Calcium
Metabolism, homeostasis disturbances
Physiology of Calcium
• 98% of the body calcium is in the skeleton
• Only 2% is in circulation and only half of this is
free calcium (ionized Ca2+)
• This only is physiologically active
• The 1% is bound to proteins
Multiple biological functions of calcium
•Cell signalling
•Neural transmission
•Muscle function
•Blood coagulation
•Enzymatic co-factor
•Membrane and cytoskeletal functions
•Secretion
•Biomineralization
Distribution of Calcium Bone Structure (cellular and non-
cellular)
Total body calcium- 1kg
99% in bone
1% in blood and body fluids
Intracellular calcium
Cytosol
Mitochondria
Other microsomes
Regulated by "pumps"
Blood calcium - 10mgs (8.5-10.5)/100
mls
Non diffusible - 3.5 mgs
Diffusible - 6.5 mgs
Inorganic (69%)
Hydroxyapatite - 99%
3 Ca10 (PO4)6 (OH)2
Organic (22%)
Collagen (90%)
Non-collagen structural proteins
proteoglycans
sialoproteins
gla-containing proteins
a2HS-glycoprotein
Functional components
growth factors
cytokines
Blood Calcium - 10mgs/100 mls (2.5
mmoles/L)
Diet
Non diffusible - 3.5 mgs
Albumin bound - 2.8
Globulin bound - 0.7
Diffusible - 6.5 mgs
Ionized - 5.3
Complexed - 1.2 mgs
bicarbonate - 0.6 mgs
citrate - 0.3 mgs
phosphate - 0.2 mgs
other
Close to saturation point
tissue calcification
kidney stones
Dietary calcium
Milk and dairy products (1qt =
1gm) Dietary supplements
Other foods
Other dietary factors regulating
calcium absorption
Lactose
Phosphorus
Calcium Absorption (0.4-1.5 g/d) Mechanisms of GI Calcium
Absorption
Primarily in duodenum
15-20% absorption
Adaptative changes
low dietary calcium
growth (150 mg/d)
pregnancy (100 mg/d)
lactation (300 mg/d)
Fecal excretion
Vitamin D dependent
Duodenum > jejunum > ileum
Active transport across cells
calcium binding proteins (e.g.,
calbindins)
calcium regulating
membranomes
Ion exchangers
Passive diffusion
Urinary Calcium Regulation of Urinary Calcium
Daily filtered load
10 gm (diffusible)
99% reabsorbed
Two general mechanisms
Active - transcellular
Passive - paracellular
Proximal tubule and Loop of Henle reabsorption
Most of filtered load
Mostly passive
Inhibited by furosemide
Distal tubule reabsorption
10% of filtered load
Regulated (homeostatic)
stimulated by PTH
inhibited by CT
vitamin D has small stimulatory effect
stimulated by thiazides
Urinary excretion
50 - 250 mg/day
0.5 - 1% filtered load
Hormonal - tubular reabsorption
PTH - decreases excretion (clearance)
CT - increases excretion (calciuretic)
1,25(OH)2D - decreases excretion
Diet
Little effect
Logarithmic
Other factors
Sodium - increases excretion
Phosphate - decreases excretion
Diuretics - thiazides vs loop
thiazides - inhibit excretion
furosemide - stimulate excretion
Balance per day
Calcium Absorption (0.4-1.5 g/d) Mechanisms of GI Calcium
Absorption
Primarily in duodenum
15-20% absorption
Adaptative changes
low dietary calcium
growth (150 mg/d)
pregnancy (100 mg/d)
lactation (300 mg/d)
Fecal excretion
Vitamin D dependent
Duodenum > jejunum > ileum
Active transport across cells
calcium binding proteins (e.g.,
calbindins)
calcium regulating
membranomes
Ion exchangers
Passive diffusion
Regulation of Calcium and Skeletal Metabolism
Minerals
Calcium (Ca)
Phosphorus (P)
Magnesium (Mg)
Organ Systems
Skeleton
Kidney
GI tract
Other
Hormones
Calcitropic hormones
Parathyroid Hormone (PTH)
Calcitonin (CT)
Vitamin D [1,25(OH2)D]
PTHrP
Other hormones
Gonadal and adrenal steroids
Thyroid hormones
Growth factor and cytokines
Calcium Homeostasis
 Bone Resorption
 Intestinal Absorption
 Renal Excretion
11
Calcium Homeostasis
Parathyroid Hormone
1,25 DHC or Vitamin D3
Calcitonin
12
Control of Ca2+ Levels
Hormone Effect Bone Gut Kidney
PTH  Ca2+  Po4
Increases
Osteoclasts
Indirect via
Vit. D
Ca reab
Po4 exr.
