Disorders of Calcium,

Phosphate and
Magnesium metabolism
Contents:
Calcium homeostasis
Biological function of calcium
Control of calcium metabolism
Investigations of abnormal calcium metabolism
Hypercalcemia
Hypocalcemia
Hypoparathyroidism
Biochemical bone diseases
Osteoporosis
Phosphate metabolism
Hypo- and hyperphosphatemia
Magnesium metabolism
Introduction

Calcium is the most abundant mineral in the body:

about 25 mol (1 kg) in a 70 kg man.

~ 99% of the body’s calcium is present in the bone, as

hydroxyapatite (Ca10(PO4)6(OH)2), where it is combined
with phosphate.

Ca2+ - means that only calcium ions are being considered.

Introduction ….. Contd

[calcium] : total conc. of calcium in plasma or urine .

Plasma [Ca2+] : the conc. of ionized calcium.

Hypercalcemia & hypocalcemia are relatively common

biochemical abnormalities, as are abnormalities in
plasma [phosphate].

 85% of the body’s phosphate content is present in the

bone.
Introduction ….. Contd

Alterations in plasma [albumin] (the major calcium-

binding protein in plasma)  abnormal plasma
[calcium] measurements.

Other cases result from  or  unbound or ionized

calcium.

To estimate the physiologic levels of [Ca+2] in states

of hypoalbuminemia:

[Ca+2]Corrected = [Ca+2]Measured + [ 0.8 (4 – Albumin)]

Pathological levels of [Ca+2] is life threatening .

Calcium homeostasis

Calcium balance:
In adults: normally, calcium intake = output .

In infancy and childhood: there is normally a positive

balance, especially at times of active skeletal growth.

In older age: calcium output > input  negative

balance; marked in women after menopause, 
postmenopausal osteoporosis.
In women, the mother loses calcium to the fetus
during pregnancy and by lactation.

External balance : when the net absorption over 24 h

= the corresponding 24 h urinary excretion; that
varies with the diet.
Overview of Calcium Balance
 Daily Calcium Balance

DIET INTESTINE
(25 mmol/day)

10 mmol/day 5 mmol/day
absorbed excreted KIDNEY

Net absorption = 5 mmol/day

BONE
URINE LOSS
(5 mmol/day)
Rapid exchange Turnover (slow)
Biological function of calcium:

Calcium is a major mechanical constituent of the bone.

Calcium in the bone acts as a reservoir that helps to

stabilize ECF [Ca2+].

Bone is a specialized mineralized connective tissue

containing:
– cellular elements (bone-forming osteoblasts and bone -
resorbing osteoclasts),
– organic matrix (type I collagen, proteoglycan, etc.)
– hydroxyapatite (the calcium-containing mineral).
There is a constant state of turnover in the skeleton
(about 5% per year of the adult skeleton is remodeled).
Maintenance of extracellular [Ca2+] is necessary for
normal excitability of nerve and muscle.

 [Ca2+]   threshold for the nerve action potential

and vice versa.

Ca2+ is required in the activation of the clotting and

complement cascades.

ECF [Ca2+] : ~ 1 mmol/L (10—3 M).

Cytosolic [Ca2+] is much lower : ~ 100 nmol/L (10—7 M).


cytosolic [Ca2+]
serves as a signal for :
Intercellular signals
(including several hormones)
  cytosolic [Ca2+] by:
• cell shape change
• cell motility
• metabolic changes
• secretory activity
• cell division
• opening Ca2+ channels
in plasma membrane
• releasing intracellular
Ca2+ stores
• combination of these
effects.
 A. PTH
Control of calcium metabolism: B. 1:25 DHCC
C. Calcitonin

Plasma [Ca2+] : ‘calcium’ in the plasma:

Reference Range
– the physiologically ( 2.12 – 2.62 mmol/L)
important component ( 3 forms)
– regulated in humans by the
- 50 - 65% in ionized form
PTH &1: 25- (DHCC)( both (the physiologically active form)
  plasma [Ca2+] and
plasma [calcium] ). - 30 - 45% bound to proteins
(predominantly albumin)

 plasma [Ca2+],  - 5 -10% complexed with anions

changes in PTH and 1 : 25- (citrate, sulfate, phosphate)

DHCC production.
 • Growth hormone
• Glucocorticoids (cortisol)
Calcium metabolism • Estrogens
is influenced also by: • Testosterone
• Thyroid hormones
- T4, thyroxin
- T3, tri-iodothyronine.
A. Parathyroid hormone (PTH) :
PTH is the principal acute regulator of plasma [Ca2+].

