AGENTS THAT AFFECT BONE

MINERALIZATION
BY DR MARY ONYANGO
CONTENT
Introduction
Hormonal regulators
Other non-hormonal regulators
INTRODUCTION
Main bone minerals
Calcium and phosphate
98% of calcium and 85% of phosphate in
an adult human are in bone
Main components involved in the
homeostasis are
Gut
Bone
Kidney
Cont.
Gut
Calcium absorption occur principally in the
duodenum and upper jejunum while secretion
occurs in the ileum
Phosphorus absorption occurs principally in the
jejunum
Kidney
Both are filtered and 98% of the filtered Ca and
85% of the filtered phosphate is reabsorbed
At steady state, renal excretion of both
balanced intestinal absorpation
Physiological Importance of Calcium
 Ca salts in bone provide structural integrity of
the skeleton.
 Ca is the most abundant mineral in the body.
 The amount of Ca is balance among intake,
storage, and excretion.
 This balance is controlled by transfer of Ca
among 3 organs: intestine, bone, kidneys.
 Ca ions in extracellular and cellular fluids is
essential to normal function of a host of
biochemical processes
Neuoromuscular excitability and signal
transduction
Blood coagulation
Hormonal secretion
Enzymatic regulation
Intake of Calcium
About 1000 mg of Ca is ingested per day.
About 200 mg of this is absorbed into the
body.
Absorption occurs in the small intestine,
and requires vitamin D (stay tuned....)
Storage of Calcium
 The primary site of storage is our bones (about
1000 grams).
 Some calcium is stored within cells
(endoplasmic reticulum and mitochondria).
 Bone is produced by osteoblast cells which
produce collagen, which is then mineralized by
calcium and phosphate (hydroxyapatite).
 Bone is remineralized (broken down) by
osteoclasts, which secrete acid, causing the
release of calcium and phosphate into the
bloodstream.
 There is constant exchange of calcium between
bone and blood.
Excretion of Calcium
The major site of Ca excretion in the
body is the kidneys.
The rate of Ca loss and reabsorption at
the kidney can be regulated.
Regulation of absorption, storage, and
excretion of Ca results in maintenance
of calcium homeostasis.
Regulation of [Calcium]
The important role that calcium plays in so
many processes dictates that its
concentration, both extracellularly and
intracellularly, be maintained within a very
narrow range.
This is achieved by an elaborate system of
controls
Regulation of Intracellular [Calcium]

Control of cellular Ca homeostasis is as

carefully maintained as in extracellular
fluids
 [Ca2+]cyt is approximately 1/1000th of
extracellular concentration
Stored in mitochondria and ER
“pump-leak” transport systems control
[Ca2+]cyt
Calcium leaks into cytosolic compartment
and is actively pumped into storage sites in
organelles to shift it away from cytosolic
pools.
Calcium and Bone
99% of Ca is found in the bone. Most is
found in hydroxyapatite crystals. Very little
Ca2+ can be released from the bone–
though it is the major reservoir of Ca 2+ in
the body.
Hormonal regulators
 Main
Parathyroid hormone
Vitamin D
 Others
Calcitonin
Glucocorticoids
Estrogens
Androgens
Growth hormone
Thyroid hormones
Insulin
Prolactin
Fibroblast growth factor 23
Bone mineral homeostasis
The hormonal interactions
controlling
bone mineral homeostasis
Cont.
Parathyroid hormone
Single chain peptide composed of 84 amino
acids
Produced as 115 aa precursor by the
parathyroid gland
The biologic activity resides in the amino
terminal region
Synthetic 1-34 PTH is fully active
(teriparatide)
Rapidly cleared mainly in the liver and
kidney
Cont.
Parathyroid hormone
 Effects
Bone
 Increases both bone formation and bone resorption
 However the net effect of excess PTH is to increase bone
resorption
 It increases the activity and number of osteoclasts
 Acts on the osteoblasts to induce a membrane bound protein
called the RANK ligand
 It caused bone remodelling
Kidney
 It increases the ability of the kidney to reabsorb Ca and Mg
 Reduces the reabsorption of Phosphate, amino acids, bicarbonate,
sodium, chloride and sulpahate
 Stimulates the production od 1,25-dihydroxy vitamin D
Net effect
 Increased serum calcium and decreased serum phosphate
 Actions of Parathyroid Hormone (PTH), Vitamin D,
and FGF23 on Gut, Bone, and Kidney
PTH Vitamin D FGF23
Intestine Increased calcium and Increased calcium and Decreased calcium and
phosphate absorption (by phosphate absorption phosphate absorption
increased 1,25[OH]2D by 1,25 (OH)2D by decreased 1,25(OH)2
production) production

Kidney Decreased calcium excretion, Calcium and phosphate Increased phosphate

increased phosphate excretion excretion may be excretion
decreased by 25(OH)D
and 1,25(OH)2D1

Bone Calcium and phosphate Increased calcium and Decreased

resorption increased by high phosphate resorption mineralization due to
doses. Low doses may by 1,25(OH)2D; bone hypophosphatemia
increase bone formation. formation may be
increased by
1,25(OH)2D and
24,25(OH)2D