Vitamin D3  Ca2+  Po4
No direct
action
 Ca2+  Po4
absorption
No direct
effect
Calcitonin  Ca2+  Po4
Inhibits
Osteoclasts
No direct
effect
Ca2+ & Po4
excretion
13
Regulation of Ca2+ in ECT
• The parathyroid gland detects
calcium levels in the ECT by the
calcium sensing receptor – CaSR
• a member of the G proteincoupled
receptor family with
seven hydrophilic
transmembrane helices
anchored in the plasma
membrane.
Expression of calcum sensor
• Parathyroid cells, thyroid C cells
(control of PTH and calcitonin
production).
• Kidney cells, osteoblasts,
hematopoietic cells, mucosal cells of
GIT.
• All these cells respond to calcium
levels in the blood.
Nature Clinical Practice Endocrinology & Metabolism volume 3, pages122–133(2007)
Functional consequences of the calcium sensor
• CaSR is found throughout the tubular system
• CaSR in the thick part of the ascending arms of the Henle loop can respond to
increased calcium levels in ECT by activating phospholipase A2, resulting in a
reduction of Na / K / 2Cl co-transporter activity and apical channel activity for K +
and a reduction in calcium and magnesium paracellular rebsorption.
• The increase in calcium in ECT antagonizes the effect of PTH on this segment of the
nephron, so that calcium itself cooperates to maintain its own homeostasis.
Inhibition of NaCl reabsorption and loss of urine NaCl in severe hypercalcaemia
may then lead to hypovolaemia.
Journal of Translational Medicine volume 9, Article number: 201 (2011)
Activation of the calcium sensor has two
major signal transduction effects:
• Activation of phospholipase C,
which leads to activation of
second messengers of
diacylglycerol and inositol
trisphosphate.
• Inhibition of adenylate cyclase,
which leads to a decrease in
intracellular cAMP concentration.
• The sensor can also activate
mitogen-activated protein kinase
(MAPK)
Scheme of an idealized mammalian cell with localization of the major mechanisms of Ca
homeostasis.
PM Ca2+ channels, generic plasma membrane Ca2+ channels (voltage-, ligand- or second
messenger–operated);
GPCR, G protein–coupled receptor; PLC, phospholipase C; PIP2,
phosphatidylinositol 4,5 bisphosphate; DAG, diacylglycerol; GFR, growth
factor receptor; ATP2C1, Golgi-resident Ca2+ ATPase; cADPR, cyclic ADP
ribose; CICR, Ca2+ induced Ca2+ release; Mt, mitochondrion.
Distribution of Calcium, Phosphorus, and Magnesium
Total body
content, g
% in skeleton % in soft tissues
Calcium 1000 99 1
Phosphorus 600 85 15
Magnesium 25 65 35
Magnesium
• Magnesemia negatively
affects PTH secretion
• However, the rate of
secretion activation is up
to 3 times less than that
of calcium
Kidney International
Volume 82, Issue 11, 1 December 2012
Calcium-phosphate equilibrium
• The role of FGF-23
• FGF23 is a hormone
• predominately produced by
osteoblasts/osteocytes
• major function – inhibition of renal
tubular phosphate reabsorption
and suppressing circulating 1,25
(OH)(2)D levels by decreasing
Cyp27b1-mediated formation and
stimulating Cyp24-mediated
catabolism of 1,25(OH)(2)D.
Altered intracellular calcium homeostasis in
diseases states
Basal
Ca++i
Ca++i response
to stimulation
Example Form
Gradually
increasing
=/ Infarction, toxin-induced
cellular death, acute pancreatitis
Acute
Increased,
sustained
 Hypertension Chronic
 Idiopathic heart failure Chronic
Normal,
sustained
 Alzheimer´s disease Chronic
 Chronic inflammatory diseases
(Crohn´s disease, rheumatoid
arthritis)
Chronic
Parathyroid glands
Parathormon (PTH)
raises blood calcium levels in 3 main ways:
• stimulates the production of the biologically
active form of vitamin D by the kidneys.
• supports mobilization of calcium and
phosphate from bone. To maintain the
calcium phosphate balance, it promotes the
excretion of phosphates by the kidney
(phosphaturic effect).