Plasma PTH levels exhibit a diurnal rhythm:

– highest in the early hours of the morning
– lowest at about 9 AM.

Active PTH :
– secreted in response to a fall in plasma [Ca2+],
–   plasma [Ca2+].

Low serum [Ca+2]   PTH secretion

High serum [Ca+2]   PTH secretion
 Role of PTH

Stimulates renal reabsorption of calcium

Inhibits renal reabsorption of phosphate
Stimulates bone resorption by osteoclasts
Inhibits bone formation and mineralization
Stimulates synthesis of calcitriol

Severe hyperparathyroidism  subperiosteal resorption

of the terminal phalanges, bone cysts & pepper skull.

 serum calcium
Net effect of PTH  serum phosphate
In the kidney:

PTH 
–  distal tubular reabsorption of calcium.
–  proximal tubular phosphate reabsorption
– promotes activity of the 1α-hydroxylation of
calcidiol.

 Renal loss of HCO3-  a mild metabolic acidosis.

Formation of 1: 25-DHCC indirectly   Ca absorption

from the small intestine.
Calcium Homeostasis
Fall in plasma [Ca2+]
On PTH release
Parathyroid glands
Stimulated by 
Plasma [Ca2+]
-ve feedback effects of
 plasma [Ca2+]

 Plasma [PTH]
On Renal
1-hydroxylase

K B
O
I  Plasma 1:25 DHCC N
D
N E
E
Y SMALL
INTESTINE  Plasma [Ca2+]
 Ca absorption
-ve feedback -ve feedback
1: 25-DihydroxychoIecalciferol (1: 25-DHCC, or calcitriol)

Most vitamin D3 (cholecalciferol) :

– synthesized by the action of UV on the vitamin D
precursor 7- dehydrocholesterol in the skin.

– found in plenty amount in (fish oils), while vitamin

D (ergosterol) is added to margarine.

– Endogenous synthesis of vitamin D3 is important.

• inadequate exposure to sunlight

Vit. D deficiency
• inadequate dietary intake.
is due to :
• combined
 Role of 1:25 DHCC (Calcitriol)

Stimulates GI absorption of both calcium and

phosphate through synthesis of a Ca2+-binding
protein in the intestinal epithelial cell necessary for
Ca2+ absorption .

Stimulates renal reabsorption of both calcium

and phosphate.
Stimulates bone resorption.

↑ serum calcium
Net effect of calcitriol
↑ serum phosphate
Deficiency of 1: 25-DHCC  defective bone mineralization.
Effect of vitamin D on
bone:

l,25-diOH D3   plasma
calcium and phosphate level
by stimulating the
mobilization of calcium and
phosphate from bone in the
presence of PTH.
Formation of 1:25- DHCC (Calcitriol)
Overview of Calcium-Phosphate Regulation
25-Hydroxylation :

occurs in the liver  25-hydroxycholecalciferol

(25-HCC, or calcidiol) production.

25-HCC, bind to a specific transport protein 

kidney for further metabolism.

Plasma [25-HCC] shows seasonal variation (highest

in summer).
1α - Hydroxylation of 25 - HCC:

occurs in the kidney  production of 1: 25-DHCC,

(the most active naturally occurring derivative of vitamin D).

The kidney also contains 24-hydroxylase 

converts 25-HCC  24 : 25-DHCC.

Renal 1α-hydroxylation  by :
– low plasma [phosphate]
– high [PTH]
– tendency to hypocalcemia.
Calcitonin :

Calcitonin   plasma [Ca2+] by:

–  osteoclast activity
–  renal reabsorption of calcium and phosphate.

its actions are transient.

chronic excess or deficiency is not associated

with disordered calcium or bone metabolism.

Used as a bone tumor marker

 Investigations of abnormal calcium
metabolism

Measurement of :
- Plasma calcium & albumin
Diagnosis of most disorders - Inorganic phosphate
of calcium metabolism - ALP
Sometimes:-
depends on: - magnesium
- PTH
- vitamin D metabolites

Plasma calcium reference range ( 2.12—2.62 mmol/L)

Clinical biochemistry laboratories only measure plasma

[calcium] routinely because of the technical difficulties
associated with the measurement of [Ca2+].
Effects of plasma [albumin] :

 plasma [albumin]   bound calcium &  total

[calcium] (and vice versa).

Under these circumstances, the unbound plasma [Ca2+],

will be maintained at normal levels by PTH.

