Calcium, Phosphate and Bone

Question 1

Homeostasis and Functions of Calcium

Answer 1

1000 mg/day intake (25 mmol/day)

• bone as the main depot in the body (35000 mmol - 99% body Ca; bone remodelling)
• calcium carbonate supplement (40% elemental Ca)

Functions:

• strength of skeleton
• coagulation cascade
• maintain cellular membrane potential
• cardiac contractility and rhythm

Question 2

Calcium in circulation (1% body Ca)

Answer 2

*Ionised free Ca is the biologically active form (50% plasma Ca)

Ca bound to plasma albumin (40%)

Complexed with anions (10%)

Total plasma Ca RR: 2.1-2.55

Question 3

Albumin-adjusted Ca

Answer 3

Total plasma Ca measured includes free ionised Ca and albumin-bound Ca

• cheaper to measure
• changes in albumin will affect Ca measurement

Adjusted Ca = measured [Ca] + [(40-albumin in g/L) x 0.025]

–> inaccurate for extremes (<25 g/L or>50g/L) – need ionised Ca measurement

Ionised Ca

• specialised collection bottle, freeze after collection
• useful in massive derangement of albumin/ neonates with high AFP (same binding as albumin - less blood required, faster measurement)

Question 4

Manifestations of hyperCa and hypoCa

Answer 4

HyperCa

• Stones, Abdominal Groans, Painful bones and psychic moans
• nephrocalcinosis
• nausea, vomiting, ileus, peptic ulcer (increased gastrin), pancreatitis (deposition of Ca in duct, Ca +ve trypsinogen)
• brown tumour (rapid bone loss, replace by haemorrhage), osteitis fibrosa cystica
• lethargy, depression
• muscle weakness, bradycardia, polyuria, polydipsia

HypoCa

• enhanced neuromuscular excitability –> +ve chvostek’s sign, trousseau’s sign, tetany, seizures, cramps
• perioral numbness, paraesthesia
• arrhythmia
• irritability
• basal ganglia calcification, sub capsular infarcts (chronic Ca deposition)

Question 5

Regulation of ionised Ca

Answer 5

1. PTH
   - increase Ca and decrease PO4
   - **Bone: increase resorption (osteoblast–>osteoclast)
   - Kidney: increase reabsorption of Ca (DT, TAL), decrease renal reabsorption of PO4 (PCT), increase 1-alpha hydroxylase (for calcitriol production)
   - Intestines: increased 1-alpha hydroxylase leads to increase Ca and PO4 reabsorption
2. Vitamin D3/ Calcitriol/ 1,25 dihydroxycholecalciferol (slower response)
   - increase Ca and PO4
   - Bone: potentiate PTH action of resorption (but suppressed at high PTH and has neg feedback on PTH)
   - Intestines: increase Ca and PO4 absorption
3. Calcitonin
   - decrease Ca and PO4
   - Bone: decrease osteoclast activity

Question 6

HyperCa: causes

Answer 6

Common:

1. Parathyroid disease
   - hyperPTH: primary e.g. adenoma, hyperplasia or tertiary (autonomous PTH secretion due to chronic hypoCa and stimulation of parathyroid glands)
   - MEN1 and MEN2a
2. Malignant disease (humoral hyperCa of malignancy)
   - lytic lesions of bone e.g. breast CA metastasis
   - malignant cells release other mediators e.g. osteoclast activating factors in myeloma
   - PTHrP release e.g. SQCC of lung, HCC, head and neck CA, oesophagus
   - ectopic production of calcitriol by lymphomas

Uncommon:

• endogenous calcitriol e.g. sarcoidosis, TB
• excessive absorption of Ca e.g. vitamin D overdose, milk-alkali syndrome
• thiazide diuretics
• familial hypocalciuric hyperCa (CaSR gene mutation; AD with full penetrance)

Question 7

Primary HyperPTH vs Hypercalcemia of Malignancy: Ca levels, onset, renal stone formation, PTH levels, PO4 levels

Answer 7

Primary HyperPTH

• Ca <3.0 mmol/L
• chronic, insidious onset
• renal stones common (takes time to form)
• *plasma PTH high or inappropriately normal
• plasma PO4 usually low

Malignancy

• Ca >3.0 mmol/L (no physiological feedback mech)
• acute onset (months)
• renal stones rare
• *plasma PTH suppressed

(both have high Ca, low PO4 in HHM, high ALP)