• It maximizes tubular reabsorption of calcium
in the kidneys, resulting in minimal urinary
calcium loss (in healthy kidneys).
• PTH is a 84 AK peptide whose bioactivity is given by 34 AK at the NH2terminal
end.
• The main regulator of PTH secretion from parathyroidism is the
calcium content in extracellular fluid (ECT).
• The relationship between ECT calcium and PTH secretion is controlled
by an inverse sigmoidal curve characterized by a maximum secretion
rate at low calcium in ECT, a "set point", an ECT calcium value in ECT
that lowers PTH to half of maximum, and a minimum secretion rate at
high levels of calcium in ECT.
Parathormon (PTH)
• An increase in calcium increases PTH
degradation, a decrease in calcium
levels in ECT results in a decrease in
intracellular PTH degradation.
• Bioinactive fragments of PTH, which
can also be formed in the liver, are
digested in the kidney.
• Low levels of calcium in ECF result in
increased transcription of the PTH
gene and increased mRNA stability for
PTH.
• Chronic hypocalcaemia can lead to the
proliferation of parathyroid glands and
increase its secretory capacity.
JASN February 2011, 22 (2) 216-224
• PTH has little effect on modulating calcium fluxes in the proximal
tubule where 65% of the filtered calcium is reabsorbed, coupled to
the bulk transport of solutes such as sodium and water.
• PTH binds to its cognate receptor, the type I PTH/PTHrP receptor
(PTHR), a 7-transmembrane-spanning G protein-coupled protein
which is linked to both the adenylate cyclase system and the
phospholipase C system. Stimulation of adenylate cyclase is
believed to be the major mechanism whereby PTH causes
internalization of the type II Na+/Pi- (inorganic phosphate) cotransporter
leading to decreased phosphate reabsorption and
phosphaturia.
• About 20% of filtered calcium is reabsorbed in the cortical thick
ascending limb of the loop of Henle (CTAL)
• 15% is reabsorbed in distal tubules, after PTH binding to PTHR, via
signal transduction via cAMP.
• In the thick parts of the ascending arms of the Henle loop, the
activity of Na / K / 2Cl co-transporter increases, which controls
NaCl reabsorption and also stimulates paracellular reabsorption of
calcium and magnesium.
1. Kidney and PTH
1. Kidney and PTH
In the distal tubule, PTH affects transcellular
calcium transport. This process involves several
steps:
• transfer of luminal Ca2+ to the renal tubular cell
via the transient receptor potential channel
(TRPV5)
• translocation of Ca2+ across tubular cell from
apical to basolateral surface by proteins like
calbindine-D28K
• active Ca2+ excretion from the tubular cell into the
blood via the Na+ /Ca2+ exchanger (NCX1).
PTH apparently stimulates Ca2+ reabsorption in the
distal tubule by increasing the activity of NCX1 by
a cAMP-dependent mechanism.
1. Kidney and PTH
• PTH, upon binding to PTHR, can also
stimulate 25(OH)D3-1-alpha hydroxylase,
resulting in increased synthesis of
1,25(OH)2D3.
PTH can also inhibit the reabsorption of Na+
and HC03- in the proximal tubule by inhibition
• Na+/H+ apical exchanger typ 3,
• Na+/K+-ATPase on basolateral membrane
• Na+/Pi--cotransport on the apical side of the
proximal tubular cell. Bioactive Food as Dietary Interventions for Diabetes (Second Edition), 2019
2. Bone and PTH
• In bone, the PTHR is localized on cells of the osteoblast phenotype which
are of mesenchymal origin but not on osteoclasts which are of
hematogenous origin.
• In the postnatal state the major physiologic role of PTH appears to be to
maintain normal calcium homeostasis by enhancing osteoclastic bone
resorption and liberating calcium into the ECF.
• This effect of PTH on increasing osteoclast stimulation is indirect, with PTH
binding to the PTHR on pre-osteoblastic stromal cells and enhancing the
production of the cytokine RANKL (receptor activator of NFkappaB
ligand), a member of the tumor necrosis factor (TNF) family.
2. Bone and PTH
• Levels of a soluble decoy receptor for RANKL,
termed osteoprotegerin, are diminished
facilitating the capacity for increased stromal cellbound
RANKL to interact with its cognate
receptor, RANK, on cells of the osteoclast series.