Abnormal calcium binding, due to  plasma [albumin]

modest but potentially misleading  in plasma [calcium]

Plasma [albumin] should always be measured at the

same time as plasma [calcium] to avoid misdiagnosis of
hypo- or hypercalcemia.
 High
Effects of plasma [albumin] on Calcium distribution
Normal
Total Calcium

Free Calcium Ions

Low

Calcium ions bound to

Albumin

Calcium complexed to
citrate

Plasma Concentrations Levels

[Total calcium] Normal Low High
[Free Ca2+] Normal Normal Normal
[Albumin] Normal Low High
[Albumin-bound Ca2+] Normal Low High
The plasma [calcium] (in mmol/L) can be
approximately ‘corrected’ to take account of an
abnormal albumin (in g/L) using a formula such
as:

‘Corrected’ [calcium] =
measured [calcium] + 0.02 x (40- [albumin])
Effects of plasma H + :

In acidosis, protonation of albumin   its ability to bind

calcium  unbound [Ca2+] and vice versa, without any
change in total [calcium].

Hyperventilation  respiratory alkalosis   plasma

[Ca2+]  Tetany.

In chronic states of acidosis or alkalosis, PTH 

readjust the plasma [Ca2+] back to normal.
Plasma phosphate (reference range O.8 — 1.4 mmol/L)
( fasting level )

Diurnal variation, especially following meals;

Variable in different age groups.

~ 85% of plasma phosphate is free and

15% protein bound.
Alkaline phosphatase:
Physiological variations in enzyme’s activity in:
– Childhood
– Adolescence
– Pregnancy.

Pathological :osteoblastic activity ALP

activity e.g.:
– Hyperparathyroidism
– Paget’s disease
– Rickets and osteomalacia

 Carcinoma osteoblastic metastases.

 HYPERCALCEMIA
• Renal damage
 plasma [Ca2+] • Cardiac arrhythmias
• General ill-health

• 1ry hyperparathyroidism (80%)

Commonest causes • Malignancies
 Clinical consequences of high [Ca2+]

Neurological Symptoms:
– Inability to concentrate
– Depression
– Confusion
Generalized Muscle weakness.
Anorexia , nausea, vomiting , constipation.
Polyuria with polydipsia.
Nephrocalcinosis, Nephrolithasis
ECG changes (shortened Q-T interval ) with
bradycardia, and first-degree block.
Pancreatitis.
Peptic ulcer.
 Etiologies of Hypercalcemia
Increased GI Absorption Increased bone turnover
- Milk-alkali syndrome - Paget’s disease of bone
- Elevated calcitriol: - Hyperthyroidism
- Vitamin D excess
- Excessive dietary intake
Decreased Bone Mineralization
- Granuomatous diseases:
- Elevated PTH - Elevated PTH
- Hypophosphatemia
- Aluminum toxicity

Increased Loss From Bone Decreased Urinary Excretion

- Increased net bone resorption
- Elevated PTH - Thiazide diuretics
(Hyperparathyroidism)
- Elevated calcitriol
- Malignancy:
- Osteolytic metastases - Elevated PTH
- PTHrP secreting tumor
 Causes of hypercalcemia
Category Examples
Common:
- Hyperparathyroidism, primary and tertiary; multiple
Parathyroid disease
endocrine neoplasia syndromes, MEN I and MEN ha
Malignant disease - Lytic lesions in bone: myeloma, breast carcinoma
- PTHrP: carcinoma of lung, esophagus, head and
neck, renal cell, ovary and bladder
- Ectopic production of 1: 25-DHCC by lymphomas
Uncommon
Endogenous production of 1: 25-DHCC - Sarcoidosis and other granulomatous diseases
Excessive absorption of calcium - Vitamin D overdose (including self-medication)
milk-alkali syndrome
Bone disease - Immobilization
Drug-induced - Thiazide diuretics, lithium

Miscellaneous (mostly rare) - Familial hypocalciuric hypercalcaemia

- Hypercalcaemia in childhood
- Thyrotoxicosis
- Addison’s disease

Artefact - Poor venepuncture technique (Venous Stasis)

 Primary hyperparathyroidism:

• Single, parathyroid adenoma.

• Diffuse hyperplasia (involving all four glands)
• Rarely, parathyroid carcinoma

 PTH

•  [Ca2+], with the potential for clinical problems.

•  Plasma [phosphate] due to its phosphaturic effect.

PTH   urinary HCO3- losses mild metabolic acidosis

 plasma [PTH]  bony problems if chronic.
Markers of  osteoblast & osteoclast activity may be .
 ‘First-line’ biochemical tests for investigating
suspected hyperparathyroidism.

