1. Calcium Metabolism, Homeostasis & Related Diseases1

2. Objectives of Lectures
By the end of these lectures, students should be able to:
Recall Calcium Sources, Distributions & Functions
Understand Organ & Endocrinal Homeostasis of Calcium with recognition of the roles of:
- Vitamin D
- Parathyroid Hormone (PTH)
- Calcitonin Hormone
Verify Main Causes of Hypocalcaemia & Hypercalcemia
Recognize the biochemical and Clinical Interrelations of Metabolic diseases of bone:
- Rickets & Osteomalacia
- Osteoporosis 2

3. Components of Bones
Bone is a specialized mineralized connective tissue containing:
1- Cellular Elements:
- Osteoblasts (bone forming cells)
- Osteoclasts (bone resorping cells)
2- Organic Matrix
- Proteins:
Type I Collagen
Proteoglycan
- Inorganic Minerals: Calcium & Phosphate
- Others: small amount of hydroxide & carbonate
Calcium is tightly regulated with phosphorous in the body

4. Calcium Calcium is the most abundant mineral in the body:
about 1 kg in a 70 kg man
~ 99% of the body’s calcium is present in the bone
where it is combined with phosphate
Calcium is the most prevalent mineral in the body where a 70 Kg adult about 1Kg of calcium is present , where 99% is present in bone mainly, while 1% is present in tissues and body fluids

5. Dietary Sources of Calcium
Rich:
Milk, milk products as cheese & yoghurt
Fair
Legumes, vegetables

6. Biological Functions of Calcium
Total Calcium
Of the Body
99 %
in bone
ICF
1 %
Blood Clotting
Excitability of Nerve & Muscle
Bone Formation
Reservoir for ECF [Ca2+]
Metabolic Regulation for Action of Hormones & Enzyme Activation
ECF
Physiologically, calcium is classified as either extracellular or intracellular. The skeleton is a major reservoir for providing calcium for both the exracellular and the intracellular pools

7. Calcium in Blood
The ionized fraction is the biologically active fraction

8. Organ Calcium Homeostasis
The concentration of calcium, phosphorous & magnesium in the plasma depend on ORGAN PHYSIOLOGY:
Net effect of bone mineral deposition & resorption
Intestinal absorption
Renal excretion

9. Organ Calcium Homeostasis cont.
The concentration of calcium, phosphorous &
magnesium in the plasma depends on
ORGAN PHYSIOLOGY:
Net effect of bone mineral deposition & resorption
Intestinal absorption
Renal excretion

10. Blood [Ca2+] Endocrinal Calcium Homeostasis Parathyroid Hormone (PTH)
Active Vitamin D (Calcitriol or 1,25 DHCC)
Calcitonin Hormone
Blood
[Ca2+]
is Regulated By:

11. Vitamin D Sources of Vitamin D
A group of sterols with a hormone-like function.
Sources of Vitamin D
1- Skin synthesis (On Exposure to Sun Lights):
In the skin, 7 dehydrocholesterol is converted to vitamin D3 by exposure to
sunlight
2- Diet:
- Animal Source Cholecalciferol (Vitamins D3)
- Plant Source: Ergocalciferol (Vitamin D2)
Vitamin D2 & D3 are NOT biologically active
Activation of cholecalciferol (vitamin D3)
Cholecalciferol (Vitamin D3) is activated in the body to the biologically active
form by two hydroxylations: first in the liver (at position 25) by 25 hydroxylase
& then in the kidney at positions 1 by 1 α hydroxylase
Active Vitamin D
1, 25 dihydroxycholecalciferol (Calcitriol or DHCC)

12. SOURCES OF VITAMIN D Vitamin D2 Vitamin D3 DIET VITAMINs D
plant source
DIET VITAMINs D
Vitamin D3
animal source
fatty fish
Liver
egg yolk
Sun
Rays
7-dehydrocholesterol
In the skin

13. Vitamin D metabolism
Cholecalciferol (Vitamin D3) is derived from 7-dehydrocholesterol in
the skin by sunlight or supplied in the diet
In liver:
Cholecalciferol is converted to 25-hydroxycholecalciferol (25-HCC)
by the enzyme 25 hydroxylase
25-hydroxycholecalciferol is the predominant form of vitamin D
in blood
25-hydroxycholecalciferol is the main storage form of vitamin
in the body
In kidneys:
The 1 α hydroxylase enzyme converts 25 hydroxycholecalciferol to
1,25-dihydroxycholecalciferol (1, 25 DHCC or Calcitriol)
which is the biologically active form of vitamin D 13

