BONE MINERAL HOMEOSTASIS BONE MINERAL HOMEOSTASIS

Calcium
Structural
skeleton, bones, teeth

support and storage

Bones serve as a basic support system protecting vital organs

and as a reservoir for calcium (1-2 kg, 98% in bone)
Functional
nerve and muscle integrity (Integrity of intracellular cement
substances)

smooth and skeletal muscle contraction

hormone and neurotransmitter signaling

exocytosis
intracellular second messenger

regulation of enzymes, channels

clotting cofactor
-Absorbed in duodenum/jejunum
-Reabsorbed by kidney
Calcium

Calcium exists in three forms:

50% ionized

40% bound to protein (especially to albumin)

10% complexes to anions.

Approximately 100-250mg of daily intake is

absorbed from the proximal intestine.

98% filtered calcium is reabsorbed.

Calcium
Structural
skeleton, bones, teeth
support and storage (1 kg, 85% in bone)
Functional

intermediary and energy metabolism (ATP)

cell membranes
nucleic acids
regulatory protein by phosphorylation
Phosphate
Second Messengers
Fig. 19-4
Phosphate

Phosphate helps maintain acid-base

equilibrium.

Buffers and allows for renal H+ excretion.

Helps regulate calcium metabolism, and is an

active intermediate of energy metabolism
(ATP).

Approximately 67% of an oral dose is absorbed

from the intestine. ( jejunum)

Excretion is via the kidney. But large amount

reabsorbed in kidney.
Calcium and phosphate
-Two most important minerals for cellular function
- Homeostasis highly regulated
Cell function wins out over storage

Free [Ca] and [P] are what is important

Ca and P form complex in solution

changing one can change the other
Ca and P also stored together in bone
-Ca and P regulation highly integrated
Abnormalities

Cellular dysfunction, tetany, coma, weakness

Osteoporosis, fractures
Despite its static appearance, bone is constantly being formed and broken down. This process, called
remodeling, is the resorption (breaking down) of existing bone and deposition of new bone to replace that
which has been broken down. At any one time, about 5% of bone surfaces in adults are undergoing
remodeling.
As a result of remodeling, most of the adult skeleton is replaced about every 10 years.A number of interrelated
hormonal, nutritional, mechanical, and genetic factors influence remodeling.
Resorption of old bone and formation of new bone are processes that continuously overlap. The importance of
these processes varies at different times throughout the life cycle. In general, from birth until about age 20, the
bones are in a phase of active growth. This stage is characterized by an increase in bone length and bone
width. Shaping of the growing bones, called modeling, also occurs at this time. Between the ages of 12 and
30, the rapid phase of bone dimensional growth tapers off and consolidation occurs with the attainment of
peak bone mass. Although dimensional bone growth ceases at maturity, adult bone is constantly being
remodeled. It is generally accepted that peak bone mass or maximum bone density and strength occurs by
age 30. Studies indicate that peak bone mass at several skeletal sites (especially the proximal femur and
vertebrae) may be reached as early as late adolescence. Peak rate of calcium accretion occurs at about age
12.5 years for girls and 14 years for boys.
Beginning in the 40s or later, resorption of existing bone starts to exceed formation of new bone, resulting in
a net loss. Age-related bone loss is influenced by both genetic and environmental factors. This also occurs at
different times in the two different types of bone trabecular and cortical. Trabecular bone, which is spongy
in appearance, forms the internal support network for the cortical shell, vertebrae, and other bones. Cortical or
compact bone forms the outer shell of almost all bones and is predominant in shafts of long bones such as
those in the arms, legs, hands, and feet.
Bone Remodeling

Osteoclasts dissolve
bone

Large multinucleated
giant cells

Osteoblasts roduce
bone

!ave recetors "or #$!%

&$% 'itamin (%
c)to*ines% and gro+t,
"actors

Main roduct is collagen

-,en osteoblasts
become encased in bone%
t,e) become osteoc)tes
Osteoblast and Osteoclast Function

Osteoblasts

Bone "ormation

S)nt,esis o" matri.

roteins

$)e / collagen

Osteocalcin

Ot,ers

Minerali0ation

1ctivation o" osteoclasts

via R123L roduction

Osteoclasts

Bone resortion

(egradation o" roteins

b) en0)mes

1cidi"ication

R123 is activated b)
R123L% and t,is leads
to cells di""erentiation
to osteoclasts