Plasma or serum Comments

- Calcium - If  [calcium], supports the diagnosis

- Albumin - Should be performed as a check on plasma

[calcium]
- Phosphate (fasting) - If  [phosphate], supports the diagnosis

- ALP - If enzymic activity , supports the diagnosis

- Total CO2 - If  , supports the diagnosis

-Creatinine / urea - Simple tests of renal function, needed in all

patients with suspected abnormalities of
calcium metabolism PTH
 PTH assay

Measurement of serum PTH is the single most

important test in the differential diagnosis of
hypercalcaemia.
Immunometric (‘sandwich’) assays that measure
serum [intact PTH] (reference range 10—55 ng/L) are
now in widespread use.
90% of patients with primary hyperparathyroidism
have an  level (high diagnostic sensitivity).
10% of patients with primary hyperparathyroidism
may have serum [intact PTH] in the upper part of the
reference range.

A sestamibi parathyroid imaging scan may also be

useful.
 Biochemical investigation of persistent hypercalcemia
Exclude
Persistent
Drug Therapy
Hypercalcemia Thiazides, Lithium
(adjusted for albumin)
Vitamin D

High Intact PTH Suppressed or

PHPT- up to 90 % of
patients have raised
levels
• PHPT : primary
Hyperparathyroidism.
• FBHH : familial Benign
Hypocalciuric Hypercalcemia.
Lower half of
Upper half of reference range
Reference range or • Exclude Malignancy
Borderline of high • Other non-parathyroid
• PHPT- up to 10 % of causes of
hypercalcemia should
patients.
be considered.
• Exclude FBHH by • Measurement of PTHrP
Calcium excretion may be helpful
and family study.

• Patients with malignancy-associated Hypercalcemia may have coexisting PHPT.

• Samples for intact PTH should be taken before any active treatment to reduce
hypercalcemia.
 Management of primary hyperparathyroidism

Parathyroid surgery Follow up

has technical difficulty. Careful clinical

not indicated in patients reassessment.
with asymptomatic
hyperparathyroidism if
Regular measurements
their plasma [calcium] is
of plasma [calcium] .
less than 3.0 mmol/L.
 Indications for parathyroidectomy:
include
(a) Presence of symptoms; a urine calcium excretion over 9
mmol/ 24 h.
(b) Cortical radial bone density over 2 SD below normal.
(c) Reduced creatinine clearance (if no other cause identified).
(d) Age under 50 years.

It is advisable to do parathyroidectomy early rather than late.

After parathyroidectomy:
• Plasma [calcium] falls rapidly, should be measured several times on
the first post-operative day and at least daily for the next few days.

• If the plasma [calcium] falls below normal:

• calcium gluconate should be given.
• 1:25-DHCC or 1-hydroxy cholecalciferol should be started.
Multiple endocrine neoplasia (MEN)
syndromes.

1ry hyperparathyroidism may be one of the

abnormalities in the so-called MEN syndrome.

3 types of MEN syndrome have been

described, all of them familial.
 Hypercalcemia of malignancy
Several factors are responsible for the hypercalcemia of
malignancy.

Depending on:
– the type of tumor
– whether or not there are bone metastases.

1. Solid tumors metastasized 2. Some solid tumors (e.g.

to bone  hypercalcaemia
(by paracrine activation of
osteoclasts).
The tumor cells  bone
resorption directly.
carcinoma of the lung, head
and neck),
in the absence of bony
metastases Hypercalcemia
3. In multiple myeloma:
Local cytokines  local bone resorption 
hypercalcemia.

Lymphomas  hypercalcemia.
Serum [intact PTH] is usually suppressed in
patients with malignancy-associated
hypercalcemia.
 PTH-related Protein (PTHrP)

An important factor in humoral hypercalcemia of

malignancy.

A peptide with marked sequence homology with PTH that

acts through the PTH receptor.
PTHrP may also be secreted by some tumors that
metastasize to bone.

Humoral and local osteolytic mechanisms combine

 hypercalcemia.

True ectopic production of PTH appears to be rare.

Assays for PTHrP are available in specialist

laboratories and may be helpful in the investigation of
patients with unexplained hypercalcemia.
Other causes of hypercalcemia Sarcoidosis

Vitamin D excess

Milk-alkali syndrome

Endocrine disorders

Tertiary hyperparathyroidism

Drugs (Thiazide diuretics, Lithium)

Familial benign hypocalciuric hypercalcemia (FBHH)

Other bone – related causes (Paget’s disease)

Vitamin D excess:
Excessive vitamin D intake ( or overdosage with
25-HCC, 1α-HCC or 1: 25-DHCC occurs)  plasma
[1 : 25-DHCC]  hypercalcemia.

Drugs:
Thiazide diuretics  mild hypercalcemia  interfere
with renal calcium excretion.