Net effect on serum levels Serum calcium increased, Serum calcium and Decreased serum
serum phosphate decreased phosphate both phosphate
increased
Cont..
Regulation of PTH
 Ca ions
Bind to a recognition site that is part of a Ga protein
coupled receptor called the calcium sensing
receptor(CaR)
This links the changes in intracellular free Ca2+ to
changes in extracellular concentration
As serum ca ion levels rise and bind to this receptor,
intracellular ca ion increase and inhibit PTH secretion
 Phosphate ions
Increased PO4 ion bind to ca ions reducing the free
ionized Ca and this leads to enhanced PTH secretion
 Both Ca and Phosphate ions inhibit the production of
1,25-dihydroxyVit D by the kidney
 Increased 1,25-(OH)2D directly inhibit PTH secretion
Cont.
vitamin D
A secosteroid produced in the skin from 7-
dehydrocholesterol under the influence of UV
radiation
Natural form is Vit D3 – cholecalciferol
Diet- Vit D2 – ergocalciferol which contains a
double bond at position C22-23 and an
additional methyl group in the side chain
Vit D if a prohormone which is sequentially
activated by hydroxylation
First in the liver to form 25-hydroxyvit D
Then in the kidney to 1,25-dihydroxy VitD and
24,25- dihydroxy Vit D
 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
1a-Hydroxyvitamin D2; doxercalciferol 1a(OH)D2
19-nor-1,25-Dihydroxyvitamin D2; paricalcitol 19-nor-
Conversion of 7-dehydrocholesterol to vitamin D3 and
metabolism
Cont..
Vitamin D
 The vit Ds circulate in plasma tightly bound to a
carrier protein – Vitamin D binding protein
 Cleared in the liver
 Excess Vit D is stored in the adipose tissue
 1,25 dihydroxyvitamin D is the most potent
 It bind to its intracellular receptors to induce
protein synthesis
 It stimulates intestinal Ca ion and phosphate
transport and bone resorption
 In bone it may regulate the mineralization process
 The net effect
Increased serum Ca and Phosphate concentration
Calcitonin
 Produced by the parafollicular cells of the thyroid
gland
 Is a single chain peptide with 32 aa with a disulphide
bond between positions 1 and 7- this is essential for
biologic activity
 Mostly cleared by the kidney
 Effects
It lowers the serum Ca and Phosphate concentrations
Bone
 Inhibits osteoclastic bone resorption
Kidney
 Reduces the reabsorption of Ca, Phosphate, Na, K, Mg

 Used in the treatment of hypercalcemia, Paget's

disease, osteoporosis
Other hormones
Glucocorticoids
Alter bone mineralization by antagonizing Vit
D stimulated Ca ion transport, stimulating
renal Ca ion excretion and blocking bone
formation
Estrogens
Reduce bone resorption action of PTH
Increase the 1,25 – dihydroxyVit D level in
blood
Non hormonal agents
a) Bisphosphonates
Examples
Etidronate
Alendronate
Pamidronate
Risedronate
Zoledronate
Ibandronate
Tiludronate
They are analogues of pyrophosphate in
which the P-O-P bond has been replaced by
P-C-P bonds
The structure of
pyrophosphate
Bisphosphonates cont.
pharmacokinetics
 Poor oral absorption – less than 10%
 Food reduces absorption further
 Nearly half of the absorbed drug accumulates in bone
the remainder is excreted unchanged in urine

 Contraindicationa
Reduced renal function, PUD and esophageal motility
disorder

 Indication
Malignancy associated hypercalcemia
Pagets disease
osteoporosis
Bisphosphonates cont..
Effects
 They retard the formation and dissolution of
hydroxyapatite crystals within and outside the
skeletal system
 Inhibit osteoclastic activity and hence bone resorption
 Others
Inhibit production of 1,25-dihydroxy Vit D
Inhibit intestinal Ca transport
Inhibit glycolysis in cells
Inhibit cell growth
Amino bisphosphonates inhibit mevalonate pathway
 Adverse effects
Gastric and esophageal irritation
Necrosis of the jaw
 DENOSUMAB

Monoclonal antibody
Binds to and prevents the action of RANKL
Inhibits osteoclast formation and activity
Calcimimetics
Cina-cal-cet
Activates the calcium sensing receptor in the
parathyroid gland
Block the PTH secretion
Used in the treatment of secondary
hyperparathyroidism in CKD and treatment of
parathyroid carcinoma
The hormonal interactions
controlling
bone mineral homeostasis
Other agents
 Plicamycin (mithramycin)
 Inhibit bone resorption
 Thiazides
 Reduce renal excretion of calcium
 Strontium ranelate
 Inhibit bone resorption
 Block differentiation of osteoclasts
 Increasing bone mineral density and decreasing fractures

 Fluoride
 Stabilize the bone structure
 Stabilize the hydroxyapatite crystal
 Produce osteomalacia in lack of Ca++
 There is no reduction in fractures