• Multinucleated osteoclasts are derived from
hematogenous precursors which commit to the
monocyte/macrophage lineage, and then
proliferate and differentiate as mononuclear
precursors, eventually fusing to form
multinucleated osteoclasts. These can then be
activated to form bone-resorbing osteoclasts.
• RANKL can drive many of these
proliferation/differentiation/fusion/activation
steps although other cytokines, notably
monocyte-colony stimulating factor (M-CSF) may
participate in this process.
Hyperparathyreoidism - primary
• Parathyroid adenoma – solitary
• 70 - 80% primary
• Idiopathic primary hyperplasia of PT
• Carcinoma PT - rare
• Familial hyperparathyroidism
• Multiple Adenomas (MEN)
• Familial benign hypocalciuric hypercalcemia
• Severe neonatal primary hyperparathyroidism
• Inactivation mutations for CaSR - AR
Hyperparathyreoidism - secondary
• Renal insuficiency
• Hypovitaminosis D
• Malasorption syndromes
• Celiac disease
• Disorders of bile and pancreatic secretion
Hypoparathyreoidism - primary
• Parathyroid damage during thyroid surgery
• Radiation
• Damage in metabolic diseases
• Wilson's disease - defect of Cu metabolism
• hemochromatosis - defect of Fe metabolism
• Autoimmune hypoparathyroidism
• Gradual decline in function
• Congenital familial hypoparathyroidism
• AD, AR and X-linked disorder
• DiGeorg syndrome
• parathyroid aplasia
• After tumor removal
Hypoparathyreoidism - seconadry
• Magnesium deficiency/
• hypomagnesaemia - chornic!
• Hypervitaminosis D
• due to attenuation of PTH secretion due to
high Ca levels!
• Increased production of PTHrP
• the level of PTH alone is low!
Hypoparathyreoidism
• Decreased PTH
- Hypocalcemia
- Rise of neuromuscular excitability
- Parestezia
- Spazmus and contractions
- hyperphosphatemia
PTH vs FGF 23
Regulation of the production and action of
humoral mediators of calcium homeostasis
Additional factors including catecholamines and other biogenic
amines, prostaglandins, cations (eg lithium and magnesium),
phosphate per se and transforming growth factor alpha (TGFa)
have been implicated in the regulation of PTH secretion.
Vitamin D (calcitriol)
Copyright ©2006 American Society for Clinical Investigation
Holick, M. F. J. Clin. Invest. 2006;116:2062-2072
Nomenclature
Vitamin D
Ergocalciferol (vitamin D2)
Cholecalciferol (vitamin D3)
25-hydroxyvitamin D [25(OH)D]
Ercalcidiol [25(OH)D2]
Calcidiol [25(OH)D3]
1,25-dihydroxyvitamin D [1,25(OH)2D]
Ercalcitriol [1,25(OH)2D2]
Calcitriol [1,25(OH)2D3]
Vitamin D receptor agonist (synthetic analogues)
Paricalcitol [19nor,1,25(OH)2D2]
Maxacalcitol [22oxa,1,25(OH)2D3]
Vitamin D receptor agonist prodrugsa
Doxercalciferol [1(OH)D2]
Alfacalcidol [1(OH)D3]
The Metabolic Activation of Vitamin D
• Vitamin D from the diet or the conversion from precursors in skin
through ultraviolet radiation (light) provides the substrate of the
indicated steps in metabolic activation.
• The pathways apply to both the endogenous animal form of vitamin D
(vitamin D3, cholecalciferol) and the exogenous plant form of vitamin
D (vitamin D2, ergocalciferol), both of which are present in humans at
a ratio of approximately 2:1.
• In the kidney, 25-D is also converted to 24-hydroxylated metabolites
which may have unique effects on chondrogenesis and
intramembranous ossification.
• The many effects of vitamin D metabolites are mediated through
nuclear receptors or effects on target-cell membranes
Cellular bone mineral transport
• For calcium, the transcellular
transport is ferried by the interaction
among a family of proteins that
include calmodulin, calbindin,
integral membrane protein, and
alkaline phosphatase; the latter
three are vitamin D dependent.
• Cytoskeletal interactions are likely
important for transcellular transport
as well. Exit from the cell is regulated
by membrane structures similar to
those that mediate entry.
Pharmacological Reviews April 2017, 69 (2) 80-92;
1,25(OH)2D-initiated gene transcription
• 1,25(OH)2D enters the target cell and binds to its receptor, VDR.