Long- term lithium therapy  stimulating PTH

secretion  hypercalcemia.
Sarcoidosis :
~ 10-20% of sarcoidosis patients have hypercalcemia.
they have hypercalciuria.
Unregulated conversion of 25-HCC  1 : 25-DHCC by
sarcoid tissue macrophages is responsible.

Tertiary hyperparathyroidism:
Development of parathyroid hyperplasia as a
complication of previous 2ry hyperparathyroidism.
 Plasma [calcium].
 serum [PTH].
 fasting plasma [phosphate] if it develops in a patient
with renal failure.
Familial benign hypocalciuric hypercalcemia
(FBHH)

Autosomal dominant disorder

Usually asymptomatic
Population prevalence of up to 1: 16.000
A mutation in the Calcium-sensing receptor gene in the
parathyroid gland, kidney and other organs
 plasma [Ca2+ ] that is sensed as ‘normal’
Normal or  plasma [PTH]
FBHH is distinguished from primary hyperparathyroidism
since parathyroidectomy (does not  plasma [Ca2+], and
no active treatment is indicated)
In FBHH:
– urinary calcium is usually low
– plasma [Mg] tends to be high normal.

Combination of family studies and measurement of

calcium excretion together with plasma [Mg] is
helpful in identifying the condition.

Calcium excretion (CE ) :

– measured on a second void spot urine and blood
sample obtained after an overnight fast
– calculated by multiplying : the urine calcium
creatinine ratio (both in mmol/L) by the serum
creatinine (in mol/L).
CaE < 14 mol/L GF suggests FBHH.
Endocrine disorders:
Hypoadrenalism, phaeochromocytoma and
thyrotoxicosis  Hypercalcemia.

Milk—alkali syndrome:

Excessive milk consumption in patients with peptic

ulceration  calcium intake .
If this is accompanied by excessive intake of alkali (e.g.
NaHCO3), as an antacid  hypercalcemia.
The alkali   urinary calcium excretion 
hypercalcemia.

Other bone-related causes:

Paget’s disease in association with immobilization.

 HYPOCALCEMIA

Misleading hypocalcemia Pathological hypocalcemia

due to: due to in plasma [Ca2+]

• Contamination of the
sample with EDTA (from - Tetany,
a full blood count tube) - Neuropsychiatric symptoms
•  plasma [albumin] - Cataract
It should be excluded
 Tetany

A symptom suggests the presence of low plasma [Ca2+].

May be caused by a rapid fall in plasma [Ca2+] e.g.:
Acute respiratory alkalosis due to hyperventilation.
IV infusion of NaHCO-3.

Occasionally it is due to a low plasma [Mg2+] in the

absence of low plasma [Ca2+],
Rarely it is due to sudden  in plasma [phosphate].
 Causes of hypocalcemia

Category Examples
- Artifact - EDTA contaminator of sample
- Hypoproteinemia - Low plasma [albumin]
- Renal disease - Hydroxylation of 25-HCC impaired
- Inadequate intake of - Deficiency of calcium or vitamin D, or of
calcium both; intestinal malabsorption
- Hypoparathyroidism - Autoimmune, post-surgical, Mg deficiency,
infiltrative disease
- Pseudohypoparathyroidism - Target organ resistance to PTH

- Neonatal hypocalcemia
- Acute pancreatitis - Calcium soaps in the abdominal cavity?
- Critical illness - Mixed pathology — not clearly defined
 Etiologies of Hypocalcemia
 GI Absorption Increased Urinary Excretion
- Poor dietary intake of calcium
- Impaired absorption of calcium Low PTH
Vitamin D deficiency - thyroidectomy
- Poor dietary intake of vitamin D
- I131 treatment
- Malabsorption syndromes
Decreased conversion of vit. D to calcitriol - Autoimmune
- Liver failure hypoparathyroidism
- Renal failure - PTH resistance
- Low PTH
- Vitamin D deficiency / low calcitriol
- Hyperphosphatemia

 Bone Resorption/  Mineralization

- Low PTH (hypoparathyroidism)
- PTH resistance ( pseudohypoparathyroidism)
- Vitamin D deficiency / low calcitriol
- Hungry bones syndrome
- Osteoblastic metastases
Clinical consequences of hypocalcemia

Enhanced neuromuscular irritability (positive

Chvostek’s sign and Trousseau’s sign); tetany

Numbness, tingling (fingers, toes, circumoral)

Muscle cramps (legs, feet, lower back)
Seizures
Irritability, personality changes
ECG changes (prolonged Q —T interval)
Basal ganglia calcification; subcapsular cataracts
(especially with low PTH)
Effect of Vitamin D deficiency:

Inadequate plasma levels of 1:25-DHCC  defective

calcium absorption  hypocalcemia (the commonest
pathological cause).

