Calcium and phosphate metabolism

Question 1

Why is bone turnover important?

Answer 1

for homeostasis of serum calcium and phosphate

Question 2

What affects homeostasis of serum calcium and phosphate?

Answer 2

Parathyroid hormone (PTH)
Vitamin D (1,25-dihydroxy D3)
Calcitonin
FGF-23

Question 3

Distribution of body calcium

Answer 3

99% in bone

1% intracellular

<0.1% extracellular (2.2-2.6mmol/L)

Question 4

FGF-23

Answer 4

hormone promoting renal phosphate excretion by reducing Na-Pi absorption from proximal tubule

synthesised and secreted by osteocytes

Question 5

lifespan of FGF-23

Answer 5

FGF-23 has a short half-life and this half-life is regulated by enzymatic cleavage of the peptide into two inactive fragments.

Question 6

How does FGF-23 cause hypophosphataemic rickets?

Answer 6

The cleavage recognition site in hypophosphataemic rickets has a single amino acid substitution (mutation) that makes it unrecognisable and the peptide isn’t cleaved, remaining active and promoting excessive phosphate loss. This leads to impaired bone mineralisation and rickets.

Question 7

FGF-23 disorders

Answer 7

Oncogenic osteomalacia (tumour secreting FGF-23)
X-linked hypophophataemic rickets
Autosomal dominant hypopho-phataemic rickets (gain of function mutation)

Question 8

Causes of Hypercalcaemia in hospitals

Answer 8

Most common cause of hypercalcaemia in HOSPITALISED patients:

• humoral e.g. lung carcinoma secreting PTHrP (PTH-related peptide)
• metastatic
• haematological (e.g. myeloma)

Question 9

Most common causes of hypocalcaemia

Less common causes of hypocalcaemia

Answer 9

Vitamin D deficiency
Renal failure

Hypoparathyroidsim

Question 10

What is the most common cause of osteomalacia?

Answer 10

Vitamin D deficiency

-usually due to combination of low dietary intake and lack of exposure to sunlight

Question 11

Who is at risk of Vitamin D deficiency?

Answer 11

Elderly- if in nursing home and not taking supplements

Breast-fed babies kept out of sunlight

Question 12

What can vitamin D deficiency result in?

Answer 12

Rickets (in children)
-failure of bone mineralisation and disordered cartilage formation

Osteomalacia (in adults)
-impaired bone mineralisation (soft bones)

Question 13

Vitamin D-dependent rickets type I

Answer 13

Disease caused by a mutation of 1a-hydroxylase enzyme:

• normal levels of vitamin D precursor
• but low levels of active calcitriol
• calcium and phosphate will be low
• PTH will be high

Question 14

Vitamin D-dependent rickets type II

Answer 14

Disease caused by a mutation of vitamin D receptor:

• precursor levels will be normal
• calcitriol levels will be high, however not effective because it is not adequately activating its receptor
• calcium and phosphate will be low
• PTH will be high

Question 15

Hypophosphataemic rickets

Answer 15

rare phosphate-wasting (excessive phosphate excretion) condition leading to bone mineralisation defects (osteomalacia)

Question 16

Cause of hypophosphataemic rickets

Answer 16

• Mutation leading to excess FGF-23 activity

- Ectopic FGF secretion (benign tumour)

Question 17

clinical features of osteomalacia

Answer 17

· Diffuse bone pain
· Waddling gait, muscle weakness
· On X-ray, stress fractures

Question 18

Osteoporosis

Answer 18

loss of bone mass/density due to the thinning of both cortical bone and the trabecular mesh

Question 19

Serum biochemistry of osteomalacia

Answer 19

• Low/normal calcium
• Hypophosphataemia
• Raised alkaline phosphatase
• Secondary hyperparathyroidism (the low calcium would stimulate PTH release)

Question 20

Causes of osteoporosis

Answer 20

· Endocrine
· Malignancy
· Drug-induced
· Renal disease
· Nutritional
· Age

Question 21

Osteoporosis vs Osteomalacia

Answer 21

Osteoporosis:
-loss of bone mass/density

Osteomalacia:
-loss of bone mineralisation

Question 22

First sign of osteoporosis

Answer 22

sustaining a fracture, usually:

• wrist
• neck of the femur (hip)
• intervertebral

Question 23

Diagnosing Osteoporosis

Answer 23

Dual Energy X-Ray Absorptiometry Scan (DEXA or DXA)

-measures bone mineral density

Question 24

How does DEXA work?

Answer 24

Bone mineral density peak = 25 years old, thereafter it slowly declines. With DEXA, we achieve a T score by taking the average bone mineral density score for a young adult and then comparing it measured bone mineral density score.

The T score = the number of standard deviations below the average bone mineral density for a young adult at peak bone density (~25 yo):

• If you are 1 standard deviation below the average →osteopenia. This is nevertheless still a loss of bone density and does tend to occur with age
• If you are 2.5 standard deviations below the average →osteoporosis

Question 25

Endocrine causes of osteoporosis

Answer 25

· Hypogonadism- notably any cause of oestrogen deficiency · Excess glucocorticoids- endogenous or exogenous · Hyperparathyroidism · Hyperthyroidism

Question 26

Significance of oestrogen levels in osteoporosis

Answer 26

Significant for women because oestrogen production terminates at menopause. The remaining oestrogen will depend on the peripheral conversion of adrenal androgens via aromatase. after menopause, there is a slight acceleration in the decline of bone density. Typically their bone mineral density may decrease to the level within the osteopenia category. The curve for a male would be pretty similar, although without the slight acceleration due to menopause. But, essentially males also become more prone to osteoporosis with age, and will certainly get osteopenia.

Question 27

Treatments for Osteoporosis

Answer 27

Postmenopausal: · Hormone Replacement Therapy- safety of long-term treatment has been questioned Bisphosphonates · Inhibit function of osteoclasts (e.g. risedronate, alendronate) PTH Analogues · Intermittent doses of PTH promote good bone remodelling (raised prolonged doses of PTH tend to favour osteoclast activity for bone reabsorption) Denosumab · Antibody against RANK ligand Romosozumab · Antibody against sclerostin protein (which usually inhibits osteoblast differentiation) Ensure adequate calcium and vitamin D intake, appropriate exercise

Question 28

Effect of renal disease failure on bone

Answer 28

Decreased renal function: - Decreased activation of calcitriol - Decreased absorption of Ca - Increased PTH (secondary hyperparathyroidsim) which causes an excess of reabsorption over formation→bone erosion Increased PTH is probably doing more harm than good because its pathways for increasing Ca i.e. reabsorption from kidney tubule and activation of vitamin D are just not as effective. reduced H+ excretion, causing metabolic acidosis which causes bone erosion. As renal failure progresses it may lead to renal osteodystrophy.