Calcium and Phosphate Metabolism

Question 1

1. Bone turnover/remodelling serves as a short term service of calcium and phosphate homeostasis, what is this also in conjunction with?

Answer 1

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

FGF-23

Question 2

2. What % of body calcium is in the bone?

- Where is the remaining %

Answer 2

99%

Remaining 1% is mainly intracellular

Question 3

3. What percentage and amount of calcium is extracellular

- Is this bound (to albumin) or free?

Answer 3

Tiny (<0.1%) extracellular fraction
Plasma extracellular Ca is 2.2-2.6 mmol/L
Around half is free, half is bound

Question 4

4. What % of the bodies phosphorus is found in bone?

- What is the remainder of phosphorus?

Answer 4

85%

Remainder is mainly intracellular

Question 5

5. What levels fluctuate more, calcium and phosphate?

Answer 5

Phosphate

Question 6

6. What are the clinical features of hypercalcaemia?

Answer 6

Depression, fatigue, anorexia, nausea, vomiting,
Abdominal pain, constipation
Renal calcification (kidney stones)
Bone pain
“painful bones, renal stones, abdominal groans, and psychic moans,”

Question 7

7. What are some severe clinical features of hypercalcaemia?

Answer 7

cardiac arrhythmias, cardiac arrest

Question 8

8. What are the most common causes of hypercalcaemia?

Answer 8

In ambulatory patients: primary hyperparathyroidism

In hospitalised patients: malignancy

Question 9

9. What are the less common causes of hypercalcaemia?

Answer 9

Hyperthyroidism

Excessive intake of vitamin D

Question 10

10. What is Alkaline phosphatase?

Answer 10

. Enzyme found in liver, bone and many other tissues. In presence of bone disease may be elevated due to increased bone turnover.

Question 11

11. What should the levels of plasma:
    -Calcium
    -Phosphate
    -Alkaline phosphatase
    -Creatinine
    -PTH
    be in a normal situation (ie the serum biochemistry)

Answer 11

• Serum calcium - modest to marked increase
• Serum phosphate (decreased reabsorption, increased excretion by PTH) - low or low normal.
• Serum alkaline phosphatase raised in ~ 20% of cases due to increased bone turnover etc.
• Serum creatinine may be elevated in longstanding disease (kidney damage)
• Serum PTH concentration should be interpreted in relation to calcium.

Question 12

12. If PTH is inappropriately normal and calcium levels are elevated –> What should you investigate for?

Answer 12

PTH inappropriately normal because they should be low if calcium is high
Investigate for hyperparathyroidism

Question 13

13. Case study:
    A 52 year old woman was investigated for
    suspected kidney stones.

Serum investigations:

Total calcium	2.82 mmol/L   (2.20 - 2.52)
Phosphate 0.69 mmol/L
(0.75 - 1.50)
Albumin 42 g/L  (35 - 48)
Alkaline phosphatase 135 U/L	 (30 - 100)
PTH	 7.3 pmol/L (1 - 6.9)
Creatinine 118 mol/L (60 - 110)

Explain these results

Answer 13

Hypercalcaemia (kidney stones) due to hyperparathyroidism.

Calcium HIGH
(PTH HIGH)
(Creatinine HIGH)

Question 14

14. What is the most common cause of hypercalcaemia in hospitalised patients
    (Hypercalcaemia of malignancy)

Answer 14

o Humoral, e.g., lung carcinoma secreting PTH related Peptide which acts on PTH receptors.

o Metastatic tumour (release cytokines that promote osteoclast differentiation for bone resorption).

o Haematological: myeloma (tumour originating in the haematopoietic stem cell lineage).

Question 15

15.What is the most common cause of hypocalcaemia?

Answer 15

Vitamin D deficiency Renal failure

Question 16

16. What is a less common cause of hypocalcaemia?

Answer 16

Hypoparathyroidism

Question 17

17. What is Rickets?

Answer 17

in children, failure of bone mineralisation of cartilaginous growth plates and disordered cartilage formation

Question 18

18. What is osteomalacia?

Answer 18

• in adults, impaired bone mineralisation of osteoid due to combination of low dietary intake and lack of sunlight exposure.

Question 19

19. Who is most at risk of osteomalacia?

Answer 19

: elderly in nursing homes and not taking supplements or breast-fed babies who are kept out of sunlight.

Question 20

20. What are some features of osteomalacia?

Answer 20

•Diffuse bone pain, waddling gait (way of walking caused by pelvic muscle weakness), muscle weakness, stress fractures (on x-rays).

Question 21

21. What is the serum biochemistry of osteomalacia?

Answer 21

Low/normal calcium, Hypophosphataemia (should increase)

Raised alkaline phosphatase, Secondary hyperparathyroidism

Question 22

22. What is osteoporosis?

Answer 22

health condition that weakens bones, making them fragile and more likely to break

Question 23

23. What are some features of osteoporosis?

Answer 23

oLoss of bone mass: endocrine, malignancy, drug-induced, renal disease, nutritional.
o Loss of bone density
increased fracture risk, increase in bone resorption over formation.