• The VDR then heterodimerizes with the retinoid X receptor (RXR). This increases the affinity of the VDR/RXR complex for
the vitamin D response element (VDRE), a specific sequence of nucleotides in the promoter region of the vitamin D
responsive gene.
• Binding of the VDR/RXR complex to the VDRE attracts a complex of proteins termed coactivators to the VDR/RXR
complex. The coactivator complex spans the gap between the VDRE and RNA polymerase II and other proteins in the
initiation complex centered at or around the TATA box (or other transcription regulatory elements).
• Transcription of the gene is initiated to produce the corresponding mRNA, which leaves the nucleus to be translated to
the corresponding protein.
Immunity and Inflammation in Health and Disease, 2018
Non-genomic actions of vit D
• Besides gene regulation activities,
vitamin D also exerts rapid nongenomic
actions through cell surface receptors.
• VDR is required for rapid nongenomic
effects of 1,25(OH)2 D3 on chloride and
calcium channels in osteoblasts.
• VDR was localized in caveolae-enriched
plasma membranes of intestinal, lung,
kidney cells and osteoblasts, where it
efficiently binds 1,25(OH)2 D3
BioMed Research International 2015:1-11
Degradation
• takes place in the kidneys, liver, bones and
intestines
• Conjugation with glucuronic acid, sulphation
and hydroxylation (in positions 23, 24, 26)
• The products are excreted in urine and bile
• 24-hydroxylase
• 1,24,25-(OH)3-D - Nonactive metabolite
• 24,25-(OH)3-D – Active form, in plasma
Regulation of 1-alfa hydroxylase (CYP27B1)
• mainly occurs in the proximal
tubule cells of the kidney,
and its activity is positively
regulated by parathyroid
hormone (PTH), parathyroid
hormone-related protein
(PTHrP), calcitonin, growth
hormone (GH) and insulinlike
growth factor I (IGF-I)
• negatively by FGF23 and
klotho or minerals - negative
regulation by Ca and
phosphate levels.
Handbook of Clinical Neurology, 2014
Vit D and immune reaction
• both VDR and RXR are expressed in several types
of cells, e.g., keratinocytes, fibroblasts,
monocytes, macrophage, DCs, and T
lymphocytes
• modulate other components of innate immunity,
such as immune cell proliferation/development
and inflammatory cytokine production
• Vitamin D has been shown to inhibit the
development and function of Th1 cells, which
are mainly involved in activating macrophages
and inflammatory responses, and Th17 cells
Front. Immunol., 12 October 2015
Country (health
authority) United States and Canada (IOM) Europe (EFSA)
Germany, Austria
and Switzerland
(DACH) UK (SACN)
Nordic European
countries (NORDEN)
DRV/DRI EAR RDA AI AI RNI RI
Target 25(OH)D in
nmol/L
40 50 50 50 25 50
Age group Vitamin D intakes in µg (international units, IU) per day (1 µg = 40 IU)
0–6 months 10 (400) 10 (400) 8.5–10 (300–400)
7–12 months 10 (400) 10 (400) 10 (400) 8.5–10 (300–400) 10 (400)
1–3 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
4–6 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
7–8 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
9–10 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
11–14 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
15–17 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
18–69 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
70–74 years 10 (400) 20 (600) 15 (600) 20 (800) 10 (400) 10 (400)
75 years and older 10 (400) 20 (600) 15 (600) 20 (800) 10 (400) 20 (800)
Pregnancy 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
Lactation 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
Dietary reference values (DRV)/dietary reference intakes (DRI) for vitamin D (reproduced from Pilz et al. (81) under the terms of the CC Attribution 4.0 International (CC BY 4.0) licence).
IOM, Institute of Medicine; EFSA, European Food Safety Authority; DACH, Germany, Austria and Switzerland; SACN, Scientific Advisory Committee on Nutrition; EAR, Estimated Average Requirement; RDA,
Recommended Dietary Allowance; AI, Adequate Intake; RNI, Reference; Nutrient Intake; RI, Recommended Intake; 25(OH)D, 25-hydroxyvitamin D.
Vitamin D deficiency
• In children rickets-deformation of long bones due to increased bone
softness.
• In adults, osteomalacia.
• Genetic defects in VDR (hereditary resistance syndromes to vitamin
D).
• Severe liver and kidney diseases.