Deficiency of 1:25-DHCC may result from:

– lack of vitamin D or
– failure at any stage in its conversion to 1: 25-DHCC

In malnutrition, vitamin D deficiency together with

inadequate dietary calcium  hypocalcemia
Defective absorption of calcium   plasma [Ca2+] +
 PTH secretion in response to the low ECF [Ca2+]
(i.e. 2ry hyperparathyroidism).

 Plasma [phosphate] due to:

– impaired absorption
– secondary hyperparathyroidism

 Plasma ALP activity reflecting  osteoblastic activity.

 Urinary calcium excretion .

Confirmation of the diagnosis of vitamin D deficiency

depends on :
– measurement of serum [25-HCC] or
– Measurement of serum [1:25-DHCC].
1. Nutritional deficiency of vitamin D:

Poor diet and/or inadequate exposure to sun light, 

vitamin D deficiency  hypocalcemia & osteomalacia .

Eliminated in developed countries with vitamin D

supplementation of food.

The elderly are at risk (as they may be immobile indoors

with an inadequate diet).
2. Malabsorption of vitamin D:

Due to:
celiac disease, or
fat malabsorption due to:
– pancreatic disease,
– biliary obstruction,
– complication of gastric or intestinal surgery
(e.g. intestinal bypass or resection).

Biliary obstruction rather than 25-HCC deficiency

in parenchymal liver disease  malabsorption
 vitamin D deficiency.
3. Renal disease:
Destruction of the renal parenchyma  loss of activity
of 1α-hydroxylase   1:25-DHCC formation  calcium
malabsorption .

 plasma [phosphate] in renal failure  interfere with

the 1α-hydroxylation step.

In vitamin D-resistant rickets, type I (a rare inherited

disorder) hypocalcemia  1α-hydroxylase deficiency.

In vitamin D-resistant rickets, type II, there is end-organ

unresponsiveness to 1:25-DHCC.
 Hypoparathyroidism
A. Primary hypoparathyroidisrn is rare.
The combination of  plasma [calcium] and  [phosphate] in
absence renal disease  diagnosis of hypoparathyroidism.
Plasma ALP activity is usually normal.
 [intact PTH] confirms the diagnosis   to < 10 ng/L
(Sometimes undetectable even by the most sensitive assays).

Failure to secrete PTH may be due to :

A complication of surgery
Familial
Destruction of parathyroid glands by:
an autoimmune process
infiltration by carcinoma of thyroid or metastasis
B. Secondary hypoparathyroidism
In patients with magnesium deficiency.

Normal magnesium levels are necessary for:

PTH release
end-organ response to PTH.

C. Pseudohypoparathyroidism :
A rare but interesting condition.
The end-organ receptors in the bone and kidneys
fail to respond normally to PTH.
There is  serum [PTH].
 Biochemical bone diseases
Generalized defects in bone mineralisation,
frequently associated with abnormal calcium or
phosphate metabolism,  "biochemical or metabolic
bone diseases".

Osteoporosis
The most Rickets
common Osteomalacia
Paget’s disease.
 Metabolic bone disease
Chemical investigations on blood specimens.

Phosphate Ca2+
Diagnosis Calcium PTH ALP
(fasting)

Hyperparathyroidism
- primary  (or N)  (or N)  or N N or  (or N)
- Secondary  or N  or N   or N N
- Tertiary  or N  or N   or N 
Rickets& osteomalacia
- Deficient intake  or N  or N  (or N) N (or )

- Renal failure  or N  or N  N

- Fanconi’s syndrome  or N  or N N N

Osteoporosis N N N N N

Paget’s disease N (or) N N  N

 Markers of bone turnover
Biochemical markers
of bone turnover

Bone formation Bone resorption

enzymes and peptides released a measure of the

by the osteoblast at the time of breakdown products of
bone formation type 1 collagen

– cannot reveal bone content in the skeleton.

– cannot substitute for bone mineral density
measurement.
Bone markers – used in the assessment of fracture risk.
– used in the monitoring of the response to
therapy.
 The most sensitive biochemical
markers of bone tumor

Formation Resorption
Serum
- Bone Alkaline phosphatase - C - telopeptide cross
links (CTX)
- Osteoclasin
- Procollagen type - N - telopeptide cross
1 N-terminal Propeptide links (NTX)

Urine - Deoxypyridinoline
 Rickets and osteomalacia

Vitamin D deficiency
Osteomalacia in adults, or
or disturbed vitamin D
Rickets in children
metabolism

– Bone pain
– Local tenderness
– Proximal myopathy
– Skeletal deformity may
be present (in rickets).
– Defective mineralisation
of osteoid tissue

In Fanconi’s syndrome, tubular phosphate loss  

plasma [phosphate]  rickets or osteomalacia.
Hypophosphatasia:

A hereditary disease .

Vitamin D-resistant rickets is the most prominent

finding.

Tissue and plasma ALP activities are usually low.

Excessive amounts of phosphoryl ethanolamine are

present in the urine.
Osteoporosis
A very common disorder.
Affects about 25% of women.
Characterized by low bone mass and susceptibility
to vertebral, forearm and hip fractures in later life.

Results of routine chemical investigations are

usually all normal.

• primary hyperparathyroidism.
The diagnosis • thyrotoxicosis.
should exclude: • corticosteroid excess.
• multiple myeloma.
• hypogonadism.
 Risk factors for osteoporosis
Unmodifiable
Age (1.4 -1.8 - fold increase per decade)
Genetic (Caucasians & Orientals > Blacks & Polynesians)
Sex (female > male)

Modifiable (Environmental)
Nutritional calcium deficiency
Physical inactivity
Smoking
Alcohol excess
Drugs (e.g. glucocorticoids, anticonvulsions)

Modifiable (Endogenous)
Endocrine (estrogen or androgen deficiency, hyperthyroidism)
Chronic diseases (gastrectomy, cirrhosis, rheumatoid arthritis)
Paget’s disease
A common disorder of the bone.

Affecting up to 5% of the population over 55 years

old in the UK.

Bone turnover , with disordered bone remodeling.

Plasma [calcium] and [phosphate] are usually

normal, although hypercalcemia can develop,
especially as a result of immobilization.

 bone turnover  plasma ALP activity and 

indices of osteoclast activity.
Renal osteodystrophy
The pathophysiology of renal osteodystrophy is
complex.
The bone changes derived from one or more of the
following mechanisms:

1. Vitamin D metabolism:
ineffective conversion of 25-HCC to 1: 25-DHCC due to
loss of renal 1α-hydroxylase.
Causes defective calcium absorption and
osteomalacia in adults, or rickets in children.

May be corrected by treatment with 1α-HCC or 1:25-

DHCC.
2. Phosphate
retention:
 plasma [phosphate], combined with defective calcium
absorption   plasma [Ca2+]  secondary
hyperparathyroidism  restore plasma [phosphate]
and plasma [calcium], towards normal.

Phosphate retention  inhibit the renal 1α-hydroxylase.

Osteitis fibrosa, if it develops, may require

parathyroidectomy.
3. Phosphate binders:

Oral phosphate binders, usually aluminium hydroxide

is used for treatment of patients with progressive
renal disease if secondary hyperparathyroidism failed
to maintain normal plasma [phosphate] .

Excess absorption of aluminium  osteomalacia and

dialysis dementia.

Plasma [aluminium] should be measured periodically.

4 . Dialysis fluid composition:

The fluid [calcium] must be carefully controlled;

– If it is too low  osteoporosis.
– If it is too high  extra skeletal calcification.

Dialysis fluid [aluminium] should be sufficiently

low.

Plasma creatinine, urea, Na+ K+, total CO2,

albumin, [calcium] & [phosphate] and ALP
activity should all be measured regularly.
 Phosphate metabolism
85 % of body phosphorus is located in bone.
15 % is intracellular as phosphate compounds.

In ECF, phosphate is mostly inorganic, as a mixture

of HPO42- and H2PO4- at physiological pH.

Intracellular phosphate is largely organic as a

component of phospholipids, phosphoproteins,
nucleic acids and nucleotides, ( ATP).

Macromolecular structure (DNA)

Intracellular phosphate Energy metabolism (ATP).
has vital functions in: Cell signaling
Enzyme activation by phosphorylation.
 Hypo- and hyperphosphatemia
Phosphate and calcium
homeostasis are linked.
A plasma [phosphate] below
0.4 mmol/L  widespread
cell dysfunction and even
death.
Muscle pain and weakness,
including respiratory muscle
weakness, associated with 
CK are possible
Urgent phosphate
supplementation is required
in hypophosphatemia.
Dietary deficiency is unusual
(phosphate occurs widely in
food)
Antacids may bind phosphate.
Metabolic and respiratory
acidosis  phosphate movement
into the cell.
Hypophosphatemia in DKA may
be worsened when insulin is
administered (insulin promotes
cellular uptake of glucose and
phosphate).
Cellular utilization of phosphate
during re-feeding starved patients
 serious hypophosphatemia.
Overview of Phosphate Balance
 Causes of hyperphosphatemia and
hypophosphatemia

Hyperphosphatemia Hypophosphatemia
 intake - IV therapy  intake/ - Vitamin D deficiency
- Phosphate enemas absorption - Malabsorption
- Oral phosphate binders

 excretion - Acute/chronic
renal failure  excretion - Primary PTH excess
- Secondary PTH excess
- Low PTH or (e.g. vit D deficiency)
resistance to PTH - Post-renal transplant
- Vitamin D toxicity - Re-feeding starved
patients

Redistribution - Tumor lysis

Redistribution - Hyperalimentation
- Rhabdomyolysis
- Recovery from DKA
- Heat stroke - Alkalosis (respiratory)
 Etiologies of Hyperphosphatemia

Increased GI Intake
- Fleet’s Phospho -Soda

Decreased Urinary Excretion

- Renal Failure
- Low PTH (hypoparathyroidism)
- thyroidectomy
- I131 treatment for Graves disease of thyroid cancer
- Autoimmune hypoparathyroidism
Cell Lysis
- Rhabdomyolysis
- Tumor lysis syndrome
 Etiologies of Hypophosphatemia
Decreased GI Absorption
- Decreased dietary intake (rare in isolation)
- Diarrhea / Malabsorption
- Phosphate binders (calcium acetate, Al & Mg containing antacids)

Decreased Bone Resorption / Increased Bone Mineralization

- Vitamin D deficiency / low calcitriol
- Hungry bones syndrome
- Osteoblastic metastases

Increased Urinary Excretion

- Elevated PTH (as in primary hyperparathyroidism)
- Vitamin D deficiency / low calcitriol
- Fanconi’s syndrome

Internal Redistribution (due to acute stimulation of glycolysis)

- Refeeding syndrome (seen in starvation, anorexia, and alcholism)
- During treatment for DKA
 Magnesium metabolism
Mg is the second most
abundant intracellular cation.
Bone contains about 50% of
the body’s magnesium.
Small proportion of the body’s
content is in the ECF.
Essential for the activity of
many enzymes, including the
phosphotransferases.
Normal dietary intake of
magnesium is about 12 mmol
(300 mg) daily.
Green vegetables, cereals and
meat are good sources.
Significant amounts are
contained in gastric and biliary
secretions.
Absorbed by active transport
across the intestinal mucosa by
a process involving vit. D.
Renal conservation of
magnesium is partly controlled
by PTH and aldosterone.
 Hypomagnesemia and
magnesium deficiency
Rarely occurs as an isolated phenomenon.

Usually accompanied by : disorders of potassium,

calcium and phosphorus metabolism.

Magnesium deficiency should be suspected in

patients with idiopathic hypocalcemia and /or
hypokalemia

Muscular weakness,
sometimes accompanied by
tetany
Magnesium deficiency Cardiac arrhythmias
CNS abnormalities
(convulsions) .
 Magnesium deficiency

Causes Examples
Abnormal losses
- GI tract - Prolonged aspiration, persistent diarrhea,
- Malabsorptive disease, fistula, jejuno-ileal by-pass, -
Small-bowel resection
Urinary tract
- Renal disease - Renal tubular acidosis, chronic pyelonephritis,
- Hydronephrosis
- Extrarenal - Conditions that modify renal function (e.g. primary
and secondary hyperaldosteronism, diuretics,
osmotic diuresis
- Conditions affecting transfer of magnesium from
cells to bone e.g. tertiary hyperparathyroidism,
ketoacidosis
Reduced intake - If severe and prolonged, protein-energy malnutrition
Mixed etiology - Chronic alcoholism, hepatic cirrhosis
Plasma [magnesium] is usually < 0.5 mmol/L.

Other tests (e.g. erythrocyte [Mg2+], muscle [Mg2+],

magnesium loading tests) should be done.

No general agreement on the best test to use.

Measurement of Urinary excretion of magnesium is

easy and useful in distinguishing renal losses of
magnesium from the other causes of hypomagnesemia.

Renal excretion of magnesium often  below

0.5 mmol/24h in non-renal causes of magnesium
deficiency.
 Hypermagnesemia
most often due to:
– acute renal failure
– advanced stages of chronic renal failure.
confirmed by measuring plasma [magnesium].
Adrenocortical hypofunction  a slight  in plasma
[magnesium].
Hypermagnesemia due to IV injection of magnesium
salts is rare.

nausea and vomiting,

If plasma [magnesium] weakness
exceeds 3.0 mmol/L impaired consciousness