SUBSTANCES AFFECTING

BONE MINERAL
HOMEOSTASIS
 INTRODUCTION:
• Calcium and phosphate are the
• main constituents of the bones,
• but they are also necessary for physiological functions
of other cells of the body.
• Bones form the principal reservoirs for the calcium
and phosphate.
• Bones are constantly
• undergoing the process
• of reabsorption and
• formation of new bone.
• During reabsorption, some of calcium and phosphate
is removed from the bone and they go to the blood and
other body fluids.
• During the formation of new bone, some calcium and
phosphate pass from the blood and other body fluids
in to the bone and cause the formation of new bone,
reabsorption of bone occurs by a special type of bone
cells, known as osteoclasts.
• Formation of new bone occurs by another type of bone
cells, known as osteoblasts.
• Bones give support to the body and also formative
elements of the blood are formed inside the bone
marrow. As calcium and phosphate are also necessary
for the functions of other cells of the body, their
deficiency can cause various types of abnormalities in
the body.
• For example:
• Deficiency of calcium and
• phosphate may cause
• muscle weakness,tetany
• and coma etc
• Calcium and phosphate are supplied to the body by
our daily diet. An average diet provides about 600-
1000mg of calcium daily.
• Only 100-250mg of this is absorbed from the intestine
in to the blood circulation.
• There is a complex system, which maintains the
balance of calcium and phosphate between body fluids
and bones and other tissues of the body. The process
which causes this balance ,is known as bone mineral
homeostasis.
• Vitamin D and parathyroid hormone are the principal
agents, which cause the regulation of bone mineral
homeostasis in the body.
• Vitamin D is a prohormone,which is converted in the
body in to 1,25 dihydroxy vitamin D (calcitrol).
• Both calcitrol and parathyroid hormone stimulate the
formation of osteoblast (bone forming cells) and
osteoclasts (cells causing bone resorption).
 SECONDARY REGULATORS OF
BONE MINERAL HOMEOSTASIS:
• Calcitonin,insulin,growth hormone, thyroid
hormone,prolactin,sex hormones, and glucocorticoids
also take part in the physiological regulation of bone
mineral homeostasis.
• They are considered to be the secondary regulators of
the bone mineral homeostasis.
 PARATHYROID HORMONE
• It is a polypeptide, which is secreted by the
parathyroid glands.
• It consists of a single chain of 84 amino acids.
• It produces the following physiological effects:
• 1-Osteoclastic activity (resorption)in the bone, causing
increase in serum calcium level.
• 2-Decreases serum phosphate by causing its increased
excretion in the urine.
• 3-In kidney, increases reabsorption of calcium and
magnesium, but decreases reabsorption of
phosphate ,bicarbonate,sulphate,amino acids and
bicarbonates.
• 4-Increases formation of 1,25-dihydroxychole calciferol in the
kidney, which increases the absorption of calcium from
intestine and renal tubules.
• 5-It causes both formation and resorption of bone, but when in
excess it mainly causes resorption of bone.
• 6-When used in low or intermittent doses, it only causes
formation of bone and no resorption occurs.
• This effect of the PTH occurs through other growth factors
including insulin-like growth factor-1(IGF-1)
• The net effect of parathyroid hormone (PTH) is to
increase the amount of ionized calcium in the blood.
• Secretion of PTH is regulated by the serum calcium,
phosphate, and magnesium. Low serum calcium and
magnesium level stimulates PTH production, while
high levels of calcium and magnesium in the serum
inhibit PTH production. High serum phosphate
increases the secretion PTH.
• A recombinant preparation of PTH is available, which
is known as teriparatide. It is a polypeptide, which
contains only 34 amino acids. It is used in the
treatment of osteoporosis.
 VITAMIN D
• It is available in two forms:
• 1. Ergocalciferol(Vitamin D2)
• 2. Cholecalciferol (Vitamin D3)
Ergocalciferol is formed in the plants, while
cholecalciferol is formed in the skin from the effect of
sunrays on the 7-Dehydrocholesterol(which present in
the skin)
Vitamin D is a prohormone. It is converted in the liver
into 25-hydroxyvitamin-D or calcifediol, which is
further hydroxylated in the kidney into 1, 25-
dihydroxy vitamin-D (1,25-(OH)2-D) or calcitriol, and
24,25 dihydroxy vitamin D.
 ACTIONS:
• 1. Calcitriol increases the
• absorption of calcium and phosphate from intestine.
• It also increases calcium +PO4 reabsorption from the
kidney.

• 2. Calcitriol inhibits PTH secretion.

• It also regulates insulin secretion.

