Agents That Affect Bone Mineral Homeostasis

• BONE PHYSIOLOGY
The skeleton is the primary structural support for the body and also
provides a protected environment for hematopoiesis. It contains both a
large mineralized matrix and a highly active cellular compartment.
Bone Remodeling.
• Growth and development of endochondral bone are driven by a process
called modeling.
• Once new bone is laid down,
it is subject to a continuous process
of breakdown and renewal called
remodeling, by which bone mass is adjusted
throughout adult life.
• Calcium and phosphate are essential for normal cellular function.
• They are the major mineral constituents of bone which is considered the
main reservoir for Ca2+ and phosphate.
• These minerals located in bone are in dynamic exchange with those in the
extracellular fluid to maintain the normal homeostasis of Ca2+ and
phosphate.
• Two regulators serve to maintain the Ca2+ and phosphate balance in the
body:
1) Parathyroid hormone (PTH) and 2) Vitamin D.
• Calcitonin also plays an important role in regulation of Ca2+ homeostasis.
In addition, other hormones such as growth hormone, sex hormones and
glucocorticoids influence Ca2+ and phosphate balance.
 1. PARATHYROID HORMONE (PTH)
• Parathormone is a single chain
polypeptide hormone secreted by the
parathyroid glands.

Physiological actions of PTH:

Parathormone maintains a constant concentration of Ca2+ and
phosphate in the extracellular fluid by the following effects:
1-In bone, PTH increases the activity and number of osteoclasts,
the cells responsible for bone resorption. However, this stimulation
of osteoclasts is not a direct effect. PTH acts on the osteoblast (the
bone-forming cell) to induce a membrane-bound protein called
RANK ligand (RANKL).
This factor acts on osteoclasts and osteoclast precursors to increase both the
numbers and the activity of osteoclasts. This action increases bone turnover or
bone remodeling, a specific sequence of cellular events initiated by osteoclastic
bone resorption and followed by osteoblastic bone formation.

Although both bone resorption and bone formation are enhanced by PTH, the
net effect of excess PTH is to increase bone resorption.
N.B:
PTH in low and intermittent doses increases bone formation without first
stimulating bone resorption.
This action appears to be indirect, involving other growth factors such as IGF-1.
**This has led to the recent approval of recombinant PTH 1-34 ( Teriparatide )
for the treatment of osteoporosis.
2- Kidnyes: It increases the reabsorption of Ca2+ from renal tubules and so
the plasma calcium level is increased.
However, renal excretion of phosphate is increased and its plasma level is
decreased.

3- GIT: It increases the absorption of Ca2+ and phosphate from GIT either
directly or indirectly through stimulation of the conversion of calcifediol to
calcitriol in the kidney.
Regulation of PTH secretion:
• Secretion PTH is regulated by the ionized Ca2+ level in the blood through
a feed-back mechanism. Thus, a decrease in the serum Ca2+ level results
in an increase in PTH secretion and vice versa.

Hypoparathyroidism:
• The symptoms of hypoparathyroidism include decreased serum Ca2+
level leading to tetany which is characterized by nervousness, excitement,
muscle twitches and convulsions.
Treatment:
• Treatment with natural PTH is usually not preferable because:
a) Severe reactions may occur and resistance rapidly develops to its actions.
b) It is also expensive and not active orally.
• Synthetic PTH (Teriparatide) is used for diagnostic purposes to distinguish
between pseudohypoparathyroidism (target organ resistance to the hormone)
and hypoparathyroidism and in treatment of osteoporosis.
• Patients with the former condition fail to show elevated serum Ca2+
concentration.
Drugs used in hypoparathyroidism include:
1. Calcium gluconate, 2. Vitamin D 3. Dihydrotachysterol.
• They are more safe and less expensive than PTH.

Hyperparathyroidism:
• It results in excessive rise in the serum Ca2+ level which leads to
precipitation of calcium in tissues such as lungs, kidneys and heart rather
than bone. The bone becomes easily broken (decalcified).
Treatment: It is treated by surgical removal of one or more of the glands.
 2. VITAMIN-D
- Vitamin D plays a major role in control of plasma level of Ca2+ ions.
- It is synthesized under the skin from 7-dehydrocholesterol under the influence of
ultraviolet radiation. It is transported by the blood into the liver and kidneys where it
is converted into a number of biologically active metabolites such as:
Calcitriol, Calcifediol and Cholecalciferol
- which circulate in the blood to regulate the activities of
various cell types.

