29- Calcium & Phosphate Metabolism

Question 1

maintaining plasma calcium & phosphate - parathyroid hormone/PTH?

Answer 1

PTH is secreted by parathyroid glands in response to low plasma calcium

increases blood calcium levels
- activates osteoblast bone resorption = promotes bone remodelling = release of calcium & phosphate
- increases calcium gut absorption by increasing vit. D to calcitriol conversion
- decreases calcium renal excretion

decreases blood phosphate levels
- increasing renal phosphate excretion

Question 2

maintaining plasma calcium & phosphate - vitamin D?

Answer 2

increases calcium and phosphate levels
- active vit. D form/ calcitriol increases Ca2+ gut absorption
- negative feedback mechanism with PTH = more Ca2+ gut absorption= increases plasma Ca2+ = decreases PTH
- promotes bone mineralisation and bone resorption = release of calcium & phosphate
- enhances renal calcium & phosphate reabsorption

Question 3

maintaining plasma calcium & phosphate - FGF23?

Answer 3

high phosphate stimulates FGF23 secretion from osteocytes

mainly decreases blood phosphate levels
- increases renal excretion
- decreases intestinal absorption by inhibiting active vit. D synthesis

decreases calcium absorption
- decreases active vit. D synthesis for Ca2+ gut absorption

Question 4

calcium & phosphate level maintenance - interactions with PTH, FGF23, vitamin D?

Answer 4

PTH released by parathyroid gland with low plasma Ca2+
- increases bine resorption to release calcium & phosphate
- enhances renal reabsorption of calcium
- increases renal phosphate excretion
- stimulates active Vit. D production to enhance calcium gut absorption
= increases calcium, decreases phosphate levels

FGF23 released from osteocytes with high phosphate
- secondary actions decrease calcium gut absorption by decreasing active vit. D synthesis
- mainly decreases phosphate by increasing renal phosphate excretion

vit D converted into active calcitriol to enhance calcium gut absorption
-PTH stimulates vit. D conversion = enhances calcium & phosphate gut absorption
- FGF23 inhibits vit. D conversion = reduces calcium & phosphate

Question 5

what is osteoporosis?

Answer 5

loss of bone mass (mineral and organic matrix)

Question 6

osteoporosis - causes?

Answer 6

endocrine causes

malignancy/ certain cancers

drug-induced
- chronic use of glucocorticoids
- anticonvulsants, aromatase inhibitors, heparin

renal disease
- leads to chronic imbalance in Ca2+ & phosphate metabolism, affects bone health

nutritional factors
- calcium & vit. D deficiencies
- poor diet

age
- post-menopausal women have decreases oestrogen which is important for bone health
- increase in bone resorption over formation with ageing

Question 7

osteoporosis - describe endocrine causes?

Answer 7

hypogonadism - causes of oestrogen deficiency (e.g. menopause)

excess glucocorticoids - endogenous (eg. Cushing’s syndrome) or exogenous (chronic therapy)

hyperparathyroidism - excessive PTH production, increases bone resorption

hyperthyroidism - excess TH levels, increases bone turnover

Question 8

osteoporosis - diagnosis?

Answer 8

bone mineral density/ BMD measurement using dual-energy X-ray absorptiometry/ DEXA or DXA scan

T-score indicates number of SDs a patient’s BMD is below average by for young adult at peak bone density - osteoporosis indicated by T-score ≤ -2.5

Z-score = compares patient BMD to average BMD of same age, sex, ethnicity

Question 9

osteoporosis - treatment?

Answer 9

ensure adequate vitamin D & calcium intake appropriate exercise to strengthen bones

hormone replacement therapy for post-menopausal women = replace oestrogen

biphosphates = inhibit osteoclast-mediated bone resorption

PTH analogues = stimulate bone formation, increases calcium

Denosumab = human monoclonal antibody against RANKL - reduces bone resorption

Romosozumab = human monoclonal antibody against sclerostin - promotes bone formation

Question 10

what is osteomalacia?

Answer 10

loss of bone mineralisation - called rickets in children

Question 11

osteomalacia - signs/ symptoms?

Answer 11

permanent deformities in bone growth
diffuse aches & pains
chronic fatigue
weak bones

Question 12

osteomalacia - expected biochemical results?

Answer 12

low calcium and phosphate - hypocalcaemia and hypophosphatemia

high alkaline phosphatase (indicates defective mineralisation)

low levels of intermediary vit. D precursors - expected with vit. D deficiencies

high PTH = secondary hyperparathyroidism from low Ca2+ levels

Question 13

osteomalacia - causes?

Answer 13

vitamin D deficiency = most common cause = reduced calcium & phosphate absorption

mutations leading to errors in vit. D metabolism

hypophosphataemia = low blood phosphate levels, can be a result of excess FGF-23

Question 14

osteomalacia - treatment?

Answer 14

vitamin D & Ca2+ supplements to correct deficiencies and support bone mineralisation

Question 15

reasons behind osteomalacia and hypocalcaemia?

Answer 15

vit. D dependent type 1 rickets - mutations affecting vit. D metabolism = affects synthesis of active vit. D for Ca2+ gut absorption

type 2 - mutations in vit D receptor, affects vit. D activity in increasing Ca2+ gut absorption

Question 16

vitamin D dependent rickets type 1 - what is it? biochemical results? specialised treatment?

Answer 16

mutations affecting vitamin D metabolism - e.g. 1-alpha-hydroxylase mutation

biochemical results: low calcium, phosphate, very low 1,25 (OH)2 D3, high PTH

treatment: with active forms of vitamin D

Question 17

vitamin D dependent rickets type 2 - what is it? specialised treatment?

Answer 17

mutations affecting vit. D receptor

treatment with high doses of calcitriol and calcium

Question 18

what factors increase vitamin D synthesis?

Answer 18

increase PTH - stimulates vitamin D synthesis & conversion

low Ca2+ - stimulates PTH secretion

low phosphate - directly stimulates vit. D synthesis

Question 19

what factors decrease vitamin D synthesis?

Answer 19

FGF-23 secretion inhibits production of active vit. D

high Ca2+

high phosphate

Question 20

reasons behind osteomalacia and hypophosphatemia?

Answer 20

1. mutations leading to excess FGF-23 activity = increases phosphate renal excretion
2. ectopic FGF-23 secretion from benign tumours

both lead to hypophosphatemia and impaired bone mineralization

Question 21

disorders of phosphate balance (affecting FGF-23 secretion)?

Answer 21

oncogenic osteomalacia - tumour secreting FGF-23, increasing phosphate renal excretion

X-linked hypophosphatemic rickets

autosomal dominant hypophosphatemic rickets with gain-of-function mutations in FGF-23 gene

all lead to excessive renal phosphate excretion & rickets

Question 22

renal osteodystrophy - what is it?

Answer 22

a spectrum of bone disorders associated with chronic kidney disease

Question 23

renal osteodystrophy - biochemical results?

Answer 23

low calcium = reduce calcium gut absorption from impaired calcitriol synthesis

high phosphate = impaired renal phosphate excretion

high PTH = secondary hyperparathyroidism from impaired phosphate excretion (high phosphate, low calcium = high PTH) - causes excess bone resorption

low vit. D intermediary = kidneys are less capable of converting vitamin D to calcitriol via one of its precursors
- precursor formed in liver is at normal levels
- precursor formed at kidneys is low

acidosis = impaired renal H+ excretion, may promote bone resorption