Question 8

Approach to HyperCa

Answer 8

1. Confirm hyperCa (albumin-adjustment)
2. PTH assessment
   - -> high/ inappropriately normal = hyperPTH (normal/ high 24 hr urine Ca; primary or tertiary depending on RFT) or familial hypocalciuric hyperCa (low 24 hr urine Ca)
   - -> suppressed = malignancy, TB, others

Question 9

DDx patterns for hyperCa

Answer 9

Low PO4

• primary hyperPTH
• PTHrP releasing malignancy

High PO4

• malignancy (primary or secondary deposits)
• post-dialysis in renal failure, tertiary hyperPTH
• TB (overproduction of Vit D)
• Vit D overdose

Question 10

DDx of hypoCa

Answer 10

Exclude artefact from contamination of tubes with EDTA or oxalate

High PO4

• hypoparathyroidism e.g. thyroidectomy, congenital absence of glands
• secondary hyperparathyroidism i.e. renal failure –> PO4 retention in CKD and failure of vitamin D activation causes hypoCa which stimulates PTH release (can lead to renal osteodystrophy)
• pseudohypoparathyroidism (tissue resistance to PTH; PTH very high)
• hypoMg – required for PTH secretion and action

Low PO4

• vitamin D deficiency e.g. little sun exposure, malnutrition, fat malabsorption –> *high ALP and low 25-OH-Vitamin D (storage form)
• acute pancreatitis –> Ca and PO4 sequestration in abdomen leading to saponification

Question 11

Beware! Vitamin D deficiency will never cause high Ca!

Answer 11

Primary hyperPTH can cause low Vitamin D (suppressed at high PTH) but will have high Ca –> not vit D deficiency!!

Question 12

Mg and causes of deficiency

Answer 12

Cofactor required for PTH secretion and action (and also affects K excretion)

Reduced intake
- alcoholism, malnutrition, total parenteral nutrition

Abnormal loss

• renal: renal disease e.g. RTA, Barter/Gitelman, chronic pyelonephritis
• extra-renal: primary or secondary hyperaldosteronism/ diuresis; primary or tertiary hyperPTH

=> insensitive to vitamin D or Ca supplement

Question 13

Metabolic Bone Diseases

Answer 13

Most with normal Ca and PO4 except rickets and osteomalacia

definition, aetiology, bone turnover markers

Question 14

Osteoporosis

Answer 14

Common disorder affecting 1/4 older women

• LOW BONE MASS and susceptibility to vertebral, forearm and hip fractures
• structure and composition of bone is normal
• -2.5 SD from peak bone mass (osteopenia if -1.5 SD)

Ca, PO4, ALP, PTH all normal

Question 15

Osteomalacia and Rickets

Answer 15

Vitamin D deficiency or disturbed metabolism of vitamin D

• SOFT BONES (DEFECTIVE MINERALISATION, abrnomal composition)
• rickets in children
• osteomalacia in adults

Diffuse bone pain, tenderness, muscle weakness
XR: decreased density and *thinning of bone cortex
Deformed bones in advanced disease e.g. concavity of vertebral bodies, bowed legs
Fissures/ Cracks (looser’s zones)

Low Ca, PO4, 25-OH-Vit D
High ALP, PTH

Question 16

Osteopetrosis

Answer 16

Marble bone disease (very rare inherited)
- bones harden and become denser

Ca, PO4, PTH normal
High ALP

Question 17

Paget’s disease of bone

Answer 17

Dysregulated bone remodelling leading to deformity and abnormal architecture

Dx:

• characteristic XR appearance
• high ALP with normal Ca and PO4 in elderly

Question 18

Osteitis Fibrosa Cystica

Answer 18

Long term effect of untreated hyperPTH
- prone to pathological fractures

Same lab picture as hyperPTH (High Ca, low PO4, High ALP and PTH)

Question 19

Renal osteodystrophy

Answer 19

Osteomalacia + secondary hyperPTH
- poor RFT

High/Low Ca
High PO4, ALP and PTH

Question 20

Treatment of acute hyperCa

Answer 20

Dx and treat underlying cause

Correct dehydration (ensure sufficient renal filtration and Ca excretion)

Bisphosphonates (inhibit osteoclast activities and improve osteoblast survival)

Further Mx: chemo in malignancy, steroids in sarcoidosis, calcitonin also inhibit osteoclasts

Biologics:
- denosumab (Ab against human RANKL) – treat osteoporosis and acute severe hyperCa