Download Vitamin D

Agents that Affect
Bone Mineral Homeostasis
By
Dr. Sasan Zaeri
(PharmD , PhD)
Department of Pharmacology
Introduction

Abnormalities in bone mineral homeostasis
can lead to:

A wide variety of cellular dysfunctions:
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Tetany
Coma
Muscle weakness
Disturbances in structural support of the body:

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Osteoporosis with fractures
Loss of hematopoietic capacity (infantile osteopetrosis)
Hormonal Regulators of Bone
Mineral Homeostasis

Primary (principal):

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
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Parathyroid hormone (PTH)
Vitamin D (metabolites)
Fibroblast growth factor 23 (FGF23)
Secondary:
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Calcitonin
Glucocorticoids
Estrogen
in pharmacologic doses are
useful therapeutically
Hormonal Regulators of Bone
Mineral Homeostasis (Cont’d)

All the principal regulators affect bone, kidney,
and intestine and also each other activity or
production

The net effect of PTH is to raise serum Ca and
reduce serum phosphate

The net effect of vitamin D is to raise both

The net effect of FGF23 is to decrease
phosphate
Hormonal interactions controlling bone
mineral homeostasis
Parathyroid Hormone

PTH is the most important stimulator for renal
production of the active metabolite of vitamin
D: 1,25(OH)2D

PTH promotes both bone formation and
resorption by stimulating the osteoblasts and
osteoclasts

PTH enhances renal retention of Ca

It promotes renal phosphate excretion
Bone Formation versus Resorption
Parathyroid Hormone (Cont’d)

Ca is the principal regulator of PTH secretion

The net effect of excess PTH is to increase bone
resorption

However, PTH in low and intermittent doses
increases bone formation

The biologic activity of PTH resides in the last 34
amino acids of amino terminal

This led to recombinant form of PTH 1-34
(Teriparatide) for the treatment of osteoporosis
Vitamin D (metabolites)

Vitamin D is produced in the skin from 7dehydrocholesterol under the influence of UV
radiation

Both the natural form (cholecalciferol) (D3) and the
plant-derived form (ergocalciferol) (D2) are present in
the diet
Vitamin D
Vitamin D synthesis and activation.
Vitamin D is synthesized in the skin in
response to ultraviolet radiation and is
also absorbed from the diet. It is then
transported to the liver, where it
undergoes 25-hydroxylation. This
metabolite is the major circulating
form of vitamin D. The final step in
hormone activation, 1-hydroxylation,
occurs in the kidney.
Vitamin D
25(OH)D
1,25(OH)2D
Vitamin D and Its Major Metabolites and Analogs
Chemical and Generic Names
Abbreviation
Vitamin D3; cholecalciferol
D3
Vitamin D2; ergocalciferol
D2
25-Hydroxyvitamin D3; calcifediol
25(OH)D3
1,25-Dihydroxyvitamin D3; calcitriol
1,25(OH)2D3
24,25-Dihydroxyvitamin D3; secalcifediol
24,25(OH)2D3
Dihydrotachysterol
DHT
Calcipotriene (calcipotriol)
None
1-Hydroxyvitamin D2; doxercalciferol
1(OH)D2
19-nor-1,25-Dihydroxyvitamin D2; paricalcitol
19-nor-1,25(OH)D2
Vitamin D (metabolites) Cont’d

1,25(OH)2D stimulates the intestinal absorption of Ca
and phosphate.

It promotes both bone formation and resorption by
stimulating the osteoblasts and osteoclasts.

Calcitriol enhances renal retention of Ca.
Vitamin D (metabolites) Cont’d

1,25(OH)2D directly inhibits PTH secretion

This is by a direct action on PTH gene transcription
and independent of its effect on Ca
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This ability is being exploited using calcitriol analogs
that have less effect on Ca

Such analogs have little of the hypercalcemic, hypercalciuric
effects of calcitriol

This is an important aspect of their use for secondary
hyperparathyroidism
Vitamin D (metabolites) Cont’d

Doxercalciferol and paricalcitol are used for secondary
hyperparathyroidism in patients with chronic kidney
disease
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Calcipotriene (calcipotriol), is being used for psoriasis
Fibroblast Growth Factor 23

Fibroblast growth factor 23 (FGF23) is the most
important inhibitor for renal production of
1,25(OH)2D.

It stimulates P excretion in the kidney.

This leads to hypophosphatemia and low levels of
1,25(OH)2D3.
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Osteoblasts and osteocytes in bone are its primary site
of production.
Calcitonin
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Human calcitonin has a half-life of 10 minutes

Salmon calcitonin (as nasal spray) half-life is 43 min,
making it more useful as a therapeutic agent

It lowers Ca and P and inhibits osteoclastic bone
resorption

At first, bone formation is not impaired, but with time
both formation and resorption of bone are reduced
Calcitonin (Cont’d)

No major problem develops in cases of calcitonin
deficiency (thyroidectomy) or excess (medullary
carcinoma of the thyroid)

Its ability to block bone resorption and lower Ca is
used in Paget's disease, osteoporosis and hypercalcemia
Glucocorticoids

Glucocorticoids antagonize vitamin D-stimulated
intestinal Ca transport

Glucocorticoids do that by stimulating renal Ca
excretion, and by blocking bone formation

They are used in reversing the hypercalcemia
associated with lymphomas, sarcoidosis, or in vitamin
D intoxication

Their prolonged administration causes osteoporosis in
adults and stunted skeletal growth in children
Estrogens

Estrogens can prevent accelerated bone loss during
the immediate postmenopausal period

Estrogens increase 1,25(OH)2D in blood

Estrogen receptors have been found in bone, and
estrogen has direct effects on bone remodeling

Long-term use of estrogen has some adverse effects

Selective estrogen receptor modulators (SERMs)
retain the beneficial effects while minimizing the
adverse effects
Results of hormone therapy regimens on bone mineral density (BMD)
of the spine and hip.
Estrogens (Cont’d)

Raloxifene is the first SERM used for the
prevention of osteoporosis

It doses not increase the risk of breast or
endometrial cancer

It may actually reduce the risk of breast cancer
Non-Hormonal Regulators of Bone
Mineral Homeostasis
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Bisphosphonate
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Thiazides
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…
Bisphosphonates

Bisphosphonates consist of : Etidronate, Pamidronate,
Alendronate, Risedronate etc.
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They increase bone density and reduce fractures over
at least 5 years

Trials between alendronate and calcitonin indicated a
greater efficacy of alendronate.
Bisphosphonates (Cont’d)

The exact mechanism by which they selectively inhibit
bone resorption is not clear

Food reduces the absorption of these drugs, so should
be administered on an empty stomach

Gastric irritation, is the complication of all
bisphosphonates

Contraindications are: decreased renal function,
esophageal motility disorders, and peptic ulcer

They are useful for the treatment of paget's disease,
hypercalcemia of malignancy, and osteoporosis
Thiazides

The principal application of thiazides is in reducing
renal Ca excretion

In the distal tubule, thiazides block sodium
reabsorption, increasing the Ca-sodium exchange,
thus enhancing Ca reabsorption into the blood.

Thiazides are useful in reducing the hypercalciuria
and incidence of stone formation in idiopathic
hypercalciuria
Calcitonin
Calcipotriol
Teriparatide