Bone mineral homeostasis

The main minerals in bone are calcium salts and phosphates. More than 90% of Ca+2 in the body is in the skeleton, mostly as crystalline hydroxyapatite (ca-phosphate crystals) which are deposited the osteoid , converting it into hard bone matrix. Bone remodeling: The process of remodeling involves the activity of: 1. Osteoblasts which secretes new bone matrix. 2. Osteoclasts which break it down.

The principal hormone involved in Ca+2 metabolism and bone remodeling are: 1. Parathyroid hormone. 2. Calcitonin. 3. Vitamin D
And the main target tissues for these hormones are: a. Bone. b. Kidney. c. Intestine. These 3 hormones and their target organs maintain serum calcium levels & bone integrity.

Parathyroid hormone (PTH) PTH or parathormone is secreted from parathyroid gland in response to free Ca+2 concentration (hypocalcemia).

It maintains serum the plasma Ca+2 by: 1. Mobilizing Ca+2from bone. 2. Promotes its absorption by the kidney. 3. synthesis of calcitriol which Ca+2absorption from the intestine. 4. PTH promotes phosphate excretion. So net effects: Ca+2in plasma, phosphate in the plasma.
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The main factors involved in maintaining the concentration of Ca+2 in the plasma & the action of drugs

 Calcitonin
Is secreted from specialized C cells found in the thyroid gland. Actions: 1. Inhibits bone resorption by inhibiting osteoclasts effects. 2. In the kidney, it decrease reabsorption of Ca+2 & phosphate in the proximal tubules.

So net effects: Ca+2in plasma, phosphate in the plasma.

Clinical uses of calcitonin Hypercalcemia. Osteoporosis.

It is given by injection & can be given intranasally. A form of calcitonin from salmon is mainly used because of longer half life & high potency.

 Vitamin D Vitamin D is prehormone ,that is converted in the body in to number of biologically active metabolites that act as a true hormone.
Sources of vitamin D: 1.Dietary ergocalciferol(D2). 2.Cholecalciferol (D3) generated in the skin from 7dehydrocholesterol by the action of ultraviolet radiation.

Vitamin D synthesis

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Action of vitamin D

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The main action of calcitriol are: 1.Stimulation of absorption of Ca+2 & phosphate in the intestine. 2. Mobilization of Ca+2 from bone. 3.Ca+2 reabsorption in the kidney tubules. The NET effect: Ca+2, phosphate.
the effect of Ca+2 on bone is complex & is clearly not confined to mobilising Ca+2!?

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Administration of vitamin D restore bone formation. one explanation may lie in the fact that calcitriol stimulates the synthesis of osteocalcin, the vitamin K-dependent Ca+2 binding protein of bone matrix.

Clinical uses of vitamin D : 1. Hypocalcemia caused by hypoparathyroidism. 2. Deficiency states :prevention & treatment of various forms of rickets, osteomalacia & deficiency owing to malabsorption. 3.In combination with calcium supplementation & hormone replacement therapy, in postmenopausal osteoporosis.

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Vitamin D Deficiency

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Actions of Parathyroid Hormone (PTH), Vitamin D, on Gut, Bone, and Kidney

Intestine PTH Increased calcium and phosphate absorption (by increased 1,25[OH]2D production) Vitamin D Increased calcium and phosphate absorption by 1,25 (OH)2D

Kidney

Decreased calcium excretion, Calcium and phosphate excretion increased phosphate may be decreased by 25(OH)D and excretion 1,25(OH)2D1

Bone

Calcium and phosphate Increased calcium and phosphate resorption increased by high resorption by 1,25(OH)2D; bone doses. formation may be increased by 1,25(OH)2D

15 Net effect on serum levels Serum calcium increased, Serum calcium and phosphate both serum phosphate decreased increased

 S/Es: Excessive intake of vitamin D causes hypercalcemia : constipation, weakness & fatigue & if persist Ca salts are deposited in the kidney & cause renal failure & kidney stones. Other drugs that involved in bone metabolism: a. Glucocorticoids : physiological concentrations of glucocorticoids are required for osteoblast differentiation. Excessive concentration of glucocorticoids inhibit bone formation by inhibiting osteoblast differentiation & osteoclast action.
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b. estrogens: During the reproductive life in female, estrogens have important role in maintenance of bone integrity. They inhibit osteoclast action & oppose bone-resorbing, Ca+2mobilizing action of PTH. Withdrawal of estrogen as happens at menopause can lead to osteoporosis. Drugs related to estrogens: Selective estrogen receptor modulator (SERM).Raloxifene Has an estrogen agonist effect on bone & antagonist activity on estrogen receptor in mammary tissue & the uterus.
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 Drugs used in bone disorders: Bisphosphonates MOA: they bone resorption by inhibiting osteoclasts & promote apoptosis & indirectly stimulate osteoblast activity.
Example: alendronate

S/Es: GI disturbances which can be sever. Esophagitis can also occur.

To prevent this oral preparation are given with sufficient amount of water & with the patient in upright position.

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 1. 2.

Clinical uses: prevention or treatment of postmenopausal osteoporosis. Hypercalcemia due to malignant disease.

Dental consideration: Concomitant use of salicylates or salicylate- containing compound with bisphosphonates is not recommended since an incidence of upper GI adverse effects.

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Fluoride
Accumulated by bones & teeth, stabilize the hydroxyapatite crystals Effective for prophylaxis of dental caries Under investigation for the treatment of osteoporosis Excess leads to mottling A/Es N., V., GIT blood loss, arthritis

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