5319The Calcium Homeostatic System

8/12/2019 5319The Calcium Homeostatic System

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BONE MINERAL HOMEOSTASISBONE MINERAL HOMEOSTASIS



CalciumStructural• skeleton, bones, teeth•support and storage•Bones serve as a basic support system protecting vital organsand as a reservoir for calcium (1-2 kg, 98% in bone)Functional

• nerve and muscle integrity (Integrity of intracellular cementsubstances)•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% ionized40% bound to protein (especially to albumin)

10% complexes to anions.

Approximately 100-250mg of daily intake isabsorbed 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-baseequilibrium.

Buffers and allows for renal H+ excretion.

Helps regulate calcium metabolism, and is anactive intermediate of energy metabolism(ATP).

Approximately 67% of an oral dose is absorbedfrom the intestine. ( jejunum)

Excretion is via the kidney. But large amountreabsorbed 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, calledremodeling, is the resorption (breaking down) of existing bone and deposition of new bone to replace thatwhich has been broken down. At any one time, about 5% of bone surfaces in adults are undergoingremodeling.

As a result of remodeling, most of the adult skeleton is replaced about every 10 years.A number of interrelatedhormonal, nutritional, mechanical, and genetic factors influence remodeling.

Resorption of old bone and formation of new bone are processes that continuously overlap. The importance ofthese processes varies at different times throughout the life cycle. In general, from birth until about age 20, thebones 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 and30, the rapid phase of bone dimensional growth tapers off and consolidation occurs with the attainment ofpeak bone mass. Although dimensional bone growth ceases at maturity, adult bone is constantly beingremodeled. It is generally accepted that peak bone mass or maximum bone density and strength occurs byage 30. Studies indicate that peak bone mass at several skeletal sites (especially the proximal femur andvertebrae) may be reached as early as late adolescence. Peak rate of calcium accretion occurs at about age12.5 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 ina net loss. Age-related bone loss is influenced by both genetic and environmental factors. This also occurs atdifferent times in the two different types of bone — trabecular and cortical. Trabecular bone, which is spongyin appearance, forms the internal support network for the cortical shell, vertebrae, and other bones. Cortical orcompact bone forms the outer shell of almost all bones and is predominant in shafts of long bones such asthose in the arms, legs, hands, and feet.



Bone Remodeling• Osteoclasts dissolve

bone

– Large multinucleatedgiant 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• ctivation o" osteoclasts

via R23L roduction

• Osteoclasts

• Bone resortion – (egradation o" roteins

b) en0)mes

– cidi"ication

• R23 is activated b)R23L% and t,is leads

to cells di""erentiationto osteoclasts

• Recetor activator o"nuclear "actor *aa-B

ligand



R23 and R23L



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 phosphorusdepends on the hormones

1. Vitamin D

2. Parathyroid hormone

3. Calcitonin





Bone mineral homeostasis



The hormonal interactions controllingbone mineral homeostasis



Properties Parathormone (PTH)

• 84 aa peptide from parathyroid glands•rapid degradation, elimination (t12 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 increaseplasma calcium and decrease phosphateconcentration.

Kidney :

PTH stimulates reabsorption of calcium by therenal tubules.

1. PTH decrease the reabsorption of phosphate

from renal tubules – this ↓plasma phosphateconcentration, which in turn ↑plasma calcium.



#$! and

3idne)

#$! actson t,e

distal

tubule



Calcium metabolism

PTH : Bone :PTH increase bone resorption bystimulating osteoclast activity which enablesthe bone calcium to enter the extra cellularpool (High dose).

PTH : GIT :

It increase calcium and phosphateabsorption by activating the synthesis of 1,25dihydroxyvitamin D-3 (Calcitriol).



Bone remodeling involves dynamic interaction ofosteoclast and osteoblast.





