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:
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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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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
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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
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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
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1,25(OH)2D directly inhibits PTH secretion
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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
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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
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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
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
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It lowers Ca and P and inhibits osteoclastic bone
resorption
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At first, bone formation is not impaired, but with time
both formation and resorption of bone are reduced
Calcitonin (Cont’d)
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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
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Glucocorticoids antagonize vitamin D-stimulated
intestinal Ca transport
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Glucocorticoids do that by stimulating renal Ca
excretion, and by blocking bone formation
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They are used in reversing the hypercalcemia
associated with lymphomas, sarcoidosis, or in vitamin
D intoxication
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Their prolonged administration causes osteoporosis in
adults and stunted skeletal growth in children
Estrogens
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Estrogens can prevent accelerated bone loss during
the immediate postmenopausal period
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Estrogens increase 1,25(OH)2D in blood
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Estrogen receptors have been found in bone, and
estrogen has direct effects on bone remodeling
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Long-term use of estrogen has some adverse effects
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Selective estrogen receptor modulators (SERMs)
retain the beneficial effects while minimizing the
adverse effects
Estrogens (Cont’d)

Raloxifene is the first SERM used for the
prevention of osteoporosis
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It doses not increase the risk of breast or
endometrial cancer
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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
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Bisphosphonates consist of : Etidronate, Pamidronate,
Alendronate, Risedronate etc.
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They increase bone density and reduce fractures over
at least 5 years
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Trials between alendronate and calcitonin indicated a
greater efficacy of alendronate.
Bisphosphonates (Cont’d)
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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
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Gastric irritation, is the complication of all
bisphosphonates
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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
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The principal application of thiazides is in reducing
renal Ca excretion
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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