• Insufficient exposure to sunlight
Vitamin D deficiency
•Sunscreens (SPF more than 8) effectively block the
synthesis of vitamin D in the skin. Usually balanced by
quality nutrition.
•Vitamin D Toxicity: Excessive sun exposure does not
lead to excessive vitamin D production.
Causes of rickets/osteomalacia
• Lack of calcium and/or phosphates
• Malabsorption of calcium and/or phosphates in GIT
• Celiac disease, Crohn's disease
• Absorption-inhibiting substances (eg fiber binding)
• Increased losses of calcium and/or phosphates in the kidneys
• Failure of mineralization process
Vitamin D deficiency rickets
• Vitamin D deficiency in diet
• Insufficient vitamin D absorption in GIT
• Insufficient vitamin D production in the skin
Rickets from disorders of vitamin D activation
and effect
• Hepatic or renal failure
• Mutation of gene for 25-hydroxylase
(CYP2R1) - rare
• Vitamin D dependent rickets type I
• Mutation of gene for 1-alphahydroxylase
(CYP27B1) - AR
• Insufficient conversion of calcidiol to
calcitriol
• Vitamin D dependent rickets type II
• Tissues do not respond to vitamin D
• AR defect of vitamin D receptor
Rickets from phosphate loss
• Familial hypophosphatemic rickets
• Urinary phosphate loss
• Vitamin D resistant rachitis - do not respond to vitamin D treatment
• X-linked hypophosphatemic rickets - mutation in PHEX leads to accumulation of FGF23
• AD hypophosphatemic rickets - mutation in the FGF23 gene
• AR hypophosphatemic rickets - mutation in gene for DMP1 (nuclear protein of dental
and bone tissue) - affecting osteoid mineralization, accumulation of FGF23
• Tubulopathy with hyperphosphaturia
• Acquired states
• Diuretics
• Hyperparathyreoza
• PTHrP
X-linked hypophosphatemic osteomalacia
• The condition is characterized by
low tubular reabsorption of
phosphate in the absence of
secondary hyperparathyroidism.
• X-linked hypophosphatemia occurs
in about 1 in 25,000 and is
considered the most common form
of genetically induced rickets.
Parathyroid Hormone Relation Peptide (PTHrP)
• PTHrP was discovered as the mediator of the syndrome of "humoral
hypercalcemia of malignancy" (HHM).
• In this syndrome a variety of cancers, essentially in the absence of skeletal
metastases, produce a PTH-like substance which can cause a constellation
of biochemical abnormalities including
• hypercalcemia,
• hypophosphatemia and
• increased urinary cyclic AMP excretion.
• These mimic the biochemical effects of PTH but occur in the absence of
detectable circulating levels of this hormone.
PTH and PTHR gene families: PTHrP, PTH and TIP39 appear to be members of
a single gene family. The receptors for these peptides, PTH1R and PTH2R, are
both 7 transmembrane-spanning G protein-coupled receptors. PTHrP binds and
activates PTH1R; it binds weakly to PTH2R and does not activate it. PTH can
bind and activate both PTH1R and PTH2R.
Effects of PTHrP
• to ion homeostasis
• to smooth muscle relaxation;
• associated with cell growth, differentiation and apoptosis.
• necessary for normal fetal calcium homeostasis
The majority of the physiological effects of PTHrP appear to occur by short-range
ie paracrine/autocrine mechanisms rather than long-range ie endocrine
mechanisms..
In the adult the major role in calcium and phosphorus homeostasis appears to be
carried out by PTH rather than by PTHrP in view of the fact that PTHrP
concentrations in normal adults are either very low or undetectable. This
situation reverses when neoplasms constitutively hypersecrete PTHrP in which
case PTHrP mimics the effects of PTH on bone and kidney and the resultant
hypercalcemia suppresses endogenous PTH secretion.
Effect of PTHrP to
• cell growth, differentiated function and programmed cell death in a
variety of different fetal and adult tissues. The most striking
developmental effects of PTHrP however have been in the skeleton. The
major alteration appears to occur in the cartilaginous growth plate where,
in the absence of PTHrP, chondrocyte proliferation is reduced and
accelerated chondrocyte differentiation and apoptosis occurs.
• increased bone formation, apparently due to secondary
hyperparathyroidism and the overall effect is a severely deformed skeleton.
