PARATHORMONEVitamin D ,

CALCITONIN, CALCIUM AND PHOSPHATE

•Calcium and phosphate are the major constituents of bone.

•98% (1-2kg) of calcium and 85% (1kg) of phosphate are found in bones.

Processes of remodelling of the bone involves:

1 .Activity of two main cells:

a. Osteoblasts, which

secrets new bone matrix.

b. Osteoclasts, which

break it down.

2 .The turnover of minerals ,

calcium and phosphate.

3 .The actions of several

hormones: PTH, Vit D ,

growth hormone, steroids

and calcitonin.

Bone loss of 0.5-1% per year starts in the 35-40 age group in both sexes.

The rate accelerates by as much as 10 fold during menopause in women or with castration in men ( due to increase in osteoclasts activity)

CALCIUMCALCIUM• Diet contains 600-1000mg of Ca

and 100-250mg of phosphate absorbed from the GIT.

• The daily turnover of bone minerals during remodeling involves about 700 mg calcium.

•Calcium has a great role in physiologic functions.

•Intracellularly is small proportion (100nmol/L) extracellularly (2.5 mmol/L).

•Plasma calcium Plasma calcium concentration is concentration is regulated byregulated by::

1. Parathormone (PTH).

2. Vitamin D.

3. Calcitonin.

PHOSPHATE•Constituent of bones.

• Important in the structure and function of all cells of the body.

•Play a significant role in enzymic reactions in the cells.

• Absorption is regulated by calcitroil.

• Phosphate deposition in bone as hydroxyapatite depends on PTH which mobilizes Ca and phosphate from bone matrix.

• Excreted by the kidneys, PTH inhibits reabsorption and thus increases excretion.

Parathormone (PTH)• PTH synthesized by cell in the parathyroid

gland and stored in vesicles.

• The main factor controlling its secretion is the concentration of free Ca in the plasma (low Ca stimulate secretion).

• It is an important physiologic regulator of Ca metabolism.

• Maintains plasma Ca concentration by:a. Mobilising Ca from bone

(activation of osteoclasts).

b. Promoting Ca reabsorption by

the kidneys.

c. Stimulating the synthesis of

calcitroil (increases

mobilization of Ca from bone.

•PTH increases phosphate excretion.

Net effect of PTH:•Increase in Ca concentration in the plasma and lower phosphate concentration.

In high dose PTH increases the rate of bone remodelling (osteoclasts activity) and increase in Ca concentration.

• In low doses a bone formation occurs (osteoblast activity).

Natural (animal) and synthetic

forms are available and they are used for diagnostic purposes.

VITAMIN D• Is prehormone that is converted in the body to a number of biologically active metabolites, that functions as true hormone.

FUNCTIONS: 1. Maintenance of plasma Ca by

increasing Ca absorption in the intestine and so of phosphate.

2. Mobilising Ca from bone.

3. Decreasing Ca excretion by the kidneys (increasing Ca and phosphate

reabsorption).

Two Sources of Vit. D:

1. D2 or ergocalciferol (calciferol), dietary, derived from erogosterol in plants.

2. D3 or cholecaliferol generated in the skin from 7-dehydrocholeserol by the action of ultraviolet irradiation.

• Vit D3 and D2 are 25- hydroxylated into more active forms in the liver.

*25- hydroxy vitamin D3

(calcifediol), which is converted in the kidneys to 1,25- dihydroxy vitamin D3

(calcitriol) which is the most active from of vit D.

Synthesis of calcitroil is controlled by:

1.1. PTH.PTH.

2.2. Phosphate concentration in the Phosphate concentration in the plasma.plasma.

3. Calcitroil concentration (negative Calcitroil concentration (negative feedback mechanism).feedback mechanism).

The main action of calcitriol are:

*Stimulation of absorption of Ca and phosphate in the intestine.

• Mobilization of Ca from bone.

• Increases Ca reabsorption in the kidneys tubules.

Vitamin D defi can be prevented by taking oral 10 micg (400 unit)of ergocalciferol- Vit D2 daily.

In Hypocalcemia and hypoPTH large doses are required-2.5mg (100000 units) daily.

Calcitriol (1micg)and alfacalcidol- one-alpha

(250 nanog) (are given IV or cap or drops (neonates) in renal failure,

hypocalcemia and hypoPTH ,.

Actions of PTH and Vit D on gut, bone and

kidneys

PTH VITAMIN D IntestineIncrease Ca and ph.

Absorption.Increase Ca and ph absorption

KidneyDecrease Ca excretion.

Increase ph excretion

Increase Ca reabsorption, Ca and ph excretion may be decreased.

BoneCa and ph resorption increased by high dose. Bone formation increase in low dose.

Increase Ca and ph resorption. Bone formation may be increased.

Effect on serum level

Serum Ca increase.

Serum ph decrease.

Serum Ca and ph increased.

CALCITONINIs a peptide hormone produced by specialized "C" cells of the thyroid gland.

Actions (mainly on the bone)Actions (mainly on the bone)1.Inhibits bone resorption by binding to a

specific receptors on osteoclasts, inhibiting their action

2. Decrease the reabsorption of both Ca and Ph in the proximal tubules.

• Net effect is to decrease serum Ca and ph concentration.

• Obtained from natural sources (salmon pork, eel) or synthesized.

• Synthetic salmon (salcatonin, salamon calcitonin) used for prolonged use.

• Given S/C, IM or intranasally to control:

1.Hypercalcemia.

2. Paget's disease (pain and relieve nerve compression)

3.Metastatic bone cancer pain.

4.Post menopausal osteoparosis.

Adverse effectsGIT upsetDizzinessAllergyNasal spray may cause rhinitis and epistaxis.

Unpleasant tast in the mouth.

Adverse Effects• Pain at the injection site.

• Nausea

• Flushing of face.

• Tingling of the hands.

DRUGS USED IN BONE

DISORDERS

Biphosphonates (Bisphosphonates)

•Aldendronate sodium (aldenronic acid), FOSAMAX Risedronate, disodium etidronate, disodium pamidronate.

• Are enzyme-resistant analogues of pyrophosphate, which normally inhibits meniralisation in bone.

• They reduce the resorption of bone in dose-dependent manner, by inhibiting recruitment and prompting cell apoptosis of osteoclasts( inhibits osteoclasts activity).

• Indirectly stimulate ostoblasts activity

• (specific inhibitors of osteoclasts-mediated bone resorption).

• Given orally on empty stomach 30 min before breakfast with glass of water sit in upright or stand for 30 min.

• Poorly absorbed (impaired by food, milk, coffee ,orange juice).

• Low bioavailability

• 50% of the dose accumulate at sites of bone meniralisation, specifically under the osteoclasts, where it remains for months or years until the bone is reabsorbed (bone formation exceeds bone resorption)

• Free drug excreted unchanged in the urine.

• Not metabolized

• Half-life 10 years ( reflecting the release of alendronate from the skeleton.

• Given 10 mg daily or 70 mg weekly

INDICATIONS1. Treatment and prevention of

osteoporosis in postmenopausal women.

2. Treatment to increase bone mass in men with osteoporosis.

3.Treatment of corticosteroid-induced osteoporosis in men and women.

4.Treatment of Paget's disease in men and women.

Cautions and contra -indications:

1. GIT problems2. Renal impairment3. Vitamin D deficiency and

hypocalcemia.4. Abnormalities in the

oesophagus5. Pregnancy and breast feeding

Adverse Effects

•GIT- upset can be severe ,abdominal pain, peptic ulcer.

• Severe oesophageal reactions

• Bone pain (back and joints)

• Headache and dizziness

• Allergy , Pyrexia.

• Photosensitivity, rash

• Factures (etidronate) demineralization of bone.

INTERACTIONSINTERACTIONS

• Food, menirals, calcium supplements, antacids.

• Must be given 30 min before meal.

Compounds related to estrogens

Decline in estrogen levels is the major factor in postmenopausal osteoporosis.

RALOXIFENEIs selective estrogen receptor modulators (SERMS).Produces a dose-dependent increase in osteoblasts activity and reduction in

osteoclasts action.