrest, zero-gravity etc
• Favouring formation - load-bearing exercise
• Osteocytes can detect mechanical stress during load bearing exercise using canaliculi network
• Can adjust secretion of RANKL (differentiation of osteoclasts), osteoprotegerin (blocks RANK), sclerostin (inhibits bone formation - reducing sclerostin = increase osteoblast differentiation)

Question 8

What bone diseases are there?

Answer 8

• Osteoporosis - generalised loss of bone density (thin bones)
• osteomalacia - loss of bone mineralisation (soft bones)
• Paget’s disease - imbalance in remodelling cycle in specific localised sites - isolated lesions

Question 9

What hormones act on bone?

Answer 9

• PTH
• Vit D
• Calcitonin

Question 10

What is PTH?

Answer 10

• Secreted by PT gland.
• Secreted in low Ca2+ conc
• As Ca levels rise, more CaSR are stimulate on the bone PT gland, decreasing PTH secretion

Question 11

What does PTH act on?

Answer 11

• kidney - increases calcium reabsorption, decreases phosphate reabsrption
• Bone - increases bone resorption by increasing osteoclast activity
• Also has anabolic effects therapeutically to treat osteoporosis
• Gut - increases calcium absorption via vit D

Question 12

What is Vit D?

Answer 12

• Calcitriol (steroid hormone rather than vitamin)
• Synthesised in skin in response to UV
• Activated by 2 metabolic steps - 25 hydroxylation in liver to form calcidiol; 1alpha hydroxylation of calcidiol in kidney to form calcitriol
• Calcitriol increases intestinal absorption of dietary calcium

Question 13

What is calcitonin?

Answer 13

• 32 AA peptide
• Secreted by C cells of thyroid
• Secreted in high Calcium conc
• Acts on:
• Kidney - decreases calcium and phosphate reabsorption
• Bone - decreases bone resorption by inhibiting osteoclasts
• Synthetic calcitonin used for Paget’s

Question 14

What are the main causes of hypercalcaemia?

Answer 14

• > 2.6mM
  Commonest
• primary hyperPT
• Malignancy

Less common

• Hyperthyroidism
• Excessive intake of Vit D

Question 15

What are the clinical features of hypercalcaemia?

Answer 15

• Renal calcification (kidney stones)
• Abdominal pain, constipation
• Anorexia, nausea, vomiting, depression, fatigue
• Bone pain in malignancy or hyperPT
• Cardiac arrhythmias, cardiac arrest

Bones, stones and psychic moans

Question 16

What is primary hyperparathyroidism?

Answer 16

• Usually due to benign adenoma
• Most common in post-menopausal women
• Often detected on screening - many asymptomatic
• ~10% of patients present with clinical evidence of bone disease
• 10-20% with kidney stones

Question 17

What would the blood results be in primary hyperPTism?

Answer 17

• Calcum increased
• Phosphate low or normal
• ALP raised in 20% (increased ALP = increased bone turnover)
• Creatinine may be elevated in longstanding disease
• PTH interpreted alongside calcium

Question 18

What malignancies can lead to hypercalcaemia?

Answer 18

• PTH-rp - secreted by lung or renal carcinoma (activates PTH receptors)
• Solid tumours with bone metastases
• Haematological malignancy (myeloma) - release cytokines to activate RANK

Question 19

What will PTH levels be like in malignancies?

Answer 19

• should be appropriately suppressed as cause of hypercalcaemia is elsewhere

Question 20

What is hypocalcaemia?

Answer 20

• Low calcium
• Vit D deficiency (low intake/lack of sun)
• Renal failure - loss of 1alpha hydroxylase -> decreased active Vit D conversion -> decreased Ca -> increased PTH -> no more Ca can be absorbed from gut as no vit D -> bone resorption and damage
• failure of acid-base regulation - decreased H+ excretion -> metabolic acidosis -> bone erosion
• HypoPTH - not common, caused by thyroid surgery or congenital