Calcium metabolism

PTH :

In low and intermittent doses, PTH increase bone formation without stimulatingbone resorption.



ctions o" #arat,)roid !ormone• Fine tunes &a5 levels in blood

– /t increases &a5

– /t decreases #i

• #arat,)roid ,ormone acts directl) on bone to stimulate resortion andrelease o" &a5 into t,e etracellular sace 6slo+7

– 8s rotein-couled recetors in osteoblasts increase cM# and activate #3

– /n,ibits osteoblast "unction – $,is occurs +,en #$! is secreted continuousl) t,e oosite occurs +,en it isgiven once dail) b) in:ection

• $+o e""ects in *idne) – #arat,)roid ,ormone acts directl) on *idne) to increase calcium reabsortion and

,os,ate ecretion 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 influenceof ultra-violet light.

Vit-D-3 is an inactive precursor of active1,25 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-3at the 25 position in the liver results in 25Hydroxyvitamin-D3 (Calcifediol).

PTH stimulates the renal hydroxylation atposition 1 resulting in1, 25 Dihydroxyvitamin D-3 (Calcitriol).





Calcium metabolism

Vitamin D :

Calcitriol’s primary effect is on the smallintestine where it increase dietary calcium and

phosphate absorption.

Vitamin D promotes mineralization boneformation.

Calcium and phosphate excretion may bedecreased by renal tubules.

# d M , i " ti " 1 ;



#roosed Mec,anism o" ction o" 1%;-

(i,)dro)(< in /ntestine



'itamin (-deendent &a5 bsortion

• (uodenum=:e:unun=ileum

• bsortion is greater at lo+ !

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

duodenum



Calcium metabolism

Vitamin D :

It inhibits parathyroid hormone secretionfrom the parathyroid gland.

Vitamin D affects the immune system bypromoting phagocytosis, anti-tumor activity,

and immunomodulatory functions.





Deficiency• hypocalcemia

– acute neuromuscular symptoms – chronic bonedisease

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 activeform, calcitriol as they cannot synthesize it.

Calcipotriol, synthetic derivative of vitamin D, isused 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 toincreased plasma calcium and it decreaseplasma calcium.

It is secreted by the parafollicular cells ofthe thyroid gland.

It is administered parenterally or nasal

inhalation. Salmon calcitonin is 100 times more potent

than human calcitonin.





Calcitonin : Principal effects are to lowerserum calcium and phosphate

It inhibits osteoclast activity, decrease boneresorption thus lowers serum calcium andphosphate and reduce bone pain.

It decrease the reabsorption of calcium andphosphate from the renal tubules.



PTHPTH VitamiVitami CalcitCalcit



PTH Vitamitan Dn D

CalcitCa c toninonin

IntestiIntesti

nene

↑↑Ca &↑Ca &↑

PO4 absorptionPO4 absorption

↑↑Ca &Ca &

P04 absorptionP04 absorption

----------

KidneKidneyy

↓↓Ca & P04↑Ca & P04↑

excretionexcretion↓↓Ca &Ca &

PO4 excretionPO4 excretion ↑↑Ca &Ca &

PO4 excretionPO4 excretion

BoneBone ↑↑boneboneresorption (H)resorption (H)

↑↑bonebone

formation (L)formation (L)

↑↑boneboneresorption (H)resorption (H)

bone↑ bone↑

formationformation

↓↓boneboneresorptionresorption

NetNeteffecteffect

↑↑plasmaplasmaCa plasma↓Ca plasma↓

PO4PO4

↑↑plasma Ca ↑plasma Ca ↑

plasma PO4plasma PO4

↓↓plasma Ca ↓plasma Ca ↓

plasma PO4plasma PO4



The hormonal interactions controllingbone mineral homeostasis



• Glucocorticoid causes osteoporosis and fractures in a highpercentage of patients.

• There is a dose-dependent effect, which is difficult to define becauseof varying durations at each dose.

Glucocorticoid have several adverse effects on bone metabolism.

1.Direct inhibition of osteoblast function2.Direct enhancement of bone resorption3.Inhibition of gastrointestinal calcium absorption4.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 withina year of initiating steroid therapy.





Pharmacological agents

1.Calcium salts2.Vitamin D preparations

3.Calcitonin

4.Bisphosphonates5.Other agents

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5319The Calcium Homeostatic System

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