• normal development of the cartilaginous growth plate. In the fetus PTH
has predominantly an anabolic role in trabecular bone whereas PTHrP
regulates the orderly development of the growth plate. In contrast, in
postnatal life, PTHrP acting as a paracrine/autocrine modulator assumes an
anabolic role for bone whereas PTH predominantly defends against a
decrease in extracellular fluid calcium by resorbing bone.
Production of bone resorbing substances by neoplasms. Tumor cells may release proteases
which can facilitate tumor cell progression through unmineralized matrix. Tumors cells can also
release PTHrP, cytokines, eicosanoids and growth factors (eg EGF) which can act on osteoblastic
stromal cells to increase production of cytokines such as M-CSF and RANKL. RANKL can bind to
its cognate receptor RANK in osteoclastic cells, which are of hepatopoietic origin, and increase
production and activation of multinucleated osteoclasts which can resorb mineralized bone.
Calcitonin
• The main source in mammals are parafollicular (C) thyroid cells. Furthermore,
other tissue - lungs, GIT.
• Peptide of 32 AK.
• Alternative splicing results in the production of a "calcitonin-gene-related
peptide" that has functions in the nervous system and circulation.
• The calcitonin receptor is again a member of the 7-transmembrane G proteincoupled
receptor family
The most important driving stimulus is the extracellular level of ionized calcium.
Hypo/hypercalcemic disorders
summary
Hypercalcemic Disorders
A. Endocrine Disorders Associated with Hypercalcemia
1.Endocrine Disorders with Excess PTH Production
•Primary Sporadic hyperparathyroidism
•Primary Familial Hyperparathyroidism
•MEN I (multiple endocrinal neoplasma)
•MEN IIA
•Familial hypocalciuric hypercalcemia - FHH
•Neonatal severe hyperparathyroidism - NSHPT
•Hyperparathyroidism - Jaw Tumor Syndrome
•Familial Isolated Hyperparathyroidism
2.Endocrine Disorders without Excess PTH Production
•Hyperthyroidism
•Hypoadrenalism
•Jansen's Syndrome
Hypercalcemic Disorders
B. Malignancy-Associated Hypercalcemia (MAH)
1.MAH with Elevated PTHrP
•Humoral Hypercalcemia of Malignancy
•Solid Tumors with Skeletal Metastases
•Hematologic Malignancies
2.MAH with Elevation of Other Systemic Factors
•MAH with Elevated 1,25(OH)2D3
•MAH with Elevated Cytokines
•Ectopic Hyperparathyroidism
•Multiple Myeloma
Hypercalcemic Disorders
C. Inflammatory Disorders Causing Hypercalcemia
1.Granulomatous Disorders
2.AIDS
D. Disorders of Unknown Etiology
1.Williams Syndrome
2.Idiopathic Infantile Hypercalcemia
E. Medication-Induced
1.Thiazides
2.Lithium
3.Vitamin D
4.Vitamin A
5.Estrogens and Antiestrogens
6.Aluminium Intoxication
7.Milk-Alkali Syndrome
Hypercalcemia
Clinical Features Associated With Hypocalcemia
Neuromuscular inability
•Chvostek's sign
•Trousseau's sign
•Paresthesias
•Tetany
•Seizures (focal, petit mal, grand mal)
•Fatigue
•Anxiety
•Muscle cramps
•Polymyositis
•Laryngeal spasms
•Bronchial spasms
Extrapyramidal signs due to calcification of basal
ganglia
Calcification of cerebral cortex or cerebellum
Personality disturbances
Irritability
Impaired intelletual ability Nonspecific EEG changes
Increased intracranial pressure
Parkinsonism
Choreoathetosis
Dystonic spasms
Neurological signs and symptoms
in hypocalcemia
Mental status in hypocalcemia
•Confusion
•Disorientation
•Psychosis
•Psychoneurosis
Ectodermal changes in hypocalcemia
• Dry skin
• Coarse hair
• Brittle nails
• Alopecia
• Enamel hypoplasia
• Shortened premolar roots
• Thickened lamina dura
• Delayed tooth eruption
• Increased dental caries
• Atopic eczema
• Exfoliative dermatitis
• Psoriasis
• Impetigo herpetiformis
Smooth muscle involvement
•Dysphagia
•Abdominal pain
•Biliary colic
•Dyspnea
•Wheezing
•Ophthalmologic manifestations in
hypocalcemia
• Subcapsular cataracts
• Papilledema
• Cardiac manifestations in hypocalcemia
• Prolonged QT interval in ECG
• Congestive heart failure
• Cardiomyopathy
Thank you for your attention