Recetor activator o"

nuclear "actor *aa-B
ligand
R123 and R123L
Physiological regulators of Ca2+
Primary

Parathyroid hormone

Vitamin D
Secondary
Calcitonin
Sex steroids

glucocorticoids

Thyroid hormone

Growth hormone

Insulin
Calcium metabolism

Control of serum calcium and phosphorus

depends on the hormones

1. Vitamin D
2. Parathyroid hormone
3. Calcitonin
Bone mineral homeostasis
The hormonal interactions controlling
bone mineral homeostasis
Properties Parathormone (PTH)
84 aa peptide from parathyroid glands

rapid degradation, elimination (t1 2 2-5 min)

G protein-coupled receptor, increases cAMP

Physiological effects

released in response to hypocalcemia

increases plasma Ca2+, reduces P

bone, kidney, vitamin D
Increases activity of osteclasts Vit D production
reabsorption of calcium from kidney
Calcium metabolism
Calcium metabolism
1. Parathormone (PTH) net effect is to increase
plasma calcium and decrease phosphate
concentration.
Kidney :

PTH stimulates reabsorption of calcium by the

renal tubules.
1. PTH decrease the reabsorption of phosphate
from renal tubules this plasma phosphate
concentration, which in turn plasma calcium.
#$! and
3idne)
#$! acts
on t,e
distal
tubule
Calcium metabolism
PTH : Bone :

PTH increase bone resorption by

stimulating osteoclast activity which enables
the bone calcium to enter the extra cellular
pool (High dose).
PTH : GIT :

It increase calcium and phosphate

absorption by activating the synthesis of 1,25
dihydroxyvitamin D-3 (Calcitriol).
Bone remodeling involves dynamic interaction of
osteoclast and osteoblast.
Calcium metabolism
PTH :

In low and intermittent doses, PTH

increase bone formation without stimulating
bone resorption.
1ctions o" #arat,)roid !ormone

Fine tunes &a

45
levels in blood

/t increases &a
45
/t decreases #
i

#arat,)roid ,ormone acts directl) on bone to stimulate resortion and

release o" &a
45
into t,e e.tracellular sace 6slo+7

8s rotein-couled recetors in osteoblasts increase c1M# and activate #31

/n,ibits osteoblast "unction

$,is occurs +,en #$! is secreted continuousl)9 t,e oosite occurs +,en it is
given once dail) b) in:ection

$+o e""ects in *idne)

#arat,)roid ,ormone acts directl) on *idne) to increase calcium reabsortion and

,os,ate e.cretion 6raid7
8s rotein-couled recetors

#arat,)roid ,ormone acts on distal tubule

&alcitonin in,ibits

Stimulates transcrition o" 1-al,a ,)dro.)lase "or 'itamin ( activation in

*idne)

'itamin ( increases calcium and ,os,ate absortion

Calcium metabolism
2. Vitamin D : It is a prohormone.

Vitamin D-3 (cholecalciferol) and Vitamin

D-2 (ergocalciferol) are the major forms of
vitamin D.

Vitamin D-3 is produced in the skin from

7-dehydrocholesterol under the influence
of ultra-violet light.

Vit-D-3 is an inactive precursor of active

1,25 dihydroxyvitamin D-3 (Calcitriol).
Elsevier Inc. items and derived items 2007 by Saunders, an imprint of Elsevier Inc.
Figure 73-2 Vitamin D activation.
Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism
'itamin ( Metabolism
Elsevier Inc. items and derived items 2007 by Saunders, an imprint of Elsevier Inc.
Figure 73-2 Vitamin D activation.
Potency: Vitamin D3< 25-hydroxy D< 1,25 di-hydroxy D
Calcium metabolism
Vitamin D : Net effect is to increase plasma
calcium and phosphate concentration.

The hydroxylation of Vitamin D-3

at the 25 position in the liver results in 25
Hydroxyvitamin-D3 (Calcifediol).

PTH stimulates the renal hydroxylation at

position 1 resulting in
1, 25 Dihydroxyvitamin D-3 (Calcitriol).
Calcium metabolism
Vitamin D :

Calcitriols primary effect is on the small

intestine where it increase dietary calcium and
phosphate absorption.