Pharmacological actions:
1- Vitamin D facilitates absorption of Ca2+ and phosphate from intestine.
2- It enhances mobilization of Ca2+ and phosphate from bones.
3. It decreases the excretion of Ca2+ and phosphate by the kidneys via promoting their
renal tubular reabsorption.

All these effects aid to maintain Ca2+ and phosphate at concentrations that are essential
for neuromuscular activity, mineralization of bone and a number of other Ca2+
dependent functions.
Vitamin D deficiency:
• Deficiency of Vitamin D leads to inadequate absorption of Ca2+ and
phosphate. The consequent decrease in plasma Ca2+ level will lead to
stimulation of PTH secretion which tends to restore plasma Ca2+ level at
the expense of bone Ca2+ .

• In infants and children this results in failure of mineralization of osteoid

tissues and causes defect in bone growth known as rickets.
• In adults it leads to osteomalacia.

Clinical indications of Vitamin D:

1- Rickets and osteomalacia.
2- Treatment of hypoparathyroidism.
3- Osteoporosis.
 3. CALCITONIN
• Calcitonin is a hypocalcemic polypeptide H secreted by the thyroid gland.
• Its secretion is controlled by plasma Ca2+ level; an increase in plasma
concentration of Ca2+ increases the amount of the hormone in plasma and
vice versa.
• The main effect of calcitonin is to lower the serum levels of Ca2+ and
phosphorus by the following actions on bones and kidneys:
1- It inhibits bone resorption by inhibiting osteoclastic activity.
In addition, some evidence indicates that calcitonin stimulates bone
formation by osteoblasts.
2- It reduces the renal reabsorption of Ca2+ and phosphorus.
Clinical uses:
Salmon calcitonin (Miacalcic) is used by intranasal administration.
Uses:
1. Calcitonin is used in hypercalcemic states such as hyperparathyroidism, vitamin D
intoxication, idiopathic hypercalcemia of infancy and osteolytic bone metastasis.
2. Calcitonin is also effective in Paget's disease.
3. In postmenopausal osteoporosis.

4. DIPHOSPHONATES
ETIDRONATE PAMIDRONATE
• ALENDRONATE Risedronate
Tiludronate zoledronate

• These drugs inhibit osteoclastic-mediated bone resorption. They are effective in the
treatment of Paget's disease, hypercalcemia of malignancy and osteoporosis.
• GLUCOCORTICOIDS
Glucocorticoid hormones alter bone mineral homeostasis by antagonizing vitamin
D-stimulated intestinal calcium transport, by stimulating renal calcium excretion,
and by blocking bone formation.
• Prolonged administration of glucocorticoids is a common cause of osteoporosis in
adults and stunted skeletal development in children .

• ESTROGENS
Estrogens can prevent accelerated bone loss during the immediate postmenopausal
period and at least transiently increase bone in the postmenopausal woman.
• The prevailing hypothesis advanced to explain these observations is that estrogens
reduce the bone-resorbing action of PTH.
• The principal therapeutic application for estrogen administration in disorders of
bone mineral homeostasis is the treatment or prevention of postmenopausal
osteoporosis.
• THIAZIDES
The principal application of thiazides in the treatment of bone mineral disorders is
in reducing renal calcium excretion. Thiazides may increase the effectiveness of
parathyroid hormone in stimulating reabsorption of calcium by the renal tubules or
may act on calcium reabsorption secondarily by increasing sodium reabsorption in
the proximal tubule.

• FLUORIDE
Fluoride is well established as effective for the prophylaxis of dental caries and has
been under investigation for the treatment of osteoporosis.

• PLICAMYCIN (MITHRAMYCIN)
Plicamycin is a cytotoxic antibiotic that has been used clinically for two disorders of
bone mineral metabolism: Paget's disease and hypercalcemia.
OSTEOPOROSIS
Osteoporosis is defined as abnormal loss of bone predisposing to
fractures. It is most common in postmenopausal women but also occurs
in men.
Treatment:
1) Dietary calcium administration.
2) Vitamin D.
3) Biphosphonates.
4) Teriparatide.
5) Calcitonin (Myacalcic).
Thank You….