Question 24

24. Because osteoporosis is usually asymptomatic , how is one usually diagnosed with it?

Answer 24

a fragility (minor falls break bones) fracture in wrists/femur or vertebral fractures.

Question 25

25. What are some endocrine associated causes of osteoporosis?

Answer 25

* Hypogonadism: especially any cause of oestrogen deficiency | * Excess endogenous or exogenous glucocorticoids, Hyperparathyroidism or Hyperthyroidism.

Question 26

26. What is the difference between a T and Z score?

Answer 26

The T-score is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex. Its a number (SDs) The Z-score is a comparison of a person's bone density with that of an average person of the same age and sex

Question 27

27. How do we diagnose osteoporosis?

Answer 27

Measurement of bone mineral density (BMD) Dual-energy X-ray absorptiometry (DEXA or DXA scan)

Question 28

28. In terms of T score, what would be seen in: -Normal -Osteopenia -Osteoporosis -Severe Osteoporosis ??

Answer 28

Normal = T-score of -1 or above Osteopenia (naturally, with age) = T-score lower than -1 and greater than -2.5 Osteoporosis =T-score of -2.5 or lower Severe osteoporosis= T-score of -2.5 or lower, and presence of at least one fragility fracture

Question 29

29. When does bone density peak?

Answer 29

•Bone density peaks at 25-30 years old after which it declines, the decline is accelerated by menopause.

Question 30

30. How is bone mass for men different to bone mass for women

Answer 30

higher peak of bone density due to larger mass and no accelerated decline due to no menopause.

Question 31

31. Does the risk of osteoporosis increase with age?

Answer 31

Yes

Question 32

32. What is the treatment for osteoporosis?

Answer 32

1. Postmenopausal: HRT (hormone replacement therapy) – effects well established but safety of long term treatment has been questioned. 2. Bisphosphonates e.g. risedronate, alendronate – inhibit function of osteoclasts. 3. PTH analogues: intermittent dose and time-dependent favour remodelling. 4. Denosumab – antibody against RANK ligand (reduced osteoclast differentiation so reduced resorption). 5. Romosozumab (approved 2019, Japan, USA, EU). - antibody against sclerostin protein so increased osteoblast differentiation. 6. Ensure adequate calcium and vit D intake, appropriate exercise.

Question 33

33. What is the brief history of HRT? | * I dont know if we need to know this guys:) *

Answer 33

* 1947. US approves Premarin (conjugated equine oestrogen: PREgnant MAre's urINe) treatment of hot flushes * 1966. Feminine Forever by gynaecologist Robert Wilson promoting HRT as lifestyle choice * 1970s. Strong association between oestrogen therapy and endometrial cancer so HRT (oestrogen only) use declines. * 1980s. Combination HRT products (progestins added to counter proliferative effects of unopposed oestrogen on endometrium) use rises again (oestrogen-progesterone). * Preventative effect on BMD, osteoporosis and other claimed benefits: e.g., CV protection – evidence from experimental literature, but no large RCTs (randomised control trials). * HRT use peaks late 1990s (15 M women in USA)

Question 34

34 . Which randomised controlled trial took place for HRT?

Answer 34

o Women's Health Initiative (WHI) in USA,, Million Women Study in UK, 2002 preliminary results from WHI published o No CV protective effects (possibly the reverse). o Claimed significantly increased breast cancer risk followed by years of controversy and debate

Question 35

35 . What were the Overall Effects from WHI: % of women per year (all ages):

Answer 35

* Fracture risks reduced massively with hormone replacement therapy. * Cancer risk reduced with just oestrogen but increased with oestrogen-progesterone combined therapy.

Question 36

36. What is relative risk versus absolute risk?

Answer 36

If something you do triples your risk, then your relative risk increases 300%. Absolute risk is the size of your own risk (Media quotes only relative risk without absolute risk--> Can be misleading)

Question 37

37. What were further analysis of the WHI results? | - How were the guidelines for HRT modified because of this

Answer 37

• The original WHI participants were older, post-menopausal women (mean age of 64 and 10 years post-menopause). • Separate analysis of <10 or >10 yrs post-menopause suggested risks were reduced in earlier group. • Guidelines for HRT modified: o Short-term therapy (3-5 years) for treating vasomotor (blood pressure) symptoms. o Lowest effective dose is to be used and long term use is not recommended.

Question 38

38 . What do the NICE guidelines for HRT in 2015 state?

Answer 38

- > HRT is the most effective treatment for relief of vasomotor symptoms although other options, including non-pharmacological ones are available - > For most symptomatic. menopausal women, the benefits of HRT outweigh the risks

Question 39

39. Give an overview of the signal networks in bone remodelling?

Answer 39

* Osteocytes detect small/minor stress fractures and cause osteoclast recruitment, proliferation, differentiation. * Activated osteoclasts result in bone resorption (digestion and release of minerals) before they die by apoptosis. * Osteoblasts are recruited to the area of resorbed bone and they replace it with osteoid which is then mineralised.