Vitamin D promotes mineralization bone

formation.

Calcium and phosphate excretion may be

decreased by renal tubules.
#roosed Mec,anism o" 1ction o" 1%4;-
(i,)dro.)(
<
in /ntestine
'itamin (-deendent &a
45
1bsortion

(uodenum=:e:unun=ileum

1bsortion is greater at lo+ !

#ea* absortion at t,e beginning o" t,e

duodenum
Calcium metabolism
Vitamin D :

It inhibits parathyroid hormone secretion

from the parathyroid gland.

Vitamin D affects the immune system by

promoting phagocytosis, anti-tumor activity,
and immunomodulatory functions.
Deficiency
hypocalcemia
acute neuromuscular symptoms chronic bone
disease
Excess
hypercalcemia
acute CNS and muscle symptoms
kidney stones, calcification of soft tissues
Vitamin D
Vitamin D is used to prevent and treat:

osteoporosis

Rickets: vit. D deficiency in children

osteomalacia

In renal failure, it is advisable to use the active

form, calcitriol as they cannot synthesize it.

Calcipotriol, synthetic derivative of vitamin D, is

used in psoriasis.
Properties

32 aa peptide from parafollicular cells of thyroid

released in response to hypercalcemia

decreases plasma Ca2+

rapidly degraded (t1/2 10 min)

Mechanisms
effects via G protein-coupled receptor

increases renal excretion of Ca2+ and phosphate

inhibits osteoclasts, may stimulate osteoblasts

Calcitonin
3. Calcitonin : It is released in response to
increased plasma calcium and it decrease
plasma calcium.

It is secreted by the parafollicular cells of

the thyroid gland.

It is administered parenterally or nasal

inhalation.

Salmon calcitonin is 100 times more potent

than human calcitonin.
Calcitonin : Principal effects are to lower
serum calcium and phosphate

It inhibits osteoclast activity, decrease bone

resorption thus lowers serum calcium and
phosphate and reduce bone pain.

It decrease the reabsorption of calcium and

phosphate from the renal tubules.
Calcitonin : It increase BMD in spine

Used in pagets disease of bone(enlarged and

deformed bones)

Osteoporosis

Hypercalcemia

Usually reserved for post menopausal

women (who cannot take estrogen).
PTH
PTH
Vitami
Vitami
n D
n D
Calcit
Calcit
onin
onin
Intesti Intesti
ne ne
Ca & Ca &
PO4 absorption PO4 absorption
Ca & Ca &
P04 absorption P04 absorption
----- -----
Kidne Kidne
y y
Ca & P04 Ca & P04
excretion excretion
Ca & Ca &
PO4 excretion PO4 excretion
Ca & Ca &
PO4 excretion PO4 excretion
Bone Bone bone bone
resorption (H) resorption (H)
bone bone
formation (L) formation (L)
bone bone
resorption (H) resorption (H)
bone bone
formation formation
bone bone
resorption resorption
Net Net
effect effect
plasma plasma
Ca plasma Ca plasma
PO4 PO4

plasma Ca plasma Ca
plasma PO4 plasma PO4

plasma Ca plasma Ca
plasma PO4 plasma PO4
The hormonal interactions controlling
bone mineral homeostasis

Glucocorticoid causes osteoporosis and fractures in a high

percentage of patients.

There is a dose-dependent effect, which is difficult to define because

of varying durations at each dose.
Glucocorticoid have several adverse effects on bone metabolism.
1.Direct inhibition of osteoblast function
2.Direct enhancement of bone resorption
3.Inhibition of gastrointestinal calcium absorption
4.Increases in urine calcium loss

Inhibition of gonadal hormones

----The trabecular bone is affected more rapidly than the cortical bone.
-----Some patients suffer multiple vertebral compression fractures within
a year of initiating steroid therapy.
Pathologies of Ca2+ regulation
1.Hypercalcemia
2.Hypocalcemia
3.Osteoporosis
4.Paget's disease
Pharmacological agents
1.Calcium salts
2.Vitamin D preparations
3.Calcitonin
4.Bisphosphonates
5.Other agents