14. Functions of Vitamin D
Active vitamin D (1, 25 DHCC or Calcitriol) regulates calcium levels in the body (calcium homeostasis)
Through:
Increasing absorption of calcium by the intestine
Minimizing loss of calcium by kidney
Stimulating resorption of bone (when necessary)
In the intestine:
1, 25-DHCC bind to vitamin D receptors forming a complex that binds to the vitamin D response element upstream of the transcription start site of vitamin D influenced genes causing enhancing gene transcription of genes of calcium transport from intestinal lumen (calcium absorption).
In the bones:
1, 25-DHCC stimulates terminal differentiation of osteoclasts precursors to osteoclasts
& also stimulates osteoblasts to influence osteoclasts to mobilize bone calcium
1, 25-DHCC does not directly affect mature osteoclastic physiology
Deficiency of Active Vitamin D (1, 25-DHCC or Calcitriol)
Defective Bone Mineralization (poor calcification) 14

15. Mechanism of Action of Vitamin D
In the intestine:
1, 25-DHCC bind to vitamin D receptors forming
a complex that binds to the vitamin D response
element upstream of the transcription start site
of vitamin D influenced genes causing
enhancing gene transcription of genes of
calcium transport from intestinal lumen
(calcium absorption).
In the bones:
1, 25-DHCC stimulates terminal differentiation
of osteoclasts precursors to osteoclasts
& also stimulates osteoblasts to influence
osteoclasts to mobilize bone calcium
1, 25-DHCC does not directly affect mature
osteoclastic physiology

16. Parathyroid hormone (PTH)

17. Functions of Parathyroid Hormone (PTH)
The active hormone is secreted in response to al fall in plasma Ca2+ resulting in in Ca2+ increase in blood.
On bone:
PTH stimulates bone resorption by osteoclasts resulting in release of
calcium ions from bones to blood in cases of hypocalcemia
On kidney:
1- PTH increases reabsorption of calcium from kidney tubules.
2- PTH promotes activity of 1a hydroxylase of the kidney (with more
hydroxylation of 25 hydroxycholecalciferol (25 HCC) to 1,25 DHCC
(activation of vitamin D) which increases intestinal absorption of
calcium
So, action of PTH on intestine is indirect (via Vitamin D)

18. Role of Parathyroid Hormone (PTH) in Hypocalcemia
is the principal
acute regulator of blood [Ca2+]
is a hypercalcemic hormone in case of hypocalcemia

19. Calcitonin Hormone Calcitonin hormone is : In cases of hypercalcemia,
Secreted by the parafollicular or “C” cells of the thyroid gland
Released in response to high blood calcium (hypercalcemia)
In cases of hypercalcemia,
Calcitonin Hormone   blood [Ca2+] by:
 Osteoclast activity (preventing release of calcium to blood)
 Renal reabsorption of calcium
Net result of its action   blood calcium
CALCITONIN IS THE ONLY HYPOCALCEMIC HORMONE

20. MAIN CAUSES of HYPERCALCEMIA
Primary hyperparathyroidism:
due to adenomas (single or multiple) of the parathyroid gld
Blood PTH is high (or upper normal range *)
Blood calcium is high & Blood phosphate is low
Urine calcium & phosphorous are high (hypercalciuria & hyperphasphatruria)
Tumors
Humoral hypercalcemia of malignancy due to PTHrP (PTH related protein) released by some kinds of tumor cells.
PTHrP is not responsive to negative feedback by calcium
Hypervitaminosis D:
Excessive intake of vitamin D
Extrarenal hydroxylation of 25HCC as in granulmotaous diseases as sarcoidosis
* Blood PTH in primary hyperparathyroidism may be INAPPROPRIATELY NORMAL as hypercalcemia tries to suppress NORMAL PARATHYROID TISSUES in an attempt to restore normal calcium levels.

21. MAIN CAUSES of HYPOCALCEMIA
Hypoparathyroidism ( PTH)
Vitamin D deficiencies
Renal disease :low 1 a hydroxylase activity & by hyperphosphaturia
Hypoalbuminemia: low blood albumin
Nutritional calcium deficiency
Intestinal disorders causing inadequate calcium or vit.D absorption

22. Metabolic Diseases of Bone: Rickets & Osteomalacia
Rickets & osteomalacia are metabolic bone diseases occurring due to poor mineralization (calcium content) of bone
Causes of poor calcification of bones:
I. Vitamin D deficiency
1- Deficiency of sources of vitamin D3:
BOTH:
Nutrional Vitamin D deficiency (vitamin D3)
Poor exposure to sun light
2- Impaired vitamin D metabolism:
Renal Rickets: deficiency of 1 hydroxylase of the kidney
Deficiency of parathyroid hormone : decrease activity of 1 α hydroxylase
Genetic defects in vitamin D metabolism (defect in its activation)
Genetic defects of vitamin D receptors or abnormal ligand binding
II. Calcium deficiency (nutritional or defect in intestinal absorption) 22

23. Rickets & Osteomalacia
Metabolic Diseases of Bones
RICKETS
Normal formation of the collagen matrix
BUT
Incomplete mineralization (poor calcification)
Soft Bones
CLINICALLY: Bone Deformity
OSTEOMALACIA
Demineralization (poor calcification) of preexisting bones
with
CLINICALLY: More Susceptibility to Fracture
Rickets & Osteomalacia

24. Renal Rickets Renal Osteodystrophy
In Chronic Renal Failure Low activity of Renal 1a-Hydroxylase Decreased ability to form the active form of vitamin D (1, 25 DHCC will be low) Treatment: 1,25 DHCC (Calcitriol)

25. Laboratory Investigations for the Diagnosis of Rickets & Osteomalacia
Investigations to confirm the diagnosis of rickets:
 Blood levels of 25-hydroxycholecalciferol (25 HCC)
Blood calcium, (hypocalcemia)
 Blood Alkaline phosphatase (ALP)
Investigations to diagnose the cause of rickets:
Kidney function tests (KFT)
Blood 1, 25 dihydroxycholecalciferol (1, 25 DHCC)
Blood PTH
Others i.e. molecular genetics (if indicated) 25

26. Metabolic Diseases of Bone: Osteoporosis
Most prevalent metabolic bone disease in adults
It means reduction in bone mass per unit volume
i.e. bone matrix composition is normal, but it is reduced
Typically silent (without symptoms) until it leads to fracture at a degree of trauma that would not have caused a fracture in a non-osteoprotic skeleton.
Fractures are called fragility or osteoporotic fractures)
Most affected: vertebral compression (may be asymptomatic) & hip fractures
(requires surgery in most cases)
Post-menopausal women lose more bone mass than men (primary osteoporosis)
Osteoporosis diagnosis is by dual energy x-ray absorpitometry (DXA) scan
Lab diagnosis: not conclusive 26

27. Metabolic Diseases of Bone Osteoporosis27

28. Secondary Osteoporosis Risk Factors
Secondary osteoporosis may be caused by reduced bone mass
with increased consequent risk of fractures
Risk Factors for osteoporosis:
Advanced age (esp. in females
Certain Drugs
Family history of osteoporosis or fractures
Immobilization
Smoking
Excess alcohol intake
Cushing’s syndrome
Long term glucocorticoids therapy
Hyperparathyroidism
Hyperthyroidism
Vitamin D disorders
Certain malignancies
In these cases, DXA is highly recommended to evaluate bone density 28

29. Case Study-1
A 27 years old man presents to his physician 3 weeks after his thyroid surgically removed for a thyroid cancer.
However, since he went home from the hospital, he noticed painful, involuntary muscular cramping.
He also felt numbness and tingling around his mouth & in his hands and feet. His parents said that he was irritable for the last 2 weeks.
He is on levothyroxine medication.
On examination
He has a well-healing thyroidectomy scar & no palpable masses in the thyroid bed.
Blood pressure cuff inflated above the systolic pressure induces involuntary muscular contracture in the ipsilateral hand after 60 seconds (Trousseau`s sign)
Tapping on the face interior to the ears cause twitching in the ipsilateral corner of the mouth (Chevostek`s sign)
Lab Investigations:
Calcium: mg/dl (N: 8.5 – 10.2)
Albumin: 4.1 g/dl (N: 3.5 – 4.8)
PTH: < 1 pg/ml (N: N: 11 – 54)

30. DIAGNOSIS of Case-1
The parathyroid glands were removed during thyroidectomy  PTH undetectable Hypocalcemia Clinical Manifestations of hypocalcemia (increased reflexes & muscular cramping)

31. Case Study-2
A 6-year old girl is brought to a pediatrician by her parents
They reported that her height is not progressing as they think it should (or like it did for her 8 year old sister & her legs look bowed.
She takes no medications
Family history: Some cousins has the same problem
Lower Lim X-Ray:
Bowing of long bones
Generalized demineralizations
Clinical Chemistry Lab Investigations:
Calcium: 7.2 mg/dl (N: 8.5 – 10.2)
Albumin: 4.1 g/dl (N: 3.5 – 4.8)
PTH: 866 pg/dl (N: 11 – 54)
25 HCC: 35 ng/dl (N: )
1, 25 DHCC: less than 1 pg/ml (N: 20 – 75)

32. Pseudohyperparathyroidism
DIAGNOSIS of Case-2
Pseudohyperparathyroidism 
In which there is genetic mutations in the stimulatory G-protein
IN ACTIVE G Protein
No activation of adenylate cyclase
NO cAMP
NO EFFECT OF PTH
HYPOCALCEMIA
INCREASE OF PTH (HYPERPARATHYROIDISM WITH HYPOCALCEMIA)
TO BE CONFIRMED by
MOLECULAR GENETIC ANALYSIS