DRUGS THAT AFFECT DRUGS THAT AFFECT BONE BONE MINERAL HOMEOSTASISMINERAL HOMEOSTASIS

Calcium exists in three forms: 50% ionized 40% bound to protein (especially to

albumin) 10% complexes to anions.

Approximately 100-250mg of daily intake is absorbed from the proximal intestine with an equal amount excreted by the kidney.

98% filtered calcium is reabsorbed.

Calcium

Calcium metabolism

Control of serum calcium and phosphorus depends on the hormones 1. Vitamin D 2. Parathyroid hormone 3. Calcitonin

Bone remodeling involves dynamic interaction of osteoclast and osteoblast.

Calcium and Phosphate are the two major constituents of the bone.

Normal extra cellular concentrations of calcium is required for proper functioning of nerves, muscles and blood coagulation.

The balance between bone resorption and bone formation is usually maintained up to fourth decade.

Calcium

•An adequate intake of Calcium and Vitamin D is essential for:

1. optimal bone formation in children

2. prevention of osteoporosis in adults.

Calcium drugs

Calcium carbonate requires stomach acidity for absorption.

Calcium citrate does not requires acidity. Calcium gluconate is the preferred i.v

preparation. Calcium and Vitamin D are used for:

A. Prevention and treatment of osteoporosis B. Hypocalcemia.

The most common adverse effect of calcium is constipation.

Calcium metabolism

1. Parathormone (PTH) net effect is to increase plasma calcium and decrease phosphate concentration.

Kidney : PTH stimulates reabsorption of calcium

by the renal tubules. PTH decrease the reabsorption of

phosphate from renal tubules – this ↓ plasma phosphate concentration, which in turn ↑ plasma calcium.

Calcium metabolism

PTH : Bone : PTH increase bone resorption by

stimulating osteoclast activity which enables the bone calcium to enter the extra cellular pool (High dose).

PTH : GIT : It increase calcium and phosphate

absorption by activating the synthesis of 1,25 dihydroxyvitamin D-3 (Calcitriol).

Calcium metabolism

PTH : In low and intermittent doses,

PTH increase bone formation without stimulating bone resorption.

TERIPARATIDE – recombinant PTH approved for the treatment of osteoporosis.

Calcium metabolism

2. Vitamin D : It is a prohormone. Vitamin D-3 (cholecalciferol) and

Vitamin D-2 (ergocalciferol) are the major forms of vitamin D.

Vitamin D-3 is produced in the skin from 7-dehydrocholesterol under the influence of ultra-violet light.

Vit-D-3 is an inactive precursor of active 1,25 dihydroxyvitamin D-3 (Calcitriol).

Calcium metabolism

Vitamin D : Net effect is to increase plasma calcium and phosphate concentration.

The hydroxylation of Vitamin D-3 at the 25 position in the liver results in 25 Hydroxyvitamin-D3 (Calcifediol).

PTH stimulates the renal hydroxylation at position 1 resulting in 1, 25 Dihydroxyvitamin D-3 (Calcitriol).

Calcium metabolism

Vitamin D : Calcitriol’s primary effect is on the small

intestine where it increase dietary calcium and phosphate absorption.

Vitamin D promotes mineralization bone formation.

Calcium and phosphate excretion may be decreased by renal tubules.

Calcium metabolism

Vitamin D : It inhibits parathyroid hormone

secretion from the parathyroid gland.

Vitamin D affects the immune system by promoting phagocytosis, anti-tumor activity, and immunomodulatory functions.

Vitamin D is used to prevent and treat: osteoporosis Rickets: vit. D deficiency in children osteomalacia

In renal failure, it is advisable to use the active form, calcitriol as they cannot synthesize it.

Calcipotriol, synthetic derivative of vitamin D, is used in psoriasis.

3. Calcitonin : It is released in response to increased plasma calcium and it decrease plasma calcium.

It is secreted by the parafollicular cells of the thyroid gland.

It is administered parenterally or nasal inhalation.

Salmon calcitonin is 100 times more potent than human calcitonin.

Calcitonin : Principal effects are to lower serum calcium and phosphate

It inhibits osteoclast activity, decrease bone resorption thus lowers serum calcium and phosphate and reduce bone pain.

It decrease the reabsorption of calcium and phosphate from the renal tubules.

Calcitonin : It increase BMD in spine Used in paget’s disease of bone(enlarged

and deformed bones)

Osteoporosis Hypercalcemia Usually reserved for post menopausal

women (who cannot take estrogen).

PTHPTHVitamin Vitamin DD

CalcitonCalcitoninin

IntestineIntestine↑ ↑ Ca &↑ PO4 Ca &↑ PO4 absorptionabsorption

↑ ↑ Ca & P04 Ca & P04 absorptionabsorption

----------

KidneyKidney↓↓Ca &↑ P04 Ca &↑ P04 excretionexcretion

↓↓Ca & PO4 Ca & PO4 excretionexcretion

↑ ↑ Ca & PO4 Ca & PO4 excretionexcretion

BoneBone↑ ↑ bone bone resorption (H)resorption (H)

↑ ↑ bone bone formation (L)formation (L)

↑ ↑ bone bone resorption resorption (H) ↑ (H) ↑ bone bone formationformation

↓ ↓ bone bone resorptionresorption

Net Net effecteffect

↑ ↑ plasma Ca plasma Ca ↓ plasma ↓ plasma PO4PO4

↑ ↑ plasma plasma Ca ↑ Ca ↑ plasma plasma PO4PO4

↓ ↓ plasma plasma Ca ↓ Ca ↓ plasma plasma PO4PO4

Phosphate

Phosphate helps maintain acid-base equilibrium.

Buffers and allows for renal H+ excretion. Helps regulate calcium metabolism, and is

an active intermediate of energy metabolism (ATP).

Approximately 67% of an oral dose is absorbed from the intestine.

Excretion is via the kidney.

Biphosphonates : Alendronate (Fosamax) Risedronate (Actonel) Ibandronate (Boniva) Zoledronate (Zometa)

These compounds have P-C-P which is nonhydrolyzable compared with Pyrophosphate P-O-P found in bone hydroxyapatite.

Calcium metabolism

Biphosphonates : It adsorbs to hydroxyapatite and

become a part of the bone structure. They are slowly released from the bone

during the bone remodeling. Biphosphonates prevent bone resorption

by inhibiting osteoclast activity Prevent attachment of osteoclast to bone.

Decrease the activity of osteoclast .

Biphosphonates : Used in steroid induced

osteoporosis, paget’s disease and hypercalcemia of malignancy

Biphosphonate result in esophagitis and GIT distress.

Miscellaneous agents : Estrogens are considered as first line of

therapy for prevention of osteoporosis in postmenopausal women.

Estrogens decrease bone resorption by: inhibiting IL-1, TNF and CSF from monocytes decrease osteoclast differentiation / activation

which slows bone loss in women. Raloxifene, selective estrogen receptor

modulator, can be used for prevention of osteoporosis in women with breast / endometrial cancer.

Fluoride : It is well established for the

prophylaxis of dental caries. It stimulates new bone formation. It increase the bone crystal size and

render the bone more resistant to resorption.

Bone

Plicamycin : A cytotoxic antibiotic is an inhibitor of

osteoclast and block the action of PTH. Used to treat Paget’s disease.

Glucocorticoids : It decrease osteoblast activity and

cause osteoporosis.

Thiazides

Treatment of bone mineral disorders. Reduce Renal Ca excretion. Increases effectiveness of PTH. Block Na reabsorption, increasing Ca

exchange (distal tubule). Reduce incidence of stone formation.