• 3. It produces cytokines from the macrophages and

lymphocytes. It also causes proliferation and
differentiation of cells, such as cancer cells.
 CLINICAL USES:
• 1.Nutritional rickets can be treated with 4000 units of
Vitamin D daily. For prophylaxis of rickets 400 units
of vitamin D daily is required. Calcitriol can also be
used for the treatment of rickets in 0.25-0.5 ug daily.
• 2. Vitamin D-Resistant rickets occurs due to defective
response of tissues receptors to calcitriol. Such cases
responds to high doses of calcitriol. Recently, it is
reported that 24, 25 dihydroxy vitamin D restores the
response to calcitriol
• in such cases.
 3. Vitamin D can also be used in hypocalcaemia.
This can occur in the adults due to following
causes.
• 1. Hypoparathyroidism
• 2. Vitamin D deficiency
• 3. Renal Failure
• 4. Malabsorption of calcium from the intestine
 CALCIMIMETICS
• This is a new group of drugs, which cause stimulation
of calcium sensory receptors(Ca R).
• CaR receptors are widely distributed in the cells of the
body, but they are especially abundant in the cells of
the parathyroid gland.
• Cinacalcet is the only drug yet available from
calcimimetics.
• Cinacalcet inhibits the production of parathyroid
hormone by causing stimulation of CaR receptors on
the cells of parathyroid gland.
• USES:
• It is used in the hyperparathyroidism of renal disease
and in carcinoma of parathyroid gland.
OTHER SUBSTANCES WHICH REGULATE
BONE MINERAL HOMEOSTASIS
• In addition to parathyroid hormone and vitamin
D,certain other agents influence the bone mineral
homeostasis in the body.
• They include the following hormonal and non-
hormonal agents:
• 1-Calcitonin
• 2-Corticosteroids
• 3-Estrogens
• 4-Bisphosphonates
• 5-Plicamycin
• 6-Thiazides
• 7-Fluoride
• 8-Strontium ranelate
 CALCITONIN
• It is a peptide, which is secreted by the
parafollicular cells of the thyroid gland.
• Its plasma half-life is about
• 10 minutes.
• ACTIONS:
• 1-It mainly decreases serum calcium and phosphates by
its effects on the bone and kidney.
• 2-It decreases both the formation and resorption of bone.
• 3-It inhibits the reabsorption of
calcium,phosphate,sodium,potassium,and magnesium
from the renal tubules.
• 4-It decreases acid secretion in the stomach by inhibiting
the secretion of gastrin.
• CLINICAL USES:
• 1-Treatment of hypercalcemia.
• 2-In Paget's disease to cause relief of pain and nerve
compression.
• 3-Osteoporosis,especially postmenopausal.
• 4-Pain due to metastasis of cancer in the bone.
• ADVERSE EFFECTS:
• It has no known adverse effects in humans, but its
effects decrease with the passage of time in cases
suffering from hypercalcemia and Paget's disease i.e.
patients become resistance to the drug.
• CORTICOSTEROIDS
• Prolonged administration of corticosteroids causes
osteoporosis in adults and decreased bone growth in
children.
• ESTROGENS
• They are very effective in the treatment and
prevention of postmenopausal osteoporosis.
BIPHOSPHONATES(BISPHOSPHONATES)
• These are inorganic compounds. The group includes
the following important drugs:
• 1-Etidronate
• 2-Pamidronate
• 3-Alendronate
• 4-Risedronate
• 5-Tiludronate
• 6-Zoledronate
• PHARMACOKINETICS:
• Less than 10% of the bisphosphonates are absorbed
from the intestine. As their absorption is decreased by
food, they are given by empty stomach.
• About 50% of the drug absorbed into the systemic
circulation binds with bone and rest of it is excreted in
the urine. Thus they are not used in cases of renal
failure.
 MECHANISM OF ACTION
• They inhibit the formation and resorption
(destruction)of bone by decreasing the formation and
dissolution of hydroxyapetite crystals in the bone and
other tissues.
• The exact mechanism by which they prevent the
destruction of bone is not known.
• This enzyme (fornesyl pyrophosphate synthase)is
essential for the life of osteoclasts,the cells, which
cause the bone resorption.Thus,inhibition of the
enzyme by amino bisphosphonates will prevent the
bone resorption.
• Statins also prevent the formation of mevalonic acid.
Thus ,they may also be useful in osteoporosis.
• CLINICAL USES:
• They are useful in the following diseases:
• Paget's disease
• Osteoporosis
• Hypercalcaemia due to cancer
• Ectopic calcification
• ADVERSE EFFECTS:
• 1-Pamidronate can cause gastric irritation, therefore
its oral preparation is not available.
• 2-Large doses of etidronate can cause
demineralization of bones with their weakness and
thus can be easily fractured.
• 3-Esophageal irritation may occur with these drugs,
which can be prevented by taking them with full glass
of water and remaining in the upright position for half
an hour.
• PLICAMYCIN:
• Is an anticancer drug, found to be useful in the treatment of
hypercalcemia and Paget's disease, but a much smaller dose is
required than is used for cancer treatment.

• THIAZIDES DIURETICS:
• Decreases the excretion of calcium in the urine, thus they
prevent the formation of calcium stones in the urinary tract.
Because they inhibit the loss of calcium in the urine, they may
be useful in disorders involving the demineralization of bones.
 FLUORIDES:
• They are found to be useful in
• prevention of caries of teeth during growth of
permanent teeth.
• Local application on the teeth (fluoride containing
tooth pastes)is most effective when the permanent
teeth are fully developed.
• Their optimum concentration in water, which is useful
for prevention of dental caries is 0.5-1 ppm.
 STRONTIUM RANELATE
• Another drug use in the treatment of osteoporosis.
• It inhibits the function of osteoclasts and thus
prevents the resorption of bone.
• It also appears to help in the formation of bone.
• Clinical studies have shown that it increases the
density of bone and decreases the incidence of fracture
in spine and hip. It is well tolerated and no significant
adverse effects